title: Functional anergy in a subpopulation of naive B cells from healthy humans that express autoreactive immunoglobulin receptors.
abstract: Self-reactive B cells not controlled by receptor editing or clonal deletion may become anergic. We report that fully mature human B cells negative for surface IgM and retaining only IgD are autoreactive and functionally attenuated (referred to as naive IgD(+)IgM(-) B cells [B(ND)]). These B(ND) cells typically make up 2.5% of B cells in the peripheral blood, have antibody variable region genes in germline (unmutated) configuration, and, by all current measures, are fully mature. Analysis of 95 recombinant antibodies expressed from the variable genes of single B(ND) cells demonstrated that they are predominantly autoreactive, binding to HEp-2 cell antigens and DNA. Upon B cell receptor cross-linkage, B(ND) cells have a reduced capacity to mobilize intracellular calcium or phosphorylate tyrosines, demonstrating that they are anergic. However, intense stimulation causes B(ND) cells to fully respond, suggesting that these cells could be the precursors of autoantibody secreting plasma cells in autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis. This is the first identification of a distinct mature human B cell subset that is naturally autoreactive and controlled by the tolerizing mechanism of functional anergy.
authors.affiliation: Immunobiology and Cancer, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Duty
authors.forename: Peter
authors.initials: P
authors.lastname: Szodoray
authors.forename: Nai-Ying
authors.initials: NY
authors.lastname: Zheng
authors.forename: Kristi A
authors.initials: KA
authors.lastname: Koelsch
authors.forename: Qingzhao
authors.initials: Q
authors.lastname: Zhang
authors.forename: Mike
authors.initials: M
authors.lastname: Swiatkowski
authors.forename: Melissa
authors.initials: M
authors.lastname: Mathias
authors.forename: Lori
authors.initials: L
authors.lastname: Garman
authors.forename: Christina
authors.initials: C
authors.lastname: Helms
authors.forename: Britt
authors.initials: B
authors.lastname: Nakken
authors.forename: Kenneth
authors.initials: K
authors.lastname: Smith
authors.forename: A Darise
authors.initials: AD
authors.lastname: Farris
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Wilson
mesh_terms: D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D000974:Antibodies, Antinuclear / Q000235:genetics / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology; D015703:Antigens, CD / Q000032:analysis / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D017635:Clonal Anergy / Q000276:immunology*; D005803:Genes, Immunoglobulin / Q000235:genetics; D006801:Humans; D007072:Immunoglobulin D / Q000032:analysis / Q000276:immunology; D007075:Immunoglobulin M / Q000032:analysis / Q000276:immunology; D016130:Immunophenotyping; D015759:Ionomycin / Q000494:pharmacology; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D009154:Mutation / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001324:Autoantigens; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; C039951:anti-IgD; C044203:anti-IgM; D014443:Tyrosine; D015759:Ionomycin