Molecular Analyses of the Genetic Control of Immune Response in Humans

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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