title: Cytokine regulation of B-cell migratory behavior favors formation of germinal centers in autoimmune disease.
abstract: Chemotaxis is essential for shaping immune responses and chemokine-receptor antagonists are now being evaluated as therapies for various inflammatory and autoimmune diseases. However, the dysregulation of chemotaxis in autoimmune disease may involve both promotion and inhibition of B-cell migration. This review focuses on the disparate mechanisms by which two inflammatory cytokines that have been associated with autoimmune disease, namely interferon-alpha (IFN-alpha) and interleukin-17 (IL-17), may regulate B-cell migratory responses. Chemotactic responses play a key role in orchestrating the cell-cell interactions in the germinal centers (GCs). This process involves active shuttling of the antigen-carrying B cells between the marginal zone and the GCs. We have shown that in autoimmune BXD2 mice, the migration of marginal zone precursor B cells is promoted by high levels of IFN-alpha produced by plasmacytoid dendritic cells in the marginal sinus that antagonize the activity of the S1P(1) chemokine receptor. In contrast, within the GCs, interleukin-17A (IL-17A) upregulates the expression of regulators of G protein signaling (RGS) in B cells to desensitize the G protein-coupled receptor (GPCR) signaling pathway of CXCL12 and CXCL13 chemokines. This promotes a prolonged stable interaction of B and T cells in the GC that induces high levels of activation-induced cytidine deaminase (AICDA) thereby enabling development of pathogenic autoantibody-producing B cells.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, 35294, USA. jdmountz@uab.edu
authors.forename: John D
authors.initials: JD
authors.lastname: Mountz
authors.forename: John H
authors.initials: JH
authors.lastname: Wang
authors.forename: Shutao
authors.initials: S
authors.lastname: Xie
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Hsu
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D002465:Cell Movement / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D018858:Germinal Center / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D018448:Models, Immunological
chemical_list: D016207:Cytokines