Fine-Mapping Resolves Eae23 into Two QTLs and Implicates ZEB1 as a Candidate Gene Regulating Experimental Neuroinflammation in Rat

This study was supported by grants from the Swedish Research Council, The Wadsworth Foundation, Söderbergs Foundation, Petrus and Augusta Hedlunds Foundation, Bibbi and Niels Jensens Foundation, Montel Williams Foundation, Åke-Wibergs Stiftelse, the Swedish Foundation for Neurologically Disabled and the EU 6TH Framework EURATools (LSHG-CT-2005-019015) and Neuropromise (LSHM-CT-2005-018637)

A role for VAV1 in experimental autoimmune encephalomyelitis and multiple sclerosis.

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

Temporal overexpression of IL-22 and Reg3 gamma differentially impacts the severity of experimental autoimmune encephalomyelitis

IL-22 is an alpha-helical cytokine which belongs to the IL-10 family of cytokines. IL-22 is produced by ROR gamma t+ innate and adaptive lymphocytes, including ILC3, gamma delta T, iNKT, Th17 and Th22 cells and some granulocytes. IL-22 receptor is expressed primarily by non-haematopoietic cells. IL-22 is critical for barrier immunity at the mucosal surfaces in the steady state and during infection. Although IL-22 knockout mice were previously shown to develop experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), how temporal IL-22 manipulation in adult mice would affect EAE course has not been studied previously. In this study, we overexpressed IL-22 via hydrodynamic gene delivery or blocked it via neutralizing antibodies in C57BL/6 mice to explore the therapeutic impact of IL-22 modulation on the EAE course. IL-22 overexpression significantly decreased EAE scores and demyelination, and reduced infiltration of IFN-gamma+IL-17A+Th17 cells into the central nervous system (CNS). The neutralization of IL-22 did not alter the EAE pathology significantly. We show that IL-22-mediated protection is independent of Reg3 gamma, an epithelial cell-derived antimicrobial peptide induced by IL-22. Thus, overexpression of Reg3 gamma significantly exacerbated EAE scores, demyelination and infiltration of IFN-gamma+IL-17A+ and IL-17A+GM-CSF+Th17 cells to CNS. We also show that Reg3 gamma may inhibit IL-2-mediated STAT5 signalling and impair expansion of Treg cells in vivo and in vitro. Finally, Reg3 gamma overexpression dramatically impacted intestinal microbiota during EAE. Our results provide novel insight into the role of IL-22 and IL-22-induced antimicrobial peptide Reg3 gamma in the pathogenesis of CNS inflammation in a murine model of MS