title: Factors supporting intrathecal humoral responses following viral encephalomyelitis.
abstract: Central nervous system (CNS) infections and autoimmune inflammatory disorders are often associated with retention of antibody-secreting cells (ASC). Although beneficial or detrimental contributions of ASC to CNS diseases remain to be defined, virus-specific ASC are crucial in controlling persistent CNS infection following coronavirus-induced encephalomyelitis. This report characterizes expression kinetics of factors associated with ASC homing, differentiation, and survival in the spinal cord, the prominent site of coronavirus persistence. Infection induced a vast, gamma interferon (IFN-γ)-dependent, prolonged increase in chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10, and CXCL11 mRNA, supporting a role for chemokine (C-X-C motif) receptor 3 (CXCR3)-mediated ASC recruitment. Similarly, CD4 T cell-secreted interleukin-21, a critical regulator of both peripheral activated B cells and CD8 T cells, was sustained during viral persistence. The ASC survival factors B cell-activating factor of the tumor necrosis factor (TNF) family (BAFF) and a proliferating-inducing ligand (APRIL) were also significantly elevated in the infected CNS, albeit delayed relative to the chemokines. Unlike IFN-γ-dependent BAFF upregulation, APRIL induction was IFN-γ independent. Moreover, both APRIL and BAFF were predominantly localized to astrocytes. Last, the expression kinetics of the APRIL and BAFF receptors coincided with CNS accumulation of ASC. Therefore, the factors associated with ASC migration, differentiation, and survival are all induced during acute viral encephalomyelitis, prior to ASC accumulation in the CNS. Importantly, the CNS expression kinetics implicate rapid establishment, and subsequent maintenance, of an environment capable of supporting differentiation and survival of protective antiviral ASC, recruited as plasmablasts from lymphoid organs.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NC30, Cleveland, OH 44195, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Phares
authors.forename: Cristina P
authors.initials: CP
authors.lastname: Marques
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Stohlman
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
authors.forename: Cornelia C
authors.initials: CC
authors.lastname: Bergmann
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000276:immunology; D017934:Coronavirus / Q000276:immunology; D018352:Coronavirus Infections / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004679:Encephalomyelitis / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013116:Spinal Cord / Q000276:immunology / Q000821:virology
chemical_list: D000914:Antibodies, Viral; D016207:Cytokines