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 TNF*B 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 TNF*B genotype in healthy individuals: those with the TNF B*2 allele secreted significantly higher levels of TNF-beta (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-beta than those with the TNF*B2 allele. No correlation was found between TNF-alpha 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-beta 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-beta secretion found in the IDDM-TNF*B2 homozygous cohort.
Whichelow
C E
CE
Department of Immunology, St. Bartholomew's & The Royal London School of Medicine & Dentistry, UK.
Hitman
G A
GA
Raafat
I
I
Bottazzo
G F
GF
Sachs
J A
JA
D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005838:Genotype; D015235:HLA-B Antigens / Q000145:classification; D006684:HLA-DR Antigens / Q000145:classification; D006239:Haplotypes; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008233:Lymphotoxin-alpha / Q000235:genetics* / Q000276:immunology; D011110:Polymorphism, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000276:immunology
D015235:HLA-B Antigens; D006684:HLA-DR Antigens; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha