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Research paper
Stimulated PBMC-produced IFN-γ and TNF-α are associated with altered relapse risk in multiple sclerosis: results from a prospective cohort study
  1. Steve Simpson Jr1,
  2. Niall Stewart2,3,
  3. Ingrid van der Mei1,
  4. Petr Otahal1,
  5. Jac Charlesworth1,
  6. Anne-Louise Ponsonby4,
  7. Leigh Blizzard1,
  8. Terence Dwyer4,
  9. Fotini Pittas2,
  10. Peter Gies5,
  11. Bruce Taylor1
  1. 1Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia
  2. 2School of Medicine, University of Tasmania, Hobart, Tasmania, Australia
  3. 3School of Pharmacy, University of Tasmania, Hobart, Tasmania, Australia
  4. 4Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia
  5. 5Ultraviolet Radiation Section, Australian Radiation Protection and Nuclear Safety Agency, Yallambie, Victoria, Australia
  1. Correspondence to Dr Steve Simpson Jr, Menzies Research Institute Tasmania, University of Tasmania, Private bag 23, Hobart, TAS 7000, Australia; steve.simpson{at}


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.

  • Multiple Sclerosis
  • Epidemiology
  • Immunology

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