Immunologic dysfunction underlies pathology in a mouse model of Rett syndrome. (111.52)

Abstract

Abstract Rett syndrome is a devastating autism spectrum disorder, characterized by tremors, breathing dysregulation, impaired locomotion, and mental retardation. Most cases are caused by mutation of the X-linked gene, MECP2, which encodes a methyl-CpG-binding protein. Although MECP2 is expressed in many cell types, pathology has been generally attributed to neuronal dysfunction. However, we recently showed striking arrest of disease in the Mecp2-null mouse model of Rett by manipulation of the immune system. LysmCre-directed wild type MECP2 expression in myeloid cells of Mecp2-null mice and bone-marrow transplantation from wild type into Mecp2-null mice both markedly improved several disease sequelae. When peripheral myeloid cells from Mecp2-null mice were examined, they were significantly impaired in cytokine production (TNF and IL-10) and growth factors (IGF-1) after stimulation, and in phagocytosis. Moreover, peripheral organs from Mecp2-mutant mice showed significantly increased levels of monocytes and granulocytes, as well as a striking skew towards a naïve (CD62LHigh/CD44low) phenotype of T cells. In addition, spleens and livers of Mecp2-mutant mice are significantly smaller than those from wild type. Importantly, these findings correlated with data from human patients, who displayed similar hematologic changes. These data suggest that loss of Mecp2 may lead to immunologic dysfunction, which could underlie pathologies seen in Rett syndrome.