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THE EFFECT OF TNF*B GENE POLYMORPHISM ON TNF‐α AND ‐β SECRETION LEVELS IN PATIENTS WITH INSULIN‐DEPENDENT DIABETES MELLITUS AND HEALTHY CONTROLS
Author(s) -
Whichelow C. E.,
Hitman G. A.,
Raafat I.,
Bottazzo G. F.,
Sachs J. A.
Publication year - 1996
Publication title -
international journal of immunogenetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.41
H-Index - 47
eISSN - 1744-313X
pISSN - 1744-3121
DOI - 10.1111/j.1744-313x.1996.tb00133.x
Subject(s) - allele , tumor necrosis factor alpha , genotype , medicine , haplotype , endocrinology , immunology , peripheral blood mononuclear cell , diabetes mellitus , secretion , biology , gene , genetics , in vitro
SUMMARY 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.