Nepom G T, Seyfried C A, Nepom B S
Pathol Immunopathol Res. 1986;5(1):37-46. doi: 10.1159/000157002.
Structural analysis of HLA class II molecular variation occurring within haplotypes implicated in specific HLA-associated diseases now provides more specific and sensitive mechanisms for investigation of genetic susceptibility to disease. Using the HLA-DR4 association with two distinct diseases, IDDM and JRA, as a model, we can conclude the following: There are at least seven distinct haplotypes which share the HLA DR4 specificity; these haplotypes include six alleles at the DR-beta genetic locus. These allelic differences are subtle, encompassing a very few clustered amino acid changes, but are sufficient to generate different patterns of T cell alloreactivity; there are at least three different alleles of DQ-beta genes associated with DR4+ haplotypes, with major structural differences recognized by biochemical analysis and by specific antibodies; different DR4-associated diseases are associated with different specific allelic variants of DR and DQ genes. DR4+ IDDM is most closely associated with the DQ 3.2 allele at DQ-beta; DR4+ JRA, on the other hand, appears to be highly associated with rare alleles at DR-beta, but not DQ. Notably, there are many alleles, and therefore DR4+ haplotypes, which are not implicated in 'HLA-DR4-associated' diseases.
对与特定HLA相关疾病有关的单倍型内发生的HLA II类分子变异进行结构分析，现在为研究疾病的遗传易感性提供了更特异、更敏感的机制。以HLA - DR4与两种不同疾病（胰岛素依赖型糖尿病和青少年类风湿性关节炎）的关联作为模型，我们可以得出以下结论：至少有七种不同的单倍型共享HLA DR4特异性；这些单倍型在DR - β基因座包括六个等位基因。这些等位基因差异很细微，只包含极少数成簇的氨基酸变化，但足以产生不同的T细胞同种异体反应模式；至少有三个与DR4 +单倍型相关的DQ - β基因的不同等位基因，通过生化分析和特异性抗体可识别出主要的结构差异；不同的与DR4相关的疾病与DR和DQ基因的不同特定等位基因变体相关。DR4 +胰岛素依赖型糖尿病与DQ - β处的DQ 3.2等位基因关系最为密切；另一方面，DR4 +青少年类风湿性关节炎似乎与DR - β处的罕见等位基因高度相关，而与DQ无关。值得注意的是，有许多等位基因，因此也有许多DR4 +单倍型，它们与“HLA - DR4相关”疾病无关。
