Enhanced B-cell receptor recognition of the autoantigen transglutaminase 2 by efficient catalytic self-multimerization

A hallmark of the gluten-driven enteropathy celiac disease is autoantibody production towards the enzyme transglutaminase 2 (TG2) that catalyzes the formation of covalent protein-protein cross-links. Activation of TG2-specific B cells likely involves gluten-specific CD4 T cells as production of the antibodies is dependent on disease-associated HLA-DQ allotypes and dietary intake of gluten. IgA plasma cells producing TG2 antibodies with few mutations are abundant in the celiac gut lesion. These plasma cells and serum antibodies to TG2 drop rapidly after initiation of a gluten-free diet, suggestive of extrafollicular responses or germinal center reactions of short duration. High antigen avidity is known to promote such responses, and is also important for breakage of self-tolerance. We here inquired whether TG2 avidity could be a feature relevant to celiac disease. Using recombinant enzyme we show by dynamic light scattering and gel electrophoresis that TG2 efficiently utilizes itself as ...乳糜泻（celiac disease，一种麸质介导的肠病）的标志性病理特征，是机体针对催化共价蛋白-蛋白交联形成的转谷氨酰胺酶2（transglutaminase 2, TG2）产生自身抗体。TG2特异性B细胞的活化过程大概率涉及麸质特异性CD4阳性T细胞，因为此类自身抗体的产生依赖于疾病相关的HLA-DQ等位基因分型与膳食麸质摄入。在乳糜泻患者的肠道病变部位，大量存在着产生低突变率TG2抗体的IgA浆细胞。在患者启动无麸质饮食方案后，此类浆细胞与血清中的TG2抗体水平会快速下降，提示机体存在短时程的滤泡外应答或生发中心反应。已知高抗原亲和力（antigen avidity）可促进此类应答，同时对于打破自身免疫耐受也具有关键作用。本研究旨在探究TG2的抗原亲和力是否可作为与乳糜泻相关的特征性指标。本研究利用重组酶，通过动态光散射（dynamic light scattering）与凝胶电泳（gel electrophoresis）实验证实，TG2可高效地以自身作为……