Submitted December 7, 2006
Accepted May 29, 2007
Macrophages prevent the differentiation of autoreactive B cells by secreting CD40 ligand and IL-6
Michelle A. Kilmon, Nikki J. Wagner, Alaina L. Garland, Li Lin, Katja Aviszus, Lawrence J. Wysocki, and Barbara J. Vilen*
Department of Microbiology and Immunolgy, and Lineberger Comprehensive Cancer Center, Univeristy of North Carolina at Chapel Hill, Chapel Hill, NC, United States
Biostatistics and Data Management, Lineberger Comprehensive Cancer Center, Univeristy of North Carolina at Chapel Hill, Chapel Hill, NC, United States
Integrated Department of Immunology, National Jewish Medical and Research Center, and University of Colorado Health Sciences Center, Denver, CO, United States
* Corresponding author; email: barb_vilen{at}med.unc.edu.
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 previously showed that TLR-stimulated dendritic cells and macrophages regulate B cell tolerance to Smith antigen, in part, through the secretion of IL-6. In this manuscript, we show that neutralization of IL-6 fails to abrogate macrophage-mediated repression and identify soluble CD40 ligand as a second repressive factor secreted by macrophages. CD40L selectively repressed Ig secretion by chronically antigen-experienced (anergic) immunoglobulin transgenic and non-transgenic B cells but not acutely stimulated B cells. The importance of macrophages in maintaining B cell tolerance was apparent in lupus-prone, MRL/lpr mice. Compared to C57BL/6 mice, macrophages from MRL/lpr mice were significantly less efficient at repressing Ig 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.
