Natural antibody to apoptotic cell membranes inhibits the proinflammatory properties of lupus autoantibody immune complexes

Objective Naturally arising IgM antibodies (NAb) to apoptotic cell (AC) determinants are present from birth and can be further induced by AC challenge. In systemic lupus erythematosus, lower anti-AC NAb levels have been associated with higher disease activity. We have recently shown that a prototypical AC-specific IgM NAb can suppress proinflammatory responses to purified agonists of Toll-like receptors and block the in vivo induction of IgG immune complex (IC)induced arthritis. Nuclear antigens, which activate dendritic cells (DCs), form complexes with IgG autoantibody, and these have been implicated in the pathogenesis of autoimmune disease. In this study, we sought to investigate potential roles of such NAb for regulating IC-mediated activation of DCs, which is believed to be involved in disease initiation and perpetuation. Methods Bone marrowderived myeloid DCs were stimulated with ICs composed of IgG autoantibody and chromatin or IgG autoantibody and RNA. Outcome was evaluated according to the production of inflammatory cytokines, as determined by enzyme-linked immunosorbent assay, and the expression of costimulatory molecules (markers of DC activation), as determined by flow cytometry. MAPK activation was evaluated by phospho-flow analysis and immunofluorescence microscopy. Results IgM anti-AC NAb dose-dependently suppressed the production of DNA IC and RNA ICinduced interleukin-6 and DNA ICinduced tumor necrosis factor a, as well as the RNA ICinduced up-regulation of CD86 and CD40 on DCs. IgM NAbmediated inhibition was associated with suppression of IC-mediated p38 MAPK activation and nuclear localization. Conclusion We demonstrated a direct in vitro inhibitory effect of IgM NAb on inflammatory responses induced by IgGnucleic acid ICs. These findings contribute to emerging evidence that regulatory NAb to AC determinants may oppose the influence of pathogenic lupus autoantibody ICs and thereby play roles in the maintenance of immune homeostasis.