title: Function and regulation of self-reactive marginal zone B cells in autoimmune arthritis.
abstract: Polyreactive innate-type B cells account for many B cells expressing self-reactivity in the periphery. Improper regulation of these B cells may be an important factor that underlies autoimmune disease. Here we have explored the influence of self-reactive innate B cells in the development of collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis. We show that splenic marginal zone (MZ), but not B-1 B cells exhibit spontaneous IgM reactivity to autologous collagen II in naı¨ve mice. Upon immunization with heterologous collagen II in complete Freund's adjuvant the collagen-reactive MZ B cells expanded rapidly, while the B-1 B cells showed a modest anti-collagen response. The MZ B cells were easily activated by toll-like receptor (TLR) 4 and 9-ligands in vitro, inducing proliferation and cytokine secretion, implying that dual engagement of the B-cell receptor and TLRs may promote the immune response to self-antigen. Furthermore, collagen-primed MZ B cells showed significant antigen-presenting capacity as reflected by cognate T-cell proliferation in vitro and induction of IgG anti-collagen antibodies in vivo. MZ B cells that were deficient in complement receptors 1 and 2 demonstrated increased proliferation and cytokine production, while Fcγ receptor IIb deficiency of the cells lead to increased cytokine production and antigen presentation. In conclusion, our data highlight self-reactive MZ B cells as initiators of the autoimmune response in CIA, where complement and Fc receptors are relevant in controlling the self-reactivity in the cells.
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Anna-Karin E
authors.initials: AK
authors.lastname: Palm
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Heike C
authors.initials: HC
authors.lastname: Friedrich
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Anja
authors.initials: A
authors.lastname: Mezger
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Maya
authors.initials: M
authors.lastname: Salomonsson
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Linda K
authors.initials: LK
authors.lastname: Myers
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kleinau
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D003094:Collagen / Q000633:toxicity; D051379:Mice; D008817:Mice, Mutant Strains; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology
chemical_list: C499172:Fcgr2b protein, mouse; D017452:Receptors, IgG; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D003094:Collagen