HLA CLASS-II ASSOCIATED POLYMORPHISM OF INTERFERON-GAMMA PRODUCTION -IMPLICATIONS FOR HLA-DISEASE ASSOCIATION

One of several possible mechanisms for the HLA-disease association is HLA-related polymorphism of cytokine expression. However, with the exc eption of the tumor necrosis factors, no evidence has been found for a relationship between HLA alleles and cytokine expression. This may be because cytokine responses to commonly employed mitogens are neither antigen nor KLA dependent, and responses to recall antigens are domina ted by the effect of prior antigen exposure. We reasoned that response s to alloantigens would be independent of prior antigen exposure and m ay therefore reveal subtle HLA-related variations in cytokine producti on. Here we demonstrate HLA Class II-related polymorphism of IFN-gamma production in the MLR performed between 32 subjects by a novel whole- blood method. KLA DR1, 2, and 6 were associated with high, whereas DR 3, 4, 5, and 7 were associated with low IFN-gamma production. Interest ingly, DQ alleles with which these DR alleles are in linkage dysequili brium, DQ1 and DQ2 and 3, were also associated with high and low IFN-g amma production, respectively. Ranking of HLA alleles according to who le-blood IFN-gamma production in response to mitogen or recall antigen s was similar to that in the MLR, although individual allele-related d ifferences did not reach statistical significance. TNF-or production w as significantly higher in DR3-positive than in DR3-negative subjects, in accord with previous studies. These findings suggest that KLA Clas s II alleles, particularly at the DQ locus, or alternatively, genes in linkage with them, regulate IFN-gamma expression by T cells. The find ing of HLA allele-related polymorphism of IFN-gamma production corrobo rates other lines of evidence that regulation of IFN-gamma expression contributes to HLA-associated susceptibility to immunoinflammatory dis eases, in particular insulin-dependent diabetes and multiple sclerosis . (C) American Society for Histocompatibility and Immunogenetics, 1997 .