Sex-Specific Regulation of Cns Autoimmunity by the Signal Lymphocytic Activation Molecule (slam) Locus

Abstract Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system (CNS). Epidemiological studies have documented a 3–6 fold increase in MS incidence and prevalence in females over the last half-century, while remaining relatively stable in males. This establishes that gene×environment×sex interactions contribute to MS susceptibility. Genome-wide association studies (GWAS) of MS patients identified multiple candidate genes, including a locus containing the signal lymphocytic activation molecule (SLAM) family of receptors, a region rich in immune-relevant genes that is highly conserved between humans and mice. There are two major Slam haplotypes segregating in laboratory mice. Slam haplotype-1 is present in C57BL/6 (B6) mice and haplotype-2 is expressed in most other common inbred laboratory strains, including 129 mice. The congenic B6.129c1 mouse possesses the 129-derived Slam haplotype-2 locus on the B6 background, which allows for assessing the potential contribution of SLAM family genes to MS susceptibility using the myelin oligodendrocyte (MOG) model of experimental autoimmune encephalomyelitis (EAE). We show that male B6.129c1 congenic mice demonstrate significant protection against MOG-EAE, but only in males. Furthermore, draining lymph nodes from immunized B6.129c1 males, but not females, had increased Foxp3+ regulatory T cells (Treg) and IL-10 levels compared with B6, suggesting that SLAM/Slam haplotypes regulate autoimmunity by modulating the generation of immunoregulatory cells in a sex-specific manner. Taken together, our results support a role for the SLAM locus is MS pathogenesis, and reveal a novel sexual dimorphism in the genetic control of this autoimmune disease