Relationship between tumour necrosis factor-alpha (TNF alpha) production and a specific multiple sclerosis (MS) associated TNF gene haplotype

Objective: To determine if monocyte TNF alpha production from patients homo zygous for a specific MS associated TNF gene haplotype is different from th at produced in patients either heterozygous for, or without this haplotype. Background: The balance between pro- and anti-inflammatory cytokines is im portant in the clinical outcome of inflammatory reactions. Levels of TNF al pha, a pro-inflammatory cytokine, is raised in MS as well as being found in acute and chronic MS lesions. A Previous population based study in Norther n Ireland with polymorphisms spanning the TNF gene region identified a cons erved MS associated haplotype in relation to three markers (130 : 118 : 127 TNF d : a : b) for which 19 MS patients were homozygous. Methods: Venous b lood collected in EDTA to give a concentration of 10(-3) M was drown from 1 6 patients with the conserved MS associated haplotype, 19 patients heterozy gous for the haplotype and 17 patients without the haplotype. Mononuclear c ells were separated and cultured by standard techniques and levels of TNF a lpha and of TNF binding proteins I and II were determined by commercial enz yme-linked immunosorbent assays. Results: There were no significant differe nces in TNF alpha production in the 3 h (P=0.28) or 24 h cultures (P=0.18) or following stimulation with interferon-gamma (P=0.17) between the group p ositive for the conserved haplotype and the group negative for this haploty pe. There was also no significant difference when compared to the heterozyg ote group. No association was found between the MS associated haplotype and levels of either TNF binding protein. A greeter proportion of patients wit h the conserved haplotype had a benign clinical course (P=0.06). Conclusion : We conclude that whilst a trend exists, we have found no significant asso ciation between peripheral TNF alpha production and a specific MS associate d TNF haplotype in this population. Paradoxically this haplotype may also p redict a more favourable clinical course.