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BACKGROUND: Altered reactivity of peripheral blood mononuclear cells (PBMC) and their production of cytokines may affect multiple sclerosis (MS) clinical course. We assessed the relationship of stimulated PBMC-produced IFN-γ, TNF-α, IL-4 and IL-10 in modulating relapse risk using a prospective cohort with established relapsing-remitting MS. METHODS: Cytokine production from PBMCs taken in summer and winter was measured by ELISA. Predictors of cytokines assessed by multilevel mixed-effects linear regression. Predictors of relapse assessed by survival analysis. RESULTS: Increasing IFN-γ was associated with increasing relapse risk, while increasing TNF-α reduced relapse risk after adjusting for IFN-γ. IL-10 and IL4 were not consistently associated with relapse risk. IFN-γ's effects on relapse were greatly attenuated by immunomodulatory therapies, by summer season and by higher serum vitamin D, whereas TNF-α's inverse association with relapse was only present in these circumstances. The TNF-α inverse association with relapse was only present among persons carrying the wild-type of the functional SNP rs1800693 in TNFRSF1A that has been previously associated with MS risk. CONCLUSIONS: We found strong effects of IFN-γ and TNF-α on relapse risk, these differing by immunomodulatory therapy, season, and serum vitamin D, as well as by genotype. These results indicate altered reactivity of immune cells modulate MS disease.

Original publication




Journal article


J Neurol Neurosurg Psychiatry

Publication Date





200 - 207


Epidemiology, Immunology, Multiple Sclerosis, Adult, Aged, Female, Genotype, Humans, Immunomodulation, Interferon-gamma, Interleukin-10, Interleukin-4, Leukocytes, Mononuclear, Male, Middle Aged, Multiple Sclerosis, Relapsing-Remitting, Polymorphism, Single Nucleotide, Prospective Studies, Receptors, Tumor Necrosis Factor, Type I, Recurrence, Risk Factors, Seasons, Survival Analysis, Tumor Necrosis Factor-alpha, Vitamin D, Young Adult