The histocompatibility antigen HLA-B8 occurs with increased frequency in patients with at least nine autoimmune diseases. It seems likely that a gene associated with HLA-B8 predisposes to the development of autoimmunity, possibly through an effect on the immune system. We have observed that many healthy young adults with HLA-B8 have alterations of immune functions when compared to sex and age matched controls without HLA-B8. These alterations include decreased T cell proliferation in response to suboptimal concentrations of mitogens, increased pokeweed mitogen driven immunoglobulin synthesis and decreased Con A induced suppression. These alterations in immune responsiveness may reflect the action of the gene or genes predisposing to autoimmune diseases. Further analysis of these immune abnormalities may help elucidate the mechanism of a genetic predisposition to autoimmunity. The proposed research has two major objectives. The first is to delineate the cellular basis of the immune abnormalities, in terms of specific functions of lymphocyte subpopulations and also production and response to lymphocyte mediators. This will involve performing the three assays in which differences of response associated with HLA-B8 are observed, using purified cell subpopulations. In addition, assays of interleukin production and response will be used to examine these lymphocyte functions. The second objective of the proposed research is to further identify the genetic basis of the altered immune function associated with HLA-B8. This will be done by typing individuals with and without the immune abnormality for alleles of additional loci besides the HLA-A, B and C alleles now determined. These would include alleles of the HLA-DR locus, alleles of complement components C2, C4 and Bf, and the GLO polymorphism. Associations will be sought at the population level between these genetic markers and the immune abnormality. In family studies, the segregation of the immune abnormality with reference to these markers will be examined in families with informative crossovers. These investigations will seek to localize and better define the gene or genes responsible for the altered immune function associated with HLA-B8. Results obtained from this research could provide new insights into the functions of genes in the major histocompatibility complex. Knowledge of the mechanism of the genetic predisposition to autoimmunity could provide the basis for preventive or therapeutic intervention.
