Rajagopalan Govindarajan, Kudva Yogish C, Chen Lieping, Wen Li, David Chella S
Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
Int Immunol. 2003 Sep;15(9):1035-44. doi: 10.1093/intimm/dxg103.
The major predisposing genetic component in type 1 diabetes (T1D) maps to the MHC locus in both mice and humans. To better understand the HLA class II association with disease pathogenesis, we bred mice expressing HLA-DQ8 and -DR3, either alone or in combination, to transgenic mice expressing the co-stimulatory molecule B7-1 in the beta cells of islets of Langerhans. Spontaneous diabetes occurred only in RIP-B7-1 transgenic mice expressing transgenic HLA-DR3 or -DQ8 molecules and the incidence of diabetes was comparable between the two (approximately 30% in either sex up to 50 weeks of age). Presence of DR3 and DQ8 together only marginally elevated the overall incidence of spontaneous disease (38%). Non-specific activation of T cells by superantigen and provision of concomitant co-stimulation through 4-1BB (CD137) by an agonistic antibody did not accelerate the incidence of diabetes over a short period of time. Neither the antibody-mediated depletion of CD25+ T cells nor sublethal, whole-body irradiation of young, naive HLA transgenic mice expressing RIP-B7-1 resulted in diabetes. However, administration of only two doses of the beta cell toxin streptozotocin (STZ; 40 mg/kg) induced autoimmune diabetes in 85% of mice within 7 weeks after STZ treatment only when B7-1 was expressed on the pancreatic beta cells. This effect was HLA dependent as none of the STZ-treated RIP-B7-1 transgenic mice lacking HLA class II developed diabetes. In conclusion, this study confirmed the diabetogenic potential of HLA-DQ8 and established the role of HLA-DR3 in the pathogenesis of T1D.
1型糖尿病（T1D）的主要遗传易感性成分在小鼠和人类中均定位于MHC基因座。为了更好地理解HLA - II类分子与疾病发病机制的关联，我们将单独或联合表达HLA - DQ8和 - DR3的小鼠与在胰岛β细胞中表达共刺激分子B7 - 1的转基因小鼠进行杂交。仅在表达转基因HLA - DR3或 - DQ8分子的RIP - B7 - 1转基因小鼠中出现自发性糖尿病，且两种小鼠的糖尿病发病率相当（50周龄以内的两性发病率约为30%）。DR3和DQ8同时存在仅使自发性疾病的总体发病率略有升高（38%）。超抗原对T细胞的非特异性激活以及通过激动性抗体通过4 - 1BB（CD137）提供伴随的共刺激在短时间内并未加速糖尿病的发病。抗体介导的CD25 + T细胞耗竭以及对表达RIP - B7 - 1的年轻、未致敏的HLA转基因小鼠进行亚致死性全身照射均未导致糖尿病。然而，仅给予两剂β细胞毒素链脲佐菌素（STZ；40 mg/kg），仅在胰腺β细胞上表达B7 - 1时，可在STZ治疗后7周内诱导85%的小鼠发生自身免疫性糖尿病。这种效应依赖于HLA，因为缺乏HLA - II类分子的STZ处理的RIP - B7 - 1转基因小鼠均未发生糖尿病。总之，本研究证实了HLA - DQ8的致糖尿病潜力，并确立了HLA - DR3在T1D发病机制中的作用。
