Clauder et al. "IgG Fc N-glycosylation translates MHCII haplotype into autoimmune skin disease"

The major histocompatibility complex (MHC)-haplotype represents the most prevalent genetic risk factor for the development of autoimmune diseases. However, the mechanisms by which MHC-associated genetic susceptibility translates into autoimmune disease are not fully understood. Epidermolysis bullosa acquisita (EBA) is an autoimmune skin blistering disease driven by autoantibodies to type VII collagen (COL7). Here, we investigated autoantigen-specific plasma cells, CD4+ T cells and IgG Fc-glycosylation in murine EBA in congenic mouse strains with the disease-permitting H2s or -non-permitting H2b MHCII 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 driver of autoimmune inflammation in this model. These results indicate that MHCII-associated susceptibility to autoimmune diseases acuminates in a proinflammatory IgG Fc N-glycosylation pattern and provide a mechanistic link to increased ROS release by neutrophils.

主要组织相容性复合体（major histocompatibility complex, MHC）单倍型是自身免疫性疾病发生最主要的常见遗传风险因素。然而，MHC相关遗传易感性转化为自身免疫性疾病的具体机制尚未完全阐明。获得性大疱性表皮松解症（Epidermolysis bullosa acquisita, EBA）是一类由针对VII型胶原（type VII collagen, COL7）的自身抗体介导的自身免疫性皮肤水疱病。本研究针对携带疾病易感型H2s或非易感型H2b MHC II类单倍型的同源基因小鼠品系中的小鼠EBA模型，探究了自身抗原特异性浆细胞、CD4+ T细胞以及IgG Fc糖基化特征。携带H2s单倍型的小鼠，其自身反应性CD4+ T细胞数量显著增多，白细胞介素21（IL-21）与干扰素γ（IFN-γ）的分泌水平升高，同时伴随携带无半乳糖基化促炎性N-聚糖结构的IgG自身抗体频率增加。机制层面，本研究证实抗体糖基化的改变会促使中性粒细胞释放更多活性氧（Reactive Oxygen Species, ROS），而中性粒细胞正是该模型中自身免疫炎症的主要驱动因素。上述结果表明，MHC II类相关的自身免疫疾病易感性可通过促炎性IgG Fc N-聚糖模式得以凸显，并为中性粒细胞活性氧释放增加提供了机制层面的关联。