title: Progression from IgD+ IgM+ to isotype-switched B cells is site specific during coronavirus-induced encephalomyelitis.
abstract: Various infections in the central nervous system (CNS) trigger B cell accumulation; however, the relative dynamics between viral replication and alterations in distinct B cell subsets are largely unknown. Using a glia-tropic coronavirus infection, which is initiated in the brain but rapidly spreads to and predominantly persists in the spinal cord, this study characterizes longitudinal changes in B cell subsets at both infected anatomical sites. The phase of T cell-dependent, antibody-independent control of infectious virus was associated with a similar recruitment of naive/early-activated IgD(+) IgM(+) B cells into both the brain and spinal cord. This population was progressively replaced by CD138(-) IgD(-) IgM(+) B cells, isotype-switched CD138(-) IgD(-) IgM(-) memory B cells (B(mem)), and CD138(+) antibody-secreting cells (ASC). A more rapid transition to B(mem) and ASC in spinal cord than in brain was associated with higher levels of persisting viral RNA and transcripts encoding factors promoting B cell migration, differentiation, and survival. The results demonstrate that naive/early-activated B cells are recruited early during coronavirus CNS infection but are subsequently replaced by more differentiated B cells. Furthermore, viral persistence, even at low levels, is a driving force for accumulation of isotype-switched B(mem) and ASC.
  
  
  OBJECTIVE
  Acute and chronic human CNS infections are associated with an accumulation of heterogeneous B cell subsets; however, their influence on viral load and disease is unclear. Using a glia-tropic coronavirus model, we demonstrate that the accumulation of B cells ranging from early-activated to isotype-switched differentiation stages is both temporally and spatially orchestrated. Acutely infected brains and spinal cords indiscriminately recruit a homogeneous population of early-activated B cells, which is progressively replaced by diverse, more differentiated subsets. The latter process is accelerated by elevated proinflammatory responses associated with viral persistence. The results imply that early-recruited B cells do not have antiviral function but may contribute to the inflammatory environment or act as antigen-presenting cells. Moreover, CNS viral persistence is a driving force promoting differentiated B cells with protective potential.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Phares
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA School of Biomedical Sciences, Kent State University, Kent, Ohio, USA.
authors.forename: Krista D
authors.initials: KD
authors.lastname: DiSano
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Stohlman
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA bergmac@ccf.org.
authors.forename: Cornelia C
authors.initials: CC
authors.lastname: Bergmann
mesh_terms: D000818:Animals; D000921:Antibody-Producing Cells / Q000276:immunology / Q000821:virology; D000938:Antigen-Presenting Cells / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000821:virology; D001921:Brain / Q000276:immunology / Q000821:virology; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D017934:Coronavirus / Q000276:immunology*; D018352:Coronavirus Infections / Q000276:immunology* / Q000821:virology; D004679:Encephalomyelitis / Q000276:immunology* / Q000821:virology; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007072:Immunoglobulin D / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D012367:RNA, Viral / Q000276:immunology; D013116:Spinal Cord / Q000276:immunology / Q000821:virology
chemical_list: D007072:Immunoglobulin D; D007075:Immunoglobulin M; D012367:RNA, Viral