Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany; Institute for Nutritional Medicine, University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, Germany.
J Invest Dermatol. 2021 Feb;141(2):285-294. doi: 10.1016/j.jid.2020.06.022. Epub 2020 Jul 10.
The major histocompatibility complex haplotype represents the most prevalent genetic risk factor for the development of autoimmune diseases. However, the mechanisms by which major histocompatibility complex-associated genetic susceptibility translates into autoimmune disease are not fully understood. Epidermolysis bullosa acquisita is an autoimmune skin-blistering disease driven by autoantibodies to type VII collagen. Here, we investigated autoantigen-specific plasma cells, CD4 T cells, and IgG fraction crystallizable glycosylation in murine epidermolysis bullosa acquisita in congenic mouse strains with the disease-permitting H2s or disease-nonpermitting H2b major histocompatibility complex II haplotypes. Mice with an H2s haplotype showed increased numbers of autoreactive CD4 T cells and elevated IL-21 and IFN-γ production, associated with a higher frequency of IgG autoantibodies with an agalactosylated, proinflammatory N-glycan moiety. Mechanistically, we show that the altered antibody glycosylation leads to increased ROS release from neutrophils, the main drivers of autoimmune inflammation in this model. These results indicate that major histocompatibility complex II-associated susceptibility to autoimmune diseases acuminates in a proinflammatory IgG fraction crystallizable N-glycosylation pattern and provide a mechanistic link to increased ROS release by neutrophils.
主要组织相容性复合体单倍型代表了自身免疫性疾病发展的最常见遗传风险因素。然而，主要组织相容性复合体相关遗传易感性转化为自身免疫性疾病的机制尚不完全清楚。获得性大疱性表皮松解症是一种由针对 VII 型胶原蛋白的自身抗体驱动的自身免疫性皮肤水疱病。在这里，我们研究了具有疾病允许的 H2s 或疾病非允许的 H2b 主要组织相容性复合体 II 单倍型的同基因小鼠系中获得性大疱性表皮松解症的自身抗原特异性浆细胞、CD4 T 细胞和 IgG 段结晶糖基化。具有 H2s 单倍型的小鼠显示出增加的自身反应性 CD4 T 细胞数量和升高的 IL-21 和 IFN-γ 产生，与具有半乳糖基化、促炎 N-聚糖部分的更高频率 IgG 自身抗体相关。从机制上讲，我们表明改变的抗体糖基化导致中性粒细胞释放更多的 ROS，这是该模型中自身免疫炎症的主要驱动因素。这些结果表明，主要组织相容性复合体 II 相关的自身免疫性疾病易感性在促炎 IgG 段结晶糖基化模式中逐渐加剧，并为中性粒细胞释放更多的 ROS 提供了一种机制联系。
