title: TLR-mediated B cell activation results in ectopic CLIP expression that promotes B cell-dependent inflammation.
abstract: Infectious pathogens produce compounds called Toll ligands that activate TLRs on lymphocytes. Acute activation triggered by certain TLRs appears to "jump start" the innate immune response, characterized by the release of inflammatory cytokines and cellular expansion. In some individuals, there is a failure to control acute inflammation, resulting in postinfectious, chronic inflammation. Susceptibility to chronic inflammation is strongly associated with an individual's MHC genes. Recent clinical trials for several autoimmune diseases characterized by chronic inflammation suggest that B lymphocyte depletion therapies dampen chronic immune activation. However, currently, there is no known mechanism that accounts for the correlation among TLR activation, MHC genetics, and a pathological role for B-lymphocytes. Our hypothesis is that TLR-activated B cells (B cells that have been polyclonally activated in the absence of antigen-specific signals) are not controlled properly by T cell-dependent B cell death, thereby causing B cell-dependent chronic inflammation. Here, we show that treatment with Toll ligands results in polyclonal B cell activation accompanied by ectopic expression of CLIP. Furthermore, by adoptively transferring purified CLIP+ B cells in syngeneic animals, we find that CLIP+ B cells induce production of TNF-α by host T cells. Finally, we demonstrate that CLIP-targeted peptide competition results in the death of polyclonally activated CLIP+ B cells.
authors.affiliation: CU Institute for Bioenergetics and Immunology, University of Colorado at Colorado Springs, Colorado, USA. newellrogers@medicine.tamhsc.edu
authors.forename: M K
authors.initials: MK
authors.lastname: Newell
authors.forename: R P
authors.initials: RP
authors.lastname: Tobin
authors.forename: J H
authors.initials: JH
authors.lastname: Cabrera
authors.forename: M B
authors.initials: MB
authors.lastname: Sorensen
authors.forename: A
authors.initials: A
authors.lastname: Huckstep
authors.forename: E M
authors.initials: EM
authors.lastname: Villalobos-Menuey
authors.forename: M
authors.initials: M
authors.lastname: Burnett
authors.forename: E
authors.initials: E
authors.lastname: McCrea
authors.forename: C P
authors.initials: CP
authors.lastname: Harvey
authors.forename: A
authors.initials: A
authors.lastname: Buddiga
authors.forename: A
authors.initials: A
authors.lastname: Bar-Or
authors.forename: M S
authors.initials: MS
authors.lastname: Freedman
authors.forename: J
authors.initials: J
authors.lastname: Nalbantoglu
authors.forename: N
authors.initials: N
authors.lastname: Arbour
authors.forename: S S
authors.initials: SS
authors.lastname: Zamvil
authors.forename: J P
authors.initials: JP
authors.lastname: Antel
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology*
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D051193:Toll-Like Receptors; C045084:invariant chain