Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF-alpha and TNF-beta by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus.
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-alpha and TNF-beta by human monocytes and peripheral blood mononuclear cells in 87 unrelated Danish male individuals. Significant differences in TNF-alpha secretory capacity between TNF NcoI restriction fragment length polymorphisms, TNFa and TNFc microsatellite alleles and DR alleles were identified. No correlation with TNF-beta secretory capacity was found for any of the markers studied. TNF genotyping allowed us to define four extended HLA haplotypes which correlate with TNF-alpha 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-alpha 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 the TNFa6 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-alpha response. These observations suggest a direct role for the TNF locus in the pathogenesis of IDDM.
Pociot
F
F
Steno Diabetes Center, Gentofte, Denmark.
Briant
L
L
Jongeneel
C V
CV
Mölvig
J
J
Worsaae
H
H
Abbal
M
M
Thomsen
M
M
Nerup
J
J
Cambon-Thomsen
A
A
D000293:Adolescent; D000328:Adult; D000483:Alleles; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D005802:Genes, MHC Class II; D008040:Genetic Linkage; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics*; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007958:Leukocyte Count; D008233:Lymphotoxin-alpha / Q000235:genetics* / Q000378:metabolism; D008297:Male; D012150:Polymorphism, Restriction Fragment Length; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
D006684:HLA-DR Antigens; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha