Bullous pemphigoid (BP) is a rare autoimmune blistering disease characterized by autoantibodies targeting BP180 with the non-collagenous 16A (NC16A) domain representing the immunodominant site. The role of additional extracellular targets of the BP180 C-terminus has not yet been unequivocally demonstrated. Here, we showed that BP180 ectodomain-reactive sera depleted for NC16A IgG induced dermal-epidermal separation in control skin after incubation with normal human leukocytes indicating the pathogenic potential of anti-BP180 C-terminal IgG. To further corroborate our in-vitro findings, we generated a new pemphigoid mouse model by transfer of rabbit IgG against a murine fusion peptide consisting of the NC1–14 domains of BP180, downstream of NC15A (murine NC16A homologue). Following subcutaneous injection of anti-NC1–14 IgG over 12 days, C57BL/6J mice presented with erythematous lesions, erosions, and crusts, particularly on the head/ neck, recapitulating a BP-like phenotype. Direct immunofluorescence and histopathological analyses of skin biopsies showed linear IgG and complement C3 deposits along the basement membrane and subepidermal cleavage with inflammatory infiltrates. Disease development was significantly abrogated in Fcγ receptor-deficient vs control mice. Following administration of anti-NC1–14 IgG to C5aR1-deficient mice, a significant reduction of skin lesions was also observed in C5aR1 knock-out vs. wildtype mice. Our data demonstrate the ability of IgG targeting the BP180 C-terminus downstream of NC16A/ NC15A to exert tissue damage driven by Fcγ receptor- and C5aR1-mediated mechanisms. The new mouse model will be instrumental to further investigate the role of BP180 C-terminal epitopes in pemphigoid diseases and identification of more specific therapies for BP.

ESDR007 - Antibodies to the BP180 C-terminus cause autoimmune blistering disease through activation of the C5a/C5aR1 axis and Fcγ receptors

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