IFNG polymorphisms are associated with gender differences in susceptibility to multiple sclerosis

Kantarci, Orhun H.; Goris, An; Hebrink, David D.; Heggarty, Shirley; Cunningham, Stephen; Alloza, Iraide; Atkinson, Elizabeth J.; Andrade, Mariza de; McMurray, Cynthia T.; Graham, Colin A.; Hawkins, Stanley; Billiau, Alfons; Dubois, Bénédicte; Weinshenker, Brian G.; Vandenbroeck, Koen

doi:10.1038/sj.gene.6364164

Cited by 58 publications

(35 citation statements)

References 80 publications

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“…Alternatively, genetic variants that affect expression or function of IFNγ might influence the susceptibility to MS and severity of the disease. Weinshenker and colleagues showed that being a carrier of the A allele of a 3′(325)*G→A single nucleotide polymorphism just 3′ to the IFNG gene is associated with increased susceptibility to MS in men (Kantarci et al, 2005). More recently, we have shown that this polymorphism is associated with decreased IFNγ protein and mRNA expression in men with MS (Kantarci et al, 2007).…”

Section: Discussionmentioning

confidence: 96%

Multiple sclerosis patients show sexual dimorphism in cytokine responses to myelin antigens

Moldovan

Cotleur

Zamor

et al. 2008

Journal of Neuroimmunology

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Multiple sclerosis affects more women than men. The reasons for this are unknown. Previously, we have shown significant differences in women versus men in inflammatory cytokine responses to the major protein component of myelin, proteolipid protein (PLP), which is thought to be a target in MS patients. Here, using the ELISPOT assay, we examined sex differences in single-cell secretion of Th1 and Th2 cytokines from freshly isolated PBMC between relapsing remitting (RR) MS patients and healthy individuals. Cells were stimulated with MS-associated antigens including proteolipid protein (PLP), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and nondisease related antigens. Our data show a sex bias in the cytokine responses to multiple MS-relevant myelin antigens: Women with MS show IFNγ-skewed responses and men with MS show IL-5-skewed responses. These data extend our previous findings (Pelfrey et al., 2002): (1) by demonstrating gender skewing in cytokine responses to an expanded myelin antigen repertoire, which includes MBP, MOG and PLP; (2) by showing TNFα and IL-10 do not display comparable gender skewing compared to IFNγ and IL5; (3) by defining the patient population as early, untreated RR MS patients to avoid confounding factors, such as different disease stages/disability and immunomodulatory therapy; and (4) by showing HLA type does not appear to underlie the gender differences. These findings may explain increased susceptibility to MS in women and could contribute to the differences in disease severity between men and women.

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Section: Discussionmentioning

confidence: 96%

Multiple sclerosis patients show sexual dimorphism in cytokine responses to myelin antigens

Moldovan

Cotleur

Zamor

et al. 2008

Journal of Neuroimmunology

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“…An increasing number of reports have pointed to sex-specific association of common gene polymorphisms with autoimmunity. For instance, CD95 was found to be associated with susceptibility to MS in women (Kantarci et al, 2004a), APOE with disease severity of MS in women (Kantarci et al, 2004b), IFNG with susceptibility to MS in men (Goris et al, 2002;Kantarci et al, 2005) and IL26 with susceptibility to RA in women (Vandenbroeck et al, 2003). These data call for a systematic whole-genome scrutiny for gender-specific autoimmune susceptibility factors.…”

Section: Discussionmentioning

confidence: 96%

Polymorphisms in the interleukin-4 and IL-4 receptor genes modify risk for chronic inflammatory arthropathies in women

Suppiah

Rooney

Vandenbroeck

2006

Experimental and Molecular Pathology

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Polymorphisms in the interleukin-4 and IL-4 receptor genes modify risk for chronic inflammatory arthropathies in women. Suppiah, V., Rooney, M., & Vandenbroeck, K. (2006). Polymorphisms in the interleukin-4 and IL-4 receptor genes modify risk for chronic inflammatory arthropathies in women. AbstractRheumatoid and juvenile idiopathic arthritis (RA, JIA) are chronic inflammatory arthropathies with polygenic autoimmune background. We analysed the IL-4 +33 C/T and IL-4R Q551R single nucleotide polymorphisms (SNPs) in 294 RA, 72 JIA and 165 controls from Northern Ireland. Analysis of the individual phenotypes (RA or JIA) showed that both the IL-4 +33 TT (P = 0.02; OR: 0.25, 95% CI: 0.07-0.87) and the IL-4R Q551R CC genotypes (P = 0.001; OR: 0.19, 95% CI: 0.06-0.56) were exclusively decreased in female RA patients compared to female controls. Similar non-significant trends were observed in female JIA patients (OR: 0.25, 95% CI: 0.03-2.11 and OR: 0.31, 95% CI: 0.07-1.47, respectively). Analysis of the common phenotype (inflammatory arthropathy; i.e. JIA and RA combined) corroborated the unique association of these polymorphisms with female inflammatory arthropathy (P = 0.013 and 0.002, respectively). This is the first demonstration of sex-specific association of the two foremost genes of the IL-4 signalling cascade with chronic inflammatory arthropathies.

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“…The protective effect of IFN-␤ therapy in MS patients has been attributed, at least in part, to down-regulation of IFN-␥ production (73). Myelin Ag-induced IFN-␥ production is more efficient in female MS patients as compared with males (74). MS patients treated with systemic IFN-␥ had a dramatic worsening of the disease (75).…”

Section: Discussionmentioning

confidence: 99%

Severe Disease, Unaltered Leukocyte Migration, and Reduced IFN-γ Production in CXCR3−/− Mice with Experimental Autoimmune Encephalomyelitis

Liu

Huang

Matsui

et al. 2006

The Journal of Immunology

135

112

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Experimental autoimmune encephalomyelitis (EAE) is a CD4+ Th1 T cell-mediated disease of the CNS, used to study certain aspects of multiple sclerosis. CXCR3, the receptor for CXCL10, CXCL9, and CXCL11, is preferentially expressed on activated Th1 T cells and has been proposed to govern the migration of lymphocytes into the inflamed CNS during multiple sclerosis and EAE. Unexpectedly, CXCL10-deficient mice were susceptible to EAE, leaving uncertain what the role of CXCR3 and its ligands might play in this disease model. In this study, we report that CXCR3−/− mice exhibit exaggerated severity of EAE compared with wild-type (CXCR3+/+) littermate mice. Surprisingly, there were neither quantitative nor qualitative differences in CNS-infiltrating leukocytes between CXCR3+/+ and CXCR3−/− mice with EAE. Despite these equivalent inflammatory infiltrates, CNS tissues from CXCR3−/− mice with EAE showed worsened blood-brain barrier disruption and more von Willebrand factor-immunoreactive vessels within inflamed spinal cords, as compared with CXCR3+/+ mice. Spinal cords of CXCR3−/− mice with EAE demonstrated decreased levels of IFN-γ, associated with reduced inducible NO synthase immunoreactivity, and lymph node T cells from CXCR3−/− mice primed with MOG35–55 secreted less IFN-γ in Ag-driven recall responses than cells from CXCR3+/+ animals. CXCR3−/− lymph node T cells also showed enhanced Ag-driven proliferation, which was reduced by addition of IFN-γ. Taken with prior findings, our data show that CXCL10 is the most relevant ligand for CXCR3 in EAE. CXCR3 does not govern leukocyte trafficking in EAE but modulates T cell IFN-γ production and downstream events that affect disease severity.

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IFNG polymorphisms are associated with gender differences in susceptibility to multiple sclerosis

Cited by 58 publications

References 80 publications

Multiple sclerosis patients show sexual dimorphism in cytokine responses to myelin antigens

Multiple sclerosis patients show sexual dimorphism in cytokine responses to myelin antigens

Polymorphisms in the interleukin-4 and IL-4 receptor genes modify risk for chronic inflammatory arthropathies in women

Severe Disease, Unaltered Leukocyte Migration, and Reduced IFN-γ Production in CXCR3−/− Mice with Experimental Autoimmune Encephalomyelitis

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