Abraham R S, Kudva Y C, Wilson S B, Strominger J L, David C S
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Diabetes. 2000 Apr;49(4):548-54. doi: 10.2337/diabetes.49.4.548.
Specific HLA DQ and DR alleles have been associated with susceptibility to type 1 diabetes. HLA DQ8 and DQ2 have been shown to strongly predispose to disease and to be in linkage disequilibrium with at-risk DR4 and DR3 alleles, respectively. Inheritance of a mixed DR3/DR4 haplotype confers the greatest risk. A double transgenic mouse expressing both DR3 and DQ8 was generated to investigate potential major histocompatibility complex class II interactions. The DR3/DQ8 transgenic mice developed a spontaneous loss of tolerance to GAD65, in which the T-cell response to GAD65 was restricted by HLA DR. Although the mice also showed spontaneous insulitis, they did not progress to overt diabetes. Mice expressing either transgene (DQ8 or DR3) alone showed mild infiltration of their islets, which disappeared when DQ8 or DR3 was co-expressed with a resistant DR2 allele or the neutral DQ6 allele. Therefore, in a fashion analogous to human diabetes, the murine model demonstrated a requirement for a combination of at-risk DR and DQ allotypes for the initiation of spontaneous autoimmunity.
特定的人类白细胞抗原（HLA）DQ和DR等位基因与1型糖尿病易感性相关。已表明HLA DQ8和DQ2分别强烈易患该疾病，且分别与高危DR4和DR3等位基因处于连锁不平衡状态。混合DR3/DR4单倍型的遗传赋予最大风险。为了研究潜在的主要组织相容性复合体II类相互作用，构建了同时表达DR3和DQ8的双转基因小鼠。DR3/DQ8转基因小鼠出现了对谷氨酸脱羧酶65（GAD65）的自发耐受性丧失，其中对GAD65的T细胞反应受HLA DR限制。尽管这些小鼠也表现出自发性胰岛炎，但并未发展为明显的糖尿病。单独表达任一转基因（DQ8或DR3）的小鼠胰岛出现轻度浸润，当DQ8或DR3与抗性DR2等位基因或中性DQ6等位基因共表达时，浸润消失。因此，与人类糖尿病类似，该小鼠模型表明启动自发自身免疫需要高危DR和DQ同种异型的组合。
