Re: mast cell은 자가면역 질환의 주요 세포

[문형철]

https://www.sciencedirect.com/science/article/abs/pii/S0198885925001053

이 논문은

비만세포(mast cells, MCs)가 전통적인 알레르기 역할에서 벗어나

자가면역질환(autoimmune diseases)의 발병과 진행에 어떻게 관여하는지,

그리고 이를 치료 타겟으로 삼을 수 있는지를 중점적으로 다룹니다.

Abstract 및 핵심 메시지

비만세포는

면역 관용(immune tolerance)을 깨뜨리고,

염증을 증폭하며,

다양한 면역세포와 상호작용함으로써

자가면역질환의 발달에 중요한 역할을 합니다.

논문은

다발성 경화증(MS),

류마티스 관절염(RA),

전신성 홍반성 루푸스(SLE),

제1형 당뇨병(T1DM)을 중심으로

MC의 병리적 기전을 검토하고,

이를 표적화한 신흥 치료 전략(단클론항체, 소분자 억제제, 신호전달 경로 억제제)을 논의합니다.

MC는

아직 완전히 밝혀지지 않은 활성화 기전에 의해

자가면역 환경에서 pro-inflammatory effector로 작용하지만,

동시에 치료 타겟으로서의 잠재력이 크다는 점을 강조합니다.

비만세포의 기본 생물학과 자가면역에서의 역할

• 기원 및 분포: 골수 CD34+ 조혈 전구세포에서 유래하며, 조직(신경 말단, 혈관 주변, 점막층)에서 성숙. 조직 미세환경(SCF, substance P, IL-33, TSLP 등)에 따라 기능이 조절됨.
• 매개체 방출:
  • Preformed: histamine, proteases (tryptase, chymase), proteoglycans (heparin), prostaglandin D2 등.
  • De novo synthesized: cytokines (IL-1β, IL-4, IL-5, IL-6, IL-15, TNF-α, TGF-β), chemokines (CCL2, CCL5), eicosanoids (LTB4 등).

• 면역 조절 기능:
  • Antigen presentation (MHC-I/II 발현, OX40L/ICOSL co-stimulation).
  • T 세포 활성화 (Th17 skewing, Treg 억제 via IL-6/histamine).
  • B 세포 상호작용 (IgE/IgA class switching, Breg 조절).
  • NKT 세포, 기타 innate immune cell과의 crosstalk.

조직별 특징:

피부(tryptase 풍부), 폐(chymase), 심장(섬유화·죽상경화), 위장관(IBD 관련) 등에서 다른 표현형을 보임.

질환별 비만세포의 구체적 역할 (Highlights 중심)

1. Multiple Sclerosis (MS)
   • Blood-brain barrier (BBB) 파괴 → 면역세포 침윤 촉진.
   • CNS 내 neuroinflammation 증폭 (cytokines/chemokines 방출).
2. Rheumatoid Arthritis (RA)
   • Synovial inflammation, autoantibody 생산 촉진.
   • Protease-mediated joint degradation (연골·골 파괴).
3. Systemic Lupus Erythematosus (SLE)
   • Immune complex deposition 강화.
   • 혈관 투과성 증가와 조직 손상.
4. Type 1 Diabetes Mellitus (T1DM)
   • 췌장 β-cell 파괴 촉진 (pro-inflammatory cytokines + immune cell recruitment via CCL2 등).

공통 기전:

염증 증폭, 자가항원 제시, 면역 관용 붕괴, 조직 재형성(ECM remodeling).

치료 전략 (Therapeutic Potential)

MC를 표적화한 접근이 자가면역질환의 진행을 수정(disease-modifying)할 수 있는 유망한 전략으로 제시됩니다:

• Monoclonal antibodies: FcεRI, 특정 mediator (e.g., anti-tryptase), 또는 cytokine 차단.
• Small molecules / Kinase inhibitors: c-Kit (KIT) 억제제, BTK/Syk 등 하류 신호전달 억제.
• Receptor targeting: Histamine H4 antagonist (chemotaxis 억제), H2 agonist (anti-inflammatory 효과) 등.
• 기타: MC degranulation 억제, cytokine 생산 조절.

도전 과제:

• MC의 비특이적 매개체/수용체 → off-target 효과.
• 조직 특이적 heterogeneity.
• 비침습적 검출 방법 부족.

미래 방향: 정밀 표적 치료(precision targeting), 비침습 모니터링, 기존 치료와의 병용 요법 최적화.

이전 논문(Baran et al., 2023)과의 비교·연결

• Baran et al. 리뷰는 주로 알레르기·아나필락시스·암 미세환경에서의 MC 타겟 치료(세포막 안정화제, biologics, BTK inhibitor, KIT inhibitor, 천연물 등)를 포괄적으로 다뤘습니다.
• 본 논문(Javan et al., 2025)은 자가면역질환에 특화하여, MC의 면역 조절·항원 제시 기능과 T/B/NKT 세포와의 상호작용을 더 깊이 강조하며, MS/RA/SLE/T1DM 같은 구체적 질환에서의 병리기전을 중점적으로 다룹니다.
• 공통점: MC의 dual role (보호 vs 병리)과 다중 타겟 접근의 필요성.
• 차이점: 본 논문은 자가면역에서의 immune tolerance disruption과 BBB/joint/pancreas 같은 장기 특이적 손상을 더 세밀하게 논의.

이 리뷰는

MC가 단순한 “알레르기 effector”가 아니라,

innate-adaptive immunity bridge로서

자가면역 네트워크의 핵심 노드(node)임을 보여줍니다.

특히

Th17/Treg balance, antigen presentation, protease-mediated tissue remodeling 기전은

향후 연구의 주요 축이 될 것입니다.

전체적으로,

2025년 기준으로 MC-targeted therapy가

알레르기 분야를 넘어 자가면역·신경면역·류마티스 분야로 확대되고 있음을 잘 반영하는 논문입니다

Review

Mast cells in autoimmune disease: Unveiling their multifaceted roles and therapeutic potential

Author links open overlay panelMohammad Reza Javan a, Masoumeh Akhlaghi b d, Ali Hormozi b d, Maryam Hosseini c, Arezou Khosrojerdi d

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https://doi.org/10.1016/j.humimm.2025.111334Get rights and content

Highlights

• •

  In MS, mast cells disrupt the blood–brain barrier, facilitating immune cell infiltration and neuroinflammation.

• •

  In RA, mast cells contribute to synovial inflammation, autoantibody production, and joint degradation.

• •

  In SLE, mast cells enhance immune complex deposition and tissue damage.

• •

  In T1DM, mast cells exacerbate β-cell destruction in the pancreas through pro-inflammatory cytokines and immune cell recruitment.

• •

  Emerging treatments use antibodies, small molecules, and receptor-targeting to modulate mast cells and reduce autoimmune inflammation.

Abstract

Mast cells play a crucial role in developing autoimmune diseases by influencing immune responses, contributing to inflammation, and disrupting immune tolerance. This review examines the involvement of mast cells in various autoimmune disorders, including multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and type 1 diabetes mellitus (T1DM).

The mechanisms through which mast cells mediate immune dysregulation are explored, focusing on their release of cytokines, role in antigen presentation, and interactions with other immune cells. Additionally, we discuss emerging therapeutic strategies aimed at targeting mast cells, such as monoclonal antibodies, small molecules, and inhibitors of signaling pathways, as potential approaches to modifying disease progression.

Although the exact triggers and activation mechanisms of mast cells in autoimmunity are not yet fully understood, there is growing evidence suggesting that they may serve as valuable therapeutic targets. Further research is needed to refine therapies that focus on mast cells, enhance non-invasive detection methods, and optimize treatment strategies. Understanding the complex role of mast cells in autoimmune diseases could lead to innovative interventions aimed at reducing disease severity and improving patient outcomes.

Introduction

Mast cells serve as essential components of the innate immune system, contributing significantly to allergic responses, pathogen defense, and chronic inflammatory conditions through the secretion of various bioactive molecules [1]. These cells originate from CD34 + hematopoietic precursors in the bone marrow and circulate in an immature state before reaching full differentiation within different tissues, including nerve endings, highly vascularized areas, smooth muscle, mucosal layers, and hair follicles [2]. Their strategic location allows them to function as frontline defenders against microbial invaders, particularly within the gastrointestinal tract, skin, and respiratory system [3].

Mast cells release an array of inflammatory mediators, such as histamine, dopamine, serotonin, proteoglycans, vascular endothelial growth factor (VEGF), fibroblast growth factor-b (FGF-b), lysosomal enzymes, biogenic amines, and a range of cytokines, including IL-4, IL-5, IL-6, IL-15, TNF-α, and TGF-β. The early release of pre-stored signaling molecules—such as prostaglandin D2 (PGD2), chemokine ligand 2 (CCL2), VEGF-A, IL-4, IL-5, IL-6, IL-15, TNF-α, and TGF-β–enhances vascular permeability, promotes blood vessel dilation, and attracts immune cells to inflamed sites [4]. Furthermore, mast cells are positioned close to T cells and become activated in various inflammatory conditions regulated by T cell activity [5].

In the intricate network of autoimmune diseases, numerous immune system components contribute to an abnormal and self-destructive immune response. Initially recognized for their role in allergy and anaphylaxis, mast cells have increasingly been implicated in autoimmunity. These versatile cells, widely distributed across different tissues and equipped with a diverse array of bioactive mediators, play a crucial role in modulating immune homeostasis and shaping inflammatory responses. Their involvement in autoimmune diseases highlights their function as key regulators of immune dysregulation. This review examines the multifaceted role of mast cells in autoimmunity, providing insight into their contributions to disease progression and potential therapeutic interventions.

Mast cells play a crucial role as guardians of the immune system, with their location in different tissues connected to their maturation and abilities. Gaining insight into where they are found can enhance our understanding of their involvement in different diseases. Below is a concise summary of their distribution across various tissues and their significance in particular conditions:

Mast cells are found in human lung tissue, within the pulmonary epithelium, and freely located in the bronchial lumen. Mast cells in human lung tissue play a crucial role in host defense due to their location and receptors for IgE and complement fragments. When activated, they release various mediators that cause immediate reactions like edema, bronchoconstriction, mucus secretion, and coughing. This triggers an influx of inflammatory cells, leading to prolonged bronchospastic responses. While these reactions can be protective, excessive or prolonged activation may lead to chronic inflammation, contributing to conditions such as asthma and pulmonary fibrosis[6].

The skin contains a significant number of mast cells, primarily located in the dermis near blood vessels, nerves, and hair follicles. These cells are essential for maintaining the skin barrier and regulating immune responses. In conditions like atopic dermatitis and urticaria, mast cells play a key role. Upon exposure to allergens or stimuli, they degranulate, releasing inflammatory mediators such as histamines and cytokines, which result in redness, swelling, and itchiness. The high density of mast cells in the skin allows for rapid immune responses to injuries or infections, as their proximity to blood vessels facilitates the swift recruitment of additional immune cells. This highlights the crucial role of mast cells in skin health and various dermatological disorders [7,8].

Mast cells are found throughout the GI tract and play a vital role in regulating various physiological functions. They release mediators like histamine, cytokines, and proteases, which influence gut motility, permeability, and secretion. Additionally, mast cells interact with the enteric nervous system, aiding in the gut's response to environmental stimuli and maintaining homeostasis. They are also crucial for the immune defense, responding to pathogens through degranulation and releasing inflammatory mediators to protect the GI lining. However, dysregulation of mast cell activity is associated with chronic gastrointestinal diseases, such as inflammatory bowel disease (IBD), celiac disease, irritable bowel syndrome (IBS), and food allergies. Increased mast cell presence and activity can exacerbate inflammation, highlighting their significant role in both health and disease in the GI tract [9].

Mast cells are immune cells present in heart tissues, including the myocardium and pericardium, and in atherosclerotic plaques. They produce various vasoactive and pro-inflammatory mediators crucial for inflammation, angiogenesis, and tissue remodeling. These cells release preformed mediators like histamine and tryptase, along with synthesized ones such as leukotriene C4 and prostaglandin D2, and secrete cytokines that activate other immune cells [10].

In cardiovascular diseases, mast cell proliferation is significant. During myocardial ischemia, their mediators can lead to coronary vasoconstriction, arrhythmias, and tissue injury. In coronary atherosclerosis, they facilitate cholesterol accumulation and plaque destabilization. In cardiac failure, mast cell chymase induces myocyte apoptosis and fibroblast proliferation, contributing to ventricular dysfunction and fibrosis [11]. Moreover, cardiac mast cells release renin, initiating local angiotensin formation, which exacerbates vasoconstriction, arrhythmias, fibrosis, and apoptosis. The effects of angiotensin are intensified by norepinephrine release from cardiac sympathetic nerves [12].

The microenvironment profoundly influences mast cell function and behavior through interactions with nearby epithelial, stromal, immune, and neural cells, as well as exposure to soluble factors like cytokines and chemokines. For example, fibroblast-derived stem cell factor (SCF) enhances mast cell survival, granule content, and cytokine release [13]. Neuropeptides like substance P stimulate degranulation and mediator release (e.g., histamine, VEGF) [14], while epithelial-derived IL-33 and TSLP trigger cytokine production (e.g., IL-6, TNF-α) without degranulation [15]. In addition, the extracellular matrix [16], oxygen levels [17], local microbiota [18], Pathogens also regulate mast cell activity, metabolism, and immune responses [19].

The tissue location determines the types of serine proteases present; skin mast cells are rich in tryptase, while lung mast cells have higher levels of chymase [20]. The types of receptors, such as the high-affinity IgE receptor (FcεRI) and c-Kit, also vary by tissue, affecting mast cell growth, survival, and response to allergens [21]. Cytokines such as IL-4 and IL-13 increase FcεRI expression‎ and allergen sensitivity [22], while IL-10 suppresses activation in mucosal tissues to promote tolerance [23].

Mast cells play a crucial role in antigen presentation to CD4 + T cells by expressing MHC-I and MHC-II molecules. Research has indicated that the co-expression‎ of OX40L and ICOSL during antigen presentation, along with the secretion of TNF-α, leads to the activation, proliferation, and increased production of IL-22 and IFN-γ by CD4 + T cells [24]. In addition to influencing CD4 + T cells, mast cells also contribute to activating CD8 + T cells via MHC-I-mediated antigen presentation. This process is facilitated by the release of various chemokines and cytokines, including CCL5 and leukotriene B4, along with the expression‎ of stimulatory molecules such as OX40L and 4-1BBL on mast cells. These interactions collectively promote the recruitment, proliferation, and activation of CD8 + T cells [24].

Furthermore, the interaction between OX40L on mast cells and OX40 on regulatory T cells (Tregs), combined with the secretion of histamine and IL-6, reduces Treg suppressive activity while encouraging Th17 cell differentiation. This Th17 differentiation is mediated through the OX40/OX40L signaling axis and IL-6 production [24,25]. However, mast cell-derived TGF-β plays a counterbalancing role by promoting Treg development [26].

Mast cells also engage CD1d-restricted natural killer T (NKT) cells by presenting lipid antigens via the CD1d molecule, which is associated with MHC class I [27]. Additionally, they play a role in B cell proliferation and support the class switching to IgA and IgE through direct interactions involving CD40L/CD40 and OX40L/OX40. This occurs in the presence of IL-4, IL-13, IL-6, and TGF-β [25,28]. The CD40/CD40L signaling pathway is particularly important in expanding regulatory B cells (Bregs), as mast cell-derived exosomes containing CD40L can stimulate Breg proliferation even in the absence of direct cellular contact [29].

Mast cells release a wide array of bioactive mediators, which are broadly categorized into pre-stored and newly synthesized mediators. Upon activation, pre-formed mediators, stored within granules, are rapidly secreted. These include proteoglycans, histamine, specific cytokines such as TNF-α, and neutral proteases. The immediate effects of these mediators include vasodilation and increased vascular permeability. In contrast, newly synthesized mediators, which are produced following mast cell activation, include lipid mediators, cytokines, chemokines, angiogenic factors, and growth factors. These mediators play essential roles in sustaining inflammation and promoting tissue repair.

Histamine, a small-molecule mediator with rapid diffusion capability, acts through four distinct histamine receptors (H1–H4). It contributes to smooth muscle contraction, vascular permeability enhancement, vasodilation, nerve stimulation, and glandular secretion [30]. The H1 receptor is central to allergic responses and is found in bronchi, smooth muscle cells, endothelial cells, chondrocytes, hepatocytes, dendritic cells (DCs), neutrophils, monocytes, and lymphocytes [31]. The H2 receptor, primarily present in the gastrointestinal tract, smooth muscle, cardiomyocytes, DCs, and T and B cells, influences cyclic adenosine monophosphate (cAMP) and intracellular calcium levels [32,33]. H2 receptor activation can downregulate immune responses by reducing the production of pro-inflammatory cytokines such as IL-12, IFN-γ, and TNF-α while simultaneously increasing IL-10 levels [34]. H2 receptor engagement on DCs promotes Th2 polarization while inhibiting Th1 differentiation, ultimately enhancing IgE production and stimulating further histamine release from mast cells [35].

H3 receptors, predominantly found in the brain regions such as the cerebral cortex, amygdala, hippocampus, striatum, thalamus, and hypothalamus, are associated with neurological functions, including cognitive processing, sleep-wake cycles, attention-deficit disorders, epilepsy, and memory [31,36]. Research suggests that H3 receptor activation enhances immune cell antigen presentation and inflammatory activity. Consequently, the use of H3 receptor antagonists may provide a potential strategy for controlling inflammatory conditions, particularly within the respiratory system [37].

The H4 receptor is primarily expressed in immune cells and organs such as the bone marrow, spleen, intestinal epithelium, thymus, and neuroendocrine tissues [38]. It plays a crucial role in regulating immune cell chemotaxis and modulating the production of pro-inflammatory cytokines and chemokines. H4 receptor activation contributes to inflammation and hypersensitivity reactions, potentially triggering conditions such as allergic dermatitis [39].

Mast cells are further classified based on their protease content, specifically into tryptase-positive, chymase-positive, or dual-expressing mast cells. Tryptase-positive mast cells are predominantly linked to allergic responses, whereas chymase-positive mast cells contribute to tissue remodeling and wound healing [40].. Those expressing both proteases exhibit a combination of these functions and are widely distributed across various tissues. Individuals with asthma exhibit an increased presence of both chymase and tryptase-positive mast cells [41].

Chymase facilitates the activation of pro-inflammatory cytokines such as proIL-1β and proIL-18, along with chemokines like CCL6, CCL9, CCL15, and CCL23. These interactions contribute to the pathogenesis of inflammatory diseases, including asthma, atherosclerosis, and cardiovascular disorders [42]. Mast cell proteases play a significant role in regulating inflammatory processes by modifying the extracellular matrix (ECM), directly or through activating other enzymes. This allows immune cells to migrate more efficiently into inflamed tissues and promotes cellular adhesion to the ECM [42].

Proteoglycans such as heparin and chondroitin sulfate, present in mast cells, assist in the transport and release of granule components while also playing additional extracellular roles. During inflammation, these molecules interact with various extracellular factors, influencing functional outcomes [30,43]. Mast cell-derived heparin, for example, regulates eosinophil recruitment by binding to CCL11. Additionally, anionic glycosaminoglycans modulate chemokine diffusion within the ECM. Released proteoglycans also play a role in complement regulation and bradykinin activation [[44], [45], [46], [47]].

Mast cell granules contain high levels of active proteases, which can be harmful if released into the cytoplasm [48]. Mast cells lacking serglycin, a proteoglycan crucial for proper granule function, show decreased sensitivity to apoptosis triggered by lysosomotropic agents [49]. Research indicates that mast cells deficient in serglycin are more likely to undergo necrotic cell death due to improper degradation of poly ADP-ribose polymerase 1 (PARP-1), which is regulated by serglycin under cellular stress conditions. This highlights the significant role serglycin plays in determining whether mast cells undergo necrosis or apoptosis [50].

Mast cells also produce eicosanoids, a group of bioactive lipids derived from 20-carbon polyunsaturated fatty acids such as arachidonic acid (ARA) [51]. These lipids are synthesized through three primary enzymatic pathways: the cyclooxygenase (COX) pathway, which produces thromboxanes (TXs) and prostaglandins (PGs); the lipoxygenase (LOX) pathway, which generates lipoxins (LXs) and leukotrienes (LTs); and the cytochrome P450 (CytP450) pathway, which forms additional derivatives. Eicosanoids produced by mast cells following activation include LTC4, LTB4, PGE2, and PGD2 [52].

PGD2 plays a role in immune modulation by preventing dendritic cell migration to lymph nodes in response to CCL5 and CCL19. When antigen-pulsed DCs are exposed to PGD2, co-cultured naive T cells exhibit increased IL-4 production [53]. PGD2 also inhibits IL-12 release from DCs, promoting Th2-skewed immune responses [54]. Additionally, mast cell-derived PGD2 enhances the production of IL-4, IL-5, and IL-13 by innate lymphoid cells, while also stimulating keratinocytes to release IL-33, IL-25, and thymic stromal lymphopoietin (TSLP) [55].

LTB4, another lipid mediator, serves as a chemoattractant for neutrophils and eosinophils, directing their migration to inflamed tissues. It also facilitates effector T-cell recruitment to the lungs in murine models of allergen-induced pulmonary inflammation [56].

Mast cells synthesize and secrete a diverse range of cytokines, including pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-12), anti-inflammatory cytokines (IL-13, IL-4, IL-5), interferons (IFN-I and IFN-II), and granulocyte–macrophage colony-stimulating factor (GM-CSF). Among these, TNF-α is one of the most abundantly secreted cytokines. It can be stored in mast cell granules for rapid release and facilitates endothelial adhesion molecule expression‎, thereby enhancing leukocyte recruitment and promoting chemokine secretion [[57], [58], [59]]. Additionally, regulatory cytokines such as TGF-β and IL-10 play crucial roles in controlling immune responses and maintaining immune balance [57,58]. Under specific conditions, mast cells can produce transcription factors such as RORγt and FoxP3, along with cytokines like IL-6, IL-21, IL-23, and TGF-β, which contribute to Th17 and Treg cell differentiation and functional plasticity [60].

Chemokines produced by mast cells include CCL2, CCL3, CCL4, CCL5, and CXCL8, all of which contribute to immune cell recruitment. The secretion of these chemokines plays a pivotal role in directing immune cell trafficking, facilitating leukocyte adhesion to endothelial cells, and maintaining inflammatory responses [[61], [62], [63]].

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Section snippetsMultiple sclerosis (MS)

Multiple sclerosis (MS) is a chronic condition that impacts the central nervous system (CNS), where self-reactive immune cells attack the myelin sheath, leading to its deterioration. This progressive disorder contributes to neurological deficits, with brain atrophy and nerve cell degeneration being key characteristics throughout its progression [64,65]. Individuals with MS commonly experience symptoms such as vision impairment, memory issues, muscle weakness, and sensory disturbances due to

Mast cell-based therapy

Mast cells play a crucial role in various inflammatory diseases, but studying them presents challenges due to the invasiveness of some research methods and the risk of severe immune reactions. Additionally, few mediators or receptors are exclusively associated with mast cells, making them difficult to target specifically. However, recent advancements have led to the development of multiple pharmaceuticals aimed at modulating mast cell activity [184]. These include monoclonal antibodies and

Conclusion and future perspective

Mast cells play a crucial role in shaping immune responses within tissues affected by autoimmune diseases. Understanding the specific triggers that activate mast cells in various autoimmune conditions is essential for developing targeted interventions. However, there remain significant gaps in knowledge regarding the precise mechanisms of mast cell activation and their extent of involvement in autoimmunity. Despite these uncertainties, the evidence strongly suggests that mast cells contribute

CRediT authorship contribution statement

Mohammad Reza Javan: Writing – original draft, Visualization. Masoumeh Akhlaghi: Writing – original draft. Ali Hormozi: Writing – original draft. Maryam Hosseini: Writing – review & editing, Supervision. Arezou Khosrojerdi: Writing – review & editing, Conceptualization.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This article is not financially supported by any source.

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