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

Norihiro Yoshimoto, Ken Muramastsu, Takamasa Ito, Miao Zheng, Kentaro Izumi, Ken Natsuga, Hiroaki Iwata, Yoshinori Hasegawa, Hideyuki Ujiie
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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.

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XVII型胶原蛋白特异性CD4+T细胞通过产生IL-5诱导大疱性类天疱疮。
大疱性类天疱疮(BP)是一种由抗十七型胶原(COL17)抗体引起的自身免疫性表皮下大疱性疾病。大疱性类天疱疮具有一些免疫学特征,如嗜酸性粒细胞浸润和 IgE 自身抗体在皮肤中沉积;然而,这些特征背后的机制在很大程度上仍不清楚。我们重点研究了被认为能调节免疫反应的自身抗原特异性 CD4+ T 细胞。我们在体外建立了 COL17 特异性 CD4+ T 细胞系。用包含 COL17 致病表位的合成肽免疫野生型小鼠,并对淋巴细胞进行限制稀释试验。我们建立了 5 个 T 细胞系,并将它们与 COL17 诱导的 B 细胞一起转移到皮肤中表达人 COL17 而非小鼠 COL17 的 Rag-2-/-/COL17 人源化小鼠体内,以检测其致病性。值得注意的是,有 3 个品系诱发了与表皮下分离和嗜酸性粒细胞浸润有关的 BP 样皮肤变化,并产生了抗 COL17 抗体。另外 2 个品系没有诱发此类表型。RNA 序列分析表明,Th2 细胞因子,尤其是 IL-5 在致病 T 细胞系中高度表达。服用抗 IL-5 抗体可明显减轻皮肤变化,并减少自身抗体的产生。因此,IL-5的产生对COL17特异性CD4+ T细胞在体内诱导BP表型至关重要。
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