Re: 알러겐 특이 패턴인지 수용체 탐구!!

[문형철]

Curr Opin Immunol. Author manuscript; available in PMC 2013 Dec 3.

Published in final edited form as:

Curr Opin Immunol. 2010 Dec; 22(6): 10.1016/j.coi.2010.10.011.

Published online 2010 Nov 17. doi: 10.1016/j.coi.2010.10.011

PMCID: PMC3848077

NIHMSID: NIHMS253823

PMID: 21093238

Allergen-Specific Pattern Recognition Receptor Pathways

Marsha Wills-Karp

Allergic diseases continue to plague modernized societies, underscoring the need to identify the molecular basis for the propensity of a small number of environmental proteins to provoke maladaptive, allergic responses. Recent data suggest that the ability of allergenic proteins to drive allergic responses in susceptible hosts is driven by their unique innate immune activating capabilities. Although the identification of allergen-specific pattern recognition receptors is in its infancy, studies to date have shown that allergens drive Th2-biased immune responses via directly engaging C-type lectin receptors (dectin-2, DC-SIGN, mannose receptor) on dendritic cells and/or mimicking toll-like receptor 4 signaling complex molecules expressed on airway structural cells. Elucidation of the specific innate immune pathways activated by allergens holds great promise in defining new therapeutic targets for the treatment of allergic diseases.

알레르기 질환은 

현대화된 사회를 계속 괴롭히고 있으며, 

소수의 환경 단백질이 부적응성 알레르기 반응을 유발하는 성향에 대한 

분자적 근거를 규명할 필요성이 강조되고 있습니다. 

최근 데이터에 따르면 

알레르기 유발 단백질이 민감한 숙주에서 

알레르기 반응을 일으키는 능력은 

고유한 선천적 면역 활성화 능력에 의해 좌우되는 것으로 나타났습니다. 

알레르겐 특이적 패턴 인식 수용체의 규명은 

초기 단계에 있지만, 

지금까지의 연구에 따르면 

알레르겐은 

수지상 세포의 C형 렉틴 수용체(덱틴-2, DC-SIGN, 만노스 수용체)와 직접 결합하거나 

기도 구조 세포에서 발현되는 Toll 유사 수용체 4 신호 복합 분자를 모방하여

Th2 편향 면역 반응을 유도하는 것으로 나타났습니다.

알레르기 항원에 의해 활성화되는

특정 선천 면역 경로를 규명하는 것은

알레르기 질환 치료를 위한 새로운 치료 표적을 정의하는 데 큰 가능성을 제시합니다.

Introduction

The preval‎ence of allergic diseases had been increasing over the last few decades and it is estimated that 20% of the world’s population is currently afflicted with one or more of these diseases [1]. Allergy is thought to result from maladaptive immune responses to ubiquitous, otherwise innocuous environmental proteins, referred to as allergens. Allergens, by definition, are environmental proteins, largely derived from complex living organisms (plants, fungi, insects, other mammals) that have the ability to elicit powerful T helper lymphocyte type 2 (Th2) responses, culminating in immunoglobulin E (IgE) antibody production (atopy) [2]. Although tremendous evidence points to the ability to elicit Th2 immune responses as a unifying feature of allergenic substances, the exact mechanisms by which these proteins drive aberrant Th2-polarized immune responses remains a mystery.

Based on the fact that allergens constitute only a small fraction of the antigens encountered by humans in their daily life and that those afflicted respond to the same allergens in the same manner, it has been proposed that there may be common structural motifs or conformational sequence patterns that underlie their allergenicity. Although our knowledge of the structure of allergens has greatly improved over the last few decades, much of the work in this area has focused on the elucidating the epitopes recognized by T and B cells. However, to date, there is no compelling evidence for common structural characteristics amongst the diverse T and B cell epitopes recognized in allergic responses [3]. Thus it appears doubtful that the presence of such B and T cell epitopes are sufficient to endow a protein with allergenic potential. Other factors such as the size, resistance to proteolysis, and enzymatic activity, have been suggested to play an important role in allergenicity. However, none of these factors have been consistently linked with allergenic potential. The current renaissance in the study of innate immunity has provided important insights into this question. Indeed, it has recently been proposed that allergens are linked by their ability to activate the innate immune system. In this review, we will discuss recent advances in our understanding of the diverse innate immune activating properties of allergens that appear to endow them with a propensity for driving Th2 immune responses-with a particular focus on their ability to activate pattern recognition receptor pathways.

알레르기 질환의 유병률은 

지난 수십 년 동안 증가해 왔으며 

현재 전 세계 인구의 20%가 한 가지 이상의 알레르기 질환을 앓고 있는 것으로 추정됩니다 [1]. 

알레르기는 

알레르겐이라고 하는 어디에나 존재하는 

무해한 환경 단백질에 대한 

부적응성 면역 반응으로 인해 발생하는 것으로 알려져 있습니다. 

정의에 따르면 

알레르겐은 

주로 복잡한 생물체(식물, 곰팡이, 곤충, 기타 포유류)에서 유래한 환경 단백질로, 

강력한 T 헬퍼 림프구 2형(Th2) 반응을 유도하여 

면역글로불린 E(IgE) 항체 생성(아토피)으로 절정에 이르는 능력을 가지고 있습니다[2]. 

알레르기 유발 물질의 공통된 특징으로 

Th2 면역 반응을 유도하는 능력이 있다는 엄청난 증거가 있지만, 

이러한 단백질이 

비정상적인 Th2 편광 면역 반응을 유도하는 

정확한 메커니즘은 여전히 미스터리로 남아 있습니다.

알레르겐은 

인간이 일상 생활에서 접하는 항원 중 극히 일부에 불과하며, 

같은 알레르겐에 동일한 방식으로 반응한다는 사실에 근거하여 

알레르기를 일으키는 공통 구조적 모티브 또는 

순형 서열 패턴이 있을 수 있다고 제안되어 왔습니다. 

지난 수십 년 동안 

알레르겐의 구조에 대한 지식이 크게 향상되었지만, 

이 분야의 많은 연구는 

T세포와 B세포가 인식하는 에피토프를 밝히는 데 중점을 두었습니다. 

그러나 

현재까지 알레르기 반응에서 인식되는 

다양한 T세포와 B세포 에피토프 사이의 

공통된 구조적 특성에 대한 설득력 있는 증거는 없습니다[3]. 

따라서 

이러한 B세포 및 T세포 에피토프의 존재가 

단백질에 알레르기 유발 가능성을 부여하기에 충분한지는 

의심스러운 것으로 보입니다. 

단백질의 크기, 

단백질 분해에 대한 저항성 및 효소 활성과 같은 

다른 요인들도 알레르기 유발성에 중요한 역할을 하는 것으로 제안되었습니다. 

그러나 

이러한 요인 중 어느 것도 알레르기 유발 가능성과 

일관되게 연관된 것은 없습니다. 

최근 선천성 면역 연구의 르네상스는 

이 문제에 대한 중요한 통찰력을 제공했습니다. 

실제로 최근에는 

알레르겐이 선천성 면역 체계를 활성화하는 능력과 관련이 있다는 주장이 제기되었습니다. 

이 리뷰에서는 

특히 패턴 인식 수용체 경로를 활성화하는 능력에 초점을 맞추어 

Th2 면역 반응을 유발하는 것으로 보이는 

알레르겐의 다양한 선천 면역 활성화 특성에 대한 최근 이해의 진전에 대해 논의합니다.

TLR signaling pathways, lipid binding activity and allergic inflammation

In the late 1980’s, Janeway and colleagues [4] put forth the paradigm that the innate immune system had evolved to recognize conserved molecular patterns referred to pathogen associated molecular patterns (PAMPs). This recognition would both initiate an immediate response from innate responding cells and set the stage for the ensuing adaptive responses. These PAMPs are recognized by the mammalian host through specific germ-line encoded pattern recognition receptors (PRRs) such as: Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and C-type lectin receptors (CLRs). PRR activation and instruction of antigen-presenting cells is a prerequisite for the initiation of immune responses, and as such presentation of exogenous antigens by dendritic cells to T cells in the absence of PRR stimulation leads to tolerance [5]. PRRs also play a role in determining the class of the adaptive immune response generated. Although tremendous progress has been made in identifying the spectrum of PRRs driving the activation of Th1 and Th17 immune responses, the identification of the exact receptors and pathways responsible for recognition of allergens and initiation of Th2-skewed immune responses has lagged behind.

1980년대 후반, Janeway와 동료들[4]은 

선천 면역 체계가 병원체 관련 분자 패턴(PAMP)이라고 하는 

보존된 분자 패턴을 인식하도록 진화했다는 패러다임을 제시했습니다. 

이러한 인식은 

선천성 반응 세포의 즉각적인 반응을 시작하고 

후속 적응 반응을 위한 단계를 설정합니다. 

이러한 PAMP는 

포유류 숙주에서 다음과 같은 

특정 생식선 인코딩 패턴 인식 수용체(PRR)를 통해 

인식됩니다:

 톨-유사 수용체(TLR), 

NOD-유사 수용체(NLR), 

RIG-I-유사 수용체(RLR),

C형 렉틴 수용체(CLR)를 통해 인식됩니다.

PRR 활성화와 항원 제시 세포의 지시는

면역 반응의 시작을 위한 전제 조건이며,

PRR 자극이 없는 상태에서

수지상 세포가 외인성 항원을 T 세포에 제시하면

내성이 발생합니다[5].

PRR은

또한 생성되는 적응 면역 반응의 종류를 결정하는 데

중요한 역할을 합니다.

Th1 및 Th17 면역 반응의 활성화를 유도하는

PRR의 스펙트럼을 확인하는 데

엄청난 진전이 있었지만,

알레르겐의 인식과

Th2 왜곡 면역 반응의 시작을 담당하는 정확한 수용체와 경로를 확인하는 것은 뒤쳐져 있습니다.

The most well studied family of PRRs in allergic inflammation is the TLR family. Epidemiological studies have consistently reported an inverse correlation between high levels of bacterial products such as LPS in the ambient environment during very early life and the subsequent development of atopy and allergic disease [6-8]. It has been postulated that such exposures drive counter-regulatory immune responses in the developing immune system [9]. On the other hand, controlled human challenge studies have shown that LPS exposure of sensitized individuals can exacerbate existing disease [10]. Although the mechanisms underlying this apparent paradox are not entirely clear, the complexity of the responses to TLR agonists may be due to several factors including the array of TLR receptors activated by complex allergens (TLR9 vs. TLR4), their relative abundance, and the timing of exposure during the life of the individual. For example, TLR9 stimulation clearly prevents and inhibits the development of experimental allergic inflammation at all doses [11, 12], whereas TLR2 and TLR4 pathway stimulation has been shown to both drive [13, 14, 15] and inhibit [16, 17] the development of Th2-mediated allergic inflammation in experimental mouse models. Bottomly and her colleagues [14] have shed some light on this complexity, demonstrating that the impact of TLR4 stimulation on allergic inflammation is highly dependent upon the dose of TLR4 agonist. Specifically they showed that co-exposure to the normally tolerizing antigen (OVA) and high concentrations of LPS (100ug) induced Th1 immune responses (likely a regulatory response), whereas lower concentrations of LPS (100 ng) drove TLR4-dependent, Th2-polarized inflammatory responses.

알레르기 염증에서 

가장 잘 연구된 PRR 계열은 

TLR 계열입니다. 

역학 연구에 따르면 

아주 어린 시절의 주변 환경에서

 LPS와 같은 높은 수준의 박테리아 생성물과 이후 

아토피 및 알레르기 질환의 발병 사이에 역의 상관관계가 있다고 

일관되게 보고되었습니다 [6-8]. 

이러한 노출은 

발달 중인 면역 체계에서 역조절 면역 반응을 유발한다는 가설이 제기되었습니다 [9]. 

반면에, 

통제된 인간 챌린지 연구에 따르면 

감작된 개인의 LPS 노출은 기존 질환을 악화시킬 수 있는 것으로 나타났습니다 [10]. 

이러한 명백한 역설의 기저에 있는 메커니즘이 완전히 명확하지는 않지만,

 TLR 작용제에 대한 반응의 복잡성은 

복합 알레르겐(TLR9 대 TLR4)에 의해 활성화되는 TLR 수용체의 배열, 

상대적 풍부함, 

개인의 일생 동안 노출되는 시기 등 여러 요인에 기인할 수 있습니다. 

예를 들어, 

TLR9 자극은 모든 용량에서 실험적 알레르기 염증의 발생을 분명히 예방하고 억제하는 반면[11, 12], 

TLR2 및 TLR4 경로 자극은 실험적 마우스 모델에서 

Th2 매개 알레르기 염증을 유발[13, 14, 15]하고 억제[16, 17]하는 것으로 나타났습니다. 

Bottomly와 그녀의 동료들[14]은 

알레르기 염증에 대한 TLR4 자극의 영향이

 TLR4 작용제의 용량에 따라 크게 달라진다는 사실을 입증하면서 

이러한 복잡성을 밝혀냈습니다. 

특히 이들은 

정상적으로 내약성이 있는 항원(OVA)과 

고농도의 LPS(100ug)에 동시 노출하면 

Th1 면역 반응(조절 반응일 가능성이 있음)이 유도되는 반면, 

저농도의 LPS(100ng)는 TLR4에 의존하는 Th2 편광 염증 반응을 유도한다는 것을 보여주었습니다.

Although these studies provided a plausible explanation for the LPS dose effects observed in epidemiological studies, they did not explain how stimulation through the same receptor could result in two distinct biological outcomes. To address this issue, Tan and colleagues [18] examined allergic responses in a series of bone marrow chimeric mice expressing TLR4 in specific compartments. They show that strong (high dose LPS) TLR4 signaling always results in a Th1 response, despite the fact that high LPS stimulation of mice expressing TLR4 only in the stromal compartment drives Th2 responses, as a result of the dominant influence of the hematopoietic cell compartment under these conditions. Surprisingly, they found that at low LPS levels, mice expressing TLR4 only in the stromal compartment did not mount Th2 or Th1 immune responses. However, when mice that had competent TLR4 signaling in both the stromal and hematopoietic compartments were exposed to low levels of LPS +OVA, they mounted Th2 immune responses suggesting that once a threshold level of TLR4 stimulation is reached in the stromal compartment, Th2 responses ensue.

이러한 연구는 

역학 연구에서 관찰된 LPS 용량 효과에 대한 그럴듯한 설명을 제공했지만, 

동일한 수용체를 통한 자극이 어떻게 두 가지 다른 생물학적 결과를 초래할 수 있는지 설명하지는 못했습니다. 

이 문제를 해결하기 위해 Tan과 동료들[18]은 

특정 구획에서 TLR4를 발현하는 일련의 골수 키메라 마우스에서 알레르기 반응을 조사했습니다. 이 연구진은 이러한 조건에서 조혈 세포 구획의 지배적인 영향으로 인해 기질 구획에서만 TLR4를 발현하는 마우스에 고용량의 LPS를 자극하면 Th2 반응이 유발되지만, 강력한(고용량) TLR4 신호가 항상 Th1 반응을 유발한다는 사실을 보여주었습니다. 놀랍게도 연구진은 낮은 LPS 수준에서 간질 구획에만 TLR4를 발현하는 마우스는 Th2 또는 Th1 면역 반응이 나타나지 않는다는 사실을 발견했습니다. 그러나 기질 구획과 조혈 구획 모두에서 유능한 TLR4 신호가 있는 마우스를 낮은 수준의 LPS +OVA에 노출시켰을 때 Th2 면역 반응이 나타나, 기질 구획에서 TLR4 자극의 역치 수준에 도달하면 Th2 반응이 이어진다는 것을 시사합니다.

The authors propose that the ability of stromal cells (presumably epithelial cells) to drive Th2 responses is likely through their ability to secrete TSLP and to promote the maturation of Th2-inducing dendritic cells that express the Notch-ligand Jagged-1, but not the Th1-inducing ligand, Delta-4. As other groups have shown that co-exposure of DCs with LPS and helminth antigens is associated with higher expression‎ of Jagged-1 relative to Delta-4 suggests that this may be an important molecular signature of TLR4-mediated Th2 immune responses [19]. In contrast to Tan’s findings, another group [15] showed that stromal cell TLR4 signaling was sufficient to drive Th2 immune responses when mice were exposed to dust mite extracts containing low levels of LPS, suggesting that the dust mite extracts might contain endogenous TLR4 agonists which shift the dose response of the stromal compartment to TLR4 stimulation into the Th2-inducing range.

저자들은 

간질 세포(상피 세포로 추정)가 Th2 반응을 유도하는 능력은 

TSLP를 분비하는 능력과 Th1 유도 리간드인 델타-4가 아닌 노치 리간드 재기드-1을 발현하는 

Th2 유도 수지상 세포의 성숙을 촉진하는 능력을 통해 가능할 수 있다고 제안합니다. 

다른 그룹에서 DC와 LPS 및 기생충 항원의 동시 노출이 Delta-4에 비해 Jagged-1의 높은 발현과 관련이 있다는 것을 보여 주었기 때문에 이것이 TLR4 매개 Th2 면역 반응의 중요한 분자적 특징일 수 있음을 시사합니다 [19]. Tan의 연구 결과와는 대조적으로, 다른 그룹[15]에서는 쥐가 낮은 수준의 LPS를 함유한 집먼지 진드기 추출물에 노출되었을 때 기질 세포 TLR4 신호가 Th2 면역 반응을 유도하기에 충분하다는 것을 보여주었는데, 이는 집먼지 진드기 추출물에 내인성 TLR4 작용제가 포함되어 있어 TLR4 자극에 대한 기질 구획의 용량 반응을 Th2 유도 범위로 이동시킬 수 있음을 시사합니다.

A recent study has provided a compelling mechanism by which endogenous components of dust mites may drive TLR4 signalling. Based on the recent discovery of a structural homology between Der p 2, one of the major house dust mite allergens, and MD-2, a member of the lipid-recognition (ML) domain family of proteins, which is the LPS-binding member of the TLR4 signaling complex [20, 21], Trompette and colleagues [22] asked the question whether Der p 2 and MD-2 exhibited functional homology as well. Indeed, they reported that Der p 2 facilitates TLR4 signaling through direct interactions with the TLR4 complex, reconstituting LPS-driven TLR4 signaling in the absence of MD-2 and facilitating such signaling in the presence of MD-2. Importantly, they showed that the in vitro functional and biochemical activity of Der p 2 mirrors its in vivo allergenicity—Der p 2 drives experimental allergic asthma in a TLR4-dependent manner, retaining this property in mice with a genetic deletion of MD-2. Although the exact mechanism by which Der p 2 activation leads to Th2 skewing is unknown, it has been shown to induce the production of several mediators important in DC activation in a bronchial epithelial cell line (BEAS2B) including granulocyte-macrophage colony-stimulating factor, IL-6, and IL-8 [23].

최근 연구에 따르면 

집먼지 진드기의 내인성 성분이 

TLR4 신호를 유도할 수 있는 강력한 메커니즘이 밝혀졌습니다. 

최근 주요 집먼지 진드기 알레르겐 중 하나인 

Der p 2와 TLR4 신호 복합체의 LPS 결합 구성원인 

지질 인식(ML) 도메인 단백질 계열의 구성원인 

MD-2 사이의 구조적 상동성이 발견됨에 따라[20, 21], Trompette와 동료들은 [22] 

Der p 2와 MD-2가 기능적으로도 상동성을 보이는지 의문을 제기했습니다. 

실제로 이들은 Der p 2가 TLR4 복합체와의 직접적인 상호작용을 통해 TLR4 신호를 촉진하고, MD-2가 없을 때는 LPS에 의한 TLR4 신호를 재구성하며, MD-2가 있을 때는 이러한 신호를 촉진한다고 보고했습니다. 중요한 것은 Der p 2의 시험관 내 기능적 및 생화학적 활성이 생체 내 알레르기 유발성을 반영한다는 것입니다. 즉, Der p 2는 TLR4 의존적인 방식으로 실험적 알레르기 천식을 유발하며, MD-2의 유전적 결실이 있는 마우스에서도 이러한 특성을 유지한다는 것입니다. Der p 2 활성화가 Th2 왜곡으로 이어지는 정확한 메커니즘은 알려져 있지 않지만, 과립구 대식세포 콜로니 자극 인자, IL-6 및 IL-8을 포함하여 기관지 상피 세포주(BEAS2B)에서 DC 활성화에 중요한 여러 매개체의 생성을 유도하는 것으로 나타났습니다 [23].

Moreover, it can both recruit and activate APCs in the surrounding tissues through its induction of ICAM-1 on airway epithelial cells. Collectively, these studies suggest that exposure to naturally occurring components of complex allergens under low ambient levels of bacterial product exposure such as those associated with increasing rates of aeroallergy in the urban, Westernized world-may shift the TLR4-response curve from the tolerizing into the Th2-inducing range through their ability to directly activate the TLR4 signaling complex on stromal cells in the airways (presumably the airway epithelium). This is of particular interest, as human airway epithelial cells are reported to express TLR4, but little to no MD-2, under homeostatic conditions [24].

또한 기도 상피 세포에서 ICAM-1을 유도하여 주변 조직에서 APC를 모집하고 활성화할 수 있습니다. 이러한 연구를 종합해 보면, 서구화된 도시에서 항공 알레르기 발생률이 증가하는 것과 같이 주변 환경의 세균성 제품 노출 수준이 낮은 상태에서 자연적으로 발생하는 복합 알레르겐 성분에 노출되면 기도 기질 세포(아마도 기도 상피)의 TLR4 신호 복합체를 직접 활성화하는 능력을 통해 TLR4 반응 곡선이 내성 범위에서 Th2 유도 범위로 이동할 수 있음을 시사합니다. 인간 기도 상피 세포는 항상성 조건에서 TLR4를 발현하지만 MD-2는 거의 또는 전혀 발현하지 않는 것으로 보고되었기 때문에 이는 특히 흥미롭습니다 [24].

The fact that the major dust mite allergen, Der p 2 is a molecular mimic of an endogenously-expressed mammalian lipid binding family member has several important implications for our understanding of allergenicity. As numerous other members of the MD-2-like lipid binding family are major allergens [25], the activation of innate immune pathways via lipid binding is likely to be a common feature of allergens. Indeed, the recently solved structures of several allergens including Der p 5 and Der p 7 suggest that they possess the propensity to bind hydrophobic compounds [26, 27]. Of note, Der p 7 has been shown to resemble the LPS binding protein (LBP), and to bind to the lipopeptide polymyxin B from gram-positive bacteria [28]. More broadly, a wide range of allergens are lipid binding proteins—[i.e. lipid transfer proteins (peach allergen Pru p 3), steroid-like molecules (cat allergen Fel d 1), lipocalins (horse allergen Equ c 1, mouse allergen Mus m 1). Further studies are clearly needed to define the lipids naturally bound by these allergens, the receptors activated by such lipids, and the precise pathways of innate and adaptive immune responses driven by such activation.

주요 집먼지 진드기 알레르겐인 Der p 2가 내인성 발현 포유류 지질 결합 계열의 분자 모방체라는 사실은 알레르기 유발성에 대한 이해에 몇 가지 중요한 시사점을 줍니다. MD-2 유사 지질 결합 계열의 다른 수많은 구성원이 주요 알레르겐이므로[25], 지질 결합을 통한 선천 면역 경로의 활성화는 알레르겐의 공통적인 특징일 가능성이 높습니다. 실제로 최근에 밝혀진 Der p 5와 Der p 7을 포함한 몇몇 알레르겐의 구조는 이들이 소수성 화합물과 결합하는 성향을 가지고 있음을 시사합니다 [26, 27]. 특히 Der p 7은 LPS 결합 단백질(LBP)과 유사하며 그람 양성 박테리아의 리포펩티드 폴리믹신 B와 결합하는 것으로 나타났습니다[28]. 보다 광범위하게는 지질 결합 단백질(예: 지질 전달 단백질(복숭아 알레르겐 Pru p 3), 스테로이드 유사 분자(고양이 알레르겐 Fel d 1), 리포칼린(말 알레르겐 Equ c 1, 마우스 알레르겐 Mus m 1) 등)이 광범위한 알레르겐입니다. 이러한 알레르겐에 자연적으로 결합하는 지질, 이러한 지질에 의해 활성화되는 수용체, 이러한 활성화에 의해 유발되는 선천성 및 적응성 면역 반응의 정확한 경로를 정의하기 위해서는 추가 연구가 분명히 필요합니다.

The fact that Der p 2 is a target of the mammalian host immune response, taken together with the fact that high titers of anti-Der p 2 IgE mAbs are strongly associated with asthma risk [29], raises the real possibility that the mammalian homolog, MD-2 may also become a target of the host’s own immune system. This is potentially a very important concept as many allergens are known to serve evolutionarily conserved biological functions (Der p 1, cysteine protease) and as such they are likely to be structural homologs of numerous mammalian proteins. Whether the human homologs are recognized by antibodies directed against their molecular mimics remains to be determined.

Der p 2가 포유류 숙주 면역 반응의 표적이라는 사실과 높은 역가의 항 Der p 2 IgE mAb가 천식 위험과 밀접한 관련이 있다는 사실[29]을 함께 고려하면 포유류 동족체인 MD-2도 숙주 자체 면역 체계의 표적이 될 수 있다는 가능성이 제기됩니다. 많은 알레르겐이 진화적으로 보존된 생물학적 기능을 하는 것으로 알려져 있고(Der p 1, 시스테인 프로테아제), 따라서 수많은 포유류 단백질의 구조적 상동체가 될 가능성이 높으므로 이는 잠재적으로 매우 중요한 개념이 될 수 있습니다. 인간 동종 단백질이 그 분자 모방체에 대한 항체에 의해 인식되는지 여부는 아직 밝혀지지 않았습니다.

Carbohydrate Structures and Allergic Sensitization

Just as the mammalian immune system has evolved mechanisms to recognize bacterial proteins in association with pathogen-associated molecular patterns (PAMPs) that induce appropriate Th1 responses, recent studies suggest an important role for complex carbohydrates in driving Th2 immune responses to both parasites and allergens. In particular, fucosylated glucans are a diverse class of naturally occurring glucose polymers, which are widely expressed in the cell walls of fungi, helminths, pollens, and certain bacteria, but they are not found in mammalian cells. Evidence is emerging that these carbohydrates drive strong Th2-biased immune responses through their interaction(s) with a large array of C-type lectin receptors (CLRs). Most notably, the Schistosoma egg antigen lacto-N-fucopentaose III (LNFPIII) has been shown to promote Th2 responses in vivo in a fucose-dependent manner [30].

포유류 면역계가 

적절한 Th1 반응을 유도하는 병원체 관련 분자 패턴(PAMP)과 관련하여 

박테리아 단백질을 인식하는 메커니즘을 진화시킨 것처럼, 

최근 연구에 따르면 

복합 탄수화물이 

기생충과 알레르겐에 대한 Th2 면역 반응을 유도하는 데 

중요한 역할을 하는 것으로 나타났습니다. 

특히 푸코실화 글루칸 fucosylated glucans 은 

곰팡이, 기생충, 꽃가루 및 

특정 박테리아의 세포벽에서 널리 발현되는 

다양한 종류의 자연 발생 포도당 중합체이지만 

포유류 세포에서는 발견되지 않습니다. 

이러한 탄수화물이 

다양한 C형 렉틴 수용체(CLR)와의 상호작용을 통해 

강력한 Th2 편향 면역 반응을 유도한다는 증거가 속속 등장하고 있습니다. 

특히, 주혈흡충란 항원 락토-N-푸코펜타오스 III(LNFPIII)는 

포도당 의존적인 방식으로 

생체 내에서 Th2 반응을 촉진하는 것으로 나타났습니다[30].

Subsequent studies have shown that LNFPIII conditions iDCs to drive Th2 differentiation via activation of a combination of CLRs, including dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN), macrophage galactose-type C-type lectin receptor (MGL), mannose receptor (MR), which synergize with TLR4 pathways to drive Th2 immune responses [31]. In support of the requirement for stimulation through multiple CLR and TLR pathways, a recent study suggests that despite its ability to drive DC activation and Th2 responses in vitro, the interaction of parasite antigens with SIGN-R alone is not sufficient to drive immune responses to the parasite in vivo [32]. Collectively, these studies suggest that carbohydrate moieties are strong Th2 PAMPs, but that they likely work in tandem with other pattern recognition receptor pathways such as TLR4 to drive Th2 responses to multi-cellular organisms.

후속 연구에 따르면 LNFPIII는 

수지상 세포 특이적 ICAM3-잡는 비인테그린(DC-SIGN), 

대식세포 갈락토스형 C형 렉틴 수용체(MGL), 

만노스 수용체(MR)를 포함한 CLR 조합의 활성화를 통해 iDC가 Th2 분화를 유도하도록 조절하며, 

이는 TLR4 경로와 시너지 효과를 발휘하여 Th2 면역 반응을 유도합니다[31]. 

여러 CLR 및 TLR 경로를 통한 자극의 필요성을 뒷받침하는 최근 연구에 따르면 

시험관 내에서 DC 활성화 및 Th2 반응을 유도하는 능력에도 불구하고 

기생충 항원과 SIGN-R의 상호작용만으로는 

생체 내에서 기생충에 대한 면역 반응을 유도하기에 충분하지 않다고 합니다 [32]. 

이러한 

연구를 종합해 볼 때 

탄수화물 모이티는 강력한 Th2 PAMP이지만 

TLR4와 같은 다른 패턴 인식 수용체 경로와 함께 작용하여 

다세포 유기체에 대한 Th2 반응을 유도할 가능성이 높다는 것을 시사합니다.

Support for a broad role for complex carbohydrates, in particular, β-glucans, in allergen-associated Th2 immune responses is emerging. Most notably, it has been reported that β-glucan structures present in the peanut glycoallergen Ara h 1 have Th2 inducing characteristics [33]. Specifically, native, but not deglycosylated, Ara h 1 was shown to activate human monocyte-derived dendritic cells and induce Th2-cytokine secreting cells. The induction of Th2 cytokines by Ara h 1 was mediated via the C-type lectin receptor, DC-SIGN. Consistent with a role for CLRs in allergen recognition, a variety of allergens including Der p 2, and Bermuda grass pollen (Cyn-dBG-60) are known to bind to and signal through the specific CLRs, DC-SIGN and L-SIGN [34]. Similarly, house dust mite extracts are known to drive epithelial chemokine production [35] and DC leukotriene production [36] through β-glucan and dectin-2 receptor-mediated pathways, respectively. In vivo, exposure to β-glucans drives the recruitment of eosinophils and lymphocytes into the mouse airway [36] and enhances responses to co-delivered antigens (OVA), concomitant with enhanced lung expression‎ of Th2 cytokines [37].

알레르겐 관련 Th2 면역 반응에서 

복합 탄수화물, 

특히 β-글루칸의 광범위한 역할에 대한 지지가 나타나고 있습니다. 

특히 

땅콩 글리코알레르겐 Ara h 1에 존재하는 

β-글루칸 구조가 Th2 유도 특성을 갖는 것으로 보고되었습니다 [33]. 

특히, 

탈글리코실화되지 않은 네이티브 Ara h 1은 

인간 단핵구 유래 수지상 세포를 활성화하고 

Th2 사이토카인 분비 세포를 유도하는 것으로 나타났습니다. 

아라 h 1에 의한 Th2 사이토카인의 유도는 C형 렉틴 수용체인 DC-SIGN을 통해 매개되었습니다. 알레르겐 인식에서 CLR의 역할과 일치하여 Der p 2 및 버뮤다 잔디 꽃가루(Cyn-dBG-60)를 포함한 다양한 알레르겐이 특정 CLR, DC-SIGN 및 L-SIGN에 결합하여 신호를 보내는 것으로 알려져 있습니다 [34]. 마찬가지로 집먼지 진드기 추출물은 각각 β-글루칸과 덱틴-2 수용체 매개 경로를 통해 상피 케모카인 생산[35]과 DC 류코트리엔 생산[36]을 촉진하는 것으로 알려져 있습니다. 생체 내에서 베타글루칸에 노출되면 호산구와 림프구가 마우스 기도로 유입되고[36], 공동 전달 항원(OVA)에 대한 반응이 향상되며, Th2 사이토카인의 폐 발현이 증가합니다[37].

Another CLR, the MR has been shown to mediate the internalization of a diverse range of allergens (Der p 1, Der p 2, dog-Can f 1, cockroach-Bla g 2, peanut-Ara h 1) into monocyte-derived DCs through their carbohydrate moieties [38]. Moreover, silencing of MR expression‎ on monocyte-derived DCs (MO-DC) reversed Der p 1-induced Th2 cell polarization. These findings taken together with previous studies showing that MR expression‎ was higher in MO-DCs from allergic patients and that they took up Der p 1 more efficiently than did MO-DCs from healthy individuals suggests that alterations in glycoallergen recognition and DC activation may contribute to susceptibility to allergic diseases [39]. Along these lines, genetic variants in the mannose receptor gene (MRC1) have been shown to be associated with asthma in two independent and ethnically diverse populations (Japanese, African American) [40]. Although the study of the role of carbohydrates as Th2-inducing PAMPs is only in its infancy, collectively the data suggests that carbohydrate moieties contained in common allergens act as strong Th2 inducers via regulation of DC function through the integration of signals derived from engaging a variety of C-type lectin receptors and other PRRs such as TLR4. Identification of the exact carbohydrate moieties contained in common allergens, the CLR-signaling pathways they activate, and the pathways by which they drive aberrant Th2 immune responses is eagerly awaited.

또 다른 CLR인 MR은 

탄수화물 모티브를 통해 

다양한 알레르겐(Der p 1, Der p 2, 개-Can f 1, 바퀴벌레-Bla g 2, 땅콩-Ara h 1)이 

단핵구 유래 DC로 내재화되는 것을 매개하는 것으로 나타났습니다 [38]. 

또한, 

단핵구 유래 DC(MO-DC)에서

 MR 발현을 침묵시키면 Der p 1에 의해 

유도된 Th2 세포 분극화가 역전되었습니다. 

이러한 결과는 

알레르기 환자의 MO-DC에서 

MR 발현이 더 높고 건강한 사람의 MO-DC보다 Der p 1을 

더 효율적으로 흡수한다는 이전 연구와 함께 

당알레르기 항원 인식 및 DC 활성화의 변화가 알레르기 질환에 대한 감수성에 기여할 수 있음을 시사합니다 [39]. 이러한 맥락에서 만노스 수용체 유전자(MRC1)의 유전적 변이는 독립적이고 인종적으로 다양한 두 집단(일본인, 아프리카계 미국인)에서 천식과 연관성이 있는 것으로 나타났습니다[40]. Th2 유도 PAMP로서 탄수화물의 역할에 대한 연구는 초기 단계에 불과하지만, 종합적으로 볼 때 일반적인 알레르겐에 포함된 탄수화물 모티프는 다양한 C형 렉틴 수용체와 TLR4와 같은 기타 PRR의 결합에서 파생된 신호의 통합을 통해 DC 기능을 조절함으로써 강력한 Th2 유도제로 작용하는 것으로 나타났습니다. 일반적인 알레르겐에 포함된 정확한 탄수화물 모티어, 활성화하는 CLR 신호 경로, 비정상적인 Th2 면역 반응을 유도하는 경로를 규명하는 것이 시급한 과제입니다.

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Conclusions

Although allergens are a diverse group of molecules, it is becoming increasingly clear that their allergenicity likely resides in their ability to activate various innate immune pathways at mucosal surfaces. It is clear that we have only begun to scratch the surface of defining the universe of allergen associated patterns recognized by the mammalian immune system, and further studies are clearly needed to define the specific receptors or combination of receptors involved in their recognition, and the pathways by which they drive Th2-skewed immune responses (See specific issues that need to be addressed, Box 1). Furthermore, as healthy individuals do not mount Th2-immune responses to environmental allergens, despite similar exposures, there are likely functional variants in these receptors and/or their downstream signalling pathways that enhance the risk of developing allergic diseases. A better understanding of the molecular and cellular substrates of allergenicity holds tremendous promise for the development of preventive and therapeutic strategies to effectively block allergen recognition and the ensuing inflammatory cascade.

알레르겐은 

다양한 분자 그룹이지만, 

점막 표면에서 다양한 선천성 면역 경로를 활성화하는 능력에 

알레르기 유발성이 있을 가능성이 점점 더 분명해지고 있습니다. 

포유류 면역계가 인식하는 알레르겐 관련 패턴의 세계를 정의하는 데 있어 

우리는 이제 겨우 표면을 긁기 시작했을 뿐이며, 

인식에 관여하는 특정 수용체 또는 

수용체의 조합과 이들이 Th2 왜곡 면역 반응을 유도하는 경로를 정의하려면 

추가 연구가 분명히 필요합니다(해결해야 할 구체적인 문제, 박스 1 참조). 

또한 건강한 사람은 

환경 알레르겐에 비슷한 노출에도 불구하고 

Th2 면역 반응을 일으키지 않기 때문에 

이러한 수용체 및/또는 그 하류 신호 경로에 알레르기 질환 발병 위험을 높이는 

기능적 변이가 있을 가능성이 있습니다. 

알레르기 유발의 분자 및 세포 기질을 더 잘 이해하면 

알레르기 항원 인식과 그에 따른 염증 계단을 효과적으로 차단하는 예방 및 

치료 전략을 개발할 수 있는 엄청난 잠재력을 갖게 됩니다.

Box 1

Insights into the role of allergen-activated pattern recognition receptor pathways in the pathogenesis of allergic diseases

What we know:

1.  
2.  
3.  
4.  
5.  

What we still need to know:

1.  
2.  
3.  
4.  
5.  
6.  
7.  

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Acknowledgements

The author acknowledges support from NIH grants HL076383, HL67736-09, AI083315, ES015903, and AI070235 to M. Wills-Karp.