SECRETION OF TUMOR-NECROSIS-FACTOR-ALPHA AND LYMPHOTOXIN-ALPHA IN RELATION TO POLYMORPHISMS IN THE TNF GENES AND HLA-DR ALLELES - RELEVANCEFOR INFLAMMATORY BOWEL-DISEASE

The genes for tumour necrosis factor alpha (TNF alpha) and lymphotoxin alpha (LT alpha; TNF beta) are tandemly arranged in the central regio n of the MHC. They may, therefore, be of importance for the aetiology of MHC-associated diseases. The authors have prospectively studied the secretion of TNF alpha and LT alpha in relation to polymorphisms at p ositions-308 and -238 in the TNF alpha gene (TNFA), and two polymorphi sms in the first intron of the LT alpha gene (LTA), as well as HLA-DR in 30 patients with chronic inflammatory bowel diseases (IBD) and 12 h ealthy controls. In the Dutch population, the alleles of these four po lymorphisms are present in only five combinations, called TNF-haplotyp es: TNF-C, -E, -H, -I, and -P. Significant associations between TNF ha plotypes and TNF alpha and LT alpha secretion were found when PBMC wer e cultured with T-cell activators, irrespective of disease. Mean TNF a lpha secretion of individuals carrying the HLA-DR3 associated TNF-E ha plotype was significantly higher, as compared to individuals without t his haplotype (26 441 pg/ml versus 19 629 pg/ml; P = 0.014). Individua ls carrying the TNF-C haplotype produced the lowest amount of TNF alph a (17 408 pg/ml; P = 0.022). The TNF-C and TNF-E haplotypes differ onl y at position -308 in the promoter of TNFA. Individuals carrying the H LA-DR1 associated TNF-I haplotype produced significantly less LT alpha when compared to those who lack this haplotype (1979 pg/ml versus 346 2 pg/ml; P = 0.006). As the TNF-I haplotype is also associated with lo w TNF alpha secretion, this haplotype thus defines a 'low secretor phe notype'. In conclusion, this is the first study to show associations b etween TNF haplotypes and TNF alpha and LT alpha secretion when T-cell stimulators are used. These findings will contribute to define diseas e heterogeneity in IBD and may be of relevance for understanding the p athogenesis of autoimmune diseases.