어린아이 알러지 행진질환(비염, 천식, 아토피 등) 탐구!!

[문형철]

1. nature  
2. signal transduction and targeted therapy  
3. review articles  
4. article

Pathogenesis of allergic diseases and implications for therapeutic interventions

Download PDF

• Review Article
• Open access
• Published: 24 March 2023

Pathogenesis of allergic diseases and implications for therapeutic interventions

• Ji Wang, 
• Yumei Zhou, 
• Honglei Zhang, 
• Linhan Hu, 
• Juntong Liu, 
• Lei Wang, 
• Tianyi Wang, 
• Haiyun Zhang, 
• Linpeng Cong & 
• Qi Wang 

Signal Transduction and Targeted Therapy volume 8, Article number: 138 (2023) Cite this article

•  
•  
•  
•  

Abstract

Allergic diseases such as allergic rhinitis (AR), allergic asthma (AAS), atopic dermatitis (AD), food allergy (FA), and eczema are systemic diseases caused by an impaired immune system. Accompanied by high recurrence rates, the steadily rising incidence rates of these diseases are attracting increasing attention. The pathogenesis of allergic diseases is complex and involves many factors, including maternal-fetal environment, living environment, genetics, epigenetics, and the body’s immune status. The pathogenesis of allergic diseases exhibits a marked heterogeneity, with phenotype and endotype defining visible features and associated molecular mechanisms, respectively. With the rapid development of immunology, molecular biology, and biotechnology, many new biological drugs have been designed for the treatment of allergic diseases, including anti-immunoglobulin E (IgE), anti-interleukin (IL)-5, and anti-thymic stromal lymphopoietin (TSLP)/IL-4, to control symptoms. For doctors and scientists, it is becoming more and more important to understand the influencing factors, pathogenesis, and treatment progress of allergic diseases. This review aimed to assess the epidemiology, pathogenesis, and therapeutic interventions of allergic diseases, including AR, AAS, AD, and FA. We hope to help doctors and scientists understand allergic diseases systematically.

요약

알레르기성 비염(AR), 

알레르기성 천식(AAS), 

아토피성 피부염(AD), 

음식 알레르기(FA), 

습진과 같은 알레르기 질환은 

면역 체계 장애로 인해 발생하는 전신 질환입니다. 

allergic rhinitis (AR),

allergic asthma (AAS),

atopic dermatitis (AD),

food allergy (FA), and

eczema

재발률이 높고, 

꾸준히 증가하는 이 질환의 발생률은 점점 더 많은 관심을 받고 있습니다. 

알레르기 질환의 병인은 복잡하며, 

모체-태아 환경, 생활 환경, 유전학, 후성유전학, 

그리고 신체의 면역 상태를 포함한 많은 요인이 관련되어 있습니다. 

알레르기 질환의 병인은 

현저한 이질성을 나타내며, 

표현형과 내형은 각각 눈에 보이는 특징과 관련된 분자 메커니즘을 정의합니다. 

면역학, 분자 생물학, 생명 공학의 급속한 발전으로 

알레르기 질환 치료를 위한 많은 새로운 생물학적 약물이 개발되었으며, 

증상 조절을 위한 

항-면역글로불린 E(IgE), 

항 인터루킨(IL)-5, 

항 흉선 기질 림포포이에틴(TSLP)/IL-4 등이 있습니다. 

의사들과 과학자들에게 

알레르기 질환의 영향 요인, 병인, 치료 진행 과정을 이해하는 것이 점점 더 중요해지고 있습니다. 

이 리뷰는 

AR, AAS, AD, FA를 포함한 알레르기 질환의 역학, 병인, 치료 개입을 평가하는 것을 목표로 합니다. 

의사들과 과학자들이 알레르기 질환을 체계적으로 이해할 수 있도록 돕고자 합니다.

Similar content being viewed by others

Allergic rhinitis

Article 03 December 2020

Allergic asthma is a risk factor for human cardiovascular diseases

Article 16 May 2022

The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment

Article Open access16 March 2023

Introduction

Allergic diseases are systemic disorders caused by an impaired immune system. Different allergic diseases, including AR, AAS, AD, FA and eczema, are caused by complex interactions between genetic and environmental factors. Allergic diseases are listed by the World Health Organization (WHO) as one of the top three disorders to be prevented and controlled in the 21st century. An allergic disease, whilst a systemic disease, can also manifest as different local maladies, all of which may lead to anaphylactic shock in severe cases. The incidence of allergic diseases is high, bringing much suffering to patients. It is estimated that nearly 500 million and 300 million individuals worldwide have AR and AAS, respectively,1 with an increasing number of cases. For AAS, mortality rates in women and men are 90 and 170 per million individuals, respectively. About 96% of asthma deaths occur in low-and-middle-income countries.2 It is currently estimated that FA affects 1–10% of the total population.3 The global preval‎ence rate of AD is 8%,4,5 with a lifetime preval‎ence reaching 20%.6 In 2019, there were 171.17 million patients worldwide with AD.7

Due to the different sites of allergic diseases, the clinical and pathological manifestations also differ. In AR, after stimulation by allergens, including airborne dust mites associated with fecal particles, cockroach remains, pet dander, molds and pollens, inflammatory cells such as mast cells, CD4+ T cells, B cells, macrophages and eosinophils infiltrate the lining of the nasal cavity, with infiltration into the nasal mucosa. T helper 2 (Th2) cells promote the release of immunoglobulin and cytokines, including interleukin (IL)-3, IL-4, IL-5, and IL-13; meanwhile, IgE is also produced by plasma cells. There is, however, still some uncertainty around the source of IgE production. Follicular helper T (Tfh) cells are a subpopulation of CD4+ T-effector cells, and in recent years it has been discovered that the key cells regulating IgE production are not Th2 cells, but Tfh cells. Allergens cross-link IgE that interact with mast cells, which further induces the release of multiple mediators (including histamine and leukotrienes), promotes arteriole dilation and vascular permeability, and causes pruritus, runny nose, mucus secretion, and pulmonary smooth muscle contraction.8 Over the next 4–8 hours, the released mediators and cytokines induce subsequent cellular inflammatory reactions (late inflammatory response), leading to the recurrence of symptoms, often nasal congestion, which generally persist.8,9 

The immunopathological profiles of AR and AAS are very similar in terms of eosinophil, mast cell and Th2 cell infiltration. Although structural changes in airway remodeling are well characterized in AAS, they may also occur in AR. There are also pathophysiological differences between AR and AAS. In the AAS disease, mucosal pathological alterations comprise epithelial hyperplasia, goblet cell metaplasia and increased mucus generation. In the submucosal layer, smooth muscle hypertrophy, collagen accumulation and large mucus glands prevail, leading to airway narrowing and enhanced mucus generation during an asthma attack,10 with symptoms such as difficulty breathing, wheezing, chest pain, and coughing.11 The pathogenesis of AD is mainly reflected by a complex interplay between epidermal barrier dysfunction, abnormal skin microbiota and dysregulated type 2 T cell immunity.12,13 

The above pathogenesis induces a series of pathological manifestations such as filamentous aggregation; weak skin barrier due to protein shortage promoting inflammatory reactions and T cell infiltration; S. aureus colonization or infection disrupting the skin barrier and inducing an inflammatory response as well as the development of epidermal edema (“spongy sclerosis”); local Th2 immune reactions further reducing the barrier function, promoting dysregulation that favors Staphylococcus species, especially S. aureus, which triggers pruritus.

FA is an IgE-dependent type I hypersensitivity to a specific food allergen. Its pathological process is divided into two stages: in the allergic sensitization stage, the initial exposure to the allergen results in tolerance breakdown, with subsequent generation of specific IgE, vasoactive substances and allergic response mediators such as histamine and platelet activating factor.14 During the provocation phase, degranulation of effector cells, such as mast cells, induces allergic inflammation, and serotonin or 5-hydroxytryptamine is released in large amounts, resulting in acute gastrointestinal symptoms, including diarrhea. Besides mast cells, an allergen also reacts with sensitized basophils in the circulation, triggering a life-threatening systemic reactions featuring multiple-organ and system involvements, hypotension and shock.15 After repeated exposure to food allergens, persistent allergic inflammatory reactions occur and tissue mast cells increase, resulting in persistent gastrointestinal reactions.16

The pathogenesis of allergic diseases is complex, involving many factors such as genetics, epigenetics, environmental factors, microecology and the body’s immune function. Their recurrence rate is high, which brings great pain to and imposes a severe financial burden on patients. Therefore, this manuscript comprehensively analyzes allergic diseases, from a brief introduction of their history to their mechanism and treatment, hoping to provide not only a systematic understanding of such diseases, but also a reference for clinical doctors and scientists.

소개

알레르기 질환은

면역 체계가 손상되어 발생하는 전신 질환입니다.

AR, AAS, AD, FA, 습진 등

다양한 알레르기 질환은

유전적 요인과 환경적 요인의 복잡한 상호 작용으로 인해 발생합니다.

알레르기 질환은

세계보건기구(WHO)가 21세기에 예방 및 관리해야 할 3대 질환 중 하나로 꼽고 있습니다.

알레르기 질환은

전신 질환이지만,

다양한 국소 질환으로 나타날 수 있으며,

이 모든 질환은 심한 경우 아나필락시스 쇼크로 이어질 수 있습니다.

알레르기 질환의 발병률이 높기 때문에

환자에게 많은 고통을 안겨 줍니다.

전 세계적으로

각각 약 5억 명과 3억 명의 사람들이 AR과 AAS를 앓고 있는 것으로 추정되며,

그 수는 계속 증가하고 있습니다.

AAS의 경우,

여성과 남성의 사망률은 각각 백만 명당 90명과 170명입니다.

천식 사망자의 약 96%가

저소득 및 중간 소득 국가에서 발생합니다.2

현재 FA는 전체 인구의 1~10%에 영향을 미치는 것으로 추정됩니다.3

AD의 전 세계 유병률은 8%이고,4 평생 유병률은 20%에 달합니다.5

2019년, 전 세계적으로 1억 7,117만 명의 AD 환자가 있었습니다.7

알레르기 질환의 부위에 따라

임상적, 병리학적 증상도 다릅니다.

AR의 경우, 대변 입자와 관련된

공기 중 먼지 진드기, 바퀴벌레, 애완동물 비듬, 곰팡이, 꽃가루 등의 알레르기 유발 물질에 의해 자극을 받은 후,

비강 점막으로 침투하면서 비강 내벽에

비만세포, CD4+ T세포, B세포, 대식세포, 호산구 등의 염증 세포가 침투합니다.

T 헬퍼 2(Th2) 세포는

면역글로불린과 인터루킨(IL)-3, IL-4, IL-5, IL-13을 포함한

사이토카인의 방출을 촉진합니다.

한편, IgE는

혈장세포에 의해서도 생성됩니다.

그러나

IgE 생성 원인에 대해서는 아직 불확실한 부분이 있습니다.

여포성 헬퍼 T(Tfh) 세포는

CD4+ T-이펙터 세포의 하위 집단이며,

최근 몇 년 동안 IgE 생산을 조절하는 핵심 세포가 Th2 세포가 아니라 Tfh 세포라는 사실이 밝혀졌습니다.

알레르기 항원은

IgE와 교차 결합하여 비만 세포와 상호 작용하고,

이로 인해 여러 매개체(히스타민과 류코트리엔 포함)의 방출이 촉진되고,

세동맥 확장과 혈관 투과성이 촉진되며,

가려움증, 콧물, 점막 부종, 천명음, 기침, 콧물,

평활근 수축을 유발합니다.8

pruritus, runny nose, mucus secretion, and pulmonary smooth muscle contraction

이후 4-8시간 동안 방출된 매개체와 사이토카인은

후속 세포 염증 반응(후기 염증 반응)을 유발하여

증상(주로 코막힘)의 재발을 유발하며,

이는 일반적으로 지속됩니다.8,9

Over the next 4–8 hours, the released mediators and cytokines induce subsequent cellular inflammatory reactions (late inflammatory response), leading to the recurrence of symptoms, often nasal congestion, which generally persist

AR과 AAS의 면역병리학적 프로파일은

호산구, 비만세포, Th2 세포의 침윤이라는 측면에서

매우 유사합니다.

기도 리모델링의 구조적 변화는

AAS에서 잘 특징지어지지만,

AR에서도 발생할 수 있습니다.

AR과 AAS 사이에는

병리생리학적 차이도 있습니다.

AAS 알레르기 천식 질환에서 점막의 병리학적 변화는

상피 증식, 잔세포 전이, 점액 생성 증가로 구성됩니다.

점막하층에서는

평활근 비대, 콜라겐 축적, 점액 분비샘의 증식이 일어나서,

천식 발작 시 기도 협착과 점액 분비 증가를 유발하여,

호흡 곤란, 쌕쌕거림, 흉통, 기침 등의 증상을 유발합니다10.11

AD 아토피의 병인은

주로 표피 장벽 기능 장애,

비정상적인 피부 미생물군,

조절되지 않는 2형 T세포 면역 간의 복잡한 상호 작용에 의해 반영됩니다12,13.

위의 병인은 다음과 같은 일련의 병리학적 증상을 유발합니다.

필라멘트 응집;

단백질 부족으로 인한 약한 피부 장벽이 염증 반응을 촉진하고 T 세포 침윤을 촉진;

황색포도상구균의 집락 또는 감염이 피부 장벽을 파괴하고

염증 반응을 유발할 뿐만 아니라 표피 부종(“스폰지 경화증”)의 발생을 유발;

국소 Th2 면역 반응이 장벽 기능을 더욱 감소시켜,

가려움증을 유발하는

황색포도상구균 종, 특히 황색포도상구균을 선호하는 조절 장애를 촉진.

The above pathogenesis induces a series of pathological manifestations such as filamentous aggregation;

weak skin barrier due to protein shortage promoting inflammatory reactions and T cell infiltration; 

S. aureus colonization or infection disrupting the skin barrier and inducing an inflammatory response as well as the development of epidermal edema (“spongy sclerosis”);

local Th2 immune reactions further reducing the barrier function, promoting dysregulation that favors Staphylococcus species, especially S. aureus, which triggers pruritus.

FA 음식알레르기는

특정 음식 알레르겐에 대한

IgE 의존성 유형 I 과민증입니다.

병리학적 과정은 두 단계로 나뉩니다:

알레르기 민감화 단계에서

알레르겐에 처음 노출되면 내성이 파괴되고,

그 결과 특정 IgE, 혈관 활성 물질,

히스타민과 혈소판 활성화 인자와 같은 알레르기 반응 매개체가 생성됩니다. 14

자극 단계 동안,

비만 세포와 같은 효과기 세포의 탈과립화는 알레르기성 염증을 유발하고,

세로토닌 또는 5-하이드록시트립타민은 대량으로 방출되어

설사를 포함한 급성 위장 증상을 유발합니다.

비만 세포 외에도 알레르기 항원은

순환계에 있는 과민성 호염기구와 반응하여 여러 기관과 시스템이 관여하는 생명을 위협하는 전신 반응을 유발하고,

저혈압과 쇼크를 유발합니다.15

음식 알레르기 항원에 반복적으로 노출되면

지속적인 알레르기 염증 반응이 발생하고

조직 비만 세포가 증가하여 지속적인 위장 반응이 발생합니다.16

알레르기 질환의 병인은 복잡하며,

유전학, 후성유전학, 환경적 요인, 미생물 생태학,

그리고 신체의 면역 기능 등 많은 요인들이 관여합니다.

재발률이 높기 때문에 환자에게

큰 고통을 안겨주고 심각한 재정적 부담을 안겨줍니다.

따라서

이 논문은 알레르기 질환의 역사부터

그 메커니즘과 치료에 이르기까지 포괄적으로 분석하여

이러한 질환에 대한 체계적인 이해를 제공할 뿐만 아니라 임상 의사 및 과학자들에게 참고 자료가 될 수 있기를 바랍니다.

A brief history of allergic diseases

Since ancient times, people have always been drawn to allergic diseases, studying their pathogenesis and developing related treatments. The earliest recorded allergic reaction in human history was the death of the Egyptian pharaoh Menes after being bitten by a bumblebee around 2641 BCE.17 Theories on the actual causes and diagnosis of allergic diseases were further developed in the 19th century, precisely in 1819, when the British physician John Bostock, at the Royal Society of Reported Medicine, attributed summer eye and nose discomfort to hay, naming the condition “hay fever”.18 Later in 1868, Eosinophilia was first observed by Henry Hyde Salter, in the sputum of a patient with an allergic disease.19

The pathogenesis and treatment of allergic diseases have made rapid progress in the 20th century. The word “allergy” was coined by Clemens von Pirquet in 1906,20,21 which is considered to be the beginning of modern allergy science. In 1911, Leonard Noon was the first to be successful in the treatment of pollen-associated AR with low-dose flower infusion, setting a precedent for immunotherapy.22 Edward Calvin Kendall discovered the adrenocortical hormone and determined its structure and physiological effects in 1935, earning the Nobel Prize in Physiology or Medicine in 1950.23 Daniel Bovet synthesized antihistamines in 1937 and earned the Nobel Prize in Physiology or Medicine in 1957, which brought hope in the treatment of allergic diseases and has been in clinical use to this day.24,25 In 1953, James F. Riley was the first to discover that histamine in the human body mainly comes from mast cell granules.26 

Up to this point in history, basic treatment methods for allergic diseases had been established, but no breakthrough had been made in mechanistic research. In terms of pathogenesis, the Ishzaka couple discovered in 1966 that the reactive hormone in the serum of patients with allergic diseases was IgE,27 providing a new experimental tool and concept for serological research. In 1989, the epidemiologist Strachan proposed the “hygiene hypothesis” on the basis that “compared with an only child, children in large families have a lower risk of developing pollen allergy and eczema”.28 The hygiene hypothesis has laid a solid foundation for studying the pathogenesis of allergic diseases from the perspectives of modern immunology, microecology, and antibiotic application. Current guidelines suggest a combined application of allergen avoidance, pharmacotherapy, and/or allergen-specific immunotherapy (AIT)29,30 (Fig. 1).

알레르기 질환의 간략한 역사

고대부터 사람들은 알레르기 질환에 매료되어 병인을 연구하고 관련 치료법을 개발해 왔습니다. 인류 역사상 가장 오래된 알레르기 반응은 기원전 2641년경에 이집트 파라오 메네스가 땅벌에 물려 죽은 사건으로 기록되어 있습니다. 알레르기 질환의 실제 원인과 진단에 관한 이론은 19세기, 정확히 1819년에 영국인 의학 연구소(Royal Society of Reported Medicine)의 영국 의사 존 보스톡(John Bostock)은 여름철 눈과 코의 불편함을 건초열로 명명하면서 건초에 기인한다고 주장했습니다.18 1868년, 헨리 하이드 솔터(Henry Hyde Salter)는 알레르기 질환 환자의 객담에서 호산구 증가증을 처음으로 관찰했습니다.19

알레르기 질환의 병인과 치료는 20세기에 급속한 발전을 이루었습니다.

“알레르기”라는 단어는

1906년 클레멘스 폰 피르케트(Clemens von Pirquet)에 의해 만들어졌으며,20,21

이는 현대 알레르기 과학의 시작으로 간주됩니다.

1911년,

레너드 눈(Leonard Noon)은 꽃가루 관련 AR을 저용량 꽃 주입으로 치료하는 데 성공한 최초의 사람이었으며,

면역 요법의 선례를 세웠습니다.22

에드워드 캘빈 켄달(Edward Calvin Kendall)은 부신피질 호르몬을 발견하고

1935년에 그 구조와 생리적 효과를 규명하여

1950년에 노벨 생리학 또는 의학상을 수상했습니다.23

다니엘 보베(Daniel Bovet)는 합성 항히스타민제를 합성했고,

1957년 노벨 생리학·의학상을 수상했습니다.

이 약은 알레르기 질환 치료에 희망을 가져다주었고,

오늘날까지 임상적으로 사용되고 있습니다.24,25

1953년, 제임스 F. 라일리는

인체 내 히스타민이 주로

비만세포 과립에서 유래한다는 사실을 최초로 발견했습니다.26

이 시점까지

알레르기 질환의 기본적인 치료 방법은 확립되었지만,

기전 연구에서는 돌파구가 없었습니다.

병인 측면에서,

이시자카 부부는

1966년에 알레르기 질환 환자의 혈청에 있는 반응성 호르몬이 IgE임을 발견했고,27

이를 통해 혈청학 연구에 새로운 실험 도구와 개념을 제공했습니다.

1989년, 역학자 스트라챈은

“외동아이에 비해 대가족의 아이들은 꽃가루 알레르기 및 습진 발병 위험이 낮다”는 근거를 바탕으로

“위생 가설”을 제안했습니다.28

위생 가설은

현대 면역학, 미생물학, 항생제 적용의 관점에서

알레르기 질환의 병인을 연구하는 데 견고한 토대를 마련했습니다.

현재의 지침은

알레르기 유발 물질 회피,

약물 치료,

그리고/또는 알레르기 유발 물질 특이 면역 요법(AIT)의 병용을 제안하고 있습니다29,30 (그림 1).

Fig. 1

Timeline of major findings related to allergic diseases. Allergic reactions in Western countries were first recorded in 2641 BCE, when the Egyptian Pharaoh Menes died after being bitten by a bumblebee. In 1911, Leonard Noon published an article in The Lancet, reporting a clinical paper treating pollinosis by subcutaneous injection of grass pollen extract, which marked the beginning of modern immunotherapy. In 1966, the Japanese scientist Ishizaka and his wife discovered IgE, which led to a leap in the understanding of immediate allergy. Following their discovery, IgE became a new indicator for the diagnosis of allergy

Full size image

Mechanism

Genetics and epigeneticsGene-environment interactions in allergy diseases

Allergic disease is a complex disorder, whose etiology and development may involve genetic and environmental factors. Although the innate and adaptive immune systems are critical in regulating the adaptation to the external microenvironment,31 allergic diseases are considered a major cause of immune dysfunction caused by the interactions of multiple genes and the external environment in cells.32,33

The research boom in genetics and epigenetics has substantially promoted research progress for allergic diseases. The application of genome-wide association studies (GWASs), single nucleotide polymorphism (SNP) analysis, and epigenome-wide association studies (EWASs) has laid a solid foundation for exploring the genetics of allergic diseases. Epigenetic studies mainly focus on DNA methylation, post-translational histone modifications, and non-coding RNAs. Epigenetics can explain the occurrence and development of allergic diseases in the external environment from various aspects, elucidate the mechanism of immune response plasticity in allergic disorders, and even provide diagnostic biomarkers and therapeutic targets for allergic disorders34,35 (Fig. 2).

메커니즘

유전학과 후성유전학 알레르기 질환의 유전자-환경 상호작용

알레르기 질환은 복잡한 장애로,

그 병인과 발달에 유전적 요인과 환경적 요인이 관여할 수 있습니다.

선천성 면역 체계와 적응성 면역 체계가

외부 미세환경에 대한 적응을 조절하는 데 중요한 역할을 하지만,31

알레르기 질환은

여러 유전자와 세포의 외부 환경이 상호작용하여 발생하는

면역 기능 장애의 주요 원인으로 간주됩니다.32,33

유전학과 후성유전학에 대한 연구가 활발해지면서

알레르기 질환에 대한 연구가 크게 진전되었습니다.

게놈 전체 연관 연구(GWAS), 단일 염기 다형성(SNP) 분석, 후성유전체 전체 연관 연구(EWAS)의 적용은 알레르기 질환의 유전학을 탐구하는 데 견고한 기반을 마련했습니다.

후성유전학 연구는 주로

DNA 메틸화,

번역 후 히스톤 변형,

비코딩 RNA에 초점을 맞추고 있습니다.

후성유전학은

외부 환경에서 알레르기 질환의 발생과 발달을 다양한 측면에서 설명하고,

알레르기 질환에서 면역 반응 가소성의 메커니즘을 밝혀낼 수 있으며,

알레르기 질환의 진단 바이오마커와 치료 표적을 제공할 수도 있습니다34,35 (그림 2).

Fig. 2

Allergic diseases are caused by a variety of factors. External factors include changes in gut microbiota and metabolites, drugs, and air pollution. Internal influencing factors include genetic and epigenetic changes

Full size image

SNPs and related GWASs in allergic diseases

When the Human Genome Project was completed in 2001,36 scientists were surprised to find that most genome sequence variations involve SNPs. SNP diversity can be found throughout different regions of the genome,37 including introns, exons, promoters, enhancers and intergenic regions, with SNPs considered as the basis of DNA sequence variation.38

알레르기 질환의 SNP 및 관련 GWAS

2001년 인간 게놈 프로젝트가 완료되었을 때,36명의 과학자들은 대부분의 게놈 서열 변이가 SNP와 관련되어 있다는 사실에 놀랐습니다. SNP 다양성은 게놈의 여러 영역에서 발견될 수 있으며,37개의 인트론, 엑손, 프로모터, 인핸서, 인터제닉 영역을 포함하며, SNP는 DNA 서열 변이의 기초로 간주됩니다.38개의

Hereditary studies

Both genetics and the environment are critical to the etiology and development of allergic diseases, and it is difficult to distinguish their independent roles in allergic diseases when they are combined. Twins’ studies can be used to separate genetics from environmental factors, providing clues to the genetic component of allergic diseases. In fact, research into the genetics of allergic disease also began in twins. Twin studies revealed that FA had high heritability, and GWAS and candidate gene studies indicated marked associations of the human leukocyte antigen(HLA)-DR and HLA-DQ region with genetic variants in multiple genes, including Filaggrin (FLG), the HLA locus, and Forkhead Box Protein P3 (FOXP3).39 Peanut allergy in 82% of identical twins far exceeds the 20% concordance rate observed in dizygotic twins,40,41 further supported by the fact that children whose parents or siblings have peanut allergy are 7 times more likely to develop the disease compared with children without family risk factors. In general, heritability estimates for FA are as high as 81%,42 while the heritability of AR is estimated at approximately 91%.42 Twin studies reveal that about 25% of phenotypic variation in asthma severity can be explained by genetic factors; for example, RAD50- IL13 on chromosome 5q and the ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3)- gasdermin B (GSDMB) locus on chromosome 17q21 were found to be associated with asthma severity.43 Besides, the concordance rate for AD in identical twins is about 80%, which is remarkably elevated compared with the 20% found in fraternal twins.44

유전 연구

유전학과 환경은

알레르기 질환의 병인과 발달에 중요한 역할을 하며,

알레르기 질환에서 두 가지 요인이 결합될 때

그 독립적인 역할을 구분하기가 어렵습니다.

쌍둥이 연구는

유전적 요인과 환경적 요인을 구분하는 데 사용될 수 있으며,

알레르기 질환의 유전적 요인에 대한 단서를 제공합니다.

실제로,

알레르기 질환의 유전학에 대한 연구는 쌍둥이에서 시작되었습니다.

쌍둥이 연구에 따르면

FA는 유전성이 높고,

GWAS와 후보 유전자 연구에 따르면

인간 백혈구 항원(HLA)-DR과 HLA-DQ 영역이 필라그린(FLG),

HLA 유전자좌,

포크헤드 박스 단백질 P3(FOXP3)를 포함한

여러 유전자의 변이형과 유의미한 연관성을 가지고 있는 것으로 나타났습니다. 39

일란성 쌍둥이 중

82%가 땅콩 알레르기를 앓고 있는 것으로 밝혀져

이란성 쌍둥이에서 관찰되는 일치율 20%를 훨씬 초과하며,40,41

부모나 형제자매가 땅콩 알레르기를 앓고 있는 아이가

가족 내 위험 요인이 없는 아이에 비해 땅콩 알레르기에 걸릴 확률이 7배 더 높다는 사실로 더욱 뒷받침됩니다.

일반적으로,

FA의 유전성 추정치는 81%에 달하는 반면,

AR의 유전성은 약 91%로 추정됩니다.42

쌍둥이 연구에 따르면

천식 중증도의 표현형 변이의 약 25%가 유전적 요인에 의해 설명될 수 있는 것으로 나타났습니다.

예를 들어, 5번 염색체상의 RAD50-IL13과 ORMDL sph ingolipid biosynthesis regulator 3 (ORMDL3)- gasdermin B (GSDMB) locus on chromosome 17q21이 천식 중증도와 관련이 있는 것으로 밝혀졌습니다.43

게다가,

일란성 쌍둥이의 AD 일치율은

약 80%로,

이란성 쌍둥이의 20%에 비해 현저히 높은 수치입니다.44

SNP and GWAS analyses in allergic diseases

To date, SNPs in no less than 34 loci and 46 genes are considered to have AD risk in different populations around the world.45 Loss-of-function mutations in FLG, which encodes filaggrin (a skin barrier protein), are considered the most important genetic risk factor for AD, although variants affecting skin and systemic immune reactions also play critical roles.46 In an AAS disease study, after analysis by GWAS, Sarnowski et al. recently detected five genetic variants related to age at onset in 5,462 asthma cases, at or around recombinant Cylindromatosis (CYLD) on 16q12 (rs1861760), IL1RL1 on 2q12 (rs10208293), HLA-DQA1 on 6p21 (rs9272346), IL33 on 9p24 (rs928413) and GSDMA on 17q12 (rs9901146), with the last four also showing associations with susceptibility to allergic diseases. Recombinant Mucin 5 Subtype AC (MUC5AC) is considered an essential factor in the natural barrier function of the airway and has a potential association with moderate to severe asthma.47 Studies have shown that SNP changes of ORMDL3 and the TSLP promoter gene are involved in AAS;48,49 polymorphisms in the alpha chain coding region of IL-4 receptor are also associated with AAS.50 Susceptibility-related GWAS data showed that asthma-related IL-33 genes are all associated with asthma and AR.51,52 Changes in IL-4 gene single nucleotide polymorphisms can increase the risk of AR;52 individuals with the Vitamin D (1,25- dihydroxyvitamin D3) receptor (VDR) rs2228570 CC and vitamin D-binding protein (VDBP) rs7041 GG genotypes have a high risk of asthma progression.53 In FA analysis, peanut allergy is clearly associated with specific locus changes in the HLA-DR and HLA-DQ genes.54 Molecular genetic analysis of the GG, GA, and AA genotypes of the IL-13 R130Q gene polymorphism revealed markedly elevated incidence rates of the GA and AA genotypes in comparison with healthy control individuals.55 Besides, the serpin B serpin (SERPINB) and cytokine gene clusters increase the risk of any FA, as well as the C11orf30/LRRC32 locus.56

In the study of AR, the largest GWAS revealed 20 novel loci associated with AR risk,57 including IL7R at 5p13.2 and SH2B adaptor protein 3 (SH2B3) on chromosome 12q24.12, which separately participate in V(D)J recombination of T cell and B cell receptors,58 blood eosinophil count59 and T cell activation pathways.60 Furthermore, we noted that AR risk loci have important effects on innate and adaptive immune responses. Loci near C-X-C chemokine receptor type 5 (CXCR5) on 11q23 and Fc Fragment of IgE Receptor Ig (FCER1G) on 1q23.3 separately encode chemokine receptor in B cells and follicular T cells61 and the γ chain of IgE receptor.62 Broad-complex,tramtrack and bric-a-brac and cap’n’collar homology 2 (BACH2) on 6q15 is critical to the induction immunomodulatory function of memory B and T cells,63,64 Leukocyte tyrosine kinase (LTK) and TYRO3 protein tyrosine kinase (TYRO3) modulate Th2-type immune responses; RAR-related orphan receptor A (RORA) regulates the development and inflammatory response of Th2 innate lymphocytes, and tumor necrosis factor (ligand) superfamily, member 11 (TNFSF11) is involved in dendritic cell activation of T cells. The Viral protein R binding protein (VPRBP) gene controls T cell proliferation and contributes to V(D)J recombination in B cells.65,66,67,68 Surprisingly, the frequencies of the tumor necrosis factor-α (TNF-α) and MRPL4 genes are starkly elevated in AR cases in Han individuals69 (Table 1).

알레르기 질환의 SNP 및 GWAS 분석

현재까지, 전 세계의 다양한 인구 집단에서 AD 위험이 있는 것으로 간주되는 SNP는 34개 이상의 유전자좌와 46개 이상의 유전자에 존재합니다.45 필라그린(피부 장벽 단백질)을 암호화하는 FLG의 기능 상실 돌연변이는 AD의 가장 중요한 유전적 위험 요소로 간주되지만, 피부 및 전신 면역 반응에 영향을 미치는 변이도 중요한 역할을 합니다.46 In an AAS 질병 연구에서, Sarnowski 등은 최근 GWAS 분석을 통해 천식 환자 5,462명의 발병 연령과 관련된 5가지 유전적 변이를 발견했습니다. 16q12(rs1861760)의 재조합 실린드로마토시스(CYLD), 2q12(rs1 0208293), HLA-DQA1 on 6p21 (rs9272346), IL33 on 9p24 (rs928413) 및 GSDMA on 17q12 (rs9901146)을 발견했으며, 마지막 4개는 알레르기 질환에 대한 감수성과도 연관성이 있는 것으로 나타났습니다. 재조합 뮤신 5 아형 AC(MUC5AC)는 기도 자연 장벽 기능의 필수 요소로 간주되며 중등도에서 중증 천식과 관련이 있을 가능성이 있습니다.47 연구에 따르면 ORMDL3와 TSLP 프로모터 유전자의 SNP 변화가 AAS에 관여하는 것으로 나타났습니다.48,49 IL의 알파 사슬 코딩 영역의 다형성 -4 수용체의 알파 사슬 코딩 영역의 다형성도 AAS와 관련이 있습니다.50 감수성 관련 GWAS 데이터에 따르면, 천식과 관련된 IL-33 유전자는 모두 천식과 AR과 관련이 있습니다.51,52 IL-4 유전자 단일 염기 다형성의 변화는 AR의 위험을 증가시킬 수 있습니다.52 비타민 D(1,25-디하이드록시비타민 D3) 수용체(VDR) rs2228570 CC 및 비타민 D 결합 단백질(VDBP) rs7041 GG 유전자형은 천식 진행 위험이 높습니다.53 FA 분석에서 땅콩 알레르기는 HLA-DR 및 HLA-DQ 유전자의 특정 유전자좌 변화와 명확하게 연관되어 있습니다.54 GG, GA, AA의 분자 유전학적 분석 유전자형에 대한 분자 유전학적 분석 결과, 건강한 대조군과 비교하여 GA 및 AA 유전자형에서 IL-13 R130Q 유전자 다형성의 발병률이 현저하게 높은 것으로 나타났습니다.55 또한, 세르핀 B 세르핀(SERPINB)과 사이토카인 유전자 클러스터는 C11orf30/LRRC32 유전자좌뿐만 아니라 모든 FA의 위험을 증가시킵니다.56

AR에 대한 연구에서, 가장 큰 규모의 GWAS는 5p13.2의 IL7R과 12q2의 SH2B adaptor protein 3(SH2B3)를 포함하여 AR 위험과 관련된 20개의 새로운 유전자좌를 밝혀냈습니다57 4.12, 이는 T세포와 B세포 수용체의 V(D)J 재조합에 개별적으로 관여하며,58 혈액 호산구 수59 및 T세포 활성화 경로에 영향을 미칩니다.60 또한, AR 위험 유전자좌가 선천성 및 후천성 면역 반응에 중요한 영향을 미친다는 사실을 확인했습니다. 11q23에 있는 C-X-C 케모카인 수용체 유형 5(CXCR5)와 1q23.3에 있는 Fc 단편 IgE 수용체 Ig(FCER1G) 근처의 유전자좌는 각각 B세포와 여포성 T세포의 케모카인 수용체를 암호화합니다61 그리고 IgE의 γ 사슬 수용체.62 6q15에 있는 광범위한 복합체, 트램트랙, 잡동사니, 캡앤콜라 상동성 2(BACH2)는 기억 B세포와 T세포의 면역 조절 기능을 유도하는 데 매우 중요합니다.63,64 백혈구 티로신 키나제(LTK)와 TYRO 3 단백질 티로신 키나아제(TYRO3)는 Th2형 면역 반응을 조절하고, RAR 관련 고아 수용체 A(RORA)는 Th2 선천성 림프구의 발달과 염증 반응을 조절하며, 종양 괴사 인자(리간드) 슈퍼패밀리, 멤버 11(TNFSF11)은 T세포의 수지상 세포 활성화에 관여합니다. 바이러스 단백질 R 결합 단백질(VPRBP) 유전자는 T 세포의 증식을 조절하고 B 세포의 V(D)J 재조합에 기여합니다.65,66,67,68 놀랍게도, 한족의 AR 사례에서 종양 괴사 인자-α(TNF-α)와 MRPL4 유전자의 빈도가 현저하게 증가합니다69 (표 1).

Table 1 Summary of genomic loci of allergic disease

Full size table

Mitochondrial inheritance in allergic disease

Maternal inheritance is considered the most critical player in allergic disease occurrence. Most offspring mitochondria are inherited from the mother, and mitochondrial inheritance is tightly associated with asthma occurrence.70,71,72,73 Mitochondrial DNA (mtDNA) variants are significantly associated with allergic disorders, including AD and asthma. A report demonstrated that in 69 mtDNA variants, the rs28357671 locus of the MT-ND6 gene was significantly associated with mitochondrial function genes in allergic diseases, including: NLR Family Member X1 (NLRX1), oculocutaneous albinism II (OCA2) and coiled-coil-helix-coiled-coil-helix domain containing 3 (CHCHD3).74 Interestingly, the genetic cause of asthma in females may be associated with a dysfunction of mitochondrial MT-ND2 and MT-RNR2 genes, while in males, mutations in the mitochondrial cytochrome-b (CYB) gene leads to changes in reactive oxygen species (ROS) and asthma development.75

Mutations affecting mitochondrial tRNA genome sequences have been observed in the placenta of asthmatic mothers and are associated with AAS;76 for example, a rare mutation in the A3243G-tRNA Leu (UUR) MELAS gene, which is thought to be associated with asthma, was found in asthmatic patients. Maternally inherited mitochondrial diseases have been reported.77 Fukuda’s team found that 9 of the 13 differentially expressed genes in allergic patients were mitochondria-related genes, including those producing cytochrome oxidases II and III, and NADH dehydrogenase.76,78,79 In addition, polymorphisms in the ADAM metallopeptidase domain 33 (ADAM33) and cytochrome b genes located on chromosome 20 have been associated with asthma susceptibility, both of which are closely associated with mitochondrial oxidative function.80 Mitochondrial haploidy and elevated serum IgE amounts are associated in Europeans,73 which may involve diverse mutations in genes that encode mitochondrial tRNAs.76 The ATP synthase mitochondrial F1 complex assembly factor 1 gene was implicated in asthma in Caucasian children.81 Some AAS is closely related to mtDNA deficiency, and alterations in more than 25 genes (ORMDL3, 2PBP2, GSDMB, PDE4D, VEGF, Wnt, MMP-12, PRKCA, JAG1, ANKRD5, TGF-β1, IL-12β, IL-10, IL-13, IL-17, IL-25, and β2-adrenergic receptors) are associated with abnormal changes in the immune system in AAS.80,82,83,84

알레르기 질환의 미토콘드리아 유전

알레르기 질환의 발생에 있어 가장 중요한 요인으로

모계 유전이 고려됩니다.

대부분의 자손의 미토콘드리아는

어머니로부터 유전되며,

미토콘드리아 유전은 천식 발생과 밀접한 관련이 있습니다.70,71,72,73

미토콘드리아 DNA(mtDNA) 변이는

AD와 천식을 포함한 알레르기 질환과 상당한 관련이 있습니다.

한 보고서에 따르면,

69개의 mtDNA 변이체 중

MT-ND6 유전자의 rs28357671 유전자좌가 알레르기 질환에서

미토콘드리아 기능 유전자와 유의미한 관련이 있는 것으로 나타났습니다.

NLR 가족 구성원 X1(NLRX1), 안구-피부 백색증 II(OCA2), 코일-코일-헬릭스-코일-헬릭스 도메인 3(CHCHD3) 등이 있습니다.74

흥미롭게도,

유전적 원인은

여성의 천식 발병 원인은

미토콘드리아 MT-ND2 및 MT-RNR2 유전자의 기능 장애와 관련이 있을 수 있는 반면,

남성의 경우 미토콘드리아 사이토크롬-b(CYB) 유전자의 돌연변이로 인해

활성산소(ROS)가 변화하고 천식이 발병합니다.75

미토콘드리아 tRNA 게놈 서열에 영향을 미치는 돌연변이는 천식 환자의 태반에서 관찰되었으며, 천식과 관련이 있는 것으로 여겨집니다. 예를 들어, 천식과 관련이 있는 것으로 여겨지는 A3243G-tRNA Leu(UUR) MELAS 유전자의 희귀 돌연변이가 천식 환자에서 발견되었습니다.76 모계 유전성 미토콘드리아 질환이 보고된 바 있습니다.77 후쿠다의 연구팀은 알레르기 환자에서 발현이 다른 13개의 유전자 중 9개가 시토크롬 산화효소 II와 III, 그리고 NADH 탈수소효소를 생산하는 유전자를 포함해 미토콘드리아 관련 유전자라는 사실을 발견했습니다.76,78,79 또한, ADAM 금속펩티다제 도메인의 다형성 33(ADAM33)과 염색체 20에 위치한 사이토크롬 b 유전자는 천식 감수성과 관련이 있으며, 둘 다 미토콘드리아 산화 기능과 밀접한 관련이 있습니다.80 유럽인의 경우, 미토콘드리아 반수체와 상승된 혈청 IgE 양은 관련이 있으며, 이는 미토콘드리아 tRNA를 암호화하는 유전자에서 다양한 돌연변이를 수반할 수 있습니다.76 ATP 신타제 미토콘드리아 F1 복합체 조립 인자 1 유전자는 백인 아동의 천식과 관련이 있습니다.81 일부 AAS는 mtDNA 결핍과 밀접한 관련이 있으며, 25개 이상의 유전자(ORMDL3, 2PBP2, GSDMB, PDE4D, VEGF, Wnt, MMP-12, PRK CA, JAG1, ANKRD5, TGF-β1, IL-12β, IL-10, IL-13, IL-17, IL-25, β2-adrenergic receptors)은 AAS의 면역계 이상 변화와 관련이 있습니다.80,82,83,84

Epigenetics and Epigenome-wide Association Study (EWAS)-related analysis of allergic diseases

Epigenetics are heritable features that affect gene expression‎ without altering the DNA sequence.85 DNA methylation is an effective factor to distinguish allergic patients from healthy people.44 DNA methylation is reflected by a methyl group added to cytosine at position 5 by DNA methyltransferases to form 5-methylcytosine,86 where a cytosine nucleotide is called a CpG, followed by a guanine nucleotide.87 CpG islands typically contain more than 200 bases, of which more than 60%-80% are guanines and cytosines (G + C).88 Methylation of CpG islands at transcription start sites (TSSs) of genes leads to gene activation or repression, and is generally thought to repress gene transcription.89

A cross-sectional study found that DNA methylation of allergy-related genes in the whole blood of allergic children may be a common parameter affecting asthma, rhinitis, and eczema; a total of 21 differential CpG loci were screened, 10 of which were in the pulmonary epithelium. The sites of replication, related to acyl-CoA thioesterase 7 (ACOT7), Lectin, Mannose Binding 2 (LMAN2) and Claudin 23 (CLDN23) genes, were all derived from eosinophils.90 Thus, changes in eosinophil levels are reflected by changes in methylation, unveiling a possible mechanism for phenotypic alterations in immune response-associated features.

In addition, methylation plays an important role in AD pathogenesis. The TSLP gene promoter is hypomethylated in the damaged skin of AD patients.91 Methylation is not specific to DNA, but is closely related to disease. Demethylation of histone H3 residues in the FOXP3 gene promoter region and hypermethylation of histone H3 residues in the RORC gene promote the differentiation of Th0 cells towards a regulatory T (Treg) phenotype. Conversely, these events cause Treg deficiency, one of the hallmarks of AD pathogenesis.34,92,93,94,95 Furthermore, CpG hypermethylation in IL-4 is negatively correlated with serum total IgE levels, explaining the role of Th2 immunity in AD.96 Enhanced hypermethylation of S100 calcium binding protein A5 (S100A5) was found in the epidermal part of lesions in AD cases in comparison with healthy individuals.97 Hypomethylation was observed in Recombinant Keratin 6 A (KRT6A) in keratinocytes, and methylation of cg07548383 in FLG also elevates AD risk.98

DNA methylation is also critical for AAS pathogenesis, occurrence, and development. An EWAS detected a total of 40,892 CpG sites methylated in important genes C-C motif chemokine ligand 26 (CCL26, a chemokine) and mucin 5 AC (MUC5AC, a mucin with airway defense function) among AAS patients compared with control cases.99 Chromosome 17q12-q21 hypermethylation contributes to asthma pathogenesis, with regulatory effects on all five protein-coding genes of this region, including IKAROS family zinc finger 3 (Aiolos) (IKZF3), zona pellucida-binding protein 2 (ZPBP2), ORMDL3, gasdermin A (GSDMA) and GSDMB.100 The STAT5A gene is hypermethylated in the 17q21.2 region and has been linked to increased Th1 responses and reduced infiltration of eosinophils in the airway epithelium.101 In childhood asthma, cg23602092 gene methylation status was linked to asthma symptoms,102 and hypomethylation of arachidonate 15-lipoxygenase (ALOX15) gene 17p13.2 and periostin, osteoblast specific factor (POSTN) gene 13q13.3 in nasal epithelial cells is associated with increased Th2 function.103 Methylation sites in multiple white blood cell (WBC) genes show significant associations with total IgE amounts, with the two most significant genes (ACOT7 and ZFPM1) associated with asthma.104 In adults, WNT2 gene hypermethylation in the 7q31.2 region in blood specimens is involved in neutrophilic asthma,105 and ORMDL3 hypermethylation in endobronchial airway epithelial cells contributes to asthma.106 Following hypermethylation at CpG sites, FOXP3 (12q15) and interferon-γ (IFN-γ) (Xp11.23) lead to altered T cell function and repressed Treg and T effector cell-related genes in blood.107 In adolescents, interleukin-5 receptor alpha (IL-5RA) (3p26.2) hypomethylation in blood was linked to asthma.108

In the AR disease, DNA methylation levels are tightly associated with CD4+ T cell amounts. DNA hypermethylation may downregulate IFN-γ in AR cases,109 while DNA hypomethylation increases the mRNA amounts of IL-13 and IgE.110 Alterations in hypermethylation at CpG sites in the melatonin receptor 1 A gene may be caused by paternal genetic variations in AR.111

DNA methylation might also contribute to FA pathogenesis. Reports have shown differences in DNA methylation in some mitogen-activated protein kinase (MAPK) signaling genes, e.g., human leukocyte antigen (HLA)-DQB1 and the Treg-specific demethylation region (TSDR) of FOXP3. Differential genetic DNA methylation might also contribute to FA diagnosis.39 In a pilot study of cow’s milk protein (CMA, milk allergy), hypermethylation was found in the DEXH (Asp-Glu-X-His) box polypeptide 58 (Dhx58), zinc finger protein 81 (ZNF281) and HtrA serine peptidase 2 (HTRA2) regions.112 Maternal peanut allergy also induces epigenetic changes in the IL-4 promoter in the offspring, which is associated with Th2 immune response (production of IL-4 and IgE).113 In a study of identical monozygotic (MZ) twins, the distance between peanut allergy and nonallergy in methylation profiles containing 12 DNAm signatures was reduced compared with randomly paired individuals without genetic relationships, indicating peanut allergy-associated DNAm signatures might be linked to genetic factors.114

후성유전학과 후성유전체-전체 연관성 연구(EWAS) 관련 알레르기 질환 분석

후성 유전학은

DNA 서열을 변경하지 않고

유전자 발현에 영향을 미치는 유전적 특징입니다.85

DNA 메틸화는

알레르기 환자와 건강한 사람을 구분하는 데 효과적인 요소입니다.44

DNA 메틸화는 DNA 메틸화 효소에 의해 5번 위치의 시토신에 메틸기가 추가되어 5-메틸시토신이 형성되는 것으로 반영됩니다.86 여기서 시토신 뉴클레오티드는 CpG라고 불리며, 그 뒤에는 구아닌 뉴클레오티드.87 CpG 섬은 일반적으로 200개 이상의 염기를 포함하며, 그 중 60%-80% 이상이 구아닌과 시토신(G + C)입니다.88 유전자의 전사 시작 부위(TSS)에서 CpG 섬의 메틸화는 유전자 활성화 또는 억제로 이어지며, 일반적으로 유전자 전사를 억제하는 것으로 여겨집니다.89

단면 연구에 따르면 알레르기 아동의 전혈에서 알레르기 관련 유전자의 DNA 메틸화가 천식, 비염, 습진에 영향을 미치는 공통적인 매개 변수일 수 있다고 합니다. 총 21개의 차별적 CpG 유전자좌가 선별되었고, 그중 10개가 폐 상피에 있었습니다. 복제 부위는 아실-CoA 티오에스테라제 7(ACOT7), 렉틴, 만노스 결합 2(LMAN2), 클라우딘 23(CLDN23) 유전자와 관련이 있으며, 모두 호산구에서 유래한 것입니다.90 따라서 호산구 수의 변화는 메틸화의 변화로 반영되어 면역 반응 관련 특징의 표현형 변화에 대한 가능한 메커니즘을 밝혀 줍니다.

또한,

메틸화는

아토피 피부염의 발병 기전에서 중요한 역할을 합니다.

아토피 피부염 환자의 손상된 피부에서 TSLP 유전자 프로모터의 메틸화가 감소합니다.91

메틸화는 DNA에만 국한된 현상이 아니라 질병과 밀접한 관련이 있습니다.

FOXP3 유전자 프로모터 영역에서 히스톤 H3 잔기의 탈메틸화와 RORC 유전자에서 히스톤 H3 잔기의 과메틸화는 조절 T(Treg) 표현형으로의 Th0 세포 분화를 촉진합니다. 반대로, 이러한 현상은 AD 병인의 특징 중 하나인 Treg 결핍을 유발합니다.34,92,93,94,95

또한, IL-4의 CpG 과메틸화는 혈청 총 IgE 수치와 음의 상관관계를 가지며, Th2 면역의 AD에서의 역할을 설명합니다.96 S100 칼슘 결합 단백질 A5의 강화된 과메틸화 (S100A5)는 건강한 사람에 비해 아토피 피부염 환자의 병변 표피 부분에서 발견되었습니다.97 각질 세포에서 재조합 케라틴 6A(KRT6A)의 저메틸화가 관찰되었으며, FLG의 cg07548383의 메틸화도 아토피 피부염의 위험을 높입니다.98

DNA 메틸화는 또한 AAS의 발병, 발생, 발달에 중요한 역할을 합니다. EWAS는 대조군과 비교하여 AAS 환자들 사이에서 중요한 유전자인 C-C 모티프 케모카인 리간드 26(CCL26, 케모카인)과 점액 5 AC(MUC5AC, 기도 방어 기능을 가진 점액)에서 총 40,892개의 CpG 부위가 메틸화된 것을 발견했습니다.99 염색체 17q12-q2 1개의 과메틸화는 이 지역의 5개 단백질 코딩 유전자(IKAROS family zinc finger 3(Aiolos)(IKZF3), zona pellucida-binding protein 2(ZPBP2), ORMDL3, gasdermin A(GSDMA), GSDMB)에 대한 조절 효과를 통해 천식 발병에 기여합니다.100 STAT5A 유전자 17q21.2 영역에서 과메틸화되어 있으며, Th1 반응의 증가와 기도 상피의 호산구 침윤 감소와 관련이 있습니다.101 소아 천식에서 cg23602092 유전자의 메틸화 상태는 천식 증상과 관련이 있으며,102 아라키도네이트 15-리포산화효소( ALOX15) 유전자 17p13.2와 코 상피 세포의 골아세포 특이적 인자(POSTN) 유전자 13q13.3의 저메틸화는 Th2 기능 증가와 관련이 있습니다.103 여러 백혈구(WBC) 유전자의 메틸화 부위는 총 IgE 양과 유의미한 연관성을 보이며, 가장 유의미한 두 유전자(ACOT7 및 ZFPM1)은 천식과 관련이 있습니다.104 성인의 경우, 혈액 표본의 7q31.2 영역에서 WNT2 유전자의 과메틸화는 호산 구성 천식에 관여하며,105 기관지 내 상피 세포에서 ORMDL3의 과메틸화는 천식에 기여합니다.106 CpG 부위의 과메틸화에 이어, FOXP3 (12 q15)와 인터페론-γ(IFN-γ) (Xp11.23)는 혈액 내 T세포 기능의 변화와 조절 T세포 및 T세포 효과기 관련 유전자의 억제를 유발합니다.107 청소년의 경우, 혈액 내 인터루킨-5 수용체 알파(IL-5RA) (3p26.2)의 저메틸화는 천식과 관련이 있습니다.108

AR 질환에서 DNA 메틸화 수준은 CD4+ T 세포의 양과 밀접한 관련이 있습니다. DNA 과메틸화는 AR 사례에서 IFN-γ를 하향 조절할 수 있으며,109 DNA 저메틸화는 IL-13과 IgE의 mRNA 양을 증가시킵니다.110 멜라토닌 수용체 1A 유전자의 CpG 부위에서 과메틸화의 변화는 AR의 부계 유전적 변이에 의해 야기될 수 있습니다.111

DNA 메틸화는

또한 FA의 발병 기전에 기여할 수 있습니다.

보고에 따르면, 일부 미토겐 활성화 단백질 키나아제(MAPK) 신호 전달 유전자(예: 인간 백혈구 항원(HLA)-DQB1 및 FOXP3의 Treg 특이적 탈메틸화 영역(TSDR))에서 DNA 메틸화의 차이가 나타났습니다. 유전적 DNA 메틸화의 차이는 또한 FA 진단에 기여할 수 있습니다.39 젖소 우유 단백질(CMA, 우유 알레르기)에 대한 예비 연구에서 DEXH(Asp-Glu-X-His) 박스 폴리펩티드 58(Dhx58), 아연 핑거 단백질 81(ZNF281), HtrA 세린 펩티다제 2(HTRA2) 영역에서 과메틸화가 발견되었습니다.112 모체 땅콩 알레르기는 또한 Th2 면역 반응(IL-4와 IgE의 생성)과 관련된 IL-4 프로모터의 후성유전학적 변화를 자손에게 유발합니다.113 일란성 쌍둥이(MZ)에 대한 연구에서, 땅콩 알레르기와 비알레르기의 메틸화 프로파일 사이의 거리는 유전적 관계가 없는 무작위 쌍을 이룬 개인에 비해 12개의 DNAm 서명이 포함된 메틸화 프로파일에서 감소했는데, 이는 땅콩 알레르기와 관련된 DNAm 서명이 유전적 요인과 관련이 있을 수 있음을 나타냅니다.114

땅콩 알레르기는 또한 후손의 IL-4 프로모터에 후성적 변화를 유발하는데, 이는 Th2 면역 반응(IL-4와 IgE의 생성)과 관련이 있습니다.113 일란성 쌍둥이(MZ)를 대상으로 한 연구에서, 땅콩 알레르기와 비알레르기의 메틸화 프로파일 사이의 거리가 유전적 관계가 없는 무작위 쌍을 이룬 개인에 비해 12개의 DNAm 서명이 포함된 메틸화 프로파일에서 감소한 것으로 나타났습니다. 이는 땅콩 알레르기와 관련된 DNAm 서명이 유전적 요인과 관련이 있을 수 있음을 시사합니다.114

Histone modifications

The DNA is packaged into an organized chromatin structure formed by a core histone protein consisting of H2A, H2B, H3 and H4.115 Post-translational histone modifications mainly comprise acetylation, methylation, phosphorylation, ubiquitination, SUMOylation, and adenosine diphosphate (ADP) ribosylation of core histone tails, which reflect the epigenetic inheritance of many diseases, including AAS.115 Histone acetyltransferase (HAT)-mediated histone acetylation often loosens chromatin structure, facilitating access to transcription factors that induce gene expression‎. Conversely, histone deacetylation by histone deacetylases (HDACs) also leads to gene silencing. Higher levels of histone acetylation are generally associated with increased gene transcriptional activity and expression‎. Whether histone methylation is transcriptionally permissive or repressive depends largely on the number of methyl groups added and the position of the target amino acid residue in the histone tail.34,116,117,118

In adult asthmatic patients, lysine 18 acetylation of histone 3 (H3K18) and lysine 9 trimethylation of histone 3 (H3K9me3) are elevated in epithelial cells, and acetylation of H3K18 increases ΔNp63 (a p63 splice variant), epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 6 (STAT6) mRNA amounts.119 An imbalance of HAT and HDAC underlies impaired gene expression‎ and is a determinant of asthma.120 HATs and HDACs have opposite functions, as the acetylation function of HATs promotes gene expression‎, while the deacetylation function of HDACs is responsible for gene silencing. In children with asthma, H3 acetylation of the FOXP3 gene contributes to Treg differentiation, and H3 histone acetylation critically affects the IL-13 gene promoter.121 Stefanowicz and collaborators assessed gene-specific alveolar epithelial histone acetylation and methylation statuses in asthma and healthy control cases, and found increased levels of H3K18ac and H3K9me3 in asthmatic patients.119 Acetylation of C-C Motif Chemokine 8 (CCL8), a neutrophil activator found in macrophages, as well as H3K18, results in elevated secreted amounts of this activator in airway smooth muscle.122 In asthma, the levels of CCR4 and CCL5 are high. CCR4 controls Th2 cell infiltration, while CCL5 is a leukocyte chemokine, and a single nucleotide polymorphism of CCR4 and CCL5 dimethylation (H3K4me2) is associated with Th2 differentiation.123 Resistance to steroid therapy in AAS has emerged, mainly due to IL-17A-induced steroid resistance resulting from decreased HDAC2 activity.123 Increased enrichment of transcriptionally active H3ac and H4ac histone markers found in AAS cases are associated with IL-13 upregulation in CD4+ T cells.121

In AR, increased HDAC activity may be involved in the pathogenetic mechanism by elevating pro-inflammatory cytokine amounts and reducing anti-inflammatory cytokine levels. Early responses are characterized by increased IL-4 expression‎,124 H3K9 acetylation, and H3K4 trimethylation at the IL4 locus.125 A study showed HDAC1 upregulation in nasal epithelial cells from AR patients,126 and IL-4 increased HDAC1 expression‎, leading to nasal epithelial barrier dysfunction. HDAC1 inhibition promotes the master regulators of T cell function, including IL-10 and CCL8, and prevents excessive activation of immune cells.127 Histone acetylation is also critical for AD pathogenesis. In AD pathogenesis, the demethylation, acetylation, and methylation of the H3 residue in the FOXP3 promoter gene region, along with the hypermethylation of the RORC gene and the methylation of the H3 residue, promote the regulation of Th0 cells. The differentiation of Tregs,34,92,94,95 thereby reduce the levels of histone acetylation at Th1 and regulatory sites.128

히스톤 변형

DNA는

H2A, H2B, H3, H4로 구성된 핵심 히스톤 단백질에 의해 형성된

조직화된 크로마틴 구조로 포장됩니다.115

번역 후 히스톤 변형은

주로 아세틸화, 메틸화, 인산화, 유비퀴틴화, SUMO화, 아데노신 디포스페이트(adenosine diphosphate)로 구성됩니다.

아데노신 디포스페이트(ADP) 리보실화, 코어 히스톤 꼬리의 리보실화는

AAS를 포함한 많은 질병의 후성유전적 유전을 반영합니다.115

히스톤 아세틸화효소(HAT)에 의한 히스톤 아세틸화는 종종 염색질 구조를 느슨하게 만들어 유전자 발현을 유도하는 전사 인자에 대한 접근을 용이하게 합니다. 반대로, 히스톤 탈아세틸화효소(HDAC)에 의한 히스톤 탈아세틸화는 또한 유전자 침묵을 유발합니다. 높은 수준의 히스톤 아세틸화는 일반적으로 유전자 전사 활동과 발현의 증가와 관련이 있습니다. 히스톤 메틸화가 전사적으로 허용적이거나 억제적인지는 주로 추가된 메틸기의 수와 히스톤 꼬리 부분의 목표 아미노산 잔기의 위치에 따라 달라집니다.34,116,117,118

성인 천식 환자의 경우, 상피 세포에서 히스톤 3(H3K18)의 리신 18 아세틸화와 히스톤 3(H3K9me3)의 리신 9 트리메틸화가 증가하며, H3K18의 아세틸화는 ΔNp63(p63 스플라이스 변이체), 표피 성장 인자 수용체(EGFR)를 증가시킵니다. 그리고 신호 전달 및 전사 활성화 인자 6(STAT6) mRNA 양.119 HAT와 HDAC의 불균형은 유전자 발현 장애의 근본 원인이며, 천식의 결정 요인입니다.120 HAT와 HDAC는 반대 기능을 가지고 있습니다. HAT의 아세틸화 기능은 유전자 발현을 촉진하는 반면, HDAC의 탈아세틸화 기능은 유전자 침묵을 담당합니다. 천식이 있는 어린이의 경우, FOXP3 유전자의 H3 아세틸화는 Treg 분화에 기여하고, H3 히스톤 아세틸화는 IL-13 유전자 프로모터에 결정적인 영향을 미칩니다.121 Stefanowicz와 공동 연구자들은 천식 및 건강한 대조군 사례에서 유전자 특이적인 폐포 상피 히스톤 아세틸화 및 메틸화 상태를 평가했고, H3K18ac 및 H 3K9me3이 증가하는 것을 발견했습니다.119 대식세포에서 발견되는 호중구 활성화 인자 C-C 모티프 케모카인 8(CCL8)의 아세틸화와 H3K18의 아세틸화는 기도 평활근에서 이 활성화 인자의 분비량을 증가시킵니다.122 천식에서는 CCR4와 CCL5의 수치가 높습니다. CCR4는 Th2 세포의 침윤을 조절하는 반면, CCL5는 백혈구 케모카인이고, CCR4와 CCL5의 단일 뉴클레오티드 다형성(H3K4me2)은 Th2 분화와 관련이 있습니다.123 AAS에서 스테로이드 치료에 대한 저항성이 나타났습니다. 주로 HDAC2 활성의 감소로 인한 IL-17A 유발 스테로이드 저항성 때문입니다.123 AAS 사례에서 발견되는 전사 활성 H3ac 및 H4ac 히스톤 마커의 농도 증가는 CD4+ T 세포에서 IL-13의 상향 조절과 관련이 있습니다.121

AR에서,

HDAC 활성의 증가는

전염증성 사이토카인의 양을 증가시키고

항염증성 사이토카인의 수준을 감소시킴으로써 병인 기전에 관여할 수 있습니다.

초기 반응은 IL-4 발현 증가,124 H3K9 아세틸화, IL4 유전자좌에서의 H3K4 트리메틸화를 특징으로 합니다.125 한 연구에 따르면, AR 환자의 비강 상피 세포에서 HDAC1의 발현이 증가하는 것으로 나타났으며,126 IL-4가 HDAC1 발현을 증가시켜 비강 상피 장벽의 기능 장애를 유발하는 것으로 밝혀졌습니다. HDAC1 억제는 IL-10과 CCL8을 포함한 T 세포 기능의 주요 조절 인자를 촉진하고 면역 세포의 과도한 활성화를 방지합니다.127 히스톤 아세틸화는 또한 AD 발병 기전에 중요합니다. AD 병인에서 FOXP3 프로모터 유전자 영역의 H3 잔기에서의 탈메틸화, 아세틸화, 메틸화와 RORC 유전자의 과메틸화 및 H3 잔기의 메틸화는 Th0 세포의 조절을 촉진합니다. Tregs의 분화는34,92,94,95 따라서 Th1과 조절 부위에서의 히스톤 아세틸화 수준을 감소시킵니다.128

Non-coding RNAs in allergic diseases

Long noncoding RNAs (lncRNAs) are defined as transcripts longer than 200 nucleotides in length; functional RNAs that are not translated include micro-RNAs (miRNAs), small interfering RNAs (siRNAs), lncRNAs and Pivi-interacting RNAs (piRNAs). They are essential signaling and regulatory tools that affect transcriptional processes and may also alter gene expression‎ post-transcriptionally, with critical roles in the development of allergic diseases. We take microRNAs as an example to explain their important roles in allergic diseases.

miRNA-21, high expression‎ of miRNA155, and low levels of Let-7a were detected in peripheral blood specimens from asthmatic children. These markers can be used for the diagnosis and prognosis of childhood asthma;129 up-regulation of miR-126 in peripheral circulation is related to immune imbalance and is considered a biomarker for asthma diagnosis.130

MicroRNAs have critical functions in the development of allergic diseases. MiR-19b reduced airway remodeling and inflammation as well as oxidative stress by downregulating TSLP to inhibit Stat3 signaling in mice with experimental asthma.131 MMP-16 and ATG7 via miR-192-5p molecules reduce airway inflammation and remodeling.132 MiR-221 can control the enhanced airway smooth muscle cell proliferation in severe asthma cases.133 The circular RNA (circHIPK3) contributes to smooth muscle cell proliferation and airway remodeling in asthma patients via miR-326/ stromal interaction molecule 1 (STIM1) signaling.134 MiR-130a-3p and miR-142-5p mediate lung macrophage polarization and are associated with airway remodeling.135 MiR-155 and miR-221 are closely associated with the regulation of Th2 responses and airway smooth muscle hyperproliferation in asthmatic patients.133,136 Vascular endothelial growth factor A (VEGF-A) amounts are elevated in sputum and serum samples from asthmatics, and has-miR-15a is associated with VEGF-A downregulation in CD4+ T cells.137 MiR-21 downregulates IL-3, IL-5 and IL-12, and inhibits IFN-γ and IL-12 production by dendritic cells, and reduces IFN-γ biosynthesis in CD4+ T cells.138 MiR-21 overexpression‎ was also associated with the differentiation of Th2 cells in vitro. In granulocyte-infiltrating asthma, miR-221-3p in epithelial cells and sputum was inversely associated with airway eosinophilia.139 Downregulated miR-28-5p and miR-146a/b activate blood CD8+ T cells in severe asthma.140 MiR-223-3p, miR-142-3p, and miR-629-3p are involved in severe neutrophilic cellular asthma.141 MiR-126 induces Th2-type eosinophilic asthma,142 and miR-23-27-24 regulates T cell function and differentiation; meanwhile, miR-24 and miR-27 suppress Th2 cell differentiation, leading to IL-4 cytokines.143 Recently published reports revealed miR-200a is involved in asthma pathogenesis via phosphatidylinositol 3 kinase (PI3K)/ RAC-alpha serine/threonine-protein kinase (AKT) signaling.144,145,146 In childhood asthma, the miR-29c/B7-H3 axis controls the differentiation of Th2/Th17 cells, and the above microRNA studies might point to novel research directions for developing treatments for AAS.147

In AR, aberrantly expressed circulating lnc-NEAT1 and miR-125a were associated with Th2 cell percentage and symptoms in pediatric AR.148 In AD, Liew et al. found decreased expression‎ of miR-335 in AD lesions compared with healthy control skin.149 Nuclear factor kappa-B (NF-κB) (p65) is a critical modulator of inflammatory immune response, and miR-124 is associated with inflammatory response and may constitute a new effector and regulator of NF-κB.150,151 In diseased skin, miR-124 is downregulated in AD patients.152 In macrophages, miR-155 targets IL-13Rα1.153 In dendritic cells (DCs), miR-221 knockdown or miR-155 overexpression‎ promotes apoptosis, while miR-155 overexpression‎ in mDCs enhances the production of IL-12p70.154 The study of microRNA would bring new hope in the treatment and understanding of allergic diseases.

알레르기 질환의 비코딩 RNA

긴 비코딩 RNA(lncRNA)는 200 뉴클레오타이드보다 긴 전사체로 정의됩니다. 번역되지 않는 기능적 RNA에는 마이크로RNA(miRNA), 작은 간섭 RNA(siRNA), lncRNA, Pivi 상호작용 RNA(piRNA) 등이 포함됩니다. 이것들은 전사 과정에 영향을 미치고 전사 후 유전자 발현을 변화시킬 수 있는 필수적인 신호 전달 및 조절 도구이며, 알레르기 질환의 발달에 중요한 역할을 합니다. 우리는 알레르기 질환에서 중요한 역할을 하는 microRNA를 예로 들어 설명합니다.

천식 아동의 말초 혈액 표본에서 miRNA-21의 높은 발현, miRNA155의 높은 발현, Let-7a의 낮은 수준이 검출되었습니다. 이러한 표지자는 소아 천식의 진단과 예후에 사용될 수 있습니다. 말초 순환에서 miR-126의129 상향 조절은 면역 불균형과 관련이 있으며 천식 진단의 바이오마커로 간주됩니다.130

마이크로RNA는

알레르기 질환의 발생에 중요한 역할을 합니다.

MiR-19b는 실험용 천식 쥐에서 TSLP를 하향 조절하여 Stat3 신호를 억제함으로써 기도 리모델링과 염증, 산화 스트레스를 감소시켰습니다.131 MMP-16과 ATG7은 miR-192-5p 분자를 통해 기도 염증과 리모델링을 감소시킵니다.132 MiR-221은 중증 천식 사례에서 기도 평활근 세포 증식을 조절할 수 있습니다. .133 순환 RNA(circHIPK3)는 miR-326/stromal interaction molecule 1(STIM1) 신호를 통해 천식 환자의 평활근 세포 증식과 기도 리모델링에 기여합니다.134 MiR-130a-3p와 miR-142-5p는 폐 대식세포 분화를 매개하고 기도 리모델링과 관련이 있습니다.135 MiR -155와 miR-221은 천식 환자의 Th2 반응 조절과 기도 평활근 과증식과 밀접한 관련이 있습니다.133,136 혈관 내피 성장 인자 A(VEGF-A)의 양은 천식 환자의 가래와 혈청 샘플에서 증가하며, has-miR-15a는 VEGF-A와 관련이 있습니다. CD4+ T 세포의 VEGF-A 하향 조절과 관련이 있습니다.137 MiR-21은 IL-3, IL-5, IL-12를 하향 조절하고, 수지상 세포에 의한 IFN-γ와 IL-12 생성을 억제하며, CD4+ T 세포에서 IFN-γ 생합성을 감소시킵니다.138 MiR-21의 과발현은 체외에서 Th2 세포의 분화와도 관련이 있습니다. 과립구 침윤성 천식에서 상피 세포와 가래의 miR-221-3p는 기도 호산구 증가증과 반비례 관계가 있습니다.139 miR-28-5p와 miR-146a/b의 하향 조절은 중증 천식에서 혈액 CD8+ T 세포를 활성화합니다.140 MiR-223-3p, miR-142-3p, miR-62 9-3p는 중증 호산구 세포성 천식에 관여합니다.141 MiR-126은 Th2형 호산구성 천식을 유발하고,142 miR-23-27-24는 T세포 기능과 분화를 조절합니다. 한편, miR-24와 miR-27은 Th2세포 분화를 억제하여 IL-4 사이토카인을 생성합니다.143 최근 발표된 보고서에 따르면 miR-200a는 천식 발병에 관여합니다. 포스파티딜이노시톨 3 키나제(PI3K)/RAC-알파 세린/트레오닌-단백질 키나제(AKT) 신호 전달을 통해 천식의 발병에 관여합니다.144,145,146 소아 천식에서 miR-29c/B7-H3 축은 Th2/Th17 세포의 분화를 조절하며, 위의 마이크로RNA 연구는 AAS 치료법 개발에 대한 새로운 연구 방향을 제시할 수 있습니다.147

AR에서 비정상적으로 발현된 순환 lnc-NEAT1과 miR-125a는 소아 AR의 Th2 세포 비율과 증상과 관련이 있었습니다.148 AD에서 Liew 등은 건강한 대조군 피부에 비해 AD 병변에서 miR-335의 발현이 감소하는 것을 발견했습니다.149 핵 인자 kappa-B(NF-κB) (p65)는 염증성 면역 반응의 중요한 조절자이며, miR-124는 염증 반응과 관련이 있으며 NF-κB의 새로운 효과기 및 조절자가 될 수 있습니다.150,151 병든 피부에서 miR-124는 AD 환자에서 하향 조절됩니다.152 대식세포에서 miR-155는 IL- 13Rα1.153 수지상 세포(DCs)에서 miR-221의 저하 또는 miR-155의 과발현은 세포 사멸을 촉진하는 반면, mDCs에서 miR-155의 과발현은 IL-12p70의 생성을 향상시킵니다.154 마이크로RNA에 대한 연구는 알레르기 질환의 치료와 이해에 새로운 희망을 가져다줄 것입니다.

Cell signaling pathways play critical roles in allergic diseases

Allergic diseases are immune disorders caused by an imbalance of the immunity, in which immune cells play an important role. Signaling pathways are important in intercellular signaling. This review provides a systematic review of the signaling pathways involved in allergic diseases from the nucleus to the cell membrane, in the hope of laying a solid foundation for the study of allergic diseases.

세포 신호 전달 경로는 알레르기 질환에서 중요한 역할을 합니다.

알레르기 질환은 

면역 세포가 중요한 역할을 하는 면역 기능의 불균형으로 인해 발생하는 면역 질환입니다. 

신호 전달 경로는 세포 간 신호 전달에 중요합니다. 

이 리뷰는 

알레르기 질환 연구의 견고한 토대를 마련하기 위해 

핵에서 세포막에 이르는 알레르기 질환과 관련된 신호 전달 경로를 체계적으로 검토합니다.

Notch signaling pathway

In the 1910s, the Notch gene was detected in Drosophila melanogaster with notched wings.155,156 Notch signaling is highly conserved. In mammals, NOTCH has four paralogs, including NOTCH1-4, with redundancy and distinct roles.157 Human Notch1-4 genes map to chromosomes 9, 1, 19 and 6, respectively. The NOTCH receptor undergoes three cleavages and is transferred to the nuclear compartment to regulate target genes transcriptionally. Notch signaling is divided into the canonical and non-canonical pathways with complex functions, but the pathway is now well known.158 It is mainly involved in diverse molecular events across species, including tissue functional damage and repair; abnormal Notch pathway might lead to different pathological processes.

In AAS, eosinophilic asthma is dominated by Th2-type immune responses, and Notch signaling upregulates the key transcription factor Gata3.159,160 NOTCH4 is known to be critical for asthma development (Fig. 3). Repeated allergen exposure induces Tregs that produce high amounts of Notch4, which activates downstream Wnt and Hippo pathways, thereby promoting the transformation of iTregs into Th2 and Th17 cells, and exacerbating AAS.160,161

노치 신호 전달 경로

1910년대에 노치 날개를 가진 Drosophila melanogaster에서

노치 유전자가 발견되었습니다.155,156

노치 신호 전달은 매우 잘 보존되어 있습니다.

포유류에서 NOTCH는 NOTCH1-4를 포함한 4개의 유사 유전자를 가지고 있으며, 중복성과 뚜렷한 역할을 가지고 있습니다.157 인간에서 NOTCH1-4 유전자는 각각 9번, 1번, 19번, 6번 염색체에 위치합니다.

NOTCH 수용체는

세 번의 절단을 거쳐 핵 구획으로 옮겨져서 표적 유전자를 전사적으로 조절합니다.

NOTCH 신호 전달은 복잡한 기능을 가진 표준 경로와 비표준 경로로 나뉘지만, 현재는 잘 알려져 있습니다.158

주로 조직 기능 손상 및 복구를 포함한 다양한 분자 사건에 관여합니다.

비표준 NOTCH 경로는 다른 병리학적 과정을 유발할 수 있습니다.

AAS에서 호산구성 천식은 Th2형 면역 반응에 의해 지배되며, Notch 신호는 주요 전사 인자 Gata3를 상향 조절합니다.159,160 NOTCH4는 천식 발병에 중요한 것으로 알려져 있습니다(그림 3).

알레르기 유발 물질에 반복적으로 노출되면

Tregs가 생성되고,

이 세포는 Notch4를 대량으로 생성하여

다운스트림 Wnt 및 Hippo 경로를 활성화함으로써

iTregs가 Th2 및 Th17 세포로 변형되고 AAS가 악화됩니다.160,161

Fig. 3

Immune imbalance caused by dysbiosis under the combined effect of gene environment in IgE-related FA. During childhood, the human microbiota is influenced by a combination of the maternal microbiome, mode of delivery, genetics, epigenetics, environment, etc. Dysbiosis resulting from aberrant damage to the gut microbiota early in life impairs Treg differentiation. This results in imbalance of Treg and Th2 cells. Food allergens and the microbiota promote T follicular helper (Tfh) responses to induce B cells, which produce large amounts of IgE through IL-4, IL-13 cytokines, causing allergic reactions

IgE 관련 FA에서 유전자 환경의 결합된 영향에 따른 dysbiosis로 인한 면역 불균형. 

유년기 동안, 인간의 미생물총은 모체 미생물군, 분만 방식, 유전학, 후성유전학, 환경 등의 조합에 의해 영향을 받습니다. 

유년기 초기에 

장내 미생물총에 대한 비정상적인 손상으로 인한 dysbiosis는 

Treg 분화를 손상시킵니다. 

이로 인해 

Treg와 Th2 세포의 불균형이 

발생합니다. 

음식 알레르겐과 미생물총은

 T-follicular helper(Tfh) 반응을 촉진하여 

B 세포를 유도하고, 

B 세포는 IL-4, IL-13 사이토카인을 통해 

다량의 IgE를 생성하여 알레르기 반응을 일으킵니다.

In other allergic diseases, such as AR, FA, and AD, the exact underpinning mechanism remains unclear, Notch signaling also plays important roles. In a study of AR, the serum amounts of Notch1 and Jagged1 (Jag1) in AR patients were significantly increased, which was confirmed in mouse experiments. In this study, Notch signaling could downregulate Foxp3 expression‎ and inhibit Treg differentiation, thereby promoting AR occurrence and development.162 In a FA study, blocking the Notch signaling pathway could suppress Th2 polarization, increase Th1 cell differentiation and promote Th1/Th2 balance in a mouse model, thereby preliminarily verifying that blocking the Notch signaling pathway inhibits ovalbumin (OVA)-induced FA.163 In addition, Tfh cell production and function are dependent on Notch signaling, Notch receptors 1 and 2 are required for Tfh cell production, and Notch signaling enhances the production of type 2 cytokines in Tfh cells.164 Administration of a Notch signaling inhibitor inhibits IgE-mediated proliferation of intestinal mucosal mast cells (MMCs) in mice with food hypersensitivity, thereby attenuating allergic diarrhea and anaphylaxis.165 In AD, the epidermis of AD patients exhibits a marked deficiency in Notch receptors, leading to the upregulation of alarm TSLP, which triggers Th2-associated responses as well as TSLP and IL-31-related pruritus.166,167 Keratinocyte-produced TSLP and granulocyte-macrophage colony stimulating factor (GM-CSF) induce macrophage and DC activation, drive Th2 polarization, and promote eosinophil and mast cell infiltration, thereby enhancing the immune response.168,169

AR, FA, AD와 같은 다른 알레르기 질환의 경우,

정확한 기전은 아직 밝혀지지 않았지만,

노치 신호도 중요한 역할을 합니다.

AR에 대한 연구에서,

AR 환자의 혈청 내 Notch1과 Jagged1(Jag1)의 양이 유의하게 증가했으며,

이는 마우스 실험에서도 확인되었습니다.

이 연구에서 Notch 신호는

Foxp3 발현을 하향 조절하고 Treg 분화를 억제함으로써 AR의 발생과 발달을 촉진할 수 있었습니다.162

FA 연구에서

Notch 신호 경로를 차단하면

마우스 모델에서 Th2 분화를 억제하고 Th1 세포 분화를 증가시키며

Th1/Th2 균형을 촉진할 수 있으므로,

Notch 신호 경로를 차단하면 신호 전달 경로를 차단하면 OVA(오발부민)에 의한 FA가 억제된다는 것을 확인했습니다.163

또한,

Tfh 세포의 생산과 기능은

Notch 신호 전달에 의존하고,

Notch 수용체 1과 2는 Tfh 세포의 생산에 필요하며,

Notch 신호 전달은 Tfh 세포에서 2형 사이토카인의 생산을 강화합니다.164

노치 신호 전달 억제제를 투여하면

음식 과민증이 있는 쥐의 장 점막 비만 세포(MMC)의 IgE 매개 증식을 억제하여

알레르기성 설사와 아나필락시스를 완화할 수 있습니다.165

아토피 피부염 환자의 표피에는

노치 수용체가 현저하게 결핍되어 있어,

알람 TSLP의 상향 조절을 유발하고,

이로 인해 Th2 관련 반응이 촉발됩니다.

TSLP 및 IL-31 관련 가려움증도 유발합니다.166,167

각질세포에서 생성된 TSLP와 과립구-대식세포 콜로니 자극 인자(GM-CSF)는

대식세포와 DC의 활성화를 유도하고,

Th2 분화를 촉진하며,

호산구와 비만세포의 침윤을 촉진하여 면역 반응을 강화합니다.168,169

JAK/STAT signaling pathway

Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling represents a relatively simple membrane-nucleus pathway that mainly upregulates diverse key modulators involved in cancer and inflammatory processes. The well-conserved JAK/STAT pathway consists of ligand-receptor complexes, JAK and STAT. JAK consists of four cytoplasmic tyrosine kinases, i.e., JAK1, JAK2, JAK3 and TYK2. STAT proteins comprise STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. Each cytokine requires interaction with specific receptors on its target cells to activate this pathway, and these receptors contain associated intracellular domains composed of JAK family members.170 JAKs are inactive before exposure to cytokines, which induce JAK activation through phosphorylation by binding to their receptors.171,172,173 Activated JAKs phosphorylate the receptors on specific tyrosine moieties in the intracellular tail.174 STATs at receptor sites are also phosphorylated by JAKs.175,176 STATs are phosphorylated and translocated into the nuclear compartment to transcriptionally upregulate specific genes,177 often leading to cell proliferation or differentiation.

JAK/STAT signaling is highly involved in the differentiation of Th cell subsets; Th1 cell differentiation is controlled by the IFN-γ/STAT1 and IL-12/STAT4 signaling pathways.178,179 Meanwhile, Th2 cell differentiation is modulated by IL-2/STAT5 and IL-4/STAT6 signaling.180,181 The differentiation of Th17 cells mainly requires the involvement of STAT3/STAT4 signaling induced by IL-6 or IL-23.182 In allergic diseases, the JAK/STAT pathway is critical for cell proliferation and differentiation. In both rat and human bronchial smooth muscle cells, IL-13 induces JAK1-STAT6 signaling, which regulates Ras Homolog Family Member A (RhoA) activation that promotes smooth muscle contraction.183,184 IL-4 and IL-13 induce STAT6 in target cells with JAK involvement, and gene-targeted knockout mouse assays revealed STAT6 contributes to IgE synthesis, bronchial hyperresponsiveness and airway remodeling upon allergen sensitization.185,186 Further type 2 asthma-related cytokines, including IL-5 and TSLP, signal through JAK-dependent pathways. The JAK signaling pathway is critical for the differentiation of naive precursors into CD4+ Th2 cells, and the key cytokines involved are IL-2 and IL-4, which bind to cytokine receptors coupled to JAK1 and JAK3, respectively, then induce STAT5 and STAT6.187

In AAS, cytokine receptors, e.g., IL-4, IL-5, IL-13, IL-31, and TSLP, promote JAK/STAT signaling activation.188,189 In AD, Th2 immune enhancement induced by JAK/STAT signaling downstream of multiple cytokines, including IL-4, IL-5 and IL-13, is considered an essential pathogenic pathway.190 It was demonstrated that the JAK-STAT pathway regulates inflammatory processes and induces changes in the natural skin barrier, increasing TEWL (transepidermal water loss) by upregulating IFN-γ, IL-31, IL-23, and IL-22.190 STAT3 is one of the factors responsible for IL-23 expression‎ induced by IL-6 from DCs, which is critical for Th17 lymphocyte differentiation and cellular memory, leading to a disruption of epithelial barrier integration.191

JAK/STAT 신호 전달 경로

야누스 키나제/신호 전달 및 전사 활성화(JAK/STAT) 신호 전달 경로는

주로 암과 염증 과정에 관여하는

다양한 핵심 조절 인자를 상향 조절하는 비교적 단순한 막-핵 경로를 나타냅니다.

https://link.springer.com/article/10.1186/s43556-023-00151-1

잘 보존된 JAK/STAT 경로는

리간드-수용체 복합체, JAK 및 STAT로 구성됩니다.

JAK은 4개의 세포질 티로신 키나제,

즉 JAK1, JAK2, JAK3 및 TYK2로 구성됩니다.

STAT 단백질은

STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6으로 구성되어 있습니다.

각 사이토카인은 이 경로를 활성화하기 위해

표적 세포의 특정 수용체와 상호작용해야 하며,

이 수용체에는 JAK 계열 구성원으로 구성된 관련 세포 내 영역이 포함되어 있습니다.170

사이토카인에 노출되기 전에는

JAK이 비활성화되어 있으며,

사이토카인은 수용체에 결합하여 인산화 작용을 통해 JAK 활성화를 유도합니다.171,172,173

활성화된 JAK은

인산화 작용을 통해 세포 내 꼬리 부분의 특정 티로신 부분의 수용체를 인산화합니다.174

수용체 부위의 STAT도

JAK에 의해 인산화됩니다.175,176

STAT은 인산화되어 핵 구획으로 이동하여

특정 유전자를 전사적으로 상향 조절하여177

종종 세포 증식 또는 분화를 유도합니다.

JAK/STAT 신호 전달은

Th 세포 하위 집합의 분화에 매우 관여합니다;

Th1 세포 분화는 IFN-γ/STAT1 및 IL-12/STAT4 신호 전달 경로에 의해 제어됩니다.178,179

한편, Th2 세포 분화는 IL-2/STAT5 및 IL-4/STAT6 신호에 의해 조절됩니다.180,181

Th17 세포의 분화는 주로 IL-6 또는 IL-23에 의해 유도되는 STAT3/STAT4 신호에 의해 이루어집니다.182

알레르기 질환에서 JAK/STAT 경로는

세포 증식과 분화에 매우 중요합니다.

쥐와 사람의 기관지 평활근 세포 모두에서 IL-13은 JAK1-STAT6 신호를 유도하는데,

이 신호는 평활근 수축을 촉진하는 Ras Homolog Family Member A(RhoA)의 활성화를 조절합니다.183,184

IL-4와 IL-13은 JAK을 통해 표적 세포에서 STAT6을 유도합니다.

관련, 유전자 표적 결손 마우스 분석 결과 STAT6이 IgE 합성, 기관지 과민성, 알레르기 유발 물질에 대한 민감성 증가에 기여한다는 사실이 밝혀졌습니다.185,186 IL-5와 TSLP를 포함한 추가적인 제2형 천식 관련 사이토카인은 JAK 의존 경로를 통해 신호 전달합니다. JAK 신호 전달 경로는 미숙 전구세포가 CD4+ Th2 세포로 분화되는 데 매우 중요하며, 관련된 주요 사이토카인은 각각 JAK1과 JAK3에 결합하는 사이토카인 수용체에 결합한 후 STAT5와 STAT6을 유도하는 IL-2와 IL-4입니다.187

AAS에서,

사이토카인 수용체(예: IL-4, IL-5, IL-13, IL-31, TSLP)는

JAK/STAT 신호 전달의 활성화를 촉진합니다.188,189

AD에서,

IL-4, IL-5, IL-13을 포함한 여러 사이토카인의 하류에서

JAK/STAT 신호 전달에 의해 유발되는

Th2 면역 강화는 필수적인 병인 경로로 간주됩니다.190

JAK-STAT 경로가 다음을 조절한다는 것이 입증되었습니다.

염증 과정을 조절하고

자연적인 피부 장벽의 변화를 유도하여

IFN-γ, IL-31, IL-23, IL-22를 상향 조절함으로써 TEWL(표피 수분 손실)을 증가시킵니다.190

STAT3는 DC에서 IL-6에 의해 유도된 IL-23 발현을 담당하는 요소 중 하나이며,

이는 Th17 림프구 분화 및 세포 기억에 중요하며, 상피 장벽 통합의 붕괴로 이어집니다.191

STAT3은 DC에서 IL-6에 의해 유도된 IL-23 발현을 담당하는 요소 중 하나이며,

이는 Th17 림프구 분화 및 세포 기억에 중요하며, 상피 장벽 통합의 붕괴로 이어집니다.191

NF-κB/MAPK signaling pathway

By 2022, NF-κB has been known for 36 years. NF-κB (nuclear factor) is a protein factor with gene transcriptional regulation, which is present in almost all nucleated cells. When cells are stimulated by inflammatory mediators, NF-κB protein is activated in the cytoplasm and enters the nucleus to regulate the expression‎ of various inflammatory factors, playing an important role in allergic diseases.

In AAS, the NF-κB/MAPK pathway controls inflammatory and immune responses by regulating TNF-α and IL-6.192,193,194 A 2019 study demonstrated that after nuclear translocation of phosphorylated P65, inhibited NF-κB/MAPK signaling may modulate IgE and IL-4 production.195 Enhanced NF-κB nuclear binding or production was also found in inflammatory cells collected from induced sputum in asthmatic patients.196 Besides, experiments have shown enhanced NF-κB activation in airway tissues and inflammatory cells challenged by allergens such as ovalbumin (OVA) and house dust mite (HDM) extract.197,198,199 In addition, the studies related to increased Tfh cells in allergic diseases, NF-κB deficiency led to a decrease in CXCR5 (Tfh cells expressing chemokine receptors) in mice and a consequent decrease in the number of Tfh cells.200 All these studies suggest that NF-κB signaling is essential in the cellular immune response of allergic diseases, especially AAS. The following focuses on the functions of NF-κB in immune cells in allergic diseases (Fig. 4).

NF-κB/MAPK 신호 전달 경로

2022년까지 NF-κB는 36년 동안 알려져 왔습니다.

NF-κB(핵 인자)는 유전자 전사 조절을 하는 단백질 인자이며,

거의 모든 핵 세포에 존재합니다.

세포가 염증 매개체에 의해 자극을 받으면,

NF-κB 단백질이 세포질에서 활성화되어 핵으로 들어가 다양한 염증 인자의 발현을 조절하여

알레르기 질환에 중요한 역할을 합니다.

AAS에서

NF-κB/MAPK 경로는 TNF-α와 IL-6를 조절함으로써

염증과 면역 반응을 제어합니다.192,193,194

2019년의 한 연구에 따르면,

인산화된 P65의 핵 전좌 후 억제된 NF-κB/MAPK 신호가

IgE와 IL-4 생산을 조절할 수 있다는 사실이 밝혀졌습니다.195

천식 환자의 유도 객담에서 채취한 염증 세포에서도

NF-κB의 핵 결합 또는 생산이 증가하는 것이 발견되었습니다.196

또한, 실험 결과,

알레르기 유발 물질인 오발부민(OVA)과 집먼지 진드기(HDM) 추출물에 노출된 기도 조직과 염증 세포에서

NF-κB 활성화가 증가하는 것으로 나타났습니다.197,198,19 9

또한,

알레르기 질환에서 Tfh 세포의 증가와 관련된 연구에서,

NF-κB 결핍은 마우스에서 CXCR5(케모카인 수용체를 발현하는 Tfh 세포)의 감소를 초래했고,

그 결과 Tfh 세포의 수가 감소했습니다.200

이 모든 연구는

NF-κB 신호가 알레르기 질환,

특히 AAS의 세포 면역 반응에 필수적이라는 것을 시사합니다.

다음은 알레르기 질환에서 면역 세포의 NF-κB 기능에 초점을 맞춘 것입니다(그림 4).

Fig. 4

Graphical summary of NF-κB pathway’s role in allergic diseases. The NF-κB pathway is highly involved in the occurrence and development of allergic diseases by acting on different cells and releasing inflammatory factors

Full size image

Epithelial Cells

Epithelial cells play a key role in airway diseases and constitute a critical interface between the body and the environment.201 The epithelium coordinates responses to diverse invasive injuries via the production of multiple immunomodulators and inflammatory factors controlled by NF-κB. The latter mediators mostly comprise chemoattractants that induce inflammatory cell infiltration affecting epithelial function; among these, TSLP synthesized by bronchial epithelial cells is essential in Th2 responses that trigger allergic airway inflammation.201 The neutrophil-associated proteins S100A8 and S100A9 induce mucin production in airway epithelial cells through toll-like receptor 4 (TLR4)-related NF-κB pathway activation during AAS attacks.202

In isolated mouse airway epithelial cells, NF-kB activation upregulates IL-6, granulocyte colony-stimulating factor (G-CSF), GM-CSF, macrophage inflammatory Protein 2 (MIP-2), keratinocyte-derived chemokine (KC), and RANTES. NF-κB activation in mouse epithelial cells also leads to the recruitment of neutrophils for innate immune response.203 In the OVA-induced model of allergic diseases, NF-κB activation leads to airway inflammation, goblet cell hyperplasia, and induced expression‎ inflammatory cytokines, including IL-15, IL-10, and IL-9.204

상피세포

상피세포는 호흡기 질환에 중요한 역할을 하며,

신체와 환경 사이의 중요한 경계 역할을 합니다.201

상피는

NF-κB에 의해 조절되는 여러 면역 조절제와 염증 인자를 생성함으로써

다양한 침습적 손상에 대한 반응을 조정합니다.

후자의 매개체는

주로 상피 기능에 영향을 미치는 염증 세포 침윤을 유도하는 화학유인물질로 구성되어 있습니다.

그 중에서도 기관지 상피세포에 의해 합성되는

TSLP는 알레르기성 기도 염증을 유발하는

Th2 반응에 필수적입니다.201

호중구 관련 단백질인

S100A8과 S100A9는 AAS 공격 중 toll-like receptor 4(TLR4) 관련 NF-κB 경로 활성화를 통해

기도 상피세포에서 뮤신 생성을 유도합니다.202

분리된 마우스 기도 상피 세포에서 NF-kB 활성화는

IL-6,

과립구 콜로니 자극 인자(G-CSF),

GM-CSF,

대식세포 염증성 단백질 2(MIP-2),

각질세포 유래 케모카인(KC), RANTES를 상향 조절합니다.

마우스 상피 세포에서 NF-κB가 활성화되면

선천성 면역 반응을 위한 호중구 모집도 유도됩니다.203

OVA 유발 알레르기 질환 모델에서 NF-κB가 활성화되면

기도 염증, 섬모세포 증식, 그리고 IL-15, IL-10, IL-9를 포함한

염증성 사이토카인의 발현이 유도됩니다.204

Airway Smooth Muscle (ASM) Cells, Neutrophils and Eosinophils

In AAS, acute contraction of ASM is the main factor that causes bronchospasm. ASM cells contribute to persistent histological alterations in the airway wall, ASM and inflammatory cells are important players in inflammation,205 in which thrombin and IL-1α stimulate NF-κB signaling in ASM cells.206 IL-8 over-secretion by ASM cells may increase NF-κB’s binding to the IL-8 promoter.207

AAS includes eosinophilic, neutrophilic, oligogranulocytic and mixed granulocytic types, based on the type of inflammatory infiltrating cells. Of these, neutrophil infiltration is an important cause of AAS exacerbation and resistance to hormone therapy.208 Th17 lymphocytes are critical for neutrophilic asthma, and are the major producers of IL-17A, IL-17F and IL-22, whose amounts are elevated in the airways of severe steroid-refractory asthma cases.209 NF-κB signaling is associated with IL-17 and/or IL-22-related production of epithelial mucin and ASM cell proliferation.210,211,212 IL-33 promotes neutrophil polarization via c-Jun N-terminal kinase and NF-κB-related pathways. NETs induce CXCL1, CXCL2, and CXCL8 expression‎ in airway cells through TLR4/NF-κB signaling, thereby recruiting neutrophils to inflammatory sites.213 In neutrophilic asthma (NA) mice, NETs trigger the expression‎ of chemokines by airway and alveolar epithelial cells that promote the recruitment of more neutrophils through the TLR4/NF-κB pathway, leading to epithelial cell damage.214

Airway inflammation in eosinophilic allergic asthma features infiltrated and activated eosinophils, and co-culture of epithelial cells with mast cells or eosinophils induce NF-κB-dependent cytokine production by airway epithelial cells.215,216 NF-κB signaling is critical in the survival of eosinophils, exerting an anti-apoptotic effect through autocrine TNF-α.217 NF-κB suppressors on the other hand, including MG-132, reduce eosinophil amounts and alleviate allergic inflammation.218

기도 평활근(ASM) 세포, 호중구 및 호산구

AAS에서 ASM의 급성 수축은

기관지 경련을 일으키는 주요 요인입니다.

ASM 세포는

기도벽의 지속적인 조직학적 변화에 기여하며,

ASM과 염증 세포는 염증에서 중요한 역할을 합니다.205

트롬빈과 IL-1α가 ASM 세포에서 NF-κB 신호를 자극합니다.206

ASM 세포에 의한 IL-8의 과다 분비는

NF-κB가 IL-8 프로모터에 결합하는 것을 증가시킬 수 있습니다.207

AAS는

염증성 침윤 세포의 유형에 따라 호산구, 호중구, 과립구 및 혼합 과립구 유형을 포함합니다.

이 중 호중구 침윤은 AAS 악화와 호르몬 치료에 대한 내성의 중요한 원인입니다.208

Th17 림프구는

호중구성 천식에 매우 중요하며,

스테로이드에 내성이 있는 중증 천식 환자의 기도에서 그 양이 증가하는

IL-17A, IL-17F, IL-22의 주요 생산자입니다. 209

NF-κB 신호는

IL-17 및/또는 IL-22와 관련된 상피 점액의 생성 및 ASM 세포 증식과 관련이 있습니다.210,211,212

IL-33은 c-Jun N-terminal kinase 및 NF-κB 관련 경로를 통해 호중구 분화를 촉진합니다. NETs는 TLR4/NF-κB 신호를 통해 기도 세포에서 CXCL1, CXCL2, CXCL8 발현을 유도함으로써 염증 부위에 호중구를 모집합니다.213 호중구성 천식(NA) 마우스에서 NETs는 기도 및 폐포 상피 세포에 의해 화학물질의 발현을 유발하여 TLR4/NF-κB 경로를 통해 더 많은 호중구의 모집을 촉진하고, 이로 인해 상피 세포가 손상됩니다.214

호산구 알레르기성 천식의 기도 염증은 침윤된 활성화된 호산구를 특징으로 하며, 상피 세포와 비만 세포 또는 호산구의 공동 배양은 기도 상피 세포에 의한 NF-κB 의존성 사이토카인 생성을 유도합니다.215,216 NF-κB 신호 전달은 호산구의 생존에 매우 중요하며, 자가 분비 TNF-α를 통해 항-세포자멸 효과를 발휘합니다.217 반면에, MG-132를 포함한 NF-κB 억제제는 호산구 양을 줄이고 알레르기성 염증을 완화합니다.218

Dendritic cells and Lymphocytes

DCs interconnect innate and adaptive immune systems, with crucial roles in promoting immune defense and maintaining immune tolerance. Previous reports have established NF-κB signaling involvement in DC development, with NF-κB suppression preventing DC maturation associated with the upregulation of MHC and co-stimulatory molecules.219

In eosinophilic allergic asthma, naive T cells differentiate and mature into Th2 cells, which biosynthesize IL-4, IL-5 and IL-13 with NF-κB involvement, and stimulate B lymphocytes to produce immunoglobulin E (IgE).220 During CD4+ T cell differentiation, IL-6 and TGF-β are highly involved in Th17 cell differentiation.221 NF-κB signaling regulates antigen-presenting cell function and controls CD4+ T cell differentiation into Th effector cells.222,223 However, the present study is still inconclusive.

수지상 세포와 림프구

수지상 세포는 선천성 면역 체계와 후천성 면역 체계를 연결하는 역할을 하며,

면역 방어를 촉진하고 면역 관용을 유지하는 데 중요한 역할을 합니다.

이전 연구에 따르면,

수지상 세포 발달에 NF-κB 신호 전달이 관여하며,

NF-κB 억제가 MHC와 공동 자극 분자의 상향 조절과 관련된 수지상 세포 성숙을 방지한다고 합니다.219

호산구성 알레르기성 천식에서,

초기 T 세포는 분화되어 Th2 세포로 성숙하는데,

Th2 세포는 NF-κB의 관여로 IL-4, IL-5, IL-13을 생합성하고,

B 림프구를 자극하여 면역글로불린 E(IgE)를 생성합니다.220

CD4+ T 세포 동안 분화 과정에서,

L-6와 TGF-β는 Th17 세포 분화에 매우 관여합니다.221

NF-κB 신호는 항원 제시 세포 기능을 조절하고

Th 효과기 세포로의 CD4+ T 세포 분화를 제어합니다.222,223

그러나, 이 연구는 아직 결정적이지 않습니다.

Hippo signaling and allergic disease

Hippo signaling was first discovered in Drosophila and is a highly conserved pathway.224 It mainly comprises the cascade kinase cascade transcription molecule mammalian STE20-like kinase 1/2 (MST1/2), WW domain of Sav family containing protein 1 (SAV1), and MOB kinase activator 1 (MOB1), with large tumor suppressor 1/2 (LATS1/2) upstream and Yes-associated protein (YAP)/effector molecules with PDZ- binding motif (TAZ) downstream. When Hippo signaling is not activated, unphosphorylated YAP undergoes nuclear translocation and interacts with TEAD, thereby triggering the transcription of target genes. After Hippo signaling activation, TAOK induces MST1/2 phosphorylation, and phosphorylated MST1/2 interacts with SAV1 for MST1/2-SAV1 complex formation. With activated MOB1, the latter complex phosphorylates LATS1/2. In turn, LATS1/2 phosphorylation triggers YAP activation, causing YAP capture by 4-3-3 proteins in the cytosol or degradation by SCFβ-TRCP E3 ubiquitin ligase-mediated ubiquitin-proteasome signaling.225

In AAS, Hippo signaling mainly induces cell differentiation. The Notch4 protein mediates immune tolerance and leads to Treg dysfunction, thereby promoting allergic airway inflammation.226 After alveolar macrophage engulfment of allergens and particulate pollutants, Jag1 is highly expressed on alveolar macrophages, thereby activating Notch on CD4+ T cells and promoting inflammation associated with Th2 and Th17 effector T (Teff) cells;227,228 at the same time, alveolar macrophages secrete a large amount of IL-6, which promote the expression‎ of Notch4 on induced regulatory T (iTreg) cells, thereby activating Hippo signaling, which further exacerbates Th17 cell-induced inflammation (Fig. 5).161 In other allergic diseases, including AR, AD and FA, no associations with Hippo signaling have been reported.

히포 신호 전달과 알레르기 질환

히포 신호 전달은 초파리에서 최초로 발견되었으며, 매우 잘 보존된 경로입니다.224 주로 캐스케이드 키나제 캐스케이드 전사 분자 포유류 STE20 유사 키나제 1/2(MST1/2), 사바(SAV) 패밀리 단백질 1(SAV1)의 WW 도메인, V1), MOB 키나아제 활성화제 1(MOB1)이 있으며, 그 상류에는 대형 종양 억제제 1/2(LATS1/2)가, 하류에는 예-연관 단백질(YAP)/PDZ 결합 모티프를 가진 이펙터 분자(TAZ)가 있습니다. 히포 신호가 활성화되지 않으면, 인산화되지 않은 YAP가 핵으로 이동하여 TEAD와 상호 작용함으로써 표적 유전자의 전사를 유발합니다. Hippo 신호가 활성화되면, TAOK는 MST1/2 인산화를 유도하고, 인산화된 MST1/2는 MST1/2-SAV1 복합체 형성을 위해 SAV1과 상호작용합니다. 활성화된 MOB1은 후자의 복합체가 LATS1/2를 인산화하도록 합니다. 그 결과, LATS1/2의 인산화는 YAP의 활성화를 촉발하여, 세포질에서 4-3-3 단백질에 의한 YAP 포획 또는 SCFβ-TRCP E3 유비퀴틴 리간스 매개 유비퀴틴-프로테아좀 신호에 의한 YAP 분해를 유발합니다.225

AAS에서, 히포 신호는 주로 세포 분화를 유도합니다. Notch4 단백질은 면역 관용을 매개하고 Treg 기능 장애를 유발하여 알레르기성 기도 염증을 촉진합니다.226 폐포 대식세포가 알레르겐과 미립자 오염 물질을 포획한 후, Jag1은 폐포 대식세포에서 고도로 발현되어 CD4+ T 세포에서 Notch를 활성화하고 Th2 및 Th17 이펙터 T(Teff) 세포와 관련된 염증을 촉진합니다.227,228 동시에, 폐포 대식세포는 유도 조절 T(iTreg) 세포에서 Notch4의 발현을 촉진하는 다량의 IL-6을 분비하여 Hippo 신호를 활성화시키고, 이로 인해 Th17 세포에 의한 염증이 더욱 악화됩니다(그림 5).161 AR, AD, FA를 포함한 다른 알레르기 질환에서는 Hippo 신호와 관련된 사례가 보고된 바 없습니다.

Fig. 5

The roles of the hippo and Notch pathways in AAS. Under stimulation by allergens, epithelial cells synthesize large amounts of proinflammatory cytokines (IL-25, IL-33, TSLP, etc.), thereby acting on innate lymphocytes (ILC2 cells) and DCs. Jag1 on DCs interacts with Notch receptors on T cells for Notch pathway induction. Notch transforms induced Tregs into Th2 and Th17 cells. Naive CD4 + cells affect Tfh cell class switch recombination by secreting IL-5, thus acting on B cells to induce plasma cells, which produce IgE. At the same time, Th2 cells secrete IL-4 and others to activate B cells to synthesize IgE, which interacts with IgE receptors on mast cells. In case the allergen invades the body again, it directly cross-links with IgE on the cell surface and releases a variety of active mediators, which trigger the clinical symptoms of asthma. Th17 cells are activated through the Hippo pathway; Th2 cells are activated through the Wnt pathway, and GDF-15 molecules are stimulated to act on ILC2 cells to enhance the expression‎ of IL-13, although this remains controversial. Notch converts induced Tregs into Th2 and Th17 cells via hippo pathway-dependent mechanisms. IL interleukin, TSLP thymic stromal lymphopoietin, ILC2 group 2 innate lymphoid cell, DC dendritic cell, Jag1 jagged1

Full size image

The newly discovered Hippo pathway plays a critical role in the immune function of the body, with complex crosstalk with other signaling pathways, and is regulated by other signaling pathways (such as Notch, Wnt signaling pathway, etc.). As the study of Hippo signaling pathway continues to deepen, its important function in allergic diseases will be gradually discovered.

TOLL-like receptor (TLR) signaling pathway

The increasing preval‎ence of allergic diseases is not only related to changes in the modern living environment (such as pollution, low-endotoxin living environments, smoking, etc.), which may induce the disorder of immune system,229,230 but also closely related to the loss of microbial biodiversity.

TLRs represents an important group of transmembrane protein receptors that are critical for proper activation of innate immunity, are highly conserved, and comprise binding domains containing arginine-rich repeats. As molecules involved in the first line of defense, TLRs are induced by pathogen-associated molecular patterns (PAMPs), which are found in diverse pathogenic organisms and absent from the host. There are eleven known human TLRs (TLR1 to TLR11), all with functions except for TLR11.231,232 TLRs are located on and within immune and non-immune cells, respectively, and are critical for initiating adaptive immune responses, including in alveolar macrophages, mast cells, epithelial cells, neutrophils, natural killer cells, and antigen presenting cells (APCs). Different TLRs recognize various groups of molecules in diverse pathogens. For example, multiple diacyl peptides can be recognized by TLR1 and TLR6, while liposomes are recognized by TLR1/2.233 TLR5 cooperates with TLR4 to recognize bacterial flagellin.234 Studies have shown that gut microbiota regulates the activity of Th1 and Th2, thereby affecting the formation of immune tolerance in the body.235 To maintain immune homeostasis, the activation of innate immune cells requires TLR signaling molecules, and innate immunity should be activated correctly to stimulate the body’s immune response.231

The strength of the TLR signaling pathway determines the possibility of allergic diseases. Accumulation of TLR4 signaling on DC was detected in house dust extract (HDE) hypersensitivity.236,237 Bacteria belonging to the healthy lung microbiome elicit baseline TLR response, whereas those involved in asthma show stronger TLR response. Mice administered asthma-associated proteobacteria show elevated amounts of neutrophils and cytokines in comparison with animals administered commensal Provetella.238

The strength of TLR signaling does determine the occurrence of allergic reactions or its absence. Strong TLR signals are protective against allergic airway disease, while low airway amounts of TLR ligands cause airway sensitization and Th2-type immunity.239,240,241 Studies have shown that low-level flagellin (TLR5 ligand) can enhance OVA-associated hypersensitivity in mice, whereas a high flagellin dose protects the animals from hypersensitivity by producing CD25+ Treg-dependent regulatory DCs and T cells.242 Differential responses to TLR activation have been considered a shift from Th2-type immunity to Th1-type immunity with increasing stimulation intensity.

In AAS, alveolar macrophages are immune cells with critical roles in the clearance of immune antigens. Excessive inflammatory response of these cells, however, might induce tissue damage.243 Alveolar macrophages are important in developing tolerance to inhaled allergens by inhibiting T cell proliferation and APC function.244 Asthmatic patients have reduced monocyte and macrophage amounts in comparison with healthy control individuals.245 TLR2, 4, 5, 6, 7, 8 and 9 are expressed on macrophages. TLRs have a critical function in AAS; among the TLRs expressed by human lung cells, TLR1-5, 7 and 8 have the highest expression‎.246 TLR2-6 and TLR9 are highly expressed on human airway epithelial cells.247,248 Mouse alveolar macrophages highly express TLR2, 4 and 9,249 and mouse macrophages produce TLR1-7 and 9 mRNAs.250,251

Lipopeptides in Gram-positive bacterial organisms and mycoplasmas show diacylation, while lipopeptides in Gram-negative bacterial and mycobacterial species show triacylation. When TLR2 polymerizes with TLR1 or TLR6, the lipopeptide is recognized by TLR2. The TLR2/TLR6 heterodimer recognizes diacylated lipopeptides such as S-FSL1 (TLR2/6), R-FSL1 (TLR2/6/CD36) and MALP-2 (macrophage-activating lipopeptide-2). Cell wall constituents in Gram-positive bacteria, including lipoteichoic acid, also bind to the TLR2/TLR6 heterodimer.252 Phagocytic cells, airway epithelial cells, smooth muscle cells, glia, mouse bone marrow-derived mast cells, and B cells all can express the TLR2 receptor.253 In OVA-sensitized animal model, TLR2 receptor pathway induction also results in enhanced pause and increased bronchioalveolar lavage fluid (BALF) eosinophil amounts.254,255 Elevated TLR2 ligand amounts can also elevate serum IgE concentration. Though TLR6 is heterodimerized with TLR2, and the heterodimer plays an important role in AAS, TLR6 is decreased in PBMC compared with healthy controls, and is also overexpressed in severe asthma cases compared with mild asthmatic patients.256 TLR4 uses the adaptor protein TRIF via myeloid differentiation primary response gene 88 (MyD88)-dependent and MyD88-independent pathway, respectively, enhancing IRF-3 induction and IFN-β production.257 In bronchial asthma cases, it was shown that TLR4 activation of macrophages produces cytokines that affects immune balance and thus affects the Th1/Th2 balance.258 After TLR5 recognizes flagellin, it induces NF-κB signaling through MyD88 and TNF receptor associated factor 6 (TRAF6), producing cytokines to trigger an inflammatory response.245 Recently, Nawijn et al. showed that intranasal TLR2 induction by aerosolized allergens promotes allergen-specific Treg proliferation to suppress asthma in a mouse model.259 Numerous studies have shown that TLR2 stimulation by parenteral or mucosal treatment with synthetic agonists prevents APCs from triggering Th2-polarizing responses, reducing IgE antibodies and immunogenicity in a mouse model of asthma.260,261,262,263

In FA, Treg activation is an important pathway by which gut DCs and macrophages induce immune tolerance, disrupting the normal immune homeostasis of the intestine.264 All microbial pattern recognition receptors (PRRs) may be involved in food tolerance and allergen presentation. TLR2 is highly expressed by intestinal epithelial cells (IECs) and DCs, and most commensal bacteria in the intestine are gram-positive organisms, meaning they have a high ability to induce TLR2.265,266 In AR, researchers were surprised to find that TLR4 inhibits allergic response in OVA-induced AR in a mouse model.267 TLR2, 3 and 4 were highly expressed in nasal mucosa specimens from AR cases in a study of 27 healthy control individuals and 42 cases of seasonal allergic rhinitis.268 All these studies have once again confirmed that TLR is critical for the etiology and progression of allergic disorders, which is worthy of further exploration.

Wnt/β-catenin signaling

In 1982, the Wnt gene was described as integrase-1 in murine breast cancer cells and the wingless gene in Drosophila.269 Wnt signaling plays core roles in the maintenance of progenitor cells and stem cells, the differentiation of T cells, and the regulation of cellular immunity. Among the Wnt-mediated signaling pathways, the most classical Wnt/β-catenin pathway contributes to maintaining human tissue homeostasis. Wnt, which mediates extracellular signals, is a secretory glycoprotein, with 19 human Wnt proteins reported as of now. This pathway relies on β-catenin, which is activated by binding extracellular Wnt ligands to membrane receptors through autocrine and paracrine processes, inhibiting the degradation of β-catenin so that it can be stably accumulated in the cytoplasm and transferred to the nuclear compartment, where it can work together with T cell factor/lymphoenhancer binding factor to stimulate the transcription of target genes.270,271

Wnt/β-catenin contributes to airway remodeling in asthma by upregulating the tenascin C/platelet-derived growth factor receptor (PDGFR) or activating p38 MAPK and its target genes c-Myc and cyclin D1 to induce proliferation in airway smooth muscle cells.272,273 A study by Trischler et al. revealed that Wnt10b, known as the classical Wnt ligand, is highly produced by T cells in AAS, and its absence increases the activation of cultured T cells and enhances immune response in animal models.274 In addition, after mesenchymal stem cell-derived exosomes and vitamin D inhibit Wnt/β-catenin signaling, airway remodeling is reduced, thereby inhibiting chronic allergic inflammation in the airway.275,276 Upregulated Notch4 in blood Tregs from asthma patients differentiates Tregs into Th2 and Th17 T cells through a Wnt and Hippo pathway-dependent mechanism, and Wnt induction upregulates growth and differentiation factor 15 (GDF15) in Tregs, and this feedforward mechanism exacerbates inflammation.226 However, Wnt-1/β-catenin pathway induction promotes allergic airway diseases. Overexpression‎ of Wnt1 reduces DC migration to draining lymph nodes and induces an appropriate T cell tolerance response without causing T cell proliferation.277

Related literature reported that inactivation of Wnt/β-catenin signaling could reduce nasal mucosa damage and eosinophil infiltration, decrease the infiltration of nasal mast cells and enhance red blood cell immune adhesion, thereby reducing the progression of AR.278

There are few reports on this pathway in FA and AR. Research in allergic dermatitis shows that Notch deficiency is the basis for inhibiting epidermal differentiation and skin barrier defects, thus enhancing Wnt pathway, which is very important for the proliferation of epidermis cells.279

PI3K/AKT signaling

PI3K in the lipid kinase family interacts with the PH domain of the AKT protein (also known as PKB), inducing its conformational change and AKT phosphorylation. Activated AKT is transferred from the cytosol to the plasma membrane, and subsequently induces its downstream effectors, including mammalian target of rapamycin (mTOR).280

PI3K inhibitors have been considered to have great potential in the treatment of inflammation. Current evidence shows that PI3K participates in the pathogenesis of asthma through two main mechanisms. First, PI3K increases the permeability of mouse blood vessels to enhance antigen-induced airway inflammation and high reactivity.281,282,283 In the OVA-induced asthma model, inhibition of PI3K110δ subtype (PI3K-δ) reduces the activation of HIF-1α in airway epithelial cells, as well as antigen-induced airway inflammatory reactions and hyperresponsiveness, by regulating vascular leakage mediated by VEGF.284 Secondly, the PI3K pathway induces airway smooth muscle cell proliferation, promotes airway smooth muscle thickening and luminal stenosis, thereby participating in airway remodeling.285 With respect to immune cells, PI3K regulates the differentiation of Th cells and eosinophils in asthma,286,287 and affects the occurrence and development of inflammation in asthma. In an animal model of AAS, it was found that PI3K and AKT activities in lung tissue are increased, as well as the expression‎ of mTOR. After treatment with a PI3K inhibitor, some pathological manifestations of asthma (such as increased amounts of activated chemokines in eosinophils, bronchoalveolar lavage fluid IL-5 and IL-13, lung tissue eosinophilia, increased mucus secretion in the respiratory tract, airway hyperresponsiveness, etc.) are obviously inhibited, and PI3K/AKT signaling highly regulates asthma pathogenesis.288

In AR, drug development research found that the anti-allergic drug α-TCP (alpha-tocopherol) and the androgen receptor antagonist bicalutamide both play anti-inflammatory and alleviating roles in AR in animal models by inhibiting the PI3K/AKT/mTOR pathway in mast cells.289,290 A mouse model with AR shows that increased leptin enhances the expression‎ of type II innate lymphoid cell (ILC2) transcription factor and type II cytokines through the PI3K/AKT pathway.291 For mice lacking CCR3 gene in the bone marrow, the activity of PI3K/AKT signaling was also significantly reduced, and nasal eosinophil infiltration was inhibited; in addition, serum Th2 cytokines were reduced, and the symptoms of AR in mice were alleviated.292 It was found in cell experiments that ST2/PI3K/mTOR-mediated autophagy is inhibited by IL-33 secreted by nasal epithelial cells, thereby promoting mast cell degranulation in allergic asthma.293

In the skin, dysregulated PI3K/AKT pathway might result in serious pathologies featuring unchecked cell proliferation and inflammatory response.294 In addition, PI3K/AKT signaling also modulates mast cell degranulation via miRNAs in allergic skin diseases. High-expression‎ miR-126 induces IgE-mediated mast cell degranulation related to PI3K/AKT signaling by increasing Ca2+ influx.295

Serum chitinase 3-like 1 (CHI3L1) amounts are increased in individuals with allergic disorders and promote Th2-related immunity and the polarization of M2 macrophages through PI3K/AKT signaling in FA.296

mTOR signaling pathway

mTOR represents a serine/threonine protein kinase that belongs to the PI3K-associated protein kinase (PIKK) family.297 While associated with the above paths, mTOR signaling may serve as an upstream response to other signaling pathways. mTOR has catalytic subunits in two different complexes, including mTOR complex 1 (mTORC1) and mTORC2,298 which have different susceptibilities to rapamycin, substrates, and functions.299 Studies in allergic diseases have shown that mTOR is a key molecule for sensing the immune microenvironment and determining the function and differentiation of immune cells,300 because it regulates a variety of immune cells and limits pro-inflammatory mediators.301,302 For example, increasing evidence supports that mTOR is an important regulator of Tfh cell differentiation. The balance of Tfh and Th1 cell differentiation in vivo is regulated by IL-2 signaling through PI3K, AKT and mTOR, and both mTORC1 and mTORC2 essentially promote Tfh cell differentiation and germinal centers (GC) formation, which cannot be ignored in allergic diseases.303,304

In AAS, the progenitor cells of granulocytes originate from the bone marrow and move to blood vessels and lungs when inflammation occurs. Among them, eosinophils regulate Th2 immune response, which is related to the severity of the disease,305 while ablation of mTOR leads to Gata-1 overexpression‎ and increases eosinophil differentiation.306 The angiogenic factor fibroblast growth factor-binding protein 1 (FGFBP1) is highly expressed in asthma models with airway remodeling features, because activating mTORC1 and signal transducer and activator of transcription 3 (STAT3) signaling pathways enhances FGFBP1 expression‎ and secretion, thus inducing angiogenesis.307

The target protein mTOR of rapamycin is involved in the growth of keratinocytes. Studies have found IL-13 activates the mTOR signaling pathway and downregulates miR-143, followed by the downregulation of epidermal barrier related proteins. Therefore, rapamycin could treat allergic dermatitis by inhibiting mTOR.308

FcƐRI signaling pathway

Fc receptors play major roles in adaptive immunity by interacting with immunoglobulins, among which FcεRI represents a high-affinity IgE receptor found on mast cells, basophils, eosinophils and APCs.309 When IgE binds to FcεRI to trigger immunity, FcεRI aggregation induces a variety of signaling pathways to regulate the secretion of allergy-associated mediators, including histamines and leukotrienes, and induces the transcription of Th2 cytokines and tumor necrosis factor (TNF) genes,310 which leads to potentially life-threatening allergic diseases. The tetrameric form of FcεRI is present in mast cells and basophils, while the trimeric form is found in other immune cells; FcεRIα, FcεRIβ and FcεRIγ (αβγ2) are encoded by the FcεR1A, FcεR1B (MS4A2) and FcεR1G genes, respectively.311,312

The pro-inflammatory effects mediated by FcεRI in different allergic disorders have the following similar mechanisms. Signal transduction in mast cells is induced by the phosphorylation of immune receptor tyrosine activation motif (ITAM) of FcεRIβ and FcεRIγ subunits by Src-protein tyrosine kinase. This results in the recruitment of tyrosine kinase Syk, which mediates the activation of some adaptor molecules (SLP76, LAT, etc.), leading to calcium mobilization.313 Therefore, dephosphorylation of tyrosine kinase activating signals downstream of the IgE-FcεRI complex may prevent allergic diseases,314 and TLR-mediated release of cytokines from mast cells depends on the expansion effect of FcεRI, which is more important in the late reactions associated with inflammation.315 There is a synergistic effect between TLR and FcεRI-mediated activation in basophils, which promotes Th2 cell differentiation and induces degranulation and cytokine release.316,317 Platelets depend on the interaction between allergens and allergen-specific IgE and FcεRI, and are directly involved in allergic asthma.318 In addition, FcεRI signaling can also activate the PI3K signaling pathway.314

In allergic diseases, sensory neurons exposed to allergens produce action potentials; the Ca2+ flux mediated by immune complexes increases, the action potentials discharge and neuropeptides are released, thereby causing pain or itching. The IgE receptor FcɛRI highly contributes to the development and remodeling of airway inflammation in allergic asthma.319 Studies in animals with experimental allergic asthma demonstrated that when the vagus nerve, which dominates the airway, senses the invasion of allergens, pain receptor neurons overexpress the immunoglobulin receptor FcɛRI and release Substance P, which drives the polarization of Th2 cells, thus triggering allergic inflammation.320

IgE-mediated FA is very common, and FcɛRI is also upregulated in the abdominal vagus nerve of mice with experimental food allergy, which promotes the skewed Th2 polarization in the intestine.321 Functional FcɛRI also exists in intestinal neurons, and stimulation of IgE antigen activates intermuscular neurons.322

NOD-like receptors signaling pathway

Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are located in the cytoplasm, and 23 species have been found in the human body to date.323,324 This pattern recognition receptor recognizes microbial compounds such as PAMPs and Damage-Associated Molecular Patterns (DAMPs) and cooperate with TLR and related pathways to trigger antibacterial immune response. The NOD-like receptor consists of the following three domains: (i) the nucleotide sequence located in the center has a domain that binds to NACHT, which drives the activation of downstream inflammatory caspase and NF-κB; (ii) the effector domain located at the N-terminal end mediates the interaction with adaptor proteins and downstream effectors and transmitting receptor excitability information; (iii) the C-terminal region is composed of leucine-rich repeats (LRRs), which constitute the microbial pattern recognition domain.325,326 NLRs recognize many pathogen-related model molecules, including microorganisms and toxins secreted by microorganisms327 which could be used for immune surveillance and host defense. The NLR signaling pathway mainly has the following functions: signal transduction, inflammasome formation, gene transcription stimulation and autophagy.328,329

After an NLR recognizes bacteria-related ligands, γ-D-glutamyl-meso- diaminopimelic acid (iE-DAP) and muramyl dipeptides (MDP), it promotes the expression‎ of the adhesion molecule ICAM-1 on eosinophils and bronchial epithelial cells, and thus drive the cell adhesion, chemotaxis and migration of leukocytes. NLRs also induce eosinophils and bronchial epithelial cells to produce pro-inflammatory molecules such as IL-1β, IL-6, CXCL8, CCL2, CCL3, CCL4, and CCL5, thereby causing lung inflammation.330

In animal models, treatment of allergic asthma mice with NOD1 ligand induces subcutaneous fibrosis and significantly increases serum amounts of total IgE, eosinophils and the chemokine CCL5 as well as bronchoalveolar lavage fluid amounts of the Th2 cytokine IL-13.331 However, intranasal NOD2 ligand induces the expression‎ of TSLP, IL-25 and OX40L in the lung,332 and these three molecules have been reported to promote asthma-related inflammation,333,334,335 blunt the production of antigen-specific CD4+Foxp3+ adaptive Tregs, and simultaneously drive CD4 T cells to produce IL-4, change the Treg/Th2 balance, block tolerance, and promote the susceptibility of airway inflammation dominated by eosinophils.332

The nucleotide-binding oligomeric domain-like receptor family Pyrin domain 3 (NLRP3) inflammasome contains NLRP3, ASC and Caspase-1, which are important constituents of the innate immune system, with critical roles in allergic disorders.331 The NLRP3-retinoid X receptor (RXR) axis drives airway epithelial cell apoptosis as well as the production of inflammatory cytokines in the lungs of asthmatic mice.336 Further study found that NLRP3 in bone marrow cells promotes the development and progression of AAS in an inflammasome-dependent manner, and RRx-001 (an inhibitor of NLRP3) could significantly decrease inflammatory cell infiltration and mucus secretion in the airway.337 PMs can cause acute exacerbation of allergic airway inflammation, activate TLR2/NF-κB/NLRP3 signaling and aggravate allergic airway inflammation.338

It was demonstrated that NOD1 and NLRP3 in AR patients are downregulated during the pollen season.339 Activation of the NLRP3/gasdermin D/IL-1β signaling pathway mediates macrophage pyroptosis and releases inflammatory mediators to local tissues, which is involved in nasal mucosa inflammation of AR.340

The microbiota plays an essential role in the occurrence and development of allergic diseases

In 1989, Strachan observed that children with more siblings in the family were less likely to develop hay fever or eczema;28 children are frequently exposed to allergens, hence the original “hygiene hypothesis” was proposed. This hypothesis is a good explanation for the phenomenon that AAS is significantly more preval‎ent in developed countries in comparison with underdeveloped countries. From an immunological point of view, it could be understood that the development of immune tolerance to allergens depends on the amount and degree of stimulation by microbial colonization and immune stimulating environmental signals transmitted in early life.341

With the rapid development of urbanization and industrialization, excessive use of hygiene products and antibiotics, coupled with changes in diet such as fast food, etc., would decrease microbial diversity in early life,342 resulting in impaired immune protection and the destruction of normal microorganisms.343 There is increasing evidence that the microbiota is critical for the occurrence and development of allergic disorders.344 The human microbiota mainly colonizes the gastrointestinal tract (GIT), with microorganisms also present in other body parts such as the oral cavity, nasal cavity, skin, and respiratory and reproductive tracts.345 Symbiotic microorganisms in the GIT and other organs mediate the innate and adaptive immune systems through the gut-lung and gut-skin axes. Reports have shown that many environmental factors influence the colonization, composition and metabolic activities of microbial communities in early life, thereby affecting the immune function of the body and leading to the occurrence of allergic diseases.346,347,348,349

Early-life activities and dysbiosis is tightly associated with allergic diseases

It is well established that microbial colonization starts at birth, and that microbiota composition is affected by related factors such as the prenatal and postnatal environment, which are also critical for the body’s immune function. Multiple factors, including mode of delivery,350,351,352 feeding choice,353 and use of antibiotics or not,354,355 can alter the composition of the gut microbiota and modulate infant tolerance to different allergens.

The use of antibiotics during pregnancy and the early postpartum period can affect the gut microbiota in normal infants and increase the risk of developing allergic diseases.356,357 Mothers exposed to antibiotics during childbirth had significantly lower microbial diversity compared with infants born to antibiotic-free mothers. The microbiota of antibiotic-exposed infants shows reduced amounts of Bacteroidetes and Bifidobacterium, alongside increased Proteus amounts. Studies have shown antibiotic utilization during pregnancy and childbirth is associated with elevated risk of AD and asthma.358,359,360 A study of 14,572 children, 10,220 of whom were administered antibiotics in the initial 2 years of life, revealed that early exposure to antibiotics had tight associations with childhood asthma, AR and AD.361 Studies in germ-free laboratory animals further demonstrated an interdependent association of gut microbiota with immune system development.362,363,364,365

Dysbiosis is tightly associated with allergic disease occurrence, and in some way affects the balance of immune cells in allergic diseases. Most AAS begins in childhood, and HDM, cockroach remains, pet dander, fungi and pollen are the main allergens.366 A study found lower abundances of Lachnospira, Veillonella, Faecalibacterium, and Rothia in the gut of infants are associated with higher asthma risk, and inoculating these bacteria in germ-free (GF) mice could alleviate airway inflammation and prevent the development of asthma.367 Furthermore, decreased abundance of Bifidobacterium was found in adult asthmatic patients.368 Haemophilus, Moraxella and Neisseria spp. were also observed in the airway microbial composition of asthmatic patients, and Proteus was also found in mild cases not receiving inhaled corticosteroids as well as in severe asthma cases. Actinobacteria and Klebsiella species were markedly enriched in severe asthma cases in comparison with healthy controls or mild-to-moderate asthma cases.369 In AD patients, Staphylococcus aureus colonization is an important exacerbating factor in AD pathogenesis, and gut dysbiosis is also considered an important factor in AD pathogenesis. A metagenomic analysis data showed that S. aureus constituted approximately 90% of AD skin, leading to dramatically decreased skin microbial diversity.370 In animal models, alpha-hemolysin and extracellular vesicles produced by S. aureus lead to skin barrier dysfunction and promote atopic skin inflammation.371,372,373 Enterotoxins secreted by staphylococci promote allergic skin inflammation by triggering substantial T cell activation, and staphylococcal delta-toxins also cause allergic skin diseases via mast cell activation.374 Clinical cohort trials have shown an early reduction in gut microbiota diversity is strongly related to elevated AD risk,375 and the presence of gut microbiota subspecies such as Clostridium Perfringens, Clostridium difficile and Faecalibacterium prausnitzii is closely associated with reduced capability of producing short-chain fatty acids (SCFAs), while L. paracasei abundance reduces the susceptibility to AD.376,377,378 AR is a respiratory disease that occurs in the upper respiratory tract, which includes the nose and oropharynx. Firmicutes and Actinobacteria represent key microbiota constituents in the nasal cavity of humans, while Proteobacteria, Firmicutes, and Bacteroidetes represent key phyla in the oropharynx.379,380,381 Microbial diversity in seasonal AR (hay fever) did not decrease, but was instead elevated during allergy season.382 Staphylococcus aureus is a microorganism involved in perennial (non-seasonal) AR.383 The etiology of the elevated incidence of FA remains undefined and may be related to the mode of delivery (natural vs. surgery) or the changes in the microbiome in early life due to antibiotic use even in low amounts.384,385,386

The microbiota contributes to the innate and adaptive immune systems in allergic diseases

Human mucosal tissues, such as intestinal mucosa, nasal mucosa, and other surfaces, have regular exposures to complex microbial populations comprising commensal and pathogenic organisms. The host utilizes many molecular mechanisms to mediate mucosal innate immunity for microbial homeostasis. PRRs, including TLRs and NLRs, play major roles in recognizing pathogens and inducing innate immune responses.

Different gut microbiota have different activation pathways, and some gut bacteria, e.g., Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae, and Proteus vulgaris, activate HEK-293 cells through the TLR2 and TLR4 pathways.387 Flagellate bacteria, including Salmonella, Listeria, Pseudomonas, and Escherichia coli, contain flagellin, which acts by binding to TLR5.388 TLR9 functions by recognizing unmethylated CpG motifs, especially GTCGTT motifs, in the DNA of gut bacteria, including Proteus, Bacteroides and Actinobacteria, as well as Lactobacillus plantarum, etc.389 TLR signaling stimulates the maturation of innate immune cells, to properly activate APCs and initiate a moderate immune response.231 Both exposure to allergic environments and the mother’s allergic status are all factors affecting an infant’s susceptibility to allergic diseases.390 Microorganisms are present in the placenta, amniotic fluid and meconium, which are in contact with the fetus in early fetal stage; therefore, the fetus needs to develop immune tolerance during the mother-fetal period to prevent infection.391 Natural killers, DCs and macrophages in the endometrium and trophoblasts are already induced during fetal development.392,393

In allergic disorders, the microbiome exhibits a crucial function in establishing adaptive and innate immune protection. For instance, children with reduced IgG responses to specific microbial antigens than healthy counterparts are prone to allergic diseases, including asthma, AD and FD.344,394,395 In studies of babies, higher AD risk had associations with reduced levels of Proteobacteria and elevated innate inflammatory response induced by TLR-4, and Ruminococcus decrease was associated with elevated TLR2-dependent innate inflammatory response.396,397,398 FA in early stage is also closely associated with reduced gut microbial abundance.344

Epithelial cells

Epithelial cells on the nasal and bronchial mucosal surfaces are critical for maintaining the healthy state of respiratory mucosa. Continuous and coordinated ciliary movement enables the removal of foreign invading substances such as pollutants or allergens from surfaces. Epithelial cells also produce different cytokines and chemokines to activate inflammatory cells; meanwhile, hyperactivation of epithelial cells may trigger the onset of several disorders, including asthma and AR.399

Epithelial cells recognize PAMPs through innate PRRs, e.g., TLRs and NLRs, and such interactions affect the proliferation of epithelial cells. Microbiota-derived metabolites, including SCFAs, also have effects on epithelial cells. SCFAs, for example, stimulate inflammatory pathways by interacting with GPRs on epithelial cells in the intestine.400 P-cresol sulfate (PCS) is a microbial-derived product produced in the gut. PCS selectively reduces CCL20 production by airway epithelial cells due to uncoupling of epidermal growth factor receptor (EGFR) and Toll-like receptor 4 (TLR4) signaling, a pathway that acts distally on airway epithelial cells to reduce allergic airway responses.401

DCs

DCs, as APCs, are critical for immune responses in contact with commensal microbiota. The presence of SCFA butyrate, an end product of microbial fermentation, stimulates human monocyte-derived dendritic cell (moDC) maturation, increasing IL-10 amounts while decreasing IL-6 and IL-12 levels.402 Meanwhile, mice treated with SCFA propionate could produce new myeloid DC precursors with strong phagocytic capability but poor capability of promoting Th2 responses in the lung.

In humans, TLR9 is highly produced by macrophages and plasmacytoid DCs.403 The CpG motif is preval‎ent in bacteria, and the CpG motif also recognizes plasmacytoid dendritic cells (pDC) expressing TLR9 that produce pro-inflammatory cytokines, induce Th1-like immune activation patterns and activate their migration, while CpG-A oligodeoxynucleotides (ODN) induces extremely high levels of IFN-α production and CpG-B ODN induces activation of murine bone marrow-derived DCs to secrete IL-12 and IL-6.404,405

In reports assessing AAS disease models in mice and rhesus macaques, macrophage responses to TLR9 activation mainly induce Th1 type immune response, including upregulated TNFα, IL6, IL-12, IL-18, IFN-α and IFN-γ,406 resulting in the immune imbalance of Th1/2 cells.407

Macrophages

The microbiome and associated metabolites, including SCFAs, affect the function of macrophages resident in tissues. In the gut, the SCFA butyrate promotes the anti-inflammatory response of macrophages and induces Treg differentiation by activating its receptor GPR109a, which is essential in inducing tolerance to food. Besides, butyrate exerts anti-inflammatory effects on macrophages by inhibiting IL-6, IL-12 and NO production.408 In the lungs of antibiotic-treated mice, macrophages are polarized towards an M2 hypersensitivity phenotype by prostaglandin E2 (PGE 2) produced by commensal fungi.409

Lipopolysaccharide (LPS) represents a soluble cell wall constituents in common Gram-negative bacterial organisms.410 LPS can interact with complex host systems, including cellular and humoral components of the immune system, to induce the production of multiple immunomodulatory cytokines.411 It has been shown that LPS regulates lung inflammation in asthmatic mice via the TLR4 pathway in alveolar macrophages and that different doses of LPS exposure determine the type of inflammatory response.412 Improvement of AD by modulation of Th1/Th2 immune system homeostasis with LPS-activated macrophages derived from pantoid epimer (IP-PA1).413

Mast cells (MCs)

Mast cells (MCs) represent major effector cells in allergic diseases. Increasing evidence suggests that the microbiota can modulate MC function, influence MC activation through direct interactions or secreted metabolites.414 In human MCs, co-culture with Lactobacillus rhamnosus downregulates high-affinity IgE and histamine H4 receptors, while upregulating IL-8, IL-10, CCL2 and TNF-α.414 In murine experiments, Lactobacillus paracasei inhibits IgE-mediated MC activation via TLR2. However, the inhibitory effect of Lactobacillus casei is mainly through direct cell contact and not dependent on TLR or NOD1/2.414

Eosinophils

Elevated numbers of eosinophils in AD, AR and eosinophilic allergic asthma are typical symptoms for allergic diseases.415,416,417,418 Eosinophils act as major effector cells driving innate immunity in allergy and other inflammatory diseases, with an important role in clearing microbes resident in tissues.419 Meanwhile, eosinophil function is also regulated by pathogenic microorganisms; for example, Clostridium difficile stimulates the release of eosinophil-derived neurotoxins by eosinophils.420 However, when eosinophils ingest the probiotic strain Bifidobacterium, neurotoxin release is significantly reduced.420 Very interestingly, probiotics such as Lactobacillus fermentum and Lactobacillus rhamnosus, alleviate allergic inflammation involving reduced eosinophil infiltration in multiple mouse models of asthma and AD, although probiotic strains have not been shown to have a direct effect on eosinophils.421,422 NLRP12 induces allergic skin inflammation by promoting peripheral DC retention as well as neutrophil migration.423

Basophils

TLR2 was identified as the primary receptor against S. aureus,244 and intracellular NLRs also modulate microbial pathogen recognition. Intracellular NLRs, including NOD1, NOD2, NLRP1, NLRP3, NLRP4, and the interferon-inducible protein AIM2 produce a series of inflammatory molecules to resist the invasion of microorganisms.424 NOD2 is considered a major player in innate immune response to S. aureus in the skin.425 Studies have found that NOD2 expression‎ on basophils in the peripheral blood of AD cases is markedly reduced compared with that of healthy people,426 and basophils are the main effector cells involved in Th2 polarization in allergic inflammation. Acinetobacter in the skin prevents allergic inflammation and is critical for the regulation of Th1/Th2 cell balance and anti-inflammatory responses.427

Innate Lymphoid Cells (ILCs)

ILCs, a major group of innate immune cells, are present in all parts of the respiratory tract; ILC2 cells are predominantly found in mice, while ILC3 cells are predominantly found in the human respiratory tract.428,429 Microbial signaling affects the maturation of ILC tissue-specific functions. Clostridia has been shown to stimulate ILC3 to produce IL-22, which helps to strengthen epithelial barrier and reduce intestinal permeability to dietary protein.430 ILC3 cells tolerize T-cell response and prevent IL-22 production, leading to a loss of gut bacteria.409 Furthermore, when gut macrophages release IL-1β upon microbial insult, ILC3 cells release GM-CSF and induce immune tolerance.409 TNF-β produced by ILC3 cells is essential for maintaining gut microbiota homeostasis, and IL-25 is produced by epithelial tuft cells in a microbiota-dependent manner.409 The microbiota and its metabolites induce different types of ILCs and regulate their capability of preventing allergic reactions.

Tregs

Tregs are important immune regulatory cells, which suppress allergic diseases and have critical functions in controlling the immune response. Bifidobacterium longum 35624, Clostridium fragilis, and Bacteroides fragilis all induce Tregs in the intestine, whereas other bacteria do not induce Tregs.431,432 Activation of PRRs on DCs is a critical mechanism by which gut microbial organisms mediate Treg differentiation.433 Recently, it was found that infants with reduced levels of Bifidobacterium and Faecalibacterium have elevated relative risk of asthma, characterized by elevated amounts of IL-4+ Th2 cells and reduced Treg levels,434 attenuating the adaptive immune response. In IgE-induced FA studies, dysbiosis affected the differentiation of Tregs, resulting in an imbalance of Treg and Th2 cells and leading to allergic diseases (Fig. 3).435,436

Treatment

At present, the treatment of allergic diseases mainly includes five aspects: management and therapeutic education for patients and allergen avoidance, traditional pharmacotherapy, allergen immunotherapy, biologics administration and other therapies.

Management and therapeutic education for patients and allergen avoidance

Daily management of patients with allergic diseases and educational intervention plays an essential role in managing difficult-to-treat allergic cases. It is frequent and may lead to treatment failure due to poor adherence to the prescribed treatment.437 Ensuring patient education and confidence in prescribed drug is urgently required, to achieve disease control. For example, it is necessary to inform patients regarding the correct use of intranasal spray and other pharmaceutical preparations.438 What’s more, psychosomatic aspects can also contribute to complementing topical and systemic therapies.439 Furthermore, it is also a critical issue in allergic disease management to combine the limited resources and increased digitalization. For example, mobile applications can monitor symptoms, drug use, and quality of life timely with higher efficiency, e.g., the Allergy Diary.440,441

Avoiding allergens or minimizing exposure to allergens is the first step of treatment. However, since the pathogenic allergens of different patients are often different, mainly including food allergens, aeroallergens, contact allergies, and allergens in the environment that are frequently unknown, the strategy of avoiding allergens on the basis of an allergy diagnosis is often challenging.438 Therefore, teaching patients how to avoid contacting with allergens may help achieve the best treatment effect. For example, the current standard of FA care is to avoid allergens, because there is no Food and Drug Administration (FDA) approved treatment for FA at present.442 As for AR or AD, due to their multifactorial etiologies, elimination of food or environmental allergens represents an adjuvant treatment to pharmacotherapy; thus, complete remission may not be expected after mere allergen elimination.443 Other allergen avoidance measures such as environmental intervention and use of protective devices are available to reduce exposure to causative substances for maximum effectiveness, which apply to all forms of asthma aggravated by the working environment.444 It is noteworthy that determining the individual’s relevant triggers for allergic diseases may be more difficult than diagnosing the disease itself.439 To sum up, allergic diseases normally need drugs for treatment.

Traditional pharmacotherapy

Traditional pharmacotherapy is currently an efficient and rapid treatment method, which helps improve the symptoms of most patients and enhance their quality of life. At present, there are many kinds of drug treatments for allergic diseases, with good therapeutic effects (Table 2).

Table 2 Different Traditional pharmacotherapies and their mechanism of action and clinical application of drugs

Full size table

H1-antihistamines

H1-antihistamines, which serve as neutral receptor antagonists or inverse agonists of the histamine H1 receptor, can block the action of histamine.445 According to brain H1 receptor occupancy (H1RO, an indicator of antihistamines), H1‐antihistamines can be divided into the non-sedating, less-sedating and sedating groups, whose diverse chemical structures, pharmacokinetic features and potential for drug-drug and drug-food interactions make them different. First-generation H1-antihistamines have not been well studied, and because of their adverse effects, particularly sedation, they should be avoided and not recommended for use.438 New second-generation H1-antihistamines have great efficacy and safety profiles, as well as good tolerance.446 The development of second-generation H1-antihistamines occurred in the 1980s, revolutionizing allergy therapy due to no or only minimal sedative potential, including the less-sedating oral H1-antihistamines and non-sedating H1-antihistamines.447 However, because of cardiotoxic side effects, two early second-generation H1-antihistamines, i.e., astemizole and terfenadine, have now been withdrawn from the market.447,448 Third-generation oral antihistamines have improved efficacy, safety, and pharmacological and pharmacokinetic features, representing suitable candidates for the treatment of seasonal or perennial allergies, which may improve the allergic symptoms of patients.449

Corticosteroids

Corticosteroids were considered the most effective therapeutic approach for atopic disorders in the past, and could control virtually all cases of allergic diseases at high dose.450 The main role of corticosteroids is to inhibit a variety of inflammatory molecules such as cytokines, pro-inflammatory proteins, adhesion molecules and inflammatory receptors, which explain their high efficacy in complex inflammatory diseases. Corticosteroids are divided into intranasal corticosteroids (INCS), topical corticosteroids (TCS) and systemic corticosteroids (SCS).

INCS are a well-established first-line therapeutic option for adults and children with persistent or moderate-to-severe symptoms, decrease inflammation associated with AR and alleviate nasal and ocular symptoms.438,451 Their efficiency is more obvious than that of oral or intranasal antihistamines and antileukotrienes. In addition, INCS are comparable to the combination of antihistamines and antileukotrienes.452 Mechanistically, INCS exert local anti-inflammatory effects on nasal mucosal cells. New-generation inhaled corticosteroids for asthma show enhanced anti-inflammatory effects with minimal adverse effects. Undoubtedly, inhaled corticosteroids (ICS) have revolutionized asthma therapy, and are currently considered the first-line therapeutic option for all chronic asthma cases.

Topical corticosteroids (TCS) induce fewer systemic side effects, especially the recently developed topical steroids that have short half-lives, and are the first-line anti-inflammatory approach in AD.439,453 Studies have shown that topical corticosteroids used as adjunctive therapy alongside dupilumab may provide additional benefits.454 Systemic corticosteroids (SCS), one of the groups of drugs available for systemic anti-inflammatory therapy, are required for AD not sufficiently controllable with adequate topical therapies and UV light therapy. Although SCS have rapid effects, their use should be limited to 1-2 weeks because of significant risk of severe long-term side effects, as observed with methylprednisolone.439

Combination of H1-antihistamines and nasal corticosteroids

Conceptually, it is meaningful to use both nasal corticosteroids and local nasal antihistamines at the same time, because such treatment can block the main cause of direct response and reduce inflammation through significantly different mechanisms.455 A study addressed the possibility that a combination of azelastine and fluticasone (both as nasal spray) can confer significant clinical benefits in individuals with seasonal allergic rhinitis (SAR) in comparison with any drug alone.456 It has been shown that the nasal symptoms of SAR are more significantly relieved by the fixed-dose combination (FDC), containing an intranasal antihistamine (azelastine hydrochloride [HCl]) and a corticosteroid (fluticasone propionate) compared with placebo or monotherapy, and could also alleviate the nasal symptoms of perennial allergic rhinitis (PAR) more substantially than fluticasone monotherapy.457

Leukotriene receptor antagonists

Leukotrienes (LTS) are indispensable for the pathogenetic mechanisms of allergic inflammation, so inhibiting LTS represents an effective and feasible strategy in the treatment of allergic diseases, including AAS, AR, and AD. Leukotriene receptor antagonist (LTRA) is an additional treatment option for asthmatics and AR cases. In addition, some leukotriene receptor antagonists are currently used clinically for exercise-induced bronchoconstriction.458 Leukotriene is an important lipid mediator in asthma-related research.459 Leukotriene receptor antagonists improve small airway function and reduce airway inflammation in the treatment of AAS.460 In Europe, LTRAs have been approved by European Medicine Agency(EMA) only for the treatment of asthma and AR.438 Studies have shown that early intervention with a 4-week anti-leukotriene course is also beneficial for some pollen allergies.461 LTRAs are not known to cause significant congenital malformations or adverse perinatal outcomes in pregnancy safety studies. Some reports point out that LTRAs may be considered in second-line treatment of pregnant women if better treatments fail.462

Other drugs

Other drugs can also help treat allergic diseases. Mast cells can regulate angiogenesis, tissue inflammation and repair. The cells play an important role in innate and adaptive immune response, immune tolerance, and host defense. Therefore, mast cells are essential for allergic reactions. Mast cell stabilizer such as sodium cromoglicate is targeted at mast cells, which can inhibit the degranulation of allergic mediators, thus preventing allergic diseases. The side effects of sodium cromoglicate are less, and it has been clinically approved for the treatment of asthma and AR. However, the therapeutic time window of mast cell stabilizer is relatively narrow. The patient needs to be given the drug immediately before the allergen stimulation, so that the drug can play a stable and effective role.463,464,465

Some drugs are used for symptomatic treatment of allergic diseases. For example, most chromones can be administered as monotherapy for local symptoms. They are relatively safe drugs, but with low efficacy.438 Theophylline, a Phosphodiesterase 4 (PDE4) inhibitor, is another drug that promotes apoptosis by reducing the anti-apoptotic protein Bcl-2, which inhibits neutrophils and eosinophils in vitro. It was also noted that theophylline inhibits reactive oxygen species accumulation by neutrophils and reduces neutrophil chemotaxis.466 At present, there are four PDE4 inhibitors approved for treating human diseases, including AD and bronchial asthma.467 However, considering the associated systemic adverse effects, topical administration of inhaled PDE4 inhibitors might represent a promising alternative instead of systemic utilization, although these drugs are not recommended to use before or during pregnancy.462,468

Topical calcineurin inhibitors (TCIs) have substantial anti-inflammatory effects, inhibiting the biosynthesis of proinflammatory cytokines by T cells and mast cells, as well as antipruritic effects that are attributed to specific effects on skin Transient receptor potential vanilloid 1 (TRPV1) neurons.439 TCIs are especially useful in individuals requiring long-term treatment, and two of them have been approved for topical AD therapy; nevertheless, reports assessing the application of topical calcineurin inhibitors during pregnancy are limited.469 It is important to note that other immunosuppressants, including azathioprine and cyclosporine, do not induce congenital malformations; besides, cyclosporine is considered as first-line drug for long-term treatment of diseases.462,470

Bronchodilators, which are significant for preventing and relieving bronchoconstriction, including long‐acting muscarinic antagonist (LAMA) and long‐acting beta‐agonist (LABA) addition to ICS, sometimes have adverse effects, including tremors, palpitations and tachycardia.466,471,472

In general, H1-antihistamines are usually safe and widely used for the treatment of various allergic diseases, but some patients experience adverse effects, such as cardiotoxicity, central depression and anticholinergic effects. In addition, there are individual differences in the efficacy of antihistamines in clinical practice.473 INCS are effective in combating nasal and ocular symptoms and improving quality of life, and are safe for short-term use, but long-term safety data are lacking. Although generally well tolerated, adverse events can be observed that may lead to serious ocular complications.474 As for TCS and SCS, long-term continuous use of corticosteroids may result in local and systemic toxicity risks. LTRAs are well tolerated, non-hormonal anti-inflammatory drugs. LTRAs are primarily employed for long-term control treatment of patients with mild asthma and comorbid AR. It has also been shown that LTRAs are not associated with the risk of major congenital malformations and can be safely used during pregnancy to treat asthma.475 Nevertheless, the anti-inflammatory effect of LTRAs is not as strong as that of corticosteroids, so they are often used in combination with inhaled corticosteroids to enhance their efficacy in clinical practice. However, Some experiments have shown that LTRAs and oral H1-antihistamines have comparable effects in AR.438 In short, based on the side effects of these traditional drugs, other therapies are emerging as well, such as allergen immunotherapy (AIT) and biologics, etc.

AIT

AIT constitutes the sole disease-modifying therapy for patients with IgE-mediated inhalation allergic diseases.476 Compared with traditional pharmacotherapy, the advantage of AIT is that it is a medical intervention that can limit the natural process of the disease.477 The purpose of this therapy is to reduce the symptoms of allergic diseases by inducing tolerance to allergens.438 AIT is based on the administration of allergens that cause a given disease. Through long-term repeated exposure to specified doses of allergens, it can change the immune response and induce protective immunity, so that patients may tolerate future allergen exposure.478,479 In addition, this therapy reduces the long-term treatment cost for patients and the economic burden of allergy. From the perspective of public health, AIT plays a crucial role in allergy management.477

Application of AIT in allergic diseases

In allergic diseases, immune dysfunction is the key pathogenic factor, so the concept of inducing immune tolerance has gradually become one of the goals set for preventing and treating allergic diseases.477 In the routine use of AIT, it is recommended to take a 3-year course of treatment to achieve long-term efficacy, and long-term clinical benefits are achievable after stopping treatment.476,480 In adolescents and adults, AIT can be used to treat moderate-to-severe rhinitis and moderate asthma. In children, AIT can prevent rhinitis cases from further developing asthma symptoms.481 Researchers analyzed AR progress and changes in asthma symptoms after HDM allergen immunotherapy. The results showed that treatment of AR patients with HDM allergy drugs could indeed reduce the overall incidence rate of asthma, improve asthma symptoms and slow down the progression of asthma.482,483 Many experiments have revealed that AIT markedly reduces the symptoms in patients, changes the disease process, and improves the quality of life in allergic individuals.

Therapeutic principles of AIT in allergic diseases

The tolerance induced by AIT is related to changes in allergen-specific memory T and B cells as well as allergen-specific IgE and IgG antibody amounts. In addition, AIT has some impact on the activation threshold of mast cells, basophils and dendritic cells.438 Some cells utilize interleukin-10 (IL-10), IL-35, transforming growth factor-β (TGF-β), IL-10R, TGF-βR, cytotoxic T lymphocyte-associated antigen 4 (CTLA4), programmed cell death protein 1 (PD1) and other inhibitors to directly or indirectly alleviate the anaphylactic environment.484 Studies have shown that AIT regulates the follicular helper T (TFH) cell-to-follicular regulatory T (TFR) cell balance in allergic cases. The decrease and functional defect of TFR cells are associated with AR.485 Studies have also shown that AIT reduces the expression‎ of CD23 on switched memory B cells, which has a positive correlation with the clinical efficacy of AIT in AR.480

Biomarkers in AIT can predict or monitor immune responses to determine efficacy as early as possible

In AIT, biomarkers can reflect some clinical or laboratory characteristics of the immune process, which is essential for monitoring the health status of patients at all times. However, there is a lack of validated genetic or blood markers that could help predict or monitor the efficacy of AIT at the individual patient level.481 In recent years, researchers have been screening for biomarkers to detect the success of AIT. Many technologies are expected to be used to examine these biomarkers, including genomics, transcriptomics, immunology, lipidomics, metabolomics, microbiology, epigenetics and proteomics.478 According to the mechanism of anaphylaxis and the development and application of the above technologies, relatively reliable candidate biomarkers for immune detection have been reported, including immunoglobulins (allergen-specific IgD, IgE and IgG4) and some cytokines or chemokines (IL-4, IL-13, IL-9, IL-25, IL-33 and TSLP). In addition, candidate biomarkers can also include specific genes or immune-related cells such as cytokine and immunoglobin transcripts, myeloid cells, innate lymphoid cells (ILC), T cells and B cells.478

The drug delivery route affects the quality of AIT

In AIT, different drug delivery routes show different side effects and final efficacy. Conventional AIT includes subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT).476,486 Traditional SCIT has certain shortcomings that cannot be ignored. It requires frequent medical treatment and multiple injections, and in some rare cases, life-threatening allergic reactions and adverse events may occur.487 The typical local reaction in SCIT is redness and swelling at the injection site, and more serious systemic reactions include sneezing, nasal congestion and urticaria. Some serious symptoms often occur within 30 minutes, so individuals are usually allowed to leave the hospital 30 minutes after completing the injection.481,488 SLIT has become a particularly attractive alternative to AIT because of its rather easy administration. It usually involves allergen drops or tablets, which can be administered at home.489 Some new routes of AIT administration are also being developed in order to improve the safety and convenience of patients and maintain or even obtain better curative effects.476,477,490 Oral immunotherapy (OIT) is another SCIT option. OIT seems to have no effects on most respiratory allergens because they are easily digested in the gastrointestinal tract. Therefore, OIT is mainly used for anti-digestive food allergens, including milk, eggs, peanuts and some wheat.479 Studies have shown that OIT for IgE-mediated FA desensitizes patients who are at risk or have experienced severe allergies to peanuts, eggs and milk.477 Intralymphatic immunotherapy (ILIT) is also another better choice for SCIT. This method involves intralymphatic administration, because lymph nodes contain a large number of immune cells, so their direct contact with allergens would be faster than in SCIT and produce stronger protective IgG antibodies and immune regulation at the same time.479,491 In addition, studies have proposed epicutaneous immunotherapy (EPIT), which aims to cause fewer systemic side effects when administered through the epidermis.479

In conclusion, the current goal of improving AIT is to shorten the treatment time, improve its efficiency in order to promote the absorption and presentation of allergens, reduce side effects to improve safety, improve patient compliance, and ultimately significantly increase the utilization of this treatment method.492Application of biologics in allergic diseases

New studies on allergic diseases are underway, especially the development and application of new biologics.441 So far, many biologics targeting Th2/1/17 inflammatory biomarkers are available, many of which are clinically applied.493 Identifying new and reliable biomarkers and clarifying novel molecular mechanisms that persist in specific reactions have become important research directions.438 We summarized some existing biologics according to differences in the mechanisms of action and target sites, providing a certain reference for follow-up studies of biologics (Table 3, Fig. 6).

Table 3 Targets and clinical stages of biologics

Full size table

Fig. 6

Application of biologics in allergic diseases. Multiple cell interactions trigger allergic reactions. Therefore, treatment with biologics aims to target the cytokines produced by various cells, with a potential impact on the interaction between cells. Some biologics exert their effects by targeting IgE, IL-5, IL-4, IL-13, IL-31, IL-9, IL-33, and TSLP, among others

Full size image

Targeting IgE

Targeting IgE molecules is one of the most important methods for nipping allergic reactions in the body with lasting effects. Anti-IgE antibody treatment markedly reduces the serum amounts of free IgE molecules in allergic individuals, thus exerting a certain effect.494 Recombinant humanized anti-IgE antibodies, such as omalizumab, have been approved by the FDA for severe asthma, substantially improving clinical symptoms in patients with poor disease control.441,495

Targeting IL-5

Eosinophils are critical in asthma pathogenesis, and airway eosinophil inflammation is related to the severity of asthma. Biologics, including mepolizumab, reslizumab and benralizumab, have been developed to target IL-5 or IL-5Rα and then affect the survival and differentiation of eosinophils. Studies have shown that blocking the IL-5 receptor could indeed alleviate severe eosinophilic asthma and severe uncontrolled asthma.496,497,498

Targeting IL-4/IL-13

IL-4 and IL-13 represent key driving factors in type 2 immune diseases. For example, dupilumab was approved by the FDA and the EMA (EU) for adults with moderate-to-severe AD. Dupilumab is a fully humanized antibody that targets IL-4Rα subunits, thus inhibiting the IL-4/IL-13 axis. These two cytokines induce IgE production in B cells, goblet cell metaplasia, mucus production, basement membrane thickening and fibrosis. A recent experiment showed that blocking the IL-4/IL-13 pathway alleviates glucocorticoid-dependent severe asthma, moderate-to-severe uncontrolled asthma and AD. Biologics also significantly alleviate AR symptoms, especially nasal symptoms.441,496,497,499 Many biologics have been developed to target IL-4 and IL-13, inhibiting the dimerization of IL-13Rα1 and IL-4Rα or directly targeting the IL-4Rα subunits to play a role.499,500,501,502 More and more biologics that block IL-4 and IL-13 activities have been shown to alleviate nasal symptoms in patients with uncontrolled asthma and AR.503

Targeting IL-31

Monoclonal antibodies, including nemolizumab, a humanized monoclonal antibody targeting IL-31 receptor A (IL-31RA), relieve itching symptoms and IL-31 signal transduction in the pathogenesis of AD. In mice, IL-31 and its receptor IL-31RA are involved in AD-induced pruritus. In another animal experiment, the monkey scratch model, it was found that the scratch induced by IL-31 is significantly alleviated after a single injection of nemolizumab.501,504

Targeted signaling pathways

Some biologics target signaling pathways, including baricitinib, tofacitinib, upadacitinib and ruxolitinib, which target JAK/STAT signaling. Targeting JAK/STAT signaling is critical for T cell activation, and could also block the downstream pathways of many important cytokine receptors. T cells are essential for atopic inflammation. The JAK protein in cells activates STAT protein dimerization and transfer to the nucleus, thereby increasing the gene expression‎ of inflammatory mediators. Therefore, JAK/STAT pathway suppression represents an effective and feasible therapeutic approach in AD.500,501,505 Asthma is often accompanied by inflammation, and many pro-inflammatory chemokines, cytokines, adhesion molecules, airway mucins, growth and angiogenesis factors are upregulated through Rel/Nuclear Factor-κB (NF-κB) transcription factor family.218,506 So asthma and NF-κB mediated signal transduction is inextricably linked, and a series of NF-κB signaling intermediate inhibitors have been produced, e.g., DNA oligonucleotides and DNA-peptide molecules acting as NF-κB bait sequences; in addition, small molecule inhibitors and some proteasome inhibitors affect NF-κB signal transduction.218 For example, small molecule inhibitors such as TPCA-1 and AS602868 inhibit IκB kinase (IKK)-β to block NF-κB signaling. In addition, proteasome inhibitors can block NF-κB signal transduction by targeting the 20 S proteasome, ultimately regulating eosinophil function.218,507 Some biologics regulate the signal cascade by inhibiting PI3K or any downstream target, because PI3K-mediated signals pass through IKKα phosphorylation, and protein kinase B (PKB, AKT) phosphorylation directly activates IKK, which then enters NF-κB signal cascade reaction pathway. For example, idelalisib, alpelisib, copanlisib and duvelisib are PI3K inhibitors.508 The mechanistic target of rapamycin (mTOR) pathway is also considered a signaling pathway regulating innate and adaptive immune cells. It was found that rapamycin targeting mTOR inhibits eosinophil differentiation and reduces allergic airway inflammation in mouse models.505,509 Notch signaling is also associated with the pathogenesis of allergic airway inflammation. Notch is necessary to maintain Th1 and Th2 programs. As a biological agent, stapled α-helical peptide derived from mastermind-like 1 (SAHM1) targets Notch to effectively reduce the inflammatory symptoms of mice with experimental allergic airway inflammation and accelerate recovery. In addition to being related to T cells, Notch also is critical for the differentiation of lung organs and alveoli. For example, in a mouse asthma model, intranasal administration of γ-secretase inhibitors (GSIs) could block the Notch signaling pathway and reduce allergic pulmonary edema.510 Avasimibe (Ava), as a specifically targets acetyl-CoA acetyltransferase 1 (ACAT1) inhibitor, has been proven to alleviate the disruption of the airway epithelial barrier by inhibiting the Wnt/β-catenin signaling pathway. It has good safety and may be a promising drug for the clinical treatment of AAS.511

Other biologics

Currently, the use of new therapeutic targets is also being explored. For example, Toll-like receptors are involved in the activation of innate immunity in the respiratory mucosa. Some agonists can induce cytokines, including TNF-α, IL-6 and IFN-α; such biologics are well tolerated and may not cause systemic immune activation.512,513 In the study of AAS, due to its complex pathogenesis, certain new biological targets have attracted attention from researchers, e.g., epithelial cell-derived cytokines (IL-1, IL-33, IL-25 and TSLP).496,503,514,515 In addition, IL-9 is also associated with allergic diseases. In the study of asthma, mouse models overexpressing IL-9 show enhanced eosinophilic airway inflammation, IgE production and mast cell proliferation. Therefore, biologics targeting IL-9 have also been designed.516 There are also antibodies that target the costimulatory molecule OX40 (CD134), which is critical for T cell expansion.500

Chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2), also known as prostaglandin D2 receptor 2, is a 7-transmembrane G protein-coupled receptor expressed by Th2 cells, eosinophils and basophils. The CRTH2 receptors are involved in inducing the migration and activation of Th2 lymphocytes, eosinophils and basophils. At the same time, it is also involved in the up regulation of adhesion molecules and the release of proinflammatory Th2 cytokines such as IL-4, IL-5 and IL-13. Therefore, it plays a certain role in the course of allergic diseases. It has been proved that the number of CRTH2-positive cells is related to the severity of asthma. At present, some CRTH2 antagonists, such as AMG853, OC000459 and BI671800, have been developed to treat asthma, AD and AR. These CRTH2 inhibitors reduce the Th2-mediated inflammatory response by blocking the activation of mast cells, basophils and eosinophils.189,517,518

Nitric oxide (NO) is an important signal molecule in many physiological processes, such as maintenance of vascular tone and endothelial barrier function, immune defense and apoptosis. NO can also regulate cell function through post-translational modification of proteins. NO can react with glutathione to form S-nitrosoglutathione (GSNO), which effectively transduces NO signal. GSNO concentration can be regulated by GSNO-reductase (GSNOR), which provides the “brake” for signal transduction. There is evidence that GSNOR polymorphisms increase the expression‎ of GSNOR and are associated with an increased risk of asthma. Inhibition of GSNOR can lead to the preservation of endogenous GSNO and limit eosinophilic inflammation, mucus production and airway hyper reactivity (AHR). N6022 is the first small molecule inhibitor of GSNOR in the treatment of asthma. Some studies have shown that in the mouse asthma model, N6022 significantly reduces airway hyperreactivity and shows a strong anti-inflammatory effect.519,520,521

Biologics-targeted therapies target the endotypes of allergic diseases based on pathogenesis, reducing the occurrence of adverse events and improving the efficiency of treatment, and are considered promising therapeutic approaches. However, many biologics have not been developed far enough and have not been better eval‎uated. The response to treatment varies greatly from individual to individual. Therefore, the dose and duration of treatment need to be better defined and the details need to be further optimized. In addition, the relatively expensive price of biologics also limits their application to some extent.522,523,524

산화질소(NO)는

혈관 긴장도 유지, 내피 장벽 기능, 면역 방어, 세포자멸사 등

많은 생리학적 과정에서 중요한 신호 분자입니다.

NO는 또한 단백질의 번역 후 변형을 통해 세포 기능을 조절할 수 있습니다.

NO는 글루타티온과 반응하여 S-니트로소글루타티온(GSNO)을 형성할 수 있으며,

이는 NO 신호를 효과적으로 전달합니다.

GSNO 농도는 GSNO 환원효소(GSNOR)에 의해 조절될 수 있으며, 이는 신호 전달에 대한 “브레이크” 역할을 합니다. GSNOR 다형성이 GSNOR의 발현을 증가시키고 천식 위험 증가와 관련이 있다는 증거가 있습니다. GSNOR의 억제는 내인성 GSNO의 보존을 유도하고, 호산구성 염증, 점액 생성, 기도 과민성(AHR)을 제한할 수 있습니다. N6022는 천식 치료에 사용되는 최초의 GSNOR 저해제입니다. 일부 연구에 따르면, 마우스 천식 모델에서 N6022는 기도 과민성을 현저하게 감소시키고 강력한 항염증 효과를 나타냅니다.519,520,521

생물학적 표적 치료법은 병인에 근거하여 알레르기 질환의 내인성 유형을 표적으로 삼아 부작용 발생을 줄이고 치료 효율을 향상시키는 것으로, 유망한 치료법으로 간주되고 있습니다. 그러나 많은 생물학적 제제들이 충분히 개발되지 않았고, 더 나은 평가를 받지 못했습니다. 치료에 대한 반응은 개인마다 크게 다릅니다. 따라서 치료의 용량과 기간을 더 잘 정의하고 세부 사항을 더 최적화해야 합니다. 또한, 상대적으로 비싼 생물학적 제제의 가격도 어느 정도 적용을 제한합니다.522,523,524

Other therapies

Different treatment options have varying degrees of side effects; thus, a growing number of alternatives therapies have also been developed. In addition to the aforementioned treatment methods, other therapies also offer different therapeutic effects in the treatment of allergic diseases, including antibacterial and antimycotic therapies, phototherapy, early introduction therapy, circadian regulation therapy and so on.

The microbiota and allergic diseases are closely related. For example, Staphylococcus aureus is the main cause of AD, and Malassezia furfur is also associated with skin immune response and barrier function. Therefore, antibacterial and antimycotic therapies have also become an option for treating allergic diseases.439 Phototherapy has immunosuppressive and immunomodulatory effects, which can inhibit the effects of anaphylaxis and histamine release triggered by mast cell antigens. Therefore, rhinophototherapy is considered a promising non-invasive alternative treatment option for perennial or seasonal AR cases, especially low-level laser therapy (LLLT).525,526 However, it has been demonstrated that photochemotherapy has certain carcinogenicity. In addition, in AD, oral psoralen plus ultraviolet A (PUVA) as a type of phototherapy also has many side effects. Therefore, PUVA for AD treatment has been abandoned to a large extent, and it is recommended to apply combination therapy.439 In patients with FA, early consumption is more beneficial than delayed administration. A trial showed that early introduction of eggs combined with appropriate eczema treatment is practical, and may effectively reduce the odds of egg allergy in high-risk infants.527 One of the important research fields to further examine new methods to prevent or treat modern allergic diseases is to understand the relationship between circadian biology and allergy; correspondingly, it is suggested to develop a lifestyle in which the endogenous biological clock is consistent with the environmental cycle, or undergo appropriate therapeutic interventions to prevent or treat allergic disease in the future.528

References

1.  
2.  
3.  
4.  
5.  
6.  
7.  
8.  
9.  
10.  
11.  
12.  
13.  
14.  
15.  
16.  
17.  
18.  
19.  
20.