Hao W, Serreze D V, McCulloch D K, Neifing J L, Palmer J P
Department of Medicine, University of Washington, Seattle.
J Autoimmun. 1993 Dec;6(6):787-98. doi: 10.1006/jaut.1993.1064.
In NOD mice, endogenous retroviruses including intracisternal type A particles (IAP) are expressed in the pancreatic beta cells. Furthermore, in these mice, insulin autoantibodies (IAA) cross-react with retroviral protein p73 (the IAP gag gene product), suggesting molecular mimicry between insulin and p73. We therefore investigated whether IAA and insulin antibodies (IA) associated with human IDDM cross-reacted with p73. Fifty IAA positive sera from 30 newly diagnosed IDDM before insulin therapy and 20 non-diabetic first degree relatives of IDDM and 27 IA positive sera from insulin treated IDDM, initially defined as IAA or IA positive by radioimmunoassay, were evaluated. Binding to insulin and to p73 of these sera were analysed by ELISA. Approximately 65% of sera which bound insulin by ELISA also bound p73. Only one sample negative for insulin binding was positive for p73 binding. Preabsorption with either insulin or p73 inhibited binding to both insulin and p73. However, preabsorption with mouse hemoglobin had no effect on their binding. Repeat measurement of binding to insulin and p73 in 10 non-diabetic first degree relatives of IDDM over an average of 16.6 months showed that each individual's reactivity to insulin and to p73 was relatively stable over time. Furthermore, in different individuals, binding to p73 and to insulin was closely correlated over time. In addition, 75 healthy teenagers (IAA negative by RIA) were used as normal controls in this study. p73 binding was found in only two (2.7%) of the 75 subjects. These results indicate that approximately 65% of ELISA (+) IAA and IA subjects have antibodies which recognize both insulin and p73, suggesting that IAA and IA from some subjects recognize an epitope shared between human insulin and the murine gag gene product. This raises the possibility that for some subjects who are IAA positive, the immunizing antigen may be antigenically similar to p73, rather than insulin, and that endogenous retroviruses may be involved in human IDDM.
在非肥胖型糖尿病（NOD）小鼠中，包括A型颗粒内源性逆转录病毒（IAP）在内的内源性逆转录病毒在胰腺β细胞中表达。此外，在这些小鼠中，胰岛素自身抗体（IAA）与逆转录病毒蛋白p73（IAP gag基因产物）发生交叉反应，提示胰岛素与p73之间存在分子模拟。因此，我们研究了与人类胰岛素依赖型糖尿病（IDDM）相关的IAA和胰岛素抗体（IA）是否与p73发生交叉反应。对30例胰岛素治疗前新诊断的IDDM患者和20例IDDM非糖尿病一级亲属的50份IAA阳性血清，以及胰岛素治疗的IDDM患者的27份IA阳性血清进行了评估，这些血清最初通过放射免疫测定法被定义为IAA或IA阳性。通过酶联免疫吸附测定（ELISA）分析这些血清与胰岛素和p73的结合情况。通过ELISA与胰岛素结合的血清中，约65%也与p73结合。仅1份胰岛素结合阴性的样本p73结合呈阳性。用胰岛素或p73进行预吸收可抑制与胰岛素和p73的结合。然而，用小鼠血红蛋白进行预吸收对它们的结合没有影响。对10例IDDM非糖尿病一级亲属平均随访16.6个月，重复测量其与胰岛素和p73的结合情况，结果显示每个个体对胰岛素和p73的反应性随时间相对稳定。此外，在不同个体中，随着时间推移，与p73和胰岛素的结合密切相关。另外，本研究使用75名健康青少年（放射免疫测定法IAA阴性）作为正常对照。75名受试者中仅2名（2.7%）检测到p73结合。这些结果表明，约65%的ELISA（+）IAA和IA受试者具有同时识别胰岛素和p73的抗体，提示部分受试者的IAA和IA识别了人类胰岛素与鼠类gag基因产物之间共有的一个表位。这增加了一种可能性，即对于一些IAA阳性的受试者，免疫抗原可能在抗原性上与p73相似，而非胰岛素，并且内源性逆转录病毒可能参与了人类IDDM的发病过程。
