Macrophages prevent the differentiation of autoreactive B cells by secreting CD40 ligand and interleukin-6.
Activation of the innate immune system promotes polyclonal antibody secretion to eliminate invading pathogens. Inherent in this process is the potential to activate autoreactive B cells and induce autoimmunity. We showed previously that TLR-stimulated dendritic cells and macrophages regulate B cell tolerance to Smith antigen, in part through the secretion of interleukin-6 (IL-6). In this manuscript, we show that neutralization of IL-6 fails to abrogate macrophage-mediated repression and identify soluble CD40 ligand (CD40L) as a second repressive factor secreted by macrophages. CD40L selectively repressed Ig secretion by chronically antigen-experienced (anergic) immunoglobulin transgenic and nontransgenic B cells but not by transiently stimulated B cells. The importance of macrophages in maintaining B cell tolerance was apparent in lupus-prone MRL/lpr mice. Compared with C57BL/6 mice, macrophages from MRL/lpr mice were significantly less efficient at repressing immunoglobulin secretion coincident with diminished IL-6 and CD40 ligand production. These data indicate that macrophages regulate autoreactive B cells by secreting repressive factors that prohibit terminal differentiation of B cells. The regulation of autoreactive B cells by macrophages is diminished in lupus-prone mice suggesting a role in autoimmunity.
Kilmon
Michelle A
MA
Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA.
Wagner
Nikki J
NJ
Garland
Alaina L
AL
Lin
Li
L
Aviszus
Katja
K
Wysocki
Lawrence J
LJ
Vilen
Barbara J
BJ
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology; D001324:Autoantigens / Q000276:immunology / Q000494:pharmacology; D015551:Autoimmunity / Q000187:drug effects; D001402:B-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D017635:Clonal Anergy / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects; D007074:Immunoglobulin G / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D017411:Ribonucleoproteins, Small Nuclear / Q000276:immunology / Q000494:pharmacology; D055517:snRNP Core Proteins
D001324:Autoantigens; D007074:Immunoglobulin G; D015850:Interleukin-6; D017411:Ribonucleoproteins, Small Nuclear; D055517:snRNP Core Proteins; D023201:CD40 Ligand
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