Mordes John P, Leif Jean, Novak Stephen, DeScipio Cheryl, Greiner Dale L, Blankenhorn Elizabeth P
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Diabetes. 2002 Nov;51(11):3254-62. doi: 10.2337/diabetes.51.11.3254.
Viral antibody-free BBDR and WF rats never develop spontaneous diabetes. BBDR rats, however, develop autoimmune diabetes after perturbation of the immune system, e.g., by viral infection. We previously identified a disease-susceptibility locus in the BBDR rat, iddm4, which is associated with the development of autoimmune diabetes after treatment with polyinosinic:polycytidylic acid and an antibody that depletes ART2(+) regulatory cells. We have now developed lines of congenic WF.iddm4 rats and report that in an intercross of N5 generation WF.iddm4 rats, approximately 70% of animals either homozygous or heterozygous for the BBDR origin allele of iddm4 became hyperglycemic after treatment to induce diabetes. Fewer than 20% of rats expressing the WF origin allele of iddm4 became diabetic. Testing the progeny of various recombinant N5 WF.iddm4 congenic rats for susceptibility to diabetes suggests that iddm4 is centered on a small segment of chromosome 4 bounded by the proximal marker D4Rat135 and the distal marker D4Got51, an interval of <2.8 cM. The allele at iddm4 has 79% sensitivity and 80% specificity in prediction of diabetes in rats that are segregating for this locus. These characteristics suggest that iddm4 is one of the most powerful non-major histocompatibility complex determinants of susceptibility to autoimmune diabetes described to date.
无病毒抗体的BBDR和WF大鼠从不发生自发性糖尿病。然而，BBDR大鼠在免疫系统受到干扰后，例如通过病毒感染，会发生自身免疫性糖尿病。我们之前在BBDR大鼠中鉴定出一个疾病易感位点iddm4，它与用聚肌苷酸:聚胞苷酸和一种耗尽ART2(+)调节细胞的抗体治疗后自身免疫性糖尿病的发生有关。我们现在培育出了同源的WF.iddm4大鼠品系，并报告在N5代WF.iddm4大鼠的杂交中，大约70%的iddm4的BBDR起源等位基因纯合或杂合的动物在接受诱导糖尿病的治疗后出现高血糖。表达iddm4的WF起源等位基因的大鼠中不到20%患糖尿病。对各种重组N5 WF.iddm4同源大鼠的后代进行糖尿病易感性测试表明，iddm4位于4号染色体的一小段区域，该区域由近端标记D4Rat135和远端标记D4Got51界定，间隔<2.8 cM。iddm4处的等位基因在预测该位点分离的大鼠患糖尿病方面具有79%的敏感性和80%的特异性。这些特征表明，iddm4是迄今为止所描述的对自身免疫性糖尿病易感性最强大的非主要组织相容性复合体决定因素之一。
