title: Functionally responsive self-reactive B cells of low affinity express reduced levels of surface IgM.
abstract: Somatic gene rearrangement generates a diverse repertoire of B cells, many which have receptors possessing a range of affinities for self-Ag. Newly generated B cells express high and relatively uniform amounts of surface IgM (sIgM), while follicular (FO) B cells express sIgM at widely varying levels. It is plausible, therefore, that downmodulation of sIgM serves as a mechanism to maintain weakly self-reactive B cells in a responsive state by decreasing their avidity for self-Ag. We tested this hypothesis by performing comparative functional tests with FO IgM(hi) and IgM(lo) B cells from the unrestricted repertoire of WT C57BL/6 mice. We found that FO IgM(lo) B cells mobilized Ca(2+) equivalently to IgM(hi) B cells when the same number of sIgM molecules was engaged. In agreement, FO IgM(lo) B cells were functionally competent to produce an antibody response following adoptive transfer. The FO IgM(lo) cell population had elevated levels of Nur77 transcript, and was enriched with nuclear-reactive specificities. Hybridoma sampling revealed that these B-cell receptors were of low affinity. Collectively, these results suggest that sIgM downmodulation by low-affinity, self-reactive B cells preserves their immunocompetence and circumvents classical peripheral tolerance mechanisms that would otherwise reduce diversity within the B cell compartment.
authors.affiliation: Integrated Department of Immunology, National Jewish Health and University of Colorado School of Medicine, Denver, CO, USA.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Kirchenbaum
authors.forename: James B
authors.initials: JB
authors.lastname: St Clair
authors.forename: Thiago
authors.initials: T
authors.lastname: Detanico
authors.forename: Katja
authors.initials: K
authors.lastname: Aviszus
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Wysocki
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004705:Endocytosis / Q000276:immunology; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D001324:Autoantigens; D007075:Immunoglobulin M; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011947:Receptors, Antigen, B-Cell; D002118:Calcium
keywords: B-cell development; Immunocompetence; sIgM down-modulation; self-reactivity