Abstract
Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease characterized by autoantibodies against the basal membrane zone of skin and surface-close epithelia and predominant mucosal lesions. The oral cavity and conjunctivae are most frequently affected, albeit clinical manifestations can also occur on the skin. MMP-associated lesions outside the oral cavity typically lead to scarring. Mechanisms underlying scarring are largely unknown in MMP and effective treatment options are limited. Herein, we assessed the collagen architecture in tissue samples of an antibody-transfer mouse model of anti-laminin-332 MMP. In MMP mice, increased collagen fibril density was observed in skin and conjunctival lesions compared to mice injected with normal rabbit IgG. The extracellular matrix of MMP skin samples also showed altered post-translational collagen cross-linking with increased levels of both lysine- and hydroxylysine-derived collagen crosslinks supporting the fibrotic phenotype in experimental MMP compared to control animals. In addition, we evaluated a potential anti-fibrotic therapy in experimental anti-laminin-332 MMP using disulfiram, an inhibitor of the aldehyde dehydrogenase (ALDH), which has been implicated in immune-mediated mucosal scarring. In addition, disulfiram also acts as a copper chelator that was shown to block lysyl oxidase activity, an enzyme involved in formation of collagen crosslinks. Topical use of disulfiram (300 μM in 2% [w/v] methocel) did not improve ocular lesions in experimental MMP over the 12-day treatment period in disulfiram-treated mice compared to vehicle-treated mice (n=8/group). Furthermore, C57BL6/J mice (n=8/group) were treated prophylactically with 200 mg/kg p.o. disulfiram or the solvent once daily over a period of 12 days. Systemic treatment did not show any reduction in the severity of oral and ocular lesions in MMP mice, albeit some improvement in skin lesions was observed in disulfiram- vs. vehicle-treated mice (p=0.052). No reduction in fibrosis was seen, as assessed by immunohistochemistry. Whilst blocking of ALDH failed to significantly ameliorate disease activity, our data provide new insight into fibrotic processes highlighting changes in the collagenous matrix and cross-linking patterns in IgG-mediated MMP.
Highlights
Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease characterized by autoantibodies against structural proteins of the basal membrane zone of skin and surface-close epithelia and predominant mucosal lesions [1, 2]
Experimental MMP was induced in C57BL/6J mice by transfer of rabbit anti-murine laminin alpha 3 (mLama3) IgG directed at recombinant fragments of mid and C-terminal domains, as described [13]
Anti-mLama3 IgG was injected at a dose of 6 mg/mouse/injection subcutaneously into the neck of C57BL/6J mice (n = 6) every second day from Day 0 to Day 10
Summary
Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease characterized by autoantibodies against structural proteins of the basal membrane zone of skin and surface-close epithelia and predominant mucosal lesions [1, 2]. The C-terminus of BP180 (collagen XVII) and laminin-332 represent two of the critical targets in the scarring phenotype of MMP [2] Both molecules extend from the lamina lucida into the lamina densa of the basement membrane zone [6, 7], and a disruption caused by autoantibodies directed against the BP180 C-terminal stretch as well as laminin-332 triggers an inflammatory cascade and immune cells, such as macrophages, release a number of profibrotic cytokines (e.g. transforming growth factor b, interleukin-13), which in turn activate fibroblasts and initiate the fibrosis response [3, 5, 8,9,10,11,12]. A previously established mouse model of MMP, induced by antibody transfer of IgG directed against the laminin alpha 3 chain (Lama3), mimicked characteristic clinical and immunopathological features of the human disease including linear deposits of IgG and C3 at the basal membrane zone of skin and surface-close epithelia, subepithelial blistering, and erosions or blisters in the oral cavity, conjunctivae, esophagus, and skin [13]. Animal models of MMP and other pemphigoid diseases, including, bullous pemphigoid and epidermolysis bullosa acquisita, have provided mechanistic insight in disease pathways underling the inflammatory processes and blister formation in autoantibody-induced tissue injury [14,15,16], yet, the mechanisms underlying scarring fibrosis have not been investigated in these experimental models
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