title: CNS accumulation of regulatory B cells is VLA-4-dependent.
abstract: OBJECTIVE
  To investigate the role of very late antigen-4 (VLA-4) on regulatory B cells (Breg) in CNS autoimmune disease.
  
  
  METHODS
  Experimental autoimmune encephalomyelitis (EAE) was induced in mice selectively deficient for VLA-4 on B cells (CD19cre/α4(f/f)) by immunization with myelin oligodendrocyte glycoprotein (MOG) peptide (p)35-55 or recombinant human (rh) MOG protein. B-cell and T-cell populations were examined by flow cytometry and immunohistochemistry. Breg were evaluated by intracellular IL-10 staining of B cells and, secondly, by coexpression of CD1d and CD5.
  
  
  RESULTS
  As previously reported, EAE was less severe in B-cell VLA-4-deficient vs control CD19cre mice when induced by rhMOG, a model that is B-cell-dependent and leads to efficient B-cell activation and antibody production. Paradoxically, B-cell VLA-4-deficient mice developed more severe clinical disease than control mice when EAE was induced with MOG p35-55, a B-cell-independent encephalitogen that does not efficiently activate B cells. Peripheral T-cell and humoral immune responses were not altered in B-cell VLA-4-deficient mice. In MOG p35-55-induced EAE, B-cell VLA-4 deficiency reduced CNS accumulation of B but not T cells. Breg were detected in the CNS of control mice with MOG p35-55-induced EAE. However, more severe EAE in B-cell VLA-4-deficient mice was associated with virtual absence of CNS Breg.
  
  
  CONCLUSIONS
  Our results demonstrate that CNS accumulation of Breg is VLA-4-dependent and suggest that Breg may contribute to regulation of CNS autoimmunity in situ. These observations underscore the need to choose the appropriate encephalitogen when studying how B cells contribute to pathogenesis or regulation of CNS autoimmunity.
authors.affiliation: Department of Neurology and Program in Immunology (K.L.-H., S.A.S., R.C.W., C.M.S., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University School of Medicine, CA. Dr. Lehmann-Horn is currently with the Department of Neurology, Klinikum rechts der Isar, Technische Universität München; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Lehmann-Horn
authors.affiliation: Department of Neurology and Program in Immunology (K.L.-H., S.A.S., R.C.W., C.M.S., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University School of Medicine, CA. Dr. Lehmann-Horn is currently with the Department of Neurology, Klinikum rechts der Isar, Technische Universität München; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Sagan
authors.affiliation: Department of Neurology and Program in Immunology (K.L.-H., S.A.S., R.C.W., C.M.S., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University School of Medicine, CA. Dr. Lehmann-Horn is currently with the Department of Neurology, Klinikum rechts der Isar, Technische Universität München; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Winger
authors.affiliation: Department of Neurology and Program in Immunology (K.L.-H., S.A.S., R.C.W., C.M.S., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University School of Medicine, CA. Dr. Lehmann-Horn is currently with the Department of Neurology, Klinikum rechts der Isar, Technische Universität München; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Collin M
authors.initials: CM
authors.lastname: Spencer
authors.affiliation: Department of Neurology and Program in Immunology (K.L.-H., S.A.S., R.C.W., C.M.S., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University School of Medicine, CA. Dr. Lehmann-Horn is currently with the Department of Neurology, Klinikum rechts der Isar, Technische Universität München; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Claude C A
authors.initials: CC
authors.lastname: Bernard
authors.affiliation: Department of Neurology and Program in Immunology (K.L.-H., S.A.S., R.C.W., C.M.S., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University School of Medicine, CA. Dr. Lehmann-Horn is currently with the Department of Neurology, Klinikum rechts der Isar, Technische Universität München; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.affiliation: Department of Neurology and Program in Immunology (K.L.-H., S.A.S., R.C.W., C.M.S., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University School of Medicine, CA. Dr. Lehmann-Horn is currently with the Department of Neurology, Klinikum rechts der Isar, Technische Universität München; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Zamvil