Developmentoftherapies for autoimmune diseases by targeting B cellsignaling

我们通过检测CD19缺陷小鼠，评估了B细胞特异性表面分子CD19在CHS发展中的作用。CD19是Ig超家族的成员，在B细胞和滤泡树突状细胞上表达，作为B细胞反应的阳性调节因子，定义B细胞反应的关键信号阈值。接触性超敏反应（CHS）是一种主要由ag特异性效应T细胞介导的皮肤免疫反应，被认为是Th1/ tc1介导的炎症的模型，而最近的报道表明B细胞在CHS中起关键作用。虽然CD19缺失小鼠对多种跨膜信号不敏感，但CD19缺失导致CHS反应增加和延长，提示CD19表达在CHS病因学中起抑制作用。过继性转移实验表明，受体小鼠B细胞中CD19的表达是抑制CHS反应的最佳条件，表明其在诱导期的作用。此外，来自野生型小鼠的脾脏B-2细胞，特别是边缘区B细胞，能够使cd19缺陷小鼠的夸张CHS反应正常化。因此，CD19在B细胞中的表达对于终止CHS反应至关重要，可能通过“调节性B细胞”的功能。这种B细胞亚群也能改善小鼠狼疮的表现。我们还评估了自身免疫性大泡疾病患者血清BAFF和趋化因子水平，并检测了BAFF在TSK小鼠（一种系统性硬化症动物模型）中的作用。

We assessed the role of the B cell-specific surface molecule CD19 on the development of CHS through examining CD19-deficient mice. CD19 is a member of the Ig superfamily expressed on B cells and follicular dendritic cells, and serves as a positive B-cell response regulator which defines signaling thresholds critical for B cell responses. Contact hypersensitivity (CHS) is a cutaneous immune reaction mediated mainly by Ag-specific effector T cells, and regarded as a model for Th1/Tc1-mediated inflammation, while recent reports have suggested pivotal roles of B cells in CHS. Although CD19-deficient mice are hyposensitive to a variety of transmembrane signals, CD19 loss resulted in increased and prolonged reaction of CHS, suggesting an inhibitory role of CD19 expression in the etiology of CHS. Adoptive transfer experiments revealed that CD19 expression in B cells is recipient mice was required for optimal suppression of CHS response, indicating its role in elicitation phase. Furthermore, spleen B-2 cells, especially marginal zone B cells, from wild type mice were able to normalize exaggerated CHS reactions in CD19-deficient mice. Thus, CD19 expression in B cells is critical for termination of CHS responses, possibly through the function of "regulatory B cells". This B cell subset was also capable for improving murine lupus manifestations.We also assessed serum BAFF and chemokine levels in patieits with autoimmune bullous diseases, and examined BAFF roles in TSK mice, an animal model of systemic sclerosis.