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Molecular Analyses of the Genetic Control of Immune Response in Humans

人类免疫反应遗传控制的分子分析

基本信息

批准号：
63440028
负责人：
SASAZUKI Takehiko
金额：
$ 19.39万
依托单位：
Medical Institute of Bioregulation, Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (A)
财政年份：
1988
资助国家：
日本
起止时间：
1988 至 1990
项目状态：
已结题

项目摘要

HLA class multigene family consists of DR, DQ and DP genes. It is well accepted that HLA-DR acts as immune response (Ir-) gene, because there is a genetic restriction by HLA-DR in T cell-antigen presenting cell interation to respond to foreign antigens, and because anti HLA-DR monoclonal antibody completely abolish the immune response. In human population, there are low (non) responders to natural antigens such as schistosomal antigen, streptococcal antigen, tetanus toxoid, hepatitis B vaccine, etc. after either natural sensitization or planned immunization. Family analysis revealed that the low (non) responsiveness to those antigens in an HLA-linked dominant genetic trait, and therefore the low (non) response can not be explained by a lock of lr-genes. Furthermore strong immune response can be restored in low (non) responders in vitro by either delection of CD8+ T cells or addition of anti HLA-DQ monoclonal antibody suggesting that HLA-DQ may control the antigen specific low immune re … More sponsiveness through an induction of CD8+ suppressor T cells.HLA-DQ alleles of the low and high responders to streptoccocal antigen were determined by investigating a hybridization between sequence specific oligonucleotide probes and HLA genes amplified by polymerase chain reaction. The strong associations between particular HLA-DQ alleles and low or high responders were observed and heterozygotes of high and low responder haplotypes exhibited low reponsiveness confirming that the HAL-DQ linked gene controlled low responsiveness to streptococcal antigen as a dominant genetic trait. In the peripheral blood lymphocytes from low (non) responders to streptococcal antigen, CD4+ T cells restricted by HLA-DR and DQ, respectively, were observed as well as a small fraction of CD8+ T cells if challenged with the antigen. In high responders, on the other hand, only CD4+ T cells restricted by HLA-DR were detected. CD4+ T cells restriced by HLA-DQ in low responders recognized streptococcal M protein by utilizing T cell receptor Vbeta5.3 gene and propagated the proliferation and activation of CD8+T cells whereas CD4+T cells restricted by DR could not do so. The CD8+ T cells expressed T cell receptor V alpha2 and Vbeta5.2 genes and suppresed the antigen specific proliferative response of CD4+ T cells. Thus we conclude that HLA-DQ alleles controls low (non) responsiveness in humans as immune suppresssion (Is) genes. HLA-DQ alleles of the patients with Insulin dependent diabetes mellitus (IDDM) were determined by DNA typing methods desribed above to show strong association between susceptibility or resistance to IDDM. This HLA-DQ associated susceptibility or resisitance to IDDM may be explained by the genetic control of immune response via HLA-DQ as the Is-gene.In an attempt to establish a model mouse for the analysis of biological function of HLA class II molecules in vivo, both the HLA-DQw6 A and B genes were introduced into fertilized eggs of C57BL/6 (B6) mice and a stable line of HLA-DQw6 transgenic B6 mouse (DQw6-B6) was established. The DQw6-B6 acquired an immune responsiveness to SCW and lost an immune responsiveness to E. Coli antigen. Therefore, we succeeded in the alteration of mouse immune response by introducing human MHC class II genes. Less

HLA类多基因家族由DR、DQ和DP基因组成。由于HLA-DR在T细胞-抗原提呈细胞相互作用中对外源抗原的应答具有遗传限制性，且抗HLA-DR单克隆抗体可完全消除免疫应答，故HLA-DR被认为是免疫应答（Ir-）基因。在人群中，无论是自然致敏还是计划免疫后，都存在对天然抗原（如溶酶体抗原、链球菌抗原、破伤风类毒素、B型肝炎疫苗等）的低（无）应答者。家系分析表明，在HLA连锁显性遗传性状中对这些抗原的低（无）应答，因此低（无）应答不能用lr基因锁来解释。此外，通过去除CD 8 + T细胞或加入抗HLA-DQ单克隆抗体，可在体外恢复低（无）应答者的强免疫应答，提示HLA-DQ可能控制抗原特异性低免疫应答。 ...更多信息通过研究序列特异性寡核苷酸探针和聚合酶链反应扩增的HLA基因之间的杂交来确定对链球菌抗原的低应答者和高应答者的HLA-DQ等位基因。观察到特定HLA-DQ等位基因与低或高应答者之间的强关联，并且高应答者和低应答者单倍型的杂合子表现出低应答性，证实HAL-DQ连锁基因控制对链球菌抗原的低应答性作为显性遗传性状。在来自对链球菌抗原低（非）应答者的外周血淋巴细胞中，观察到分别受HLA-DR和DQ限制的CD 4 + T细胞以及小部分的CD 8 + T细胞，如果用抗原攻击。另一方面，在高应答者中，仅检测到受HLA-DR限制的CD 4 + T细胞。低应答者中HLA-DQ限制的CD 4 + T细胞通过利用T细胞受体V β 5.3基因识别链球菌M蛋白，促进CD 8 +T细胞的增殖和活化，而DR限制的CD 4 +T细胞则不能。CD 8 + T细胞表达T细胞受体V α 2和V β 5.2基因，并抑制CD 4 + T细胞的抗原特异性增殖反应。因此，我们得出结论，HLA-DQ等位基因控制低（无）反应性在人类免疫抑制（Is）基因。应用上述DNA分型方法对胰岛素依赖型糖尿病（IDDM）患者的HLA-DQ等位基因进行了检测，结果表明，IDDM的易感性与抵抗性之间存在强相关性。这种与HLA-DQ相关的对IDDM的易感性或不易感性可能是通过HLA-DQ作为Is基因对免疫应答的遗传控制来解释的。将HLA-DQw 6 A和B基因导入C57 BL/6（B6）小鼠的受精卵和稳定的HLA-DQw 6转基因B6小鼠（DQw 6-B6）系中，建立了DQw 6-B6获得了对SCW的免疫应答，而对E.大肠杆菌抗原。因此，我们成功地通过引入人MHC II类基因来改变小鼠的免疫应答。少