Developmentoftherapies for autoimmune diseases by targeting B cellsignaling

我们通过检测CD19缺陷小鼠来评估B细胞特异性表面分子CD19在CHS发展中的作用。CD19是表达在B细胞和滤泡树突状细胞上的免疫球蛋白超家族的成员，是一种正向B细胞反应调节因子，它定义了对B细胞反应至关重要的信号阈值。接触性超敏反应(CHS)是一种主要由抗原特异性效应T细胞介导的皮肤免疫反应，被认为是Th1/Tc1介导的炎症模型，而最近的报道表明B细胞在CHS中起着关键作用。虽然CD19基因缺陷小鼠对多种跨膜信号不敏感，但CD19缺失导致CHS反应增强和延长，提示CD19表达在CHS的发病机制中起抑制作用。过继转移实验表明，CD19在B细胞受体小鼠中的表达是最佳抑制CHS反应所必需的，这表明其在诱导阶段发挥作用。此外，来自野生型小鼠的脾B-2细胞，特别是边缘带B细胞，能够使CD19缺陷小鼠夸大的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，这可能是通过“调节性B细胞”的功能实现的。我们还评估了自身免疫性大疱性疾病患者的血清BAFF和趋化因子水平，并研究了BAFF在系统性硬化症动物模型TSK小鼠中的作用。

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.