Regulation of expansion of CD11c + B cells and anti-viral immunity by epithelial V-like antigen.

Prior work demonstrated that epithelial V-like antigen (EVA), a cell surface adhesion molecule, is expressed in B lymphocytes and is necessary for the efficacy of anti-alpha ₄ integrin treatment of experimental autoimmune encephalomyelitis (EAE), the mouse model of human multiple sclerosis. EVA deficiency is associated with a severe clinical phenotype of EAE in the presence or absence of treatment. Histological analysis revealed enhanced B cell-mediated autoimmunity and deposition of antibody and complement within the brain and spinal cord. Here our goal was to determine the molecular mechanism of EVA regulation of B lymphocyte function. Analysis of bone marrow from MOG-immunized mice revealed increased expansion of CD11c ⁺ B cells in EVA-deficient mice as compared to wild type controls. In vitro studies of mouse bone marrow B lymphocytes revealed enhanced proliferation of the CD11c ⁺ population in response to the Tlr7/8 agonist R848. An increase in R848-induced proliferation of CD11c ⁺ B cells was also seen in vitro in Daudi cells, a human B cell line, following knockdown of the mpzl2 gene that encodes EVA. These mechanisms were characterized further by global expression analysis of bone marrow from immunized EVA-deficient and wild type control mice. These data revealed increased expression of B cell associated genes and decreased expression of the anti-viral oligoadenylate synthase genes, Oas1 and Oas2, in the knockout condition. In Daudi cells, R848 treatment induced an increase in Oas2 expression in control cells that was not observed in EVA-deficient cells. EVA deficiency also was associated with increased transcription of an Epstein-Barr virus gene during lytic replication. These results suggest EVA expression and signaling prevent expansion of CD11c ⁺ B lymphocytes, a cellular phenotype associated with autoimmunity, increase expression of anti-viral oligoadenylate synthase genes, and reduce replication of a DNA virus.
(Copyright © 2019. Published by Elsevier GmbH.)