Relationship between tumour necrosis factor-alpha (TNFalpha) production and a specific multiple sclerosis (MS) associated TNF gene haplotype.
OBJECTIVE
To determine if monocyte TNFalpha production from patients homozygous for a specific MS associated TNF gene haplotype is different from that produced in patients either heterozygous for, or without this haplotype.


BACKGROUND
The balance between pro- and anti-inflammatory cytokines is important in the clinical outcome of inflammatory reactions. Levels of TNFalpha, 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 Northern Ireland with polymorphisms spanning the TNF gene region identified a conserved MS associated haplotype in relation to three markers (130: 118: 127 TNF d:a:b) for which 19 MS patients were homozygous.


METHODS
Venous blood collected in EDTA to give a concentration of 10(-3) M was drawn from 16 patients with the conserved MS associated haplotype, 19 patients heterozygous for the haplotype and 17 patients without the haplotype. Mononuclear cells were separated and cultured by standard techniques and levels of TNFalpha and of TNF binding proteins I and II were determined by commercial enzyme-linked immunosorbent assays.


RESULTS
There were no significant differences in TNFalpha 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 positive for the conserved haplotype and the group negative for this haplotype. There was also no significant difference when compared to the heterozygote group. No association was found between the MS associated haplotype and levels of either TNF binding protein. A greater proportion of patients with the conserved haplotype had a benign clinical course (P = 0.06).


CONCLUSIONS
We conclude that whilst a trend exists, we have found no significant association between peripheral TNFalpha production and a specific MS associated TNF haplotype in this population. Paradoxically this haplotype may also predict a more favourable clinical course.
Armstrong
M A
MA
Department of Microbiology & Immunobiology, The Queen's University of Belfast, Northern Ireland, UK.
McDonnell
G V
GV
Graham
C A
CA
Kirk
C W
CW
Droogan
A G
AG
Hawkins
S A
SA
D002478:Cells, Cultured; D016207:Cytokines / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003627:Data Interpretation, Statistical; D004797:Enzyme-Linked Immunosorbent Assay; D005819:Genetic Markers; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D009000:Monocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism; D009660:Northern Ireland; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D013268:Stimulation, Chemical; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*
D016207:Cytokines; D005819:Genetic Markers; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma