Serreze D V, Gallichan W S, Snider D P, Croitoru K, Rosenthal K L, Leiter E H, Christianson G J, Dudley M E, Roopenian D C
Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Diabetes. 1996 Jul;45(7):902-8. doi: 10.2337/diab.45.7.902.
The common class I alleles (e.g., Kd and Db) within the H2g7 major histocompatibility complex (MHC) clearly contribute to autoimmune IDDM in NOD mice, but the mechanism by which this occurs has been controversial. One laboratory has reported that the peptide transporter encoded by the Tap1 gene within H2g7 is defective, and this contributes to IDDM by impairing MHC class I-mediated antigen presentation. If true, defective MHC class I-mediated antigen presentation should segregate with the H2g7 haplotype. NOD mice, related congenic stocks, and other control strains were used to test this hypothesis. H2g7-positive strains did not differ from those expressing other MHC haplotypes in ability to present MHC class I-restricted H3aa or H3ab minor histocompatibility (H) antigens to cytotoxic T-lymphocytes (CTL). The H2g7 haplotype was found to have a reduced capacity to mediate MHC class I-restricted presentation of the H47a minor H antigen. However, MHC class I-restricted presentation of H47a was found to be Tap independent. NOD mice and control strains also did not differ in ability to activate adenovirus-specific MHC class I restricted CTL. Thus, the H2g7 haplotype is not characterized by a Tap gene defect that only impairs the inductive phase of the immune response. In addition, MHC class I-restricted presentation of either minor H or adenoviral antigens was equivalent in male and female NOD mice. Therefore, while the class I alleles of the H2g7 haplotype exert diabetogenic functions in NOD mice, this is not elicited through a Tap gene defect. The absence of female-specific Tap gene defects also indicates this cannot account for the reduced male incidence of IDDM in some NOD mouse colonies.
H2g7主要组织相容性复合体（MHC）中的常见I类等位基因（如Kd和Db）显然在非肥胖糖尿病（NOD）小鼠的自身免疫性胰岛素依赖型糖尿病（IDDM）中起作用，但其发生机制一直存在争议。一个实验室报告称，H2g7内由Tap1基因编码的肽转运体存在缺陷，这通过损害MHC I类介导的抗原呈递导致IDDM。如果这是真的，有缺陷的MHC I类介导的抗原呈递应该与H2g7单倍型分离。使用NOD小鼠、相关同源品系和其他对照品系来检验这一假设。H2g7阳性品系在向细胞毒性T淋巴细胞（CTL）呈递MHC I类限制性H3aa或H3ab次要组织相容性（H）抗原的能力上与表达其他MHC单倍型的品系没有差异。发现H2g7单倍型介导H47a次要H抗原的MHC I类限制性呈递的能力降低。然而发现H47a的MHC I类限制性呈递不依赖于Tap。NOD小鼠和对照品系在激活腺病毒特异性MHC I类限制性CTL的能力上也没有差异。因此，H2g7单倍型的特征不是仅损害免疫反应诱导阶段的Tap基因缺陷。此外，在雄性和雌性NOD小鼠中，次要H抗原或腺病毒抗原的MHC I类限制性呈递是等效的。因此，虽然H2g7单倍型的I类等位基因在NOD小鼠中发挥致糖尿病功能，但这不是通过Tap基因缺陷引发的。不存在雌性特异性Tap基因缺陷也表明这不能解释某些NOD小鼠群体中IDDM男性发病率较低的现象。
