Influence of metabolic and genetic factors on tumour necrosis factor-alpha and lymphotoxin-alpha production in insulin-dependent diabetes mellitus.
The potential role of tumour necrosis factors (TNFs) in autoimmunity and insulin-dependent diabetes mellitus (IDDM) led us to determine in vitro TNF-alpha and lymphotoxin-alpha (LT-alpha, TNF-beta) production in IDDM patients according to TNF polymorphism. LT-alpha production of peripheral blood mononuclear cells (PBMC) was lower in diabetic subjects (m = 0.30 +/- 0.2 ng.10(-6) cells) than controls (m = 0.68 +/- 0.3 ng.10(-6) cells, p < 0.05), and early age-at-onset was correlated with low LT-alpha production (rs = 0.8, p = 0.0006). TNF-alpha production was the same in patients and controls, but patients with HbA1c > or = 8% had a higher TNF-alpha production (m = 3.05 +/- 1.2 ng.10(-6) cells) than those with HbA1c < 8% (m = 1.31 +/- 0.33 ng.10(-6) cells, p < 0.05). A study of the microsatellite TNFa region close to the LTA gene showed that the presence of the TNFa1 allele in HLA-(DR3) subjects was associated with increased risk of IDDM. TNFa1-positive subjects (both patients and controls) also had lower LT-alpha production than other subjects. These results indicate that low LT-alpha production is an additional risk factor for IDDM and that poor glycaemic control in patients is associated with enhanced PBMC TNF-alpha production which causes an imbalance between TNF-alpha and LT-alpha production in IDDM patient.
Feugeas
J P
JP
Laboratory of Vascular and Cellular Biology, Hôpital Lariboisière, Paris, France.
Caillens
H
H
Poirier
J C
JC
Charron
D
D
Marcelli-Barge
A
A
Wautier
J L
JL
D000293:Adolescent; D017668:Age of Onset; D000483:Alleles; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005802:Genes, MHC Class II; D020022:Genetic Predisposition to Disease; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000096:biosynthesis*; D008297:Male; D011110:Polymorphism, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
D006680:HLA Antigens; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha