Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF‐a and TNF‐0 by human mononuclear cells: a possible link to insulin‐dependent diabetes mellitus

Abstract

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.

Polymorphisms in lymphotoxin alpha and CD14 genes influence TNFα production induced by Gram-positive and Gram-negative bacteria

“…4 This allele association has also been found in vitro using ELISA to measure LPS-induced TNFa after 20 h incubation. 16,17 In contrast, we demonstrated significantly higher TNFa mRNA levels in LTA+250GG subjects 4 h after exposure to LPS, but not after exposure to E. coli or S. pneumoniae. However, S. pneumoniae induced slightly greater TNFa mRNA production in LTA+250AA subjects at 8 h. The variation with published results may be explained by the differing incubation times or the methodologies used.…”

Role of TNF block genetic variants in HIV-associated sensory neuropathy in black Southern Africans

“…In addition, we found no association with the well-known TNF-308/rs1800869*A, which has been associated with high production of TNFa 39 and clinically with rheumatoid arthritis in Egyptians and Brazilians, 40,41 lupus nephritis in Portuguese individuals 42 and type 1 diabetes in Asians. 43 Both BAT1(intron10)*C and TNF-308*A mark FV16 and the 8.1 ancestral haplotype (HLA-A1, B8, DR3, DQ2).…”

“…43 Both BAT1(intron10)*C and TNF-308*A mark FV16 and the 8.1 ancestral haplotype (HLA-A1, B8, DR3, DQ2). 44 Although FV16 did not influence TNFa or LTa production, 37 the 8.1 ancestral haplotype has been associated with higher TNFa production in vitro 39,45,46 and with multiple autoimmune diseases. 20,47 Clearly BAT1(intron10)*C and TNF-308*A do not tag the causative SNPs in Southern Africans.…”

Genetic analysis of multiplex rheumatoid arthritis families

“…30 Thus both our results and those of Mulcahy 11 show a seemingly paradoxical association with a low TNF-producing polymorphism. This raises the question as to whether the independent effect may be due to another MHC-linked gene(s).…”