Jaume Juan Carlos, Parry Sarah Louise, Madec Anne-Marie, Sønderstrup Grete, Baekkeskov Steinunn
Diabetes Center, Department of Medicine, Division of Endocrinology and Metabolism, Department of Veterans Affairs Medical Center and University of California, San Francisco, CA 94143, USA.
J Immunol. 2002 Jul 15;169(2):665-72. doi: 10.4049/jimmunol.169.2.665.
Type 1 diabetes is a T cell-mediated disease in which B cells serve critical Ag-presenting functions. In >95% of type 1 diabetic patients the B cell response to the glutamic acid decarboxylase 65 (GAD65) autoantigen is exclusively directed at conformational epitopes residing on the surface of the native molecule. We have examined how the epitope specificity of Ag-presenting autoimmune B cell lines, derived from a type 1 diabetic patient, affects the repertoire of peptides presented to DRB1*0401-restricted T cell hybridomas. The general effect of GAD65-specific B cells was to enhance Ag capture and therefore Ag presentation. The enhancing effect was, however, restricted to T cell determinants located outside the B cell epitope region, because processing/presentation of T cell epitopes located within the autoimmune B cell epitope were suppressed in a dominant fashion. A similar effect was observed when soluble Abs formed immune complexes with GAD65 before uptake and processing by splenocytes. Thus, GAD65-specific B cells and the Abs they secrete appear to modulate the autoimmune T cell repertoire by down-regulating T cell epitopes in an immunodominant area while boosting epitopes in distant or cryptic regions.
1型糖尿病是一种T细胞介导的疾病，其中B细胞发挥关键的抗原呈递功能。在超过95%的1型糖尿病患者中，B细胞对谷氨酸脱羧酶65（GAD65）自身抗原的反应仅针对天然分子表面的构象表位。我们研究了源自一名1型糖尿病患者的抗原呈递自身免疫性B细胞系的表位特异性如何影响呈递给DRB1*0401限制性T细胞杂交瘤的肽库。GAD65特异性B细胞的总体作用是增强抗原捕获，从而增强抗原呈递。然而，增强作用仅限于位于B细胞表位区域之外的T细胞决定簇，因为位于自身免疫性B细胞表位内的T细胞表位的加工/呈递以显性方式受到抑制。当可溶性抗体在被脾细胞摄取和加工之前与GAD65形成免疫复合物时，也观察到了类似的效果。因此，GAD65特异性B细胞及其分泌的抗体似乎通过下调免疫显性区域的T细胞表位，同时增强远处或隐蔽区域的表位，来调节自身免疫性T细胞库。
