Type XVII Collagen–Specific CD4+ T Cells Induce Bullous Pemphigoid by Producing IL-5

Abstract

Bullous pemphigoid is an autoimmune subepidermal blistering disease caused by anti–type XVII collagen (COL17) antibodies. Bullous pemphigoid has some immunological features such as eosinophilic infiltration and the deposition of IgE autoantibodies in the skin; however, the mechanism behind such features remains largely unclear. We focused on the autoantigen-specific CD4⁺ T cells, which are considered to regulate immune response. We established COL17-specific CD4⁺ T cell lines in vitro. Wild-type mice were immunized with synthesized peptides that include a pathogenic epitope of COL17, and lymphocytes were subjected to a limiting dilution assay. We established 5 T cell lines and examined the pathogenicity by transferring them with COL17-primed B cells into Rag-2^−/−/COL17-humanized mice that express human COL17 but not mouse COL17 in the skin. Notably, 3 lines induced bullous pemphigoid–like skin changes associated with subepidermal separation and eosinophilic infiltration histologically and the production of anti-COL17 antibodies. The other 2 lines did not induce such phenotypes. RNA-sequencing analysis revealed that T helper 2 cytokines, particularly IL-5, were highly expressed in the pathogenic T-cell lines. Anti–IL-5 antibody administration significantly reduced the skin changes and attenuated the production of autoantibodies. Thus, the production of IL-5 is critical for COL17-specific CD4⁺ T cells to induce bullous pemphigoid phenotypes in vivo.