The effect of TNF*B gene polymorphism on TNF-alpha and -beta secretion levels in patients with insulin-dependent diabetes mellitus and healthy controls.

TNF-alpha and -beta have been implicated in the development of HLA-associated autoimmune diseases. It has been suggested that inter-individual differences in the secretion levels of these cytokines may contribute to the predisposition of certain individuals to the development of diseases such as insulin-dependent diabetes mellitus (IDDM). We have investigated whether a diallelic TNFB polymorphism detected using the enzyme Ncol influences the TNF-alpha and/or -beta secretory capacity of peripheral blood mononuclear cells (PBMC) from PHA stimulated healthy individuals and IDDM patients. We have shown that the level of TNF-beta secreted correlates with the TNFB genotype in healthy individuals: those with the TNF B2 allele secreted significantly higher levels of TNF-beta (P = 0.025) than those with the TNFB1 allele. In IDDM patients, the reverse situation was observed, with those patients with the TNFB1 allele secreting higher levels of TNF-beta than those with the TNFB2 allele. No correlation was found between TNF-alpha levels and TNFB genotype. Furthermore, when IDDM patients and controls were matched for TNFB genotype, the IDDM patients with the TNFB2 allele secreted significantly lower levels of TNF-beta than controls with this allele. On analysis of IDDM-susceptible extended HLA haplotypes in the homozygous groups, 4/7 IDDM patients with the TNFB2 allele were Bw62-DR4 compared with 0/16 matched controls. Thus, the extended haplotype Bw62-DR4-TNFB2/2 rather than IDDM per se is almost certainly responsible for the depressed TNF-beta secretion found in the IDDM-TNFB2 homozygous cohort.