Tianmeng Yan1
Zhenying Zhang2*- 1Department of Dermatology, The University of Hong Kong Shenzhen Hospital, Shenzhen, China
- 2Department of Dermatology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
Bullous pemphigoid (BP) is an autoimmune blistering disease that primarily affects elderly individuals. The presentation of BP is heterogeneous, typically manifesting as microscopic subepidermal separation with a mixed inflammatory infiltrate. The mechanism of pemphigoid development is unclear. B cells play a major role in pathogenic autoantibody production, and T cells, type II inflammatory cytokines, eosinophils, mast cells, neutrophils, and keratinocytes are also implicated in the pathogenesis of BP. Here, we review the roles of and crosstalk between innate and adaptive immune cells in BP.
1 Introduction
Bullous pemphigoid (BP) is an autoimmune blistering disease that primarily affects the elderly. As a result of aging of the population, the incidence of BP has increased (1, 2) to 2.5–42.8 cases/million/year (3). The presentation of BP is heterogeneous, typically manifesting as lesions such as tense blisters and erythematous and urticarial plaques. Subepidermal separation with inflammatory infiltrates comprising eosinophils, neutrophils, and lymphocytes has been observed (4). Linear deposition of autoantibodies and/or complement 3 (C3) along the dermo-epidermal junction has been detected by immunofluorescence analysis (4).
The pathogenesis of pemphigoid is unclear, but autoantibodies to the hemidesmosome are implicated. Subepidermal blister formation with obvious inflammatory-cell infiltration is a hallmark of BP but not pemphigus disease (5). The pathogenesis of BP involves various immune cells and factors, including B cells (6), T cells (7), complement cells (5), mast cells (8), neutrophils (9), and eosinophils (10). The pathogenetic role of interactions among the aforementioned types of inflammatory cells is unclear. Here, we review the immune cells and cytokines implicated in the pathogenesis of BP.
2 Immune cells
2.1 Adaptive immunity
2.1.1 B cells and autoantibodies
B cells are thought to play a critical role in the pathogenesis of BP, which is confirmed by the efficiency of B-cell depletion therapy for refractory pemphigoid (11). It can also be supported by the increased expression of BAFF (B-cell activating factor) in BP (12, 13) and that lower peak serum BAFF levels after rituximab treatment in BP patients predict relapse and a need for earlier intervention (12, 13). Most BP patients have serum autoantibodies to the BMZ, which are termed BP180/type XVII collagen/BPAG2 and BP230/BPAG1; these are key components of hemidesmosomes, which mediate adhesion of the epidermis to the dermis. The pathogenic autoantibodies implicated in BP are produced by B cells. The mechanism by which autoreactive B cells are activated to produce autoantibodies has been extensively investigated.
BP180 is a transmembrane protein of the hemidesmosomes in basal keratinocytes. The extracellular domain of BP180 contains 15 interrupted repeated collagenous domains, and its structure consists of a globular head, central rod, and flexible tail. BP180 is inserted into the lamina densa via the rod domain and loops back through the lamina densa via its N-terminal tail (14). Several epitopes of BP180 have been identified, and differential epitope recognition is associated with clinical severity (15). The extracellular portion of the 16th non-collagenous domain (NC16A) of BP180 is the main epitope targeted by autoantibodies. IgG autoantibodies deplete BP180 in cultured normal human keratinocytes, thereby reducing their adhesion (16). The injection of mice with rabbit anti-mouse BP180 antibody induces blisters (17). Anti-human BP180 IgG produced by immunized mCol17+/- mother mice can induce BP lesions in their neonates whose skin expressed human but not mouse COL17 (18, 19). BP180 NC-16A-specific IgG autoantibodies are of the IgG1 and IgG4 subclasses (20). After binding to BP180-NC16A antigen, IgG1 recruits C3 to activate the complement cascade (21). In contrast, anti-NC16A IgG4 autoantibodies are complement-independent (22). IgG4-antigen complexes recruit various inflammatory cells, which release cytokines that induce the separation of the BMZ and local inflammation. IgG4 autoantibodies may block IgG1 and IgG3 by binding to NC16A, thereby inhibiting inflammation (23). IgG1 and IgG4 autoantibody titers are implicated in disease activity in BP (20). BP230, a cytoplasmic protein of the hemidesmosomes, is a plakin-family protein consisting of N-terminal, C-tail, globular, and central rod domains. BP230 serves as a bridge by binding to BP180 via its N-terminal domain and to the intermediate filament-binding domain via its C-tail domain. Anti-BP230 IgG autoantibodies, which are of the IgG1 and IgG4 subclasses, are present in most BP patients and typically target the C-tail and intermediate filament domains (24). The pathogenic role of anti-BP230 autoantibodies is unclear. The anti-BP230 IgG titer is not associated with disease severity but is implicated in atypical BP phenotypes (25, 26). In an anti-BP230 mouse model, anti-BP230 autoantibodies induced blister formation in the absence of BP180 (27).
IgE-mediated autoimmunity may be involved in BP blister development (28, 29). IgE autoantibodies target the intracellular domain of BP180. IgE autoantibodies induce BP180 internalization from the surface of basal keratinocytes, thereby suppressing their adhesion (30). IgE deposition along the dermo-epidermal junction was detected in perilesional skin (31–33). Circulating total IgE is elevated in 60%–85% of BP patients. BP180 IgE was detected in 22%–100% of BP patients (34, 35). BP230-specific IgE is prevalent in BP (35, 36). The high IgE autoantibody level in BP patients may necessitate aggressive treatment (37). However, the relationship between BP180NC16 IgE and disease severity is unclear (32, 38).
IgE production and its downstream effects are regulated by a complex network of cell-bound and soluble receptors, such as FcϵRI and CD23/FcϵRII. The expression of CD23 and FcϵRI on circulating eosinophils, mast cells, basophils, and B cells is increased in BP patients (39–42). Similarly, soluble CD23 expression is elevated in serum and blister fluid from BP patients (43, 44).
2.1.2 T cells
Autoreactive T cells have been detected in the peripheral blood of BP patients with active disease but not in the blood of those in remission (45, 46). T-cell activation by an autoantibody molecule can induce a variety of responses of B cells to a cross-reactive version of the original epitope (47). In BP, CXCL12, which is derived from infiltrated CD3+ T cells in lesions, induced the chemotaxis and accumulation of CXCR4+ B cells by activating the transcription factor c-Myc, thus promoting B-cell differentiation into autoantibody-secreting cells and facilitating autoantibody production (48). CD3+ T cells are categorized as cytotoxic (CD8+) or helper (CD4+) T cells (Th cells). CD4+ Th cells play a central role in activating immune cells in BP. CD4+ T cells are classified as Th1, Th2, Th17, T follicular helper (Tfh) cells, or regulatory T (Treg) cells depending on the inflammatory reaction (49). The Th1/Th2, Th17/Treg, and Tfh/Treg ratios are important for immune tolerance (50–53).
Th2 cells and IL-4 play a role in the pathogenesis of BP by promoting autoantibody production by B cells (54). B-cell activation by Th2 cells or surface-clustered immunoglobulins bound to the epitope of the antigen initiates this process (55). P2 (492–506 aa, VRKLKARVDELERIR) and P5 (501–515 aa, ELERIRRSILPYGDS), which are both peptides of BP180 NC16A (the main antigen in BP), are important for IL-4 production by Th2 cells and autoantibody production by B cells (54). The activation of Th2 cells in BP is consistent with predominant IgG4 autoantibody production: IL-4 regulates IgG isotype switching, thereby amplifying IgG4 production (56). IL-4 also promotes IgE isotype switching to stimulate IgE production (57, 58). IL-4 and IL-13 are mainly secreted by Th2 cells. The efficacy of dupilumab (autoantibody against IL-4 and IL-13R) in BP implicates type II inflammation in its pathogenesis (59). Moreover, autoreactive Th2 and Th1 cells regulate the autoantibody response to the immunodominant sequences of BP230 (46). In experimental BP models, CD4+ T cells were crucial to promoting the production of pathogenic anti-hCOL17NC16A IgG, leading to active disease (60).
Treg cells maintain peripheral immune tolerance by suppressing autoreactive T cells (61). The contribution of Treg cells to BP is controversial. In a mouse model, Tregs alleviate pemphigoid lesions by altering the migratory capabilities of myeloid cells (62), and an absence of Treg cells leads to pemphigoid lesions (63). In another mouse model, Treg cells suppressed steady-state autoimmune reactions to BP230 and COL17 (64). CD4+ CD25brightFOXP3+ Treg-cell expression is increased in peripheral blood and skin lesions from BP patients (65, 66). In conventional BP patients, the expression levels of total Tregs and Treg subsets were increased before, and decreased after, systemic corticosteroid treatment. The expression of CD45RA−Foxp3hi effector Treg cells is positively correlated with disease severity in conventional BP, and CD45RA+Foxp3lo-naive Treg cell expression is positively correlated with disease severity in DPP-4i related BP (67). Differences in results among studies may be explained by the use of different markers of Tregs.
Tfh cells promote the production of high-affinity autoantibodies by B cells in germinal centers. CXCR5, ICOS, Bcl-6, CD40 ligand (CD40L), and PD-1 are membrane-bound markers of Tfh cells (68). IL-21 is preferentially expressed by Tfh cells and regulates humoral responses by modulating B-cell proliferation and class switching (69). BP patients have high plasma levels of Tfh cells and IL-21 and increased CXCR5 expression in lesions (70). In addition, CXCL13, which recruits CXCR5+ Tfh cells, is increased in BP lesions and peripheral blood and is positively correlated with the serum anti-BP180-NC161 titer (71). The inhibition of Tfh-cell factors (e.g., CD40L, PD-1, ICOS, and IL-21) suppresses autoantibody production (72–75).
The role of Th17 cells in the pathogenesis of BP is controversial. Th17 cells promote autoimmune pathology by secreting IL-17, IL-21, IL-22, IFN-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF) (76). Two single-nucleotide polymorphisms, rs2201841 and rs7530511, of IL‐23R encoding the receptor for IL-23, which is an upstream cytokine of IL-17, are associated with BP (77). IL-17A+CD4+ lymphocytes were elevated in BP peripheral blood and skin lesions (53, 78). The absence of the NC14A domain of BP180 in mice induced an IL-17-associated autoimmune response against the cutaneous basement membrane, which was ameliorated after anti-17A treatment (79). IL-17A-deficient mice were protected against autoantibody-induced BP (78). IL-17 upregulates CXCL10, which increases matrix metalloproteinase-9 (MMP-9) secretion in monocytes and neutrophils, and promotes blister formation (80, 81). Clinical trials with biologics targeting the IL-17/IL-23 axis (NCT04117932 and NCT04465292) were conducted in BP patients.
2.2 Innate immunity
2.2.1 Eosinophils
Eosinophilic infiltrates and peripheral eosinophilia are features of BP and are associated with disease severity and outcome (82, 83). Eosinophil degranulation is prominent in early BP lesions and is essential for blister formation (84). The localization of eosinophils to the BMZ is dependent on IgG and complement fixation (85). However, the interaction of eosinophils with IgE may induce their degranulation (86). Eosinophils highly express FcϵRI, which promotes their interaction with BP IgE autoantibodies (which results in eosinophil degranulation and blister formation) (28, 40). Eosinophils also promote initiation of the coagulation cascade (87). In BP patients treated with omalizumab, an autoantibody targeting IgE, disease severity was closely related to peripheral eosinophils, but not IgG (29).
Eosinophils exposed to eotaxin, GM-CSF, IL-5, IFN-γ, and thymic stromal lymphopoietin cytokine (TSLP) promote the release of toxic granule proteins, including major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and MMP-9; in turn, these induce a local inflammatory response (84, 88–91). Eosinophil extracellular traps (EETs), which have a web-like structure containing nuclear DNA and proteins, were also discovered in BP lesions (92). IL-5, which is elevated in blister fluid, is essential for toxic protein release by eosinophils and the separation of keratinocytes (93). ECP, MBP, and EPO are increased in BP lesions and plasma and directly promote the separation of keratinocytes (94). In addition, ECP and eosinophil-derived neurotoxin (EDN) are decreased in plasma after immunosuppressive treatment, suggesting that these markers are associated with disease activity (95). An initially low level of ECP may promote remission within the first year (95). Benralizumab, a humanized IgG1κ monoclonal autoantibody against the IL-5R α subunit, and bertilimumab, a humanized monoclonal autoantibody targeting eotaxin-1 (CCL-11), are currently being evaluated in clinical trials as treatments for BP (NCT02226146 and 04612790).
2.2.2 Neutrophils
Neutrophils infiltrate BP skin lesions and release proteolytic enzymes and reactive intermediates to promote inflammation. A BP model suggests that neutrophils are a determinant of disease phenotype (96, 97). The cytokines and proteases secreted by neutrophils include myeloperoxidase (MPO), neutrophil elastase (NE), MMP-9, and neutrophil-derived nicotinamide adenine dinucleotide phosphate (NADPH). These cytokines degrade the extracellular matrix and split dermal–epidermal junctions, thus exerting an immunomodulatory effect in autoimmune diseases (81, 98, 99). The formation of neutrophil extracellular traps (NETs), like EETs, is increased in BP peripheral blood and lesions and correlates with disease activity (100, 101). In vitro, BP180-NC16A antigen-antibody complexes can induce NETosis, releasing NETs through a cell death process (9). Elevated NETs in BP patients boost autoantibody production by inducing B-cell differentiation into plasma cells, an effect mediated by MAPK P38 cascade activation (9).
2.2.3 Mast cells
Mast cells accumulate and degranulate in early BP lesions (8). The role of mast cells in pemphigoid is debated (102, 103). FcϵRI, an IgE receptor expressed on mast cells, may induce IgE-mediated inflammation, urticarial plaques, skin edema, and eosinophil accumulation and activation (8). Mast cells with IgE and BP180 peptides are present in BP lesions and induce mast cell degranulation (104). Multiple inflammatory cytokines and proteases are released from mast cell granules following their activation. Tryptase, a marker of mast cells, is increased in blisters of BP and related to the BP autoantibody titer to the BMZ. Moreover, the plasma level of tryptase is related to BP autoantibodies (105). IL-5, released by mast cells, promotes eosinophil accumulation and activation in BP. In BP models, activated mast cells release mouse mast cell protease-4 (MCP-4), a homolog of human chymase, which activates MMP-9 and cleaves BP180 (106). MCP-4 also activates NET release by neutrophils, thereby stimulating autoantibody production by B cells (9, 107).
Mast cells express IgG receptors (FcγRIII, FcγRIIa, and FcγRI) and C3a and C5a receptors (C3aRs and C5aRs, respectively), which are important for complement activation and IgG-induced inflammation (108, 109).
2.2.4 Keratinocytes
Keratinocytes are implicated in the pathogenesis of BP. The separation of keratinocytes, induced by BP autoantibodies via Rac1/proteasome activation, is critical for blister formation (110). Keratinocytes secrete thymus and activation-regulated chemokine (TARC/CCL17), a ligand for CCR4 and CCR8 important for the migration of these receptor-expressing cells (111). TARC is increased in BP plasma and lesions (112, 113). Keratinocytes express tissue plasminogen activator (tPA) after BP180 autoantibody activation (114). tPA, a component of the plasminogen/plasmin system, may interact with MMP-9 or NE to promote inflammation (115, 116).
2.2.5 Complement
Linear complement deposition along the dermal–epidermal junction occurs in >80% of BP patients (117). A role for the classical and, to a lesser degree, alternative complement pathways in BP blister formation has been reported (118).
The anti-BP180 NC16A IgG serum level is significantly higher in patients with C3 deposition, and patients without blisters have significantly fewer C3 deposits (117). Antigen-IgG1 autoantibodies binding to the BMZ trigger complement activation (21). C3 activation at the dermal–epidermal junction leads to the formation of chemotactic peptides (activated third component of complement [C3a] and activated fifth component of complement [C5a]) and the recruitment of neutrophils, eosinophils, and macrophages to this site (85, 108, 118, 119). The activated fifth component of complement (C5a), along with C5a receptor 1 (C5aR1), but not C5aR2, plays a role in the early phase of BP by promoting neutrophil standstill and leukotriene release in the endothelium; in turn, this induces neutrophil migration to the interstitial space via an autocrine/paracrine circuit (120, 121). C5- and C4-deficient mice showed no blisters after mCol17 IgG injection (118). Also, no BP lesions appeared in non-C1q-binding anti-hCol17 IgG1 mutation COL17 humanized mice (21). A targeted C1s inhibitor is under evaluation as a BP treatment in a clinical trial (122).
3 Interactions among immune cells
3.1 Clinical heterogeneity may be associated with different types of pathogenesis
The mechanism of blister formation in BP is unclear. Some BP patients primarily show eczema lesions for several years (123), and others have BP autoantibodies but not lesions (124, 125). Some BP patients present with blisters and bullous without obvious erythema, whereas others show patchy erythema with few or no blisters (126). In most BP patients, autoantibodies can be detected using commercial products, although in a small proportion of patients, the tests are negative (125). Most infiltrating immune cells in BP are eosinophils, along with some neutrophils (127, 128) and other cell types. Some BP patients respond well to topical steroids, whereas others need systemic steroids and immunosuppressants. Also, refractory BP patients respond differently to rituximab, dupilumab, and omalizumab (11, 129). Different immune cells induce inflammation in various BP models (89, 96, 130). Whether autoantibodies or inflammatory cells are more important in the pathogenesis of BP is unclear. The pathogenesis of BP may involve several immune pathways and infiltrating cell types; clinical presentations and the response to different treatment regimens vary (131–133).
3.2 Crosstalk among immune cells
Autoantibody binding to pathogenic antigen cause the separation of the BMZ in a complement-dependent or -independent manner (5, 21, 85, 118) (Figure 1). Antigen–IgG1 binding to the BMZ triggers complement activation. C3a and C5a induce neutrophil and eosinophil chemotaxis, as well as mast cell degranulation, which in turn induce inflammation and blister formation (21, 109, 118, 121).
Figure 1 Innate and adaptive immunity in bullous pemphigoid: B cells produce IgE, IgG1, and IgG4 autoantibodies to bind antigens to the BMZ. Antigen–IgG1 binding to the BMZ triggers complement activation. C3 activation at the dermal-epidermal junction leads to the formation of chemotactic peptides (C3a and C5a), which recruit neutrophils and eosinophils and induce mast cell degranulation, thereby contributing to blister formation. Antigen–IgG4 binding leads to the recruitment of neutrophils and eosinophils and, consequently, to the release of proteolytic enzymes. BP180-specific IgG autoantibodies modulate IL-6, IL-8, and tPA expression in human keratinocytes. TARC/CCL17 secreted by keratinocytes can recruit and activate Th2 cells. IgE autoantibodies amplify the inflammation in BP by interacting with eosinophils, mast cells, and B cells. IgE autoantibodies could also induce BP180 internalization in basal keratinocytes, thereby suppressing their adhesion. Tfh cells promote the production of high-affinity autoantibodies from B cells via regulation by IL-21 and ICOS-ICOSL. Activated Th2 cells secrete IL-4, which regulates IgG isotype and IgE switching. Mast cells activated by IgE degranulate and release IL-5 to promote eosinophil accumulation and activation. Eosinophils are attracted to the BMZ by IgG autoantibodies and complement fixation, and degranulate after interacting with IgE. Eosinophils secrete EETs and toxic granule proteins, including ECP, MBP, EPO, and MMP-9, which are involved in the local inflammatory cascade. In addition, activated mast cells release MCP-4, which activates neutrophils. Activated neutrophils release cytokines and proteases, including NE and MMP-9, which degrade the extracellular matrix and split dermal-epidermal junctions. Neutrophils also release NETs and stimulate autoantibody production by B cells. Neutrophils and mast cells release IL-17 and IL-23, thereby significantly enhancing MMP-9 and NE production by neutrophils. tPA, a component of the plasminogen/plasmin system secreted by keratinocytes, may interact with MMP-9 or NE to promote inflammation. What’s more, tPA, MMP-9, NE and eosinophils all could lead to the activation of coagulation system, inducing thrombotic and bleeding risk of skin. BMZ, basement membrane zone; C3, complement 3; EETs, eosinophil extracellular traps; MMP-9, matrix metalloproteinase-9; NE, neutrophil elastase; NETs, neutrophil extracellular traps; MCP-4, mast cell protease-4; C3a, activated third component of complement; C5a, activated fifth component of complement; C3aRs and C5aRs, C3a and C5a receptors, respectively; RBC, red blood cell; EOS, eosinophil; Th, helper T cell; Tfh, T follicular helper cell; Neu, neutrophil; B, B cell; Mast, mast cell; MBP, major basic protein; ECP, eosinophil cationic protein; EPO, eosinophil peroxidase; TARC, thymus and activation-regulated chemokine; tPA, tissue plasminogen activator.
Antigen–IgG4 induced the separation of the BMZ through a complement-independent pathway (5, 22, 134). The antigen–antibody combination leads to the recruitment of neutrophils and eosinophils in BP, and, consequently, to the release of proteolytic enzymes (5). Eosinophils trigger the separation of the BMZ in the presence of IgE or IgG (84, 86, 89). The activation of intracellular pathways leads to pyrolytic hemidesmosomes and attracts immune cells, inducing the inflammatory cascade.
BP180 IgG autoantibodies modulate IL-6, IL-8, and tPA expression in human keratinocytes (114). tPA activates plasmin and MMP-9. Activated MMP-9 hydrolyzes the α1 protease inhibitor, which is an NE inhibitor, thus enhancing NE activity (115, 116). Keratinocytes secrete TARC/CCL17, thereby activating Th2 cells (111).
Tfh cells promote the production of high-affinity autoantibodies by B cells in germinal centers. Activated Th2 cells in BP secrete IL-4, which regulates IgG isotype and IgE switching, thereby amplifying the production of IgG4 and IgE (56, 135, 136). IgE autoantibodies induce BP180 internalization in basal keratinocytes, which reduces their adhesion (30). IgE autoantibodies interact with eosinophils, mast cells, basophils, and B cells via CD23 and FcϵRI (39–42). Mast cells, activated by IgE, degranulate and release IL-5 to promote eosinophil accumulation and activation (8, 104). Eosinophils are attracted to the BMZ by IgG autoantibodies and complement fixation (85) and degranulate after interacting with IgE (86).
Eosinophils secrete EETs and toxic granule proteins, such as ECP, MBP, EPO, and MMP-9, after exposure to GM-CSF, IL-5, IFN-γ, eotaxin, and TSLP, which are involved in the local inflammatory cascade (84, 88–91). In addition, activated mast cells release MCP-4, which activates neutrophils. Activated neutrophils release cytokines and proteases, including NE and MMP9, which degrade the extracellular matrix and split dermal–epidermal junctions (81, 98, 99, 106). tPA, MMP-9, NE, and eosinophils can all lead to the activation of the coagulation system, inducing possible thrombotic and bleeding risks of skin and internal organs (137). Neutrophils also release NETs and stimulate autoantibody production by B cells (9, 107). Neutrophils, lymphocytes, monocytes, and mast cells release IL-17 and IL-23, thereby significantly enhancing MMP-9 and NE production by neutrophils (81, 138, 139). Mast cells express IgG receptors (FcγRIII, FcγRIIa, and FcγRI), C3a, and C5aRs, which interact with complement and IgG (108, 109).
In conclusion, a variety of immune cells and cytokines are implicated in the pathogenesis of BP, including T cells, B cells, eosinophils, mast cells, neutrophils, complement, and plasminogen/plasmin. However, the underlying pathways require further investigation.
Author contributions
TY wrote the manuscript, and ZZ revised the article for important intellectual content. All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
BP, bullous pemphigoid; NC16A, 16th non-collagenous domain; Th cells, helper T cells; Tfh, T follicular helper cells; Treg, regulatory T cells; CD40L, CD40 ligand; BMZ, basement membrane zone; C3, complement 3; EETs, eosinophil extracellular traps; MMP-9, matrix metalloproteinase-9; NE, neutrophil elastase; NETs, neutrophil extracellular traps; MCP-4, mast cell protease-4; C3a, activated third component of complement; C5a, activated fifth component of complement; C3aRs and C5aRs, C3a and C5a receptors, respectively; MPO, myeloperoxidase; NADPH, neutrophil-derived nicotinamide adenine dinucleotide phosphate; CCL, CC chemokine ligand; CCR, CC chemokine receptor; IL, interleukin; IFN, interferon; GM-CSF, granulocyte-macrophage colony-stimulating factor; TSLP, thymic stromal lymphopoietin cytokine; BAFF, B-cell activating factor; MBP, major basic protein; ECP, eosinophil cationic protein; EPO, eosinophil peroxidase; EDN, eosinophil-derived neurotoxin; TARC, thymus and activation-regulated chemokine; tPA, tissue plasminogen activator.
References
1. Joo JS, Yun SJ, Lee SC, Lee JB. Incidence of bullous pemphigoid and pemphigus in Korea. Ann Dermatol (2021) 33(2):193–5. doi: 10.5021/ad.2021.33.2.193
2. Bax CE, Werth VP. The incidence of bullous pemphigoid continues to increase in England. Br J Dermatol (2021) 184(1):5–6. doi: 10.1111/bjd.19207
3. Alpsoy E, Akman-Karakas A, Uzun S. Geographic variations in epidemiology of two autoimmune bullous diseases: pemphigus and bullous pemphigoid. Arch Dermatol Res (2015) 307(4):291–8. doi: 10.1007/s00403-014-1531-1
4. Bernard P, Antonicelli F. Bullous pemphigoid: A review of its diagnosis, associations and treatment. Am J Clin Dermatol (2017) 18(4):513–28. doi: 10.1007/s40257-017-0264-2
5. Cole C, Vinay K, Borradori L, Amber KT. Insights into the pathogenesis of bullous pemphigoid: The role of complement-independent mechanisms. Front Immunol (2022) 13:912876. doi: 10.3389/fimmu.2022.912876
6. Berkani N, Joly P, Golinski ML, Colliou N, Lim A, Larbi A, et al. Author correction: B-cell depletion induces a shift in self antigen specific b-cell repertoire and cytokine pattern in patients with bullous pemphigoid. Sci Rep (2019) 9(1):18991. doi: 10.1038/s41598-019-54421-6
7. Fang H, Li Q, Wang G. The role of T cells in pemphigus vulgaris and bullous pemphigoid. Autoimmun Rev (2020) 19(11):102661. doi: 10.1016/j.autrev.2020.102661
8. Fang H, Zhang Y, Li N, Wang G, Liu Z. The autoimmune skin disease bullous pemphigoid: The role of mast cells in autoantibody-induced tissue injury. Front Immunol (2018) 9:407. doi: 10.3389/fimmu.2018.00407
9. Fang H, Shao S, Xue K, Yuan X, Qiao P, Zhang J, et al. Neutrophil extracellular traps contribute to immune dysregulation in bullous pemphigoid via inducing b-cell differentiation and antibody production. FASEB J (2021) 35(7):e21746. doi: 10.1096/fj.202100145R
10. Jones VA, Patel PM, Amber KT. Eosinophils in bullous pemphigoid. Panminerva Med (2021) 63(3):368–78. doi: 10.23736/S0031-0808.20.03997-X
11. Cao P, Xu W, Zhang L. Rituximab, omalizumab, and dupilumab treatment outcomes in bullous pemphigoid: A systematic review. Front Immunol (2022) 13:928621. doi: 10.3389/fimmu.2022.928621
12. Hall RP 3rd, Streilein RD, Hannah DL, McNair PD, Fairley JA, Ronaghy A, et al. Association of serum b-cell activating factor level and proportion of memory and transitional b cells with clinical response after rituximab treatment of bullous pemphigoid patients. J Invest Dermatol (2013) 133(12):2786–8. doi: 10.1038/jid.2013.236
13. Asashima N, Fujimoto M, Watanabe R, Nakashima H, Yazawa N, Okochi H, et al. Serum levels of BAFF are increased in bullous pemphigoid but not in pemphigus vulgaris. Br J Dermatol (2006) 155(2):330–6. doi: 10.1111/j.1365-2133.2006.07305.x
14. Tuusa J, Kokkonen N, Tasanen K. BP180/Collagen XVII: A molecular view. Int J Mol Sci (2021) 22(22):12233. doi: 10.3390/ijms222212233
15. Thoma-Uszynski S, Uter W, Schwietzke S, Schuler G, Borradori L, Hertl M, et al. Autoreactive T and b cells from bullous pemphigoid (BP) patients recognize epitopes clustered in distinct regions of BP180 and BP230. J Immunol (2006) 176(3):2015–23. doi: 10.4049/jimmunol.176.3.2015
16. Hiroyasu S, Ozawa T, Kobayashi H, Ishii M, Aoyama Y, Kitajima Y, et al. Bullous pemphigoid IgG induces BP180 internalization via a macropinocytic pathway. Am J Pathol (2013) 182(3):828–40. doi: 10.1016/j.ajpath.2012.11.029
17. Liu Z, Zhao M, Li N, Diaz LA, Mayadas TN. Differential roles for beta2 integrins in experimental autoimmune bullous pemphigoid. Blood (2006) 107(3):1063–9. doi: 10.1182/blood-2005-08-3123
18. Ujiie H, Shibaki A, Nishie W, Sawamura D, Wang G, Tateishi Y, et al. A novel active mouse model for bullous pemphigoid targeting humanized pathogenic antigen. J Immunol (2010) 184(4):2166–74. doi: 10.4049/jimmunol.0903101
19. Nishie W, Sawamura D, Natsuga K, Shinkuma S, Goto M, Shibaki A, et al. A novel humanized neonatal autoimmune blistering skin disease model induced by maternally transferred antibodies. J Immunol (2009) 183(6):4088–93. doi: 10.4049/jimmunol.0800389
20. Zhou XP, Liu B, Xu Q, Yang Y, He CX, Zuo YG, et al. Serum levels of immunoglobulins G1 and G4 targeting the non-collagenous 16A domain of BP180 reflect bullous pemphigoid activity and predict bad prognosis. J Dermatol (2016) 43(2):141–8. doi: 10.1111/1346-8138.13051
21. Li Q, Ujiie H, Shibaki A, Wang G, Moriuchi R, Qiao HJ, et al. Human IgG1 monoclonal antibody against human collagen 17 noncollagenous 16A domain induces blisters via complement activation in experimental bullous pemphigoid model. J Immunol (2010) 185(12):7746–55. doi: 10.4049/jimmunol.1000667
22. Ujiie H, Sasaoka T, Izumi K, Nishie W, Shinkuma S, Natsuga K, et al. Bullous pemphigoid autoantibodies directly induce blister formation without complement activation. J Immunol (2014) 193(9):4415–28. doi: 10.4049/jimmunol.1400095
23. Zuo Y, Evangelista F, Culton D, Guilabert A, Lin L, Li N, et al. IgG4 autoantibodies are inhibitory in the autoimmune disease bullous pemphigoid. J Autoimmun (2016) 73:111–9. doi: 10.1016/j.jaut.2016.06.019
24. Hayakawa T, Teye K, Hachiya T, Uehara R, Hashiguchi M, Kawakami T, et al. Clinical and immunological profiles of anti-BP230-type bullous pemphigoid: Restriction of epitopes to the c-terminal domain of BP230, shown by novel ELISAs of BP230-domain specific recombinant proteins. Eur J Dermatol (2016) 26(2):155–63. doi: 10.1684/ejd.2015.2719
25. Shih YC, Wang B, Yuan H, Zheng J, Pan M. Role of BP230 autoantibodies in bullous pemphigoid. J Dermatol (2020) 47(4):317–26. doi: 10.1111/1346-8138.15251
26. Ramcke T, Bolduan V, Vicari E, Yilmaz K, Bertlich I, Goletz S, et al. Anti-BP230 only bullous pemphigoid constitutes a distinct disease subgroup with characteristic serological and clinical features. J Invest Dermatol (2022) 142(11):3110–13. doi: 10.1016/j.jid.2022.05.1084
27. Makita E, Matsuzaki Y, Fukui T, Matsui A, Minakawa S, Nakano H, et al. Autoantibodies to BPAG1e trigger experimental bullous pemphigoid in mice. J Invest Dermatol (2021) 141(5):1167–1176 e3. doi: 10.1016/j.jid.2020.08.031
28. Messingham KN, Crowe TP, Fairley JA. The intersection of IgE autoantibodies and eosinophilia in the pathogenesis of bullous pemphigoid. Front Immunol (2019) 10:2331. doi: 10.3389/fimmu.2019.02331
29. Alexandre M, Bohelay G, Gille T, Le Roux-Villet C, Soued I, Morin F, et al. Rapid disease control in first-line therapy-resistant mucous membrane pemphigoid and bullous pemphigoid with omalizumab as add-on therapy: A case series of 13 patients. Front Immunol (2022) 13:874108. doi: 10.3389/fimmu.2022.874108
30. Moriuchi R, Nishie W, Ujiie H, Natsuga K, Shimizu H. In vivo analysis of IgE autoantibodies in bullous pemphigoid: a study of 100 cases. J Dermatol Sci (2015) 78(1):21–5. doi: 10.1016/j.jdermsci.2015.01.013
31. Lamberts A, Kotnik N, Diercks GFH, Meijer JM, Di Zenzo G, Pas HH, et al. IgE autoantibodies in serum and skin of non-bullous and bullous pemphigoid patients. J Eur Acad Dermatol Venereol (2021) 35(4):973–80. doi: 10.1111/jdv.16996
32. van Beek N, Luttmann N, Huebner F, Recke A, Karl I, Schulze FS, et al. Correlation of serum levels of IgE autoantibodies against BP180 with bullous pemphigoid disease activity. JAMA Dermatol (2017) 153(1):30–8. doi: 10.1001/jamadermatol.2016.3357
33. Kamata A, Kurihara Y, Funakoshi T, Takahashi H, Kuroda K, Hachiya T, et al. Basement membrane zone IgE deposition is associated with bullous pemphigoid disease severity and treatment results. Br J Dermatol (2020) 182(5):1221–7. doi: 10.1111/bjd.18364
34. Ishiura N, Fujimoto M, Watanabe R, Nakashima H, Kuwano Y, Yazawa N, et al. Serum levels of IgE anti-BP180 and anti-BP230 autoantibodies in patients with bullous pemphigoid. J Dermatol Sci (2008) 49(2):153–61. doi: 10.1016/j.jdermsci.2007.08.008
35. Hashimoto T, Ohzono A, Teye K, Numata S, Hiroyasu S, Tsuruta D, et al. Detection of IgE autoantibodies to BP180 and BP230 and their relationship to clinical features in bullous pemphigoid. Br J Dermatol (2017) 177(1):141–51. doi: 10.1111/bjd.15114
36. Shih YC, Yuan H, Shen J, Zheng J, Pan M. BP230 IgE autoantibodies in topical-steroid-resistant bullous pemphigoid. J Dermatol (2021) 48(9):1372–80. doi: 10.1111/1346-8138.15952
37. Iwata Y, Komura K, Kodera M, Usuda T, Yokoyama Y, Hara T, et al. Correlation of IgE autoantibody to BP180 with a severe form of bullous pemphigoid. Arch Dermatol (2008) 144(1):41–8. doi: 10.1001/archdermatol.2007.9
38. Bing L, Xiping Z, Li L, Jun P, Yi-Xia W, Min Y, et al. Levels of anti-BP180 NC16A IgE do not correlate with severity of disease in the early stages of bullous pemphigoid. Arch Dermatol Res (2015) 307(9):849–54. doi: 10.1007/s00403-015-1598-3
39. Freire PC, Munoz CH, Stingl G. IgE autoreactivity in bullous pemphigoid: eosinophils and mast cells as major targets of pathogenic immune reactants. Br J Dermatol (2017) 177(6):1644–53. doi: 10.1111/bjd.15924
40. Messingham KN, Holahan HM, Frydman AS, Fullenkamp C, Srikantha R, Fairley JA, et al. Human eosinophils express the high affinity IgE receptor, FcepsilonRI, in bullous pemphigoid. PloS One (2014) 9(9):e107725. doi: 10.1371/journal.pone.0107725
41. Seyed Jafari SM, Gadaldi K, Feldmeyer L, Yawalkar N, Borradori L, Schlapbach C, et al. Effects of omalizumab on FcepsilonRI and IgE expression in lesional skin of bullous pemphigoid. Front Immunol (2019) 10:1919. doi: 10.3389/fimmu.2019.01919
42. Inaoki M, Sato S, Takehara K. Elevated expression of CD23 on peripheral blood b lymphocytes from patients with bullous pemphigoid: correlation with increased serum IgE. J Dermatol Sci (2004) 35(1):53–9. doi: 10.1016/j.jdermsci.2004.03.009
43. Schmidt E, Brocker EB, Zillikens D. High levels of soluble CD23 in blister fluid of patients with bullous pemphigoid. Arch Dermatol (1995) 131(8):966–7. doi: 10.1001/archderm.1995.01690200106030
44. Furukawa F, Kumagai S, Sakamoto Y, Takigawa M, Imamura S. Elevated serum levels of IgE-binding factor/soluble CD23 in bullous pemphigoid. J Dermatol Sci (1994) 7(2):150–4. doi: 10.1016/0923-1811(94)90089-2
45. Pickford WJ, Gudi V, Haggart AM, Lewis BJ, Herriot R, Barker RN, et al. T Cell participation in autoreactivity to NC16a epitopes in bullous pemphigoid. Clin Exp Immunol (2015) 180(2):189–200. doi: 10.1111/cei.12566
46. Didona D, Scarsella L, Fehresti M, Solimani F, Juratli HA, Gobel M, et al. Autoreactive peripheral blood T helper cell responses in bullous pemphigoid and elderly patients with pruritic disorders. Front Immunol (2021) 12:569287. doi: 10.3389/fimmu.2021.569287
47. Singh RR. Prevention and control of reciprocal T-b cell diversification: implications for lupus-like autoimmunity. Mol Immunol (2004) 40(14-15):1137–45. doi: 10.1016/j.molimm.2003.11.029
48. Fang H, Xue K, Cao T, Li Q, Dang E, Liu Y, et al. CXCL12/CXCR4 axis drives the chemotaxis and differentiation of b cells in bullous pemphigoid. J Invest Dermatol (2023) 143(2):197–208 e6. doi: 10.1016/j.jid.2022.08.041
49. Dong C. Cytokine regulation and function in T cells. Annu Rev Immunol (2021) 39:51–76. doi: 10.1146/annurev-immunol-061020-053702
50. Ding T, Su R, Wu R, Xue H, Wang Y, Su R, et al. Frontiers of autoantibodies in autoimmune disorders: Crosstalk between Tfh/Tfr and regulatory b cells. Front Immunol (2021) 12:641013. doi: 10.3389/fimmu.2021.641013
51. Zhang W, Liu X, Zhu Y, Liu X, Gu Y, Dai X, et al. Transcriptional and posttranslational regulation of Th17/Treg balance in health and disease. Eur J Immunol (2021) 51(9):2137–50. doi: 10.1002/eji.202048794
52. Belmesk L, Muntyanu A, Cantin E, AlHalees Z, Jack CS, Le M, et al. Prominent role of type 2 immunity in skin diseases: Beyond atopic dermatitis. J Cutan Med Surg (2022) 26(1):33–49. doi: 10.1177/12034754211027858
53. Arakawa M, Dainichi T, Ishii N, Hamada T, Karashima T, Nakama T, et al. Lesional Th17 cells and regulatory T cells in bullous pemphigoid. Exp Dermatol (2011) 20(12):1022–4. doi: 10.1111/j.1600-0625.2011.01378.x
54. Zhang J, Fang H, Shen S, Dang E, Li Q, Qiao P, et al. Identification of immunodominant Th2-cell epitopes in Chinese patients with bullous pemphigoid. J Invest Dermatol (2018) 138(9):1917–24. doi: 10.1016/j.jid.2018.03.1515
55. Cornaby C, Gibbons L, Mayhew V, Sloan CS, Welling A, Poole BD, et al. B cell epitope spreading: mechanisms and contribution to autoimmune diseases. Immunol Lett (2015) 163(1):56–68. doi: 10.1016/j.imlet.2014.11.001
56. Akiyama M, Yasuoka H, Yoshimoto K, Takeuchi T. Interleukin-4 contributes to the shift of balance of IgG subclasses toward IgG4 in IgG4-related disease. Cytokine (2018) 110:416–9. doi: 10.1016/j.cyto.2018.05.009
57. Lin AA, Freeman AF, Nutman TB. IL-10 indirectly downregulates IL-4-Induced IgE production by human b cells. Immunohorizons (2018) 2(11):398–406. doi: 10.4049/immunohorizons.1800076
58. Yanagihara Y, Ikizawa K, Kajiwara K, Koshio T, Basaki Y, Akiyama K, et al. Functional significance of IL-4 receptor on b cells in IL-4-induced human IgE production. J Allergy Clin Immunol (1995) 96(6 Pt 2):1145–51. doi: 10.1016/S0091-6749(95)70199-0
59. Abdat R, Waldman RA, de Bedout V, Czernik A, McLeod M, King B, et al. Dupilumab as a novel therapy for bullous pemphigoid: A multicenter case series. J Am Acad Dermatol (2020) 83(1):46–52. doi: 10.1016/j.jaad.2020.01.089
60. Ujiie H, Shibaki A, Nishie W, Shinkuma S, Moriuchi R, Qiao H, et al. Noncollagenous 16A domain of type XVII collagen-reactive CD4+ T cells play a pivotal role in the development of active disease in experimental bullous pemphigoid model. Clin Immunol (2012) 142(2):167–75. doi: 10.1016/j.clim.2011.10.002
61. Ng WF, Duggan PJ, Ponchel F, Matarese G, Lombardi G, Edwards AD, et al. Human CD4(+)CD25(+) cells: a naturally occurring population of regulatory T cells. Blood (2001) 98(9):2736–44. doi: 10.1182/blood.V98.9.2736
62. Bieber K, Sun S, Witte M, Kasprick A, Beltsiou F, Behnen M, et al. Regulatory T cells suppress inflammation and blistering in pemphigoid diseases. Front Immunol (2017) 8:1628. doi: 10.3389/fimmu.2017.01628
63. Haeberle S, Wei X, Bieber K, Goletz S, Ludwig RJ, Schmidt E, et al. Regulatory T-cell deficiency leads to pathogenic bullous pemphigoid antigen 230 autoantibody and autoimmune bullous disease. J Allergy Clin Immunol (2018) 142(6):1831–1842 e7. doi: 10.1016/j.jaci.2018.04.006
64. Muramatsu K, Ujiie H, Kobayashi I, Nishie W, Izumi K, Ito T, et al. Regulatory T-cell dysfunction induces autoantibodies to bullous pemphigoid antigens in mice and human subjects. J Allergy Clin Immunol (2018) 142(6):1818–1830 e6. doi: 10.1016/j.jaci.2018.03.014
65. Antiga E, Quaglino P, Volpi W, Pierini I, Del Bianco E, Bianchi B, et al. Regulatory T cells in skin lesions and blood of patients with bullous pemphigoid. J Eur Acad Dermatol Venereol (2014) 28(2):222–30. doi: 10.1111/jdv.12091
66. Quaglino P, Antiga E, Comessatti A, Caproni M, Nardo T, Ponti R, et al. Circulating CD4+ CD25brightFOXP3+ regulatory T-cells are significantly reduced in bullous pemphigoid patients. Arch Dermatol Res (2012) 304(8):639–45. doi: 10.1007/s00403-012-1213-9
67. Muramatsu K, Zheng M, Yoshimoto N, Ito T, Ujiie I, Iwata H, et al. Regulatory T cell subsets in bullous pemphigoid and dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid. J Dermatol Sci (2020) 100(1):23–30. doi: 10.1016/j.jdermsci.2020.08.004
68. Olatunde AC, Hale JS, Lamb TJ. Cytokine-skewed tfh cells: functional consequences for b cell help. Trends Immunol (2021) 42(6):536–50. doi: 10.1016/j.it.2021.04.006
69. Long D, Chen Y, Wu H, Zhao M, Lu Q. Clinical significance and immunobiology of IL-21 in autoimmunity. J Autoimmun (2019) 99:1–14. doi: 10.1016/j.jaut.2019.01.013
70. Li Q, Liu Z, Dang E, Jin L, He Z, Yang L, et al. Follicular helper T cells (Tfh) and IL-21 involvement in the pathogenesis of bullous pemphigoid. PloS One (2013) 8(7):e68145. doi: 10.1371/journal.pone.0068145
71. Ohuchi K, Fujimura T, Lyu C, Amagai R, Muto Y, Aiba S, et al. Possible roles of CXCL13/CXCR5 axis in the development of bullous pemphigoid. J Dermatol (2021) 48(3):353–9. doi: 10.1111/1346-8138.15713
72. Karnell JL, Albulescu M, Drabic S, Wang L, Moate R, Baca M, et al. A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity. Sci Transl Med (2019) 11(489):eaar6584. doi: 10.1126/scitranslmed.aar6584
73. Voynova E, Mahmoud T, Woods LT, Weisman GA, Ettinger R, Braley-Mullen H, et al. Requirement for CD40/CD40L interactions for development of autoimmunity differs depending on specific checkpoint and costimulatory pathways. Immunohorizons (2018) 2(1):54–66. doi: 10.4049/immunohorizons.1700069
74. Shen C, Xue X, Zhang X, Wu L, Duan X, Su C, et al. Dexamethasone reduces autoantibody levels in MRL/lpr mice by inhibiting tfh cell responses. J Cell Mol Med (2021) 25(17):8329–37. doi: 10.1111/jcmm.16785
75. Latham LE, Wikenheiser DJ, Stumhofer JS. ICOS signaling promotes a secondary humoral response after re-challenge with plasmodium chabaudi chabaudi AS. PloS Pathog (2020) 16(4):e1008527. doi: 10.1371/journal.ppat.1008527
76. Liu T, Li S, Ying S, Tang S, Ding Y, Li Y, et al. The IL-23/IL-17 pathway in inflammatory skin diseases: From bench to bedside. Front Immunol (2020) 11:594735. doi: 10.3389/fimmu.2020.594735
77. Tabatabaei-Panah PS, Moravvej H, Aghaei S, Akbari M, Rajabi S, Kia A, et al. TH17/IL23 cytokine gene polymorphisms in bullous pemphigoid. Mol Genet Genomic Med (2020) 8(12):e1519. doi: 10.1002/mgg3.1519
78. Chakievska L, Holtsche MM, Kunstner A, Goletz S, Petersen BS, Thaci D, et al. IL-17A is functionally relevant and a potential therapeutic target in bullous pemphigoid. J Autoimmun (2019) 96:104–12. doi: 10.1016/j.jaut.2018.09.003
79. Lindgren O, Le Menn G, Tuusa J, Chen ZJ, Tasanen K, Kokkonen N, et al. Absence of NC14A domain of COLXVII/BP180 in mice results in IL-17−Associated skin inflammation. J Invest Dermatol (2023) 143(1):48–56 e7. doi: 10.1016/j.jid.2022.07.019
80. Le Jan S, Plee J, Vallerand D, Dupont A, Delanez E, Durlach A, et al. Innate immune cell-produced IL-17 sustains inflammation in bullous pemphigoid. J Invest Dermatol (2014) 134(12):2908–17. doi: 10.1038/jid.2014.263
81. Riani M, Le Jan S, Plee J, Durlach A, Le Naour R, Haegeman G, et al. Bullous pemphigoid outcome is associated with CXCL10-induced matrix metalloproteinase 9 secretion from monocytes and neutrophils but not lymphocytes. J Allergy Clin Immunol (2017) 139(3):863–872 e3. doi: 10.1016/j.jaci.2016.08.012
82. Farnaghi F, Ehsani AH, Kamyab-Hesary K, Abbasian S, Seirafi H, Nasimi M, et al. Correlation of dermal and blood eosinophilia with bullous pemphigoid disease severity. Int J Womens Dermatol (2020) 6(3):171–5. doi: 10.1016/j.ijwd.2020.01.005
83. Gore Karaali M, Koku Aksu AE, Cin M, Leblebici C, Kara Polat A, Gurel MS, et al. Tissue eosinophil levels as a marker of disease severity in bullous pemphigoid. Australas J Dermatol (2021) 62(2):e236–41. doi: 10.1111/ajd.13547
84. de Graauw E, Sitaru C, Horn M, Borradori L, Yousefi S, Simon HU, et al. Evidence for a role of eosinophils in blister formation in bullous pemphigoid. Allergy (2017) 72(7):1105–13. doi: 10.1111/all.13131
85. Messingham KN, Wang JW, Holahan HM, Srikantha R, Aust SC, Fairley JA, et al. Eosinophil localization to the basement membrane zone is autoantibody- and complement-dependent in a human cryosection model of bullous pemphigoid. Exp Dermatol (2016) 25(1):50–5. doi: 10.1111/exd.12883
86. Lin L, Hwang BJ, Culton DA, Li N, Burette S, Koller BH, et al. Eosinophils mediate tissue injury in the autoimmune skin disease bullous pemphigoid. J Invest Dermatol (2018) 138(5):1032–43. doi: 10.1016/j.jid.2017.11.031
87. Tedeschi A, Marzano AV, Lorini M, Balice Y, Cugno M. Eosinophil cationic protein levels parallel coagulation activation in the blister fluid of patients with bullous pemphigoid. J Eur Acad Dermatol Venereol (2015) 29(4):813–7. doi: 10.1111/jdv.12464
88. Gounni Abdelilah S, Wellemans V, Agouli M, Guenounou M, Hamid Q, Beck LA, et al. Increased expression of Th2-associated chemokines in bullous pemphigoid disease. role of eosinophils in the production and release of these chemokines. Clin Immunol (2006) 120(2):220–31. doi: 10.1016/j.clim.2006.03.014
89. Amber KT, Valdebran M, Kridin K, Grando SA. The role of eosinophils in bullous pemphigoid: A developing model of eosinophil pathogenicity in mucocutaneous disease. Front Med (Lausanne) (2018) 5:201. doi: 10.3389/fmed.2018.00201
90. Choi Y, Kim YM, Lee HR, Mun J, Sim S, Lee DH, et al. Eosinophil extracellular traps activate type 2 innate lymphoid cells through stimulating airway epithelium in severe asthma. Allergy (2020) 75(1):95–103. doi: 10.1111/all.13997
91. Choi Y, Le Pham D, Lee DH, Lee SH, Kim SH, Park HS, et al. Biological function of eosinophil extracellular traps in patients with severe eosinophilic asthma. Exp Mol Med (2018) 50(8):1–8. doi: 10.1038/s12276-018-0136-8
92. Simon D, Hoesli S, Roth N, Staedler S, Yousefi S, Simon HU, et al. Eosinophil extracellular DNA traps in skin diseases. J Allergy Clin Immunol (2011) 127(1):194–9. doi: 10.1016/j.jaci.2010.11.002
93. Wakugawa M, Nakamura K, Hino H, Toyama K, Hattori N, Okochi H, et al. Elevated levels of eotaxin and interleukin-5 in blister fluid of bullous pemphigoid: correlation with tissue eosinophilia. Br J Dermatol (2000) 143(1):112–6. doi: 10.1046/j.1365-2133.2000.03599.x
94. Amber KT, Chernyavsky A, Agnoletti AF, Cozzani E, Grando SA. Mechanisms of pathogenic effects of eosinophil cationic protein and eosinophil-derived neurotoxin on human keratinocytes. Exp Dermatol (2018) 27(12):1322–7. doi: 10.1111/exd.13782
95. Giusti D, Gatouillat G, Le Jan S, Plee J, Bernard P, Antonicelli F, et al. Eosinophil cationic protein (ECP), a predictive marker of bullous pemphigoid severity and outcome. Sci Rep (2017) 7(1):4833. doi: 10.1038/s41598-017-04687-5
96. de Graauw E, Sitaru C, Horn MP, Borradori L, Yousefi S, Simon D, et al. Monocytes enhance neutrophil-induced blister formation in an ex vivo model of bullous pemphigoid. Allergy (2018) 73(5):1119–30. doi: 10.1111/all.13376
97. Liu Z, Giudice GJ, Zhou X, Swartz SJ, Troy JL, Fairley JA, et al. A major role for neutrophils in experimental bullous pemphigoid. J Clin Invest (1997) 100(5):1256–63. doi: 10.1172/JCI119639
98. Lin L, Betsuyaku T, Heimbach L, Li N, Rubenstein D, Shapiro SD, et al. Neutrophil elastase cleaves the murine hemidesmosomal protein BP180/type XVII collagen and generates degradation products that modulate experimental bullous pemphigoid. Matrix Biol (2012) 31(1):38–44. doi: 10.1016/j.matbio.2011.09.003
99. Niimi Y, Pawankar R, Kawana S. Increased expression of matrix metalloproteinase-2, matrix metalloproteinase-9 and matrix metalloproteinase-13 in lesional skin of bullous pemphigoid. Int Arch Allergy Immunol (2006) 139(2):104–13. doi: 10.1159/000090385
100. Giusti D, Bini E, Terryn C, Didier K, Le Jan S, Gatouillat G, et al. NET formation in bullous pemphigoid patients with relapse is modulated by IL-17 and IL-23 interplay. Front Immunol (2019) 10:701. doi: 10.3389/fimmu.2019.00701
101. Sugiyama S, Yamamoto T, Aoyama Y. Neutrophil to lymphocyte ratio is predictive of severe complications and mortality in patients with dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid: A retrospective longitudinal observational study. J Am Acad Dermatol (2022) 86(6):1387–90. doi: 10.1016/j.jaad.2021.05.043
102. Nsiah-Dosu S, Scholz C, Orinska Z, Sadik CD, Ludwig RJ, Schmidt E, et al. Mast cell-deficient mice Mcpt5Cre/Dicer (fl/fl) redefine the role of mast cells in experimental bullous pemphigoid. Skin Health Dis (2022) 2(1):e70. doi: 10.1002/ski2.70
103. Chen R, Fairley JA, Zhao ML, Giudice GJ, Zillikens D, Diaz LA, et al. Macrophages, but not T and b lymphocytes, are critical for subepidermal blister formation in experimental bullous pemphigoid: macrophage-mediated neutrophil infiltration depends on mast cell activation. J Immunol (2002) 169(7):3987–92. doi: 10.4049/jimmunol.169.7.3987
104. Dimson OG, Giudice GJ, Fu CL, Van den Bergh F, Warren SJ, Janson MM, et al. Identification of a potential effector function for IgE autoantibodies in the organ-specific autoimmune disease bullous pemphigoid. J Invest Dermatol (2003) 120(5):784–8. doi: 10.1046/j.1523-1747.2003.12146.x
105. D'Auria L, Pietravalle M, Cordiali-Fei P, Ameglio F. Increased tryptase and myeloperoxidase levels in blister fluids of patients with bullous pemphigoid: correlations with cytokines, adhesion molecules and anti-basement membrane zone antibodies. Exp Dermatol (2000) 9(2):131–7. doi: 10.1034/j.1600-0625.2000.009002131.x
106. Lin L, Bankaitis E, Heimbach L, Li N, Abrink M, Pejler G, et al. Dual targets for mouse mast cell protease-4 in mediating tissue damage in experimental bullous pemphigoid. J Biol Chem (2011) 286(43):37358–67. doi: 10.1074/jbc.M111.272401
107. Chen R, Bankaitis E, Heimbach L, Li N, Abrink M, Pejler G, et al. Mast cells play a key role in neutrophil recruitment in experimental bullous pemphigoid. J Clin Invest (2001) 108(8):1151–8. doi: 10.1172/JCI11494
108. Elieh Ali Komi D, Shafaghat F, Kovanen PT, Meri S. Mast cells and complement system: Ancient interactions between components of innate immunity. Allergy (2020) 75(11):2818–28. doi: 10.1111/all.14413
109. Kanagaratham C, El Ansari YS, Lewis OL, Oettgen HC. IgE and IgG antibodies as regulators of mast cell and basophil functions in food allergy. Front Immunol (2020) 11:603050. doi: 10.3389/fimmu.2020.603050
110. Tie D, Da X, Natsuga K, Yamada N, Yamamoto O, Morita E, et al. Bullous pemphigoid IgG induces cell dysfunction and enhances the motility of epidermal keratinocytes via Rac1/Proteasome activation. Front Immunol (2019) 10:200. doi: 10.3389/fimmu.2019.00200
111. Vestergaard C, Johansen C, Christensen U, Just H, Hohwy T, Deleuran M, et al. TARC augments TNF-alpha-induced CTACK production in keratinocytes. Exp Dermatol (2004) 13(9):551–7. doi: 10.1111/j.0906-6705.2004.00202.x
112. Suzuki M, Yamaguchi Y, Nakamura K, Kanaoka M, Matsukura S, Takahashi K, et al. Serum thymus and activation-regulated chemokine (TARC/CCL17) may be useful to predict the disease activity in patients with bullous pemphigoid. J Eur Acad Dermatol Venereol (2021) 35(2):e121–4. doi: 10.1111/jdv.16851
113. Nin-Asai R, Muro Y, Sekiya A, Sugiura K, Akiyama M. Serum thymus and activation-regulated chemokine (TARC/CCL17) levels reflect the disease activity in a patient with bullous pemphigoid. J Eur Acad Dermatol Venereol (2016) 30(2):327–8. doi: 10.1111/jdv.12719
114. Schmidt E, Wehr B, Tabengwa EM, Reimer S, Brocker EB, Zillikens D, et al. Elevated expression and release of tissue-type, but not urokinase-type, plasminogen activator after binding of autoantibodies to bullous pemphigoid antigen 180 in cultured human keratinocytes. Clin Exp Immunol (2004) 135(3):497–504. doi: 10.1111/j.1365-2249.2004.02401.x
115. Dupre N, Arabo A, Orset C, Maucotel J, Detroussel Y, Hauchecorne M, et al. Neonatal cerebral hypoxia-ischemia in mice triggers age-dependent vascular effects and disabilities in adults; implication of tissue plasminogen activator (tPA). Exp Neurol (2020) 323:113087. doi: 10.1016/j.expneurol.2019.113087
116. Laridan E, Denorme F, Desender L, Francois O, Andersson T, Deckmyn H, et al. Neutrophil extracellular traps in ischemic stroke thrombi. Ann Neurol (2017) 82(2):223–32. doi: 10.1002/ana.24993
117. Stander S, Holtsche MM, Schmidt E, Hammers CM, Zillikens D, Ludwig RJ, et al. Presence of cutaneous complement deposition distinguishes between immunological and histological features of bullous pemphigoid-insights from a retrospective cohort study. J Clin Med (2020) 9(12):3928. doi: 10.3390/jcm9123928
118. Nelson KC, Zhao M, Schroeder PR, Li N, Wetsel RA, Diaz LA, et al. Role of different pathways of the complement cascade in experimental bullous pemphigoid. J Clin Invest (2006) 116(11):2892–900. doi: 10.1172/JCI17891
119. Sezin T, Murthy S, Attah C, Seutter M, Holtsche MM, Hammers CM, et al. Dual inhibition of complement factor 5 and leukotriene B4 synergistically suppresses murine pemphigoid disease. JCI Insight (2019) 4(15):e128239. doi: 10.1172/jci.insight.128239
120. Karsten CM, Beckmann T, Holtsche MM, Tillmann J, Tofern S, Schulze FS, et al. Tissue destruction in bullous pemphigoid can be complement independent and may be mitigated by C5aR2. Front Immunol (2018) 9:488. doi: 10.3389/fimmu.2018.00488
121. Sadik CD, Miyabe Y, Sezin T, Luster AD. The critical role of C5a as an initiator of neutrophil-mediated autoimmune inflammation of the joint and skin. Semin Immunol (2018) 37:21–9. doi: 10.1016/j.smim.2018.03.002
122. Freire PC, Munoz CH, Derhaschnig U, Schoergenhofer C, Firbas C, Parry GC, et al. Specific inhibition of the classical complement pathway prevents C3 deposition along the dermal-epidermal junction in bullous pemphigoid. J Invest Dermatol (2019) 139(12):2417–2424 e2. doi: 10.1016/j.jid.2019.04.025
123. Nakatani T, Inaoki M, Takehara K. Bullous pemphigoid with a prolonged prodrome. J Dermatol (2008) 35(7):433–6. doi: 10.1111/j.1346-8138.2008.00498.x
124. Wang Y, Mao X, Wang D, Hammers CM, Payne AS, Wang Y, et al. Anti-BP180 autoantibodies are present in stroke and recognize human cutaneous BP180 and BP180-NC16A. Front Immunol (2019) 10:236. doi: 10.3389/fimmu.2019.00236
125. Nakama K, Koga H, Ishii N, Ohata C, Hashimoto T, Nakama T, et al. Clinical and immunological profiles of 14 patients with bullous pemphigoid without IgG autoantibodies to the BP180 NC16A domain. JAMA Dermatol (2018) 154(3):347–50. doi: 10.1001/jamadermatol.2017.5465
126. Moar A, Azzolini A, Tessari G, Schena D, Girolomoni G. Non-bullous pemphigoid: A single-center retrospective study. Dermatology (2021) 237(6):1039–45. doi: 10.1159/000515954
127. Min Y, Xiao-Man G, Jian-Min C. Linear arrangement of neutrophils along the basal layer in a case of bullous pemphigoid. Indian J Dermatol Venereol Leprol (2015) 81(4):416–8. doi: 10.4103/0378-6323.158654
128. Morris LM, Lewis HA, Cornelius LA, Chen DY, Rosman IS. Neutrophil-predominant bullous pemphigoid induced by checkpoint inhibitors: A case series. J Cutan Pathol (2020) 47(8):742–6. doi: 10.1111/cup.13687
129. James T, Salman S, Stevenson B, Bundell C, Kelly G, Nolan D, et al. IgE blockade in autoimmunity: Omalizumab induced remission of bullous pemphigoid. Clin Immunol (2019) 198:54–6. doi: 10.1016/j.clim.2018.12.015
130. Liu Z, Sui W, Zhao M, Li Z, Li N, Thresher R, et al. Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model. J Autoimmun (2008) 31(4):331–8. doi: 10.1016/j.jaut.2008.08.009
131. Stander S, Hammers CM, Vorobyev A, Schmidt E, Zillikens D, Ghorbanalipoor S, et al. The impact of lesional inflammatory cellular infiltrate on the phenotype of bullous pemphigoid. J Eur Acad Dermatol Venereol (2021) 35(8):1702–11. doi: 10.1111/jdv.17303
132. Margaroli C, Bradley B, Thompson C, Brown MR, Giacalone VD, Bhatt L, et al. Distinct compartmentalization of immune cells and mediators characterizes bullous pemphigoid disease. Exp Dermatol (2020) 29(12):1191–8. doi: 10.1111/exd.14209
133. Ujiie H. What's new in the pathogeneses and triggering factors of bullous pemphigoid. J Dermatol (2023) 50(2):140–9. doi: 10.1111/1346-8138.16654
134. Bao L, Perez White BE, Li J, Patel PM, Amber KT, et al. Gene expression profiling of laminin alpha3-blocked keratinocytes reveals an immune-independent mechanism of blistering. Exp Dermatol (2022) 31(4):615–21. doi: 10.1111/exd.14501
135. Berkowska MA, Heeringa JJ, Hajdarbegovic E, van der Burg M, Thio HB, van Hagen PM, et al. Human IgE(+) b cells are derived from T cell-dependent and T cell-independent pathways. J Allergy Clin Immunol (2014) 134(3):688–697 e6. doi: 10.1016/j.jaci.2014.03.036
136. Maspero J, Adir Y, Al-Ahmad M, Celis-Preciado CA, Colodenco FD, Giavina-Bianchi P, et al. Type 2 inflammation in asthma and other airway diseases. ERJ Open Res (2022) 8(3):00576-2021. doi: 10.1183/23120541.00576-2021
137. Marzano AV, Tedeschi A, Fanoni D, Bonanni E, Venegoni L, Berti E, et al. Activation of blood coagulation in bullous pemphigoid: role of eosinophils, and local and systemic implications. Br J Dermatol (2009) 160(2):266–72. doi: 10.1111/j.1365-2133.2008.08880.x
138. Silva RNF, Dallarmi LB, Araujo AKC, Alencar RCG, Mendonca EF, Silva TA, et al. Immunohistochemical analysis of neutrophils, interleukin-17, matrix metalloproteinase-9, and neoformed vessels in oral squamous cell carcinoma. J Oral Pathol Med (2018) 47(9):856–63. doi: 10.1111/jop.12762
Keywords: bullous pemphigoid, adaptive immunity, innate immunity, crosstalk, pathogenesis
Citation: Yan T and Zhang Z (2023) Adaptive and innate immune pathogenesis of bullous pemphigoid: A review. Front. Immunol. 14:1144429. doi: 10.3389/fimmu.2023.1144429
Received: 14 January 2023; Accepted: 24 February 2023;
Published: 10 March 2023.
Edited by:
Nina Van Beek, University Hospital Schleswig-Holstein, GermanyReviewed by:
Artem Vorobyev, University Medical Center Schleswig-Holstein, GermanyXiaoguang Li, Dalian University, China
Copyright © 2023 Yan and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Zhenying Zhang, zhangzhy276@mail.sysu.edu.cn