Hich of the Reviewed Autoimmune Blistering Diseases Is Thought to Be Most Prevalent?
Front Immunol. 2018; ix: 407.
The Autoimmune Skin Disease Bullous Pemphigoid: The Role of Mast Cells in Autoantibody-Induced Tissue Injury
Hui Fang
1Department of Dermatology, Xijing Infirmary, Fourth Military Medical University, Xi'an, Red china
Yang Zhang
twoDepartment of Dermatology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, U.s.a.
3Department of Dermatology, The Second Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Mainland china
Ning Li
2Department of Dermatology, School of Medicine, University of N Carolina at Chapel Hill, Chapel Hill, NC, United States
Gang Wang
oneDepartment of Dermatology, Xijing Hospital, Fourth Military Medical Academy, 11'an, China
Zhi Liu
twoDepartment of Dermatology, Schoolhouse of Medicine, University of North Carolina at Chapel Loma, Chapel Loma, NC, U.s.
ivDepartment of Microbiology and Immunology, School of Medicine, University of Due north Carolina at Chapel Hill, Chapel Loma, NC, United States
5Lineberger Comprehensive Cancer Center, University of Northward Carolina at Chapel Hill, Chapel Loma, NC, United States
Received 2017 Nov 29; Accepted 2018 February 14.
Abstract
Bullous pemphigoid (BP) is an autoimmune and inflammatory skin affliction associated with subepidermal blistering and autoantibodies directed against the hemidesmosomal components BP180 and BP230. Animal models of BP were developed by passively transferring anti-BP180 IgG into mice, which recapitulates the key features of human BP. By using these in vivo model systems, key cellular and molecular events leading to the BP disease phenotype are identified, including binding of pathogenic IgG to its target, complement activation of the classical pathway, mast cell degranulation, and infiltration and activation of neutrophils. Proteinases released by infiltrating neutrophils cleave BP180 and other hemidesmosome-associated proteins, causing DEJ separation. Mast cells and mast cell-derived mediators including inflammatory cytokines and proteases are increased in lesional skin and cicatrice fluids of BP. BP beast model testify also implicates mast cells in the pathogenesis of BP. However, recent studies questioned the pathogenic office of mast cells in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and epidermolysis bullosa acquisita. This review highlights the current knowledge on BP pathophysiology with a focus on a potential function for mast cells in BP and mast prison cell-related critical issues needing to exist addressed in the futurity.
Keywords: autoantibodies, bullous pemphigoid, hemidesmosome, mast cells, skin autoimmunity
Mast Cells (MCs) and MC Receptors
Mast cells are derived from hematopoietic progenitor cells and have been considered every bit a central player in functional interaction between innate and adaptive amnesty. MCs are initially located in the claret vessel and the lymphatic organization before homing to tissues, where they acquire their final effector characteristics (ane). At that place are at least ii subpopulations of murine MCs based on the composition of chymases and tryptases inside their granules. While MCT prison celldue south are the prominent MC type inside the mucosa of the respiratory and gastrointestinal tracts, MCTC cells are localized within connective tissues including the dermis, submucosa of the conjunctivae, gastrointestinal tract, heart, and perivascular tissues (ii). The maturation of MCs in the tissue mainly relies on stem cell gene (SCF) expressed on the homing tissue, which is the ligand of KIT (one).
Mast cells limited KIT (CD117) and FcεRI on their surface, which are the receptors of SCF and IgE, respectively. MCs besides express other cell surface receptors, including IgG receptors (FcγRIII, FcγRIIa, and FcγRI), C3a and C5a receptors (C5aRs), Toll-like receptors, and receptors for many cytokines/chemokines (iii). These receptors mediate activation of MCs. Upon activation, MCs release their mediators to the homing sites, which deed in host defense and various pathological weather condition (4). Mediators produced by MCs are divided into two categories: preformed and newly synthesized (5). Many mediators are preformed and stored in granules, such every bit histamine, serine proteases (tryptase and chymase), and TNF-α (6). Upon activation of MCs, these preformed mediators are released into the extracellular surroundings within minutes (7–ix).
After the initial activation, the synthesized bioactive metabolites of arachidonic acid, prostaglandins, leukotrienes (LTs), and cytokines/chemokines will be released into the affected tissue sites rapidly. The 2d release of granules will amplify the firsthand hypersensitivity reaction through the interaction with local cells and infiltrating immune cells (4).
MCs in Non-Skin Autoimmune Diseases Multiple Sclerosis (MS) and Rheumatoid Arthritis
Mast cells have been considered equally key effector cells in many immune activities, especially IgE-associated immune responses, including host defense to parasites, allergic diseases, chronic inflammatory disorders (10, 11), and cancer (12, xiii). MCs have also been implicated in autoimmune diseases (14–19), such equally MS, rheumatoid arthritis (RA), and the autoimmune pare blistering diseases bullous pemphigoid (BP) and epidermolysis bullosa acquisita (EBA).
Multiple sclerosis is an autoimmune illness of the central nervous organization characterized past chronic inflammation and progressive demyelination (20). MCs and activated MCs are present in the target tissues of MS patients and correlated with affliction severity (21–24). The animal model of MS, experimental autoimmune encephalomyelitis (EAE), tin can be induced by active immunization of susceptible mouse strains with myelin components such equally myelin bones protein and myelin oligodendrocyte glycoprotein (MOG) (25). RA is an autoimmune affliction of the joints characterized by chronic inflammation and cartilage destruction (26). Increased MCs and MC-derived inflammatory mediators are found in the inflamed joints of RA patients (27–29). Thousand/BxN mouse serum contains autoantibodies against the glucose-6-phosphate isomerase and, when passively transferred to mice, induces experimental RA (30).
Function of MCs in Experimental MS and Rheumatoid Arthritis
Mast jail cell-deficient mice have been widely used to determine the role of MCs in various physiological and pathological conditions, including autoimmune diseases. Whether MCs actively participate in the pathogenesis of MS and RA has been extensively debated recently due to controversial results obtained from different MC-scarce mouse strains. For a more comprehensive and in-depth review, please refer to the studies by Yu et al. and Rivellese et al. (15, 31). In MOG-induced EAE, MC-deficient Kit W/W-v mice (caused by Kit mutations) developed a significantly reduced disease, and reconstitution of MC-deficient Kit W/Westward-5 mice with wild-type bone marrow-derived MCs restored the disease (32). Similarly, MC-deficient Kit W/W-v mice were protected from K/BxN serum-induced RA (33). K/BxN serum also failed to induce RA in Mgf Sl/Sl-d mice, another MC-deficient strain caused past mutations in the factor encoding the Kit ligand SCF (33). Since MC deficiency past Kit or SCF mutations too acquired a variety of immunological abnormalities, new Kit-independent MC-specific deletion mouse strains were adult recently. Information technology turned out that MCs were not required in the development of EAE and serum-induced RA (34).
BP: Clinical and Immunohistological Features
Bullous pemphigoid is an autoimmune subepidermal blistering disease induced by autoantibodies confronting the two components of the hemidesmosome, BP180 and BP230. BP is the most common autoimmune blistering disease and most prevalent in the elderly. BP typically presents with tense, mostly clear blisters, and erythema, oft in conjunction with urticarial plaques (35). Blisters occur on either a normal or a erythematous base, containing serous or serosanguinous fluid (36). The illness has a symmetric distribution, and the predilection sites include the lower abdomen, flexor surfaces of the limbs, groin, and axillae (37). In about all patients, severe pruritus is present. Virtually x–xx% of patients show mucosal interest, with the oral mucosa being the most common mucosal site (38, 39). Two prospective studies showed that up to 20% of patients with BP take no obvious blistering at the fourth dimension of diagnosis (38–40).
Histopathologically, hematoxylin and eosin staining of early bulla in BP reveals subepidermal blistering with dense inflammatory infiltrate consisting predominantly of eosinophils, just too lymphocytes, neutrophils, and MCs. Eosinophils are seen within the cicatrice and in the edematous papillary dermis (41). In the early non-bullous phase, subepidermal clefts and eosinophilic spongiosis (epidermal spongiosis with eosinophils within the epidermis) can be plant (41). Therefore, BP is an autoimmune and inflammatory disease (Figure 1). Straight immunofluorescence staining exhibits linear deposition of IgG and/or complement components (C3 and/or C5) at the dermal–epidermal junction. IgG deposition sometimes is combined with weaker linear IgA or IgE staining. To identify circulating autoantibodies to the DEJ, indirect immunofluorescence (IIF) with normal human skin as the substrate is usually examined. Artificial blisters tin can be induced by incubating the skin specimen with 1 M NaCl solution. Since BP180 and BP230 are on the epidermal side of the artificial blisters, autoantibodies from BP patients are known to react with the epidermal side of the blisters (42). In contrast, autoantibodies from other autoimmune baking diseases, including EBA and anti-laminin γ1 pemphigoid, react with the dermal side of the artificial blisters (35). Thus, IIF with the salt-split skin every bit a substrate is helpful in distinguishing BP from other autoimmune blistering disorders.
Human bullous pemphigoid (BP). (A) Large, tense bullae, and erythematous patches seen in BP patient. (B) Histology reveals dermal–epidermal junction separation with inflammatory cell infiltration. Immunofluorescence shows linear deposition of IgG (C) and complement C3 (D) at the basement membrane zone (BMZ). d, dermis; due east, epidermis. Pointer, the BMZ. Original magnification, 100× for panels (B–D).
BP Autoantigens
Bullous pemphigoid autoantibodies target two hemidesmosomal components BP180 (BPAG2) and BP230 (BPAG1), which are involved in dermal–epidermal cohesion (43–45). BP180 is a type II transmembrane glycoprotein with a globular cytoplasmic domain and a big extracellular region containing 15 collagenous and xvi non-collagenous (NC1-sixteen) domains. The 16th non-collagenous (NC16A) domain is the immunodominant region in BP (46). Anti-NC16A IgG autoantibodies are detected in more than 90% of BP patients (47) and have been shown to exist pathogenic in peel organ civilisation system and in beast models of BP (48–l) (run into below). BP230 is a 230-kDa intracellular component of the hemidesmosomal plaque and belongs to the plakin family of proteins. Anti-BP230 autoantibodies are detected in nearly 60% of BP patients (51). In improver to IgG reactivity, anti-BP180/BP230 IgE autoantibodies are present in serum samples from most patients (47, 52, 53).
Genetics of BP
Genetic, environmental, and stochastic factors contribute to susceptibility to well-nigh autoimmune diseases. The human MHC encodes many glycoproteins that include the HLA class I and grade 2 molecules, which provide a pivotal role in the recognition of antigenic peptides past T cells. A lot of polymorphisms of HLA-2 grade alleles take been identified in several populations of patients with BP (54–58). These polymorphisms HLA class II alleles occur likely due to changes in the charge of the active binding site on the HLA molecules for binding of autoantigenic peptides. A common HLA class Ii allele, HLA-DQB1*03:01, is positively associated with BP in multiple populations (54, 55, 58) and also appears to be associated with distinct clinical pemphigoid variants (59–61). In addition, the activation of BP180-autoreactive T cells from a accomplice of BP patients with HLA-DQB1*03:01 was establish to be restricted by this BP-associated HLA course II allele (55).
T Cell Response in BP
CD4+ T helper (Thursday) cells are thought to participate in early on disease evolution and perpetuation of autoantibody-mediated autoimmune blistering diseases. Th cells, upon proper costimulation, are activated and produce and secrete distinct cytokines that stimulate B cells. This Thursday–B jail cell interaction thus fosters plasma cell development and autoantibody production (62). In BP, autoreactive CD4+ T lymphocytes recognize unique epitopes within the extracellular region of BP180 (63). The majority of BP patients examined have both Th1 and Th2 responses confronting the BP180 ectodomain (55, 64). BP180-reactive Thursday cells and IgG autoantibodies recognized similar or identical epitopes amassed in singled-out regions of the BP180 ectodomain and BP230 (49, 62, 65). Li et al. found that follicular T helper (Tfh) cells and IL-21 were crucial for the secretion of antibodies confronting BP180NC16A domain in T cell/B cell co-culture system, indicating that these Tfh cells may be involved in the pathogenesis of BP (66).
MCs in Human BP
In 1978, Wintroub et al. plant that increased MCs and increased degranulation of MCs at the BP lesional sites are the primeval events in BP lesion formation (67). The development of clinical BP lesions is associated with a sequence of histopathologic events, starting with MC alternation and proceeding to immune cell infiltration beginning with lymphocytes followed by eosinophils and basophils. Electron and lite microscopy revealed that MCs are mainly nowadays in the papillary dermis adjacent to the dermal–epidermal junction and demonstrate a unique, focal, irregular loss of granule contents (68).
Various inflammatory mediators have been constitute in lesional/perilesional skin, blister fluids, and/or blood of patients with BP, including C5a, histamine, LTs, and many cytokines/chemokines (e.g., IL-1, IL-two, IL-5, IL-6, IL-8, TNF-α, eotaxins, and IFN-γ) (69–75). These mediators can recruit and directly activate MCs and leukocytes. Moreover, MCs tin can influence biological responses through the production of multifunctional cytokines and enzymes (76–78). Evidence suggests that metalloproteinase (MMP9 in particular), leukotrienes (LT), heparin and platelet activating factor (PAF) derived from MCs also play a function in the inflammatory procedure during cicatrice germination (67). Tryptase is a specific proteolytic enzyme synthesized and stored in MCs and released by MCs when activated by various stimulating factors. Tryptase, therefore, is considered a reliable mark for the presence of MCs (79). A previous study showed that tryptase levels in BP blister fluid were increased compared with the respective sera and significantly correlated with several cytokines/chemokines (IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, and RANTES), VEGF, and sICAM-1. Nigh importantly, the blister fluid tryptase levels were also positively correlated with titers of autoantibodies against basement membrane zone antigens (80), which relates to the severity of the disease. Increased levels of cytokines (including IL-1β, IL-5, IL-6, IL-x, IL-15, and TNF-α) and chemokines (such as CCL2, CCL5, CCL11, CCL13, and CCL18, and IL-8) were identified in serum samples and blister fluids of patients with BP, and some of these mediators parallel disease activity (81). Bieber et al. investigated serum parameters related to activation of different inflammatory cells and establish higher serum concentrations of MCs tryptase during ongoing disease. The serum levels of MCs tryptase significantly decreased at the time of clinical remission of the patients. In add-on, serum concentrations of MCs tryptase were significantly associated with levels of circulating anti-BP180 autoantibodies (82). These data suggested that increased concentrations of MCs tryptase in BP blister fluids and/or serum partly correlate with cytokines, autoantibodies, and clinical disease severity in BP patients.
BP180-specific IgG autoantibodies are the nearly abundant immunoglobulin isotype; even so, IgE autoantibodies with the same or similar epitope specificity are as well present in about 70–xc% of BP patients (83, 84). It has been speculated that IgE autoantibody–mediated activation of MCs in the skin may be involved in the development of certain clinical symptoms typical of BP, such as urticarial plaques, dermal edema, and eosinophilic inflammation. Dimson et al. found IgE-coated MCs in the perilesional skin of the BP patients, and BP180 peptides were co-localized on these MCs, suggesting that BP180-specific IgE that bind to the surface of MCs through IgE receptors, when interacting with BP180 peptides, result in MC degranulation. Moreover, basophils obtained from untreated BP patients stimulated with recombinant BP180NC16A released significantly higher histamine compared to NC16-stimulated basophils from normal control or from treated BP patients (83). In addition, Freire et al. reported that IgE co-localized with MCs in the perilesional pare of BP patients, and IgE-BP180 complexes could activate MCs via the high-affinity IgE receptor (FcεRI), conceivably triggering MC degranulation-mediated events resulting in tissue inflammation (85).
Omalizumab is a recombinant humanized monoclonal antibody that inhibits the binding of IgE to FcεRI on the surface of MCs and basophils. Patients with BP treated with omalizumab showed reduced illness severity including decreased itching and blister count, reduced urticarial plaques, and reduced eosinophilic inflammation (86, 87). Together, these clinical inquiry and clinical trial information suggest that IgE autoantibodies in BP patients are involved in BP development likely through FcεRI-induced degranulation of MCs and basophils. However, pathogenic anti-BP180 IgE autoantibodies could also act on eosinophils in BP tissue injury since eosinophils express IgE receptors and are predominant infiltrating immune cells in BP (41).
Animate being Models of BP
Bullous pemphigoid autoantibodies were thought to exist responsible for blister formation in BP; yet, passive transfer of IgG autoantibodies from BP patients could not induce a BP-like disease in animals (88, 89). Information technology turned out that BP autoantibodies reacting with NC16A domain that harbors immunodominant and potentially pathogenic epitopes fail to cantankerous-react with mouse BP180; therefore, BP IgG autoantibodies cannot be tested for pathogenicity in a conventional passive transfer mouse model. In 1993, Liu et al. (ninety) subcloned a segment of the murine BP180 poly peptide homologous with the human BP180 NC16A (mBP180 NC14A), generated rabbit polyclonal antibodies confronting mBP180 NC14A, and administrated the purified rabbit anti-mBP180 IgG intradermally or intraperitoneally into neonatal BALB/c mice. This experimental BP model reproduced all of the primal clinical, histological, and immunopathological features of BP, including degradation of rabbit anti-mBP180 IgG and mouse complement C3 at dermal–epidermal junction, infiltration of inflammatory cells, and subepidermal blistering (90) (Figure 2). Anti-BP180 IgG-induced BP blistering required complement activation and neutrophil recruitment (91, 92). Subsequently, BP serum-purified IgG autoantibodies confronting BP180 or NC16A domain were also demonstrated to be pathogenic in BP180 humanized mouse models (93, 94).
Mouse bullous pemphigoid. The anti-BP180 IgG induce extensive baking disease in neonatal B6 mice clinically (A) and histologically (B). The skin of these animals shows linear degradation of anti-BP180 IgG (C) and murine C3 (D) at the BMZ, as determined by direct IF. Toluidine blue staining shows resting and degranulating mast cells in the dermis (E). d, dermis; east, epidermis; v, vesicle; pointer, the BMZ. Original magnification, 200× for panels (B–D), 400× for panel (E). (E) Arrows for degranulating mast cells, and arrow heads for normal resting mast cells.
BP180-specific IgE autoantibodies purified from serum of BP patients when passively transferred into human peel grafted onto athymic nude mice induced skin lesions that recapitulated the initial phase of disease. The features of the early phase of the disease are characterized by increased plaques and MC degranulation in comparison with injection of normal control human IgE (95). Lesional skin of the anti-BP180 IgE-injected mice besides exhibited infiltration of neutrophils and eosinophils (95). However, information technology remains to be adamant whether the pathogenic activeness of anti-BP180 IgE depends on eosinophils, MCs, or both.
Role of MCs in Experimental BP
To decide whether MCs were involved in experimental BP, Chen et al. (19) demonstrated that wild-type MC-sufficient mice administrated intradermally with pathogenic anti-mBP180 IgG adult BP affliction with extensive MC degranulation in the upper dermis, which preceded infiltration of neutrophils and subsequent dermal–epidermal separation. In contrast, MC-deficient Kit W/W-v and Mgf Sl/Sl-d mice failed to develop BP (19). Moreover, these MC-scarce mice reconstituted with wild-type os marrow-derived MCs, and polymorphonuclear leukocytes from these MC-deficient mice or by intradermal injection of IL-8 (a neutrophil chemoattractant) became susceptible to experimental BP (19). Blocking MC degranulation by treating MC-sufficient mice with an MC degranulation inhibitor also significantly reduced disease phenotype (19).
To determine the functional relationship between MCs and neutrophils, Chen et al. found that anti-BP180 antibody-induced neutrophil infiltration depends mainly on MCs in experimental BP (19). Without MCs, Kit W/W-5 and Mgf Sl/Sl-d mice injected with pathogenic IgG evidence about 70% reduction of infiltrating neutrophils in the peel (96). Further examination of the experimental BP model also implicated macrophages in anti-BP180 IgG-triggered neutrophil infiltration in mice, and that macrophage-mediated neutrophil infiltration depends on MC activation (96). The findings that neutrophil recruitment is not completely impaired in MC-deficient mice in experimental BP suggest that at least two neutrophil recruitment pathways could exist: MC-dependent and MC-independent (96). Nevertheless, these data suggest a major office of MCs in infiltration of neutrophils into the dermis in this animal model setting.
Mast cells express surface receptors that directly demark the cleaved products of the activated complement cascade (97). Peel MCs express the C5aR (98), and upon the molecular interaction of C5a and C5aR, MCs degranulate, releasing several pro-inflammatory cytokines including TNF-α, IL-1, IL-6, and GM-CSF (99). Moreover, human C3a and C5a could degranulate MCs in vitro to release histamine and tryptase. Heimbach et al. (100) demonstrated that interaction of C5a–C5aR on MCs activated the p38 MAPK pathway that trigger MC degranulation and subsequent tissue injury and blister germination.
Mast cells store proteases in large quantities in the secretory granules, and these fully functional enzymes are a major class of inflammatory mediators (101, 102). Human cutaneous MCs incorporate a unmarried chymase, and mouse MC protease-four (mMCP-4) has been generally recognized as the likely homolog of the human chymase (103–105). Chiefly, mMCP-4 can activate MMP-9, a key proteolytic enzyme for tissue injury in experimental BP (106). Interestingly, mMCP-four−/− mice are resistant to anti-BP180 IgG-induced experimental BP (107). In experimental BP, mMCP-4 activates MMP-nine and directly cleaves BP180. mMCP-4, MMP-9, and other proteolytic enzymes work together to degrade BP180 and other hemidesmosomal proteins and proteins in extracellular matrix of the BMZ (107), leading to clinical and histological BP-like blistering.
Taken together, results of these studies using MC-deficient and C5aR and mMCP-4 knockout mice implicate a pathogenic role of MCs in BP (Figure three). However, since the studies on the role of MCs in anti-BP180 IgG-induced experimental BP accept been performed only in MC-scarce Kit Westward/Westward-v and Mgf Sl/Sl-d mice, KIT-contained MC-specific deletion mouse strains demand to be tested to confirm or clarify the interest of MCs in experimental BP.
Proposed function of mast cells (MCs) in bullous pemphigoid (BP). Anti-BP180 IgG binding to BP180 on the surface of basal keratinocytes activates the complement (C), generating C5a. C5a acts on C5a receptor (C5aR) to cause MCs to degranulate and release pro-inflammatory cytokines/chemokines (due east.g., TNFα) and proteolytic enzymes including mouse MC protease-4 (mMCP-4). Anti-BP180 IgE could also actuate MCs. The released pro-inflammatory mediators interact with local cells to recruit neutrophils (PMN) and eosinophils (Eos). Infiltrating PMN and Eos, upon activation through interactions betwixt immobilized anti-BP180 IgG/IgE and FcγR/FcεR, release neutrophil elastase (NE), MMP-9, and other proteolytic enzymes. mMCP-4 activates MMP-9 and also direct cleaves BP180 and other BP180-associated proteins in concert with MMP-9 and NE, resulting in subepidermal blistering.
Role of MCs in Epidermal Bullosa Acquisita (EBA)
Epidermal bullosa acquisita is another autoimmune subepidermal blistering skin disease acquired by autoantibodies confronting collagen 7 (108). Experimental EBA can be induced by passive transfer of anticollagen Seven IgG (109, 110). Immunopathogenically, experimental EBA shares many primal features with experimental BP such as their dependency on complement, C5a-C5aR signaling, and neutrophils (109, 111). However, anticollagen VII IgG causes like illness severity in both wild-type command and MC-scarce Kit W/W-v mice (112). KIT-independent MC-specific deletion mice are besides not protected from experimental EBA (112). These studies demonstrate that MCs practise not contribute to experimental EBA, farther emphasizing a need to revisit the role of MCs in experimental BP using KIT-independent MC-specific deletion strains.
Terminal Remarks
We presented several lines of BP brute model evidence, together with clinical observations, implicating that MCs are likely to be involved in the immunopathogenesis of BP. The office of MCs in experimental BP, even so, was investigated exclusively in KIT-dependent MC-deficient mice. Based on the observed discrepancies in different MC-deficient models of EAE, RA, and EBA, it is necessary to perform anti-BP180 IgG-induced BP studies in KIT-independent MC-specific deletion strains to clarify whether MCs play a part in BP.
Bullous pemphigoid patients also take anti-BP180 IgE autoantibodies, which are involved in tissue injury (95); therefore, a potential part of MCs in anti-BP180 IgE-induced BP should be adamant in both KIT-dependent and KIT-contained MC-scarce strains. Futurity studies could also investigate whether and how MCs collaborate with anti-BP180 IgG, anti-BP180 IgE, and eosinophils during disease development. Giving the fact that MCs accept a variety of immunomodulatory activities (14), MC contribution to BP could be multifaceted. Avant-garde tools need to exist adult to clarify and fully appreciate the contribution of MCs to BP and assist uncover new therapeutic targets for this potentially fatal skin autoimmune disease.
Author Contributions
HF, YZ, NL, GW, and ZL wrote the manuscript; HF, YZ, and NL prepared the figures.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed equally a potential conflict of interest.
Acknowledgments
We give thanks our colleagues and collaborator for their support. We apologize for not mentioning and citing some related studies due to space limitations. This work was supported by the National Institutes of Health (grants R01 AI40768 and R01 AR070276 to ZL) and National Natural Science Foundation of Cathay (no. 81220108016 to GW).
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837973/
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