Peptide and major histocompatibility complex-specific breaking of humoral tolerance to native insulin with the B9-23 peptide in diabetes-prone and normal mice
Peptide and major histocompatibility complex-specific breaking of humoral tolerance to native insulin with the B9-23 peptide in diabetes-prone and normal mice
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DOI：
10.2337/diabetes.50.6.1274
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发表时间：
2001-06-01
期刊：
影响因子：
7.7
通讯作者：
Eisenbarth, GS
中科院分区：
文献类型：
--
作者：
Abiru, N;Maniatis, AK;Eisenbarth, GS
NOD小鼠自发地产生抗胰岛素自身抗体和糖尿病。NOD小鼠T细胞克隆识别的优势肽是胰岛素B链肽B 9 -23。当皮下给予NOD小鼠时，该肽减少糖尿病的发展。在本研究中，我们评估了给予B 9 -23肽后对天然胰岛素的自身抗体应答。在NOD小鼠中，给予在不完全弗氏佐剂中的B 9 -23肽以更高的水平和更长的持续性增强其胰岛素自身抗体应答。在给药2周内，在非糖尿病易感性BALB/c小鼠和NOR小鼠中观察到B 9 -23肽诱导胰岛素自身抗体，但在C57 BL/6小鼠中未观察到。一系列A链、其他B链和胰岛素原肽均未诱导胰岛素自身抗体。诱导的抗胰岛素自身抗体不能单独用肽吸收，但可以用天然胰岛素吸收。当给予BALB/c小鼠时，B 9 -23内两个鉴定的表位的B13-23肽锥（peptide Cone）诱导自身抗体，而肽B 9 -16不诱导。诱导的自身抗体定位于主要组织相容性复合体（MHC）而不是背景基因。I-A（d）/I-E-d或I-Ag-7/I-E-null的脾细胞都将B 9 -23肽呈递给NOD胰岛来源的T细胞克隆。最后，给BALB/c小鼠施用B 9 -23肽，即使没有佐剂，也可以诱导胰岛素自身抗体。我们的结果表明，B细胞对完整胰岛素的耐受性很容易被B 9 -23胰岛素肽的呈递所破坏，这取决于宿主的特异性MHC。
NOD mice spontaneously develop anti-insulin autoantibodies and diabetes. A dominant peptide recognized by T-cell clones from NOD mice is insulin B- chain peptide B9-23. When administered subcutaneously to NOD mice, this peptide decreases the development of diabetes, In this study, we evaluated the autoantibody response to native insulin after administration of the B9-23 peptide. In NOD mice, administration of the B9-23 peptide in incomplete Freund's adjuvant enhanced their insulin autoantibody response with a higher level and longer persistence. Induction of insulin autoantibodies with the B9-23 peptide was observed in non-diabetes-prone BALB/c mice and NOR mice within 2 weeks of administration, but this was not observed in C57BL/6 mice, A series of A-chain, other B-chain, and proinsulin peptides did not induce insulin autoantibodies, Induced anti-insulin autoantibodies could not be absorbed with the peptide alone but could be absorbed with native insulin. The B13-23 peptide Cone of two identified epitopes within B9-23) when administered to BALB/c mice, induced autoantibodies, whereas peptide B9-16 did not. Induction of autoantibodies mapped to the major histocompatibility complex (MHC) rather than to the background genes, Both splenocytes with I-A(d)/I-E-d or I-Ag-7/I-E-null presented the B9-23 peptide to NOD islet-derived T-cell clones. Finally, administration of the B9-23 peptide to BALB/c mice, even without adjuvant, could induce insulin autoantibodies, Our results indicate that B-cell tolerance to intact insulin is readily broken with the presentation of the B9-23 insulin peptide, depending on the host's specific MHC.