THE EFFECT OF TNF*B GENE POLYMORPHISM ON TNF‐α AND ‐β SECRETION LEVELS IN PATIENTS WITH INSULIN‐DEPENDENT DIABETES MELLITUS AND HEALTHY CONTROLS

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Abstract
TNF-α and -β 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 TNF*B polymorphism detected using the enzyme Ncol influences the TNF-α and/or -β secretory capacity of peripheral blood mononuclear cells (PBMC) from PHA stimulated healthy individuals and IDDM patients. We have shown that the level of TNF-β secreted correlates with the TNF*B genotype in healthy individuals: those with the TNF B*2 allele secreted significantly higher levels of TNF-β (P= 0.025) than those with the TNF*B1 allele. In IDDM patients, the reverse situation was observed, with those patients with the TNF*B1 allele secreting higher levels of TNF-β than those with the TNF*B2 allele. No correlation was found between TNF-α levels and TNF*B genotype. Furthermore, when IDDM patients and controls were matched for TNF*B genotype, the IDDM patients with the TNF*B2 allele secreted significantly lower levels of TNF-β than controls with this allele. On analysis of IDDM-susceptible extended HLA haplotypes in the homozygous groups, 4/7 IDDM patients with the TNF*B2 allele were Bw62-DR4 compared with 0/16 matched controls. Thus, the extended haplotype Bw62-DR4-TNF*B2/2 rather than IDDM per se is almost certainly responsible for the depressed TNF-β secretion found in the IDDM-TNF*B2 homozygous cohort.