Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF‐a and TNF‐0 by human mononuclear cells: a possible link to insulin‐dependent diabetes mellitus

Abstract

We have investigated the correlation between different tumor necrosis factor (TNF) and class II major histocompatibility complex alleles in the lipopolysaccharide‐ or phytohemagglutinin‐induced secretion of TNF‐α and TNF‐β by human monocytes and peripheral blood mononuclear cells in 87 unrelated Danish male individuals. Significant differences in TNF‐α secretory capacity between TNF Ncol restriction fragment length polymorphisms, TNFa and TNFc micro‐satellite alleles and DR alleles were identified. No correlation with TNF‐β secretory capacity was found for any of the markers studied. TNF genotyping allowed us to define four extended HLA haplotypes which correlate with TNF‐α secretory capacity. Two of these are DR4 positive: DQw8, DR4, TNFB*1, TNFa6, B44, A2 and DQw8, DR4, TNFB*2, TNFa2, B15, A2. Individuals carrying the TNFB*2, TNFa2 haplotype had a higher TNF‐α secretory capacity than those carrying the TNFB*1, TNFa6 haplotype. In a group of DR3/DR4 heterozygous patients with insulin‐dependent diabetes mellitus (IDDM), the frequency of the TNFa2 allele was higher than in HLA‐DR matched controls, whereas theTNFa6 allele was more frequent in control individuals. In the DR3/DR4 heterozygous diabetic group 12/26 had the alleles combination DQw8, DR4 (Dw4), C4A3, TNFB*2, TNFa2, B15, whereas only 1/18 controls had this haplotype. This diabetogenic haplotype is identical to the DR4 haplotype which correlates with a higher TNF‐α response. These observations suggest a direct role for the TNF locus in the pathogenesis of IDDM.