Stimulated PBMC-produced IFN-γ and TNF-α are associated with altered relapse risk in multiple sclerosis: results from a prospective cohort study.
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.
Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
Steve
http://orcid.org/0000-0001-6521-3056
S
Simpson
School of Medicine, University of Tasmania, Hobart, Tasmania, Australia School of Pharmacy, University of Tasmania, Hobart, Tasmania, Australia.
Niall
N
Stewart
Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
Ingrid
I
van der Mei
Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
Petr
P
Otahal
Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
Jac
J
Charlesworth
Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
Anne-Louise
AL
Ponsonby
Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
Leigh
L
Blizzard
Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
Terence
T
Dwyer
School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.
Fotini
F
Pittas
Ultraviolet Radiation Section, Australian Radiation Protection and Nuclear Safety Agency, Yallambie, Victoria, Australia.
Peter
P
Gies
Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
Bruce
B
Taylor
D000328:Adult; D000368:Aged; D005260:Female; D005838:Genotype; D006801:Humans; D056747:Immunomodulation; D007371:Interferon-gamma / Q000097:blood* / Q000378:metabolism; D016753:Interleukin-10 / Q000097:blood / Q000378:metabolism; D015847:Interleukin-4 / Q000097:blood / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D012008:Recurrence; D012307:Risk Factors; D012621:Seasons; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000097:blood* / Q000378:metabolism; D014807:Vitamin D / Q000097:blood; D055815:Young Adult
C508609:IL10 protein, human; C508598:IL4 protein, human; D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D014807:Vitamin D; D015847:Interleukin-4; D007371:Interferon-gamma
Epidemiology; Immunology; Multiple Sclerosis