A Role for VAV1 in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

Abstract

Multiple sclerosis, the most common cause of progressive neurological disability in young adults, is a chronic inflammatory disease. There is solid evidence for a genetic influence in multiple sclerosis, and deciphering the causative genes could reveal key pathways influencing the disease. A genome region on rat chromosome 9 regulates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Using interval-specific congenic rat lines and association of single-nucleotide polymorphisms with inflammatory phenotypes, we localized the gene of influence to Vav1, which codes for a signal-transducing protein in leukocytes. Analysis of seven human cohorts (12,735 individuals) demonstrated an association of rs2546133-rs2617822 haplotypes in the first VAV1 intron with multiple sclerosis (CA: odds ratio, 1.18; CG: odds ratio, 0.86; TG: odds ratio, 0.90). The risk CA haplotype also predisposed for higher VAV1 messenger RNA expression. VAV1 expression was increased in individuals with multiple sclerosis and correlated with tumor necrosis factor and interferon-gamma expression in peripheral blood and cerebrospinal fluid cells. We conclude that VAV1 plays a central role in controlling central nervous system immune-mediated disease and proinflammatory cytokine production critical for disease pathogenesis.

IL-22RA2 Associates with Multiple Sclerosis and Macrophage Effector Mechanisms in Experimental Neuroinflammation

“…For example, crosses between the highly polymorphic DA and PVG. AV1 rat strains, which demonstrate differential susceptibilities to EAE, have led to successful identification of several candidate genes that have also been translated as MS risk genes, including MHCIITA, VAV1, IL-21R, and CCL chemokines (13,(15)(16)(17). Importantly, congenic lines can be established for risk genes and thereby offer a tool in further studying their functional relevance.…”

“…A follow-up study was then performed using a Norwegian cohort including 548 patients (396 female patients) and 554 control subjects (323 female subjects) (15). All patients of the Norwegian cohorts gave written informed consent to participate.…”

T Cell Apoptosis and Induction of Foxp3+ Regulatory T Cells Underlie the Therapeutic Efficacy of CD4 Blockade in Experimental Autoimmune Encephalomyelitis

“…Genetic risk factors indicate that the heritable risk of developing MS is associated with allelic variants of predominantly immune-related genes (3)(4)(5)(6)(7). The strongest association is conferred by the human leukocyte/Ag locus (8).…”

New avenues in MS

“…In a paper published in Science Translational Medicine, a Karolinska team reported that increased levels of Vav 1 guanine nucleotide exchange factor (VAV1), a protein involved in T and B cell activation, are associated with MS. 2 Meanwhile, the University of Tokyo researchers identified microsomal prostaglandin E synthase-1 (PTGES; mPGES-1) as a target involved in the development of pathogenic T cells. That study was published in the Proceedings of the National Academy of Sciences.…”

“…Recent studies have shown that dysfunctional T helper type 1 (TH1) and TH17 cells cause autoreactivity, which can prompt the immune system to attack the myelin sheath around neurons. 1 Thus, many groups are focused on identifying the pathways that lead to the aberrant T cell activation.In a paper published in Science Translational Medicine, a Karolinska team reported that increased levels of Vav 1 guanine nucleotide exchange factor (VAV1), a protein involved in T and B cell activation, are associated with MS. 2 Meanwhile, the University of Tokyo researchers identified microsomal prostaglandin E synthase-1 (PTGES; mPGES-1) as a target involved in the development of pathogenic T cells. That study was published in the Proceedings of the National Academy of Sciences.…”