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

Abstract

Objective Naturally-arising IgM antibodies (NAbs) 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 prototypic AC-specific NAb IgM can suppress pro-inflammatory responses to purified agonists for Toll-like receptors, and also block the in vivo induction of IgG-immune complex (IC)-induced arthritis. IgG autoantibody-complexes with nuclear antigens, which activate dendritic cells (DCs), have been implicated in autoimmune pathogenesis. Here, we sought to investigate potential roles of such NAbs for regulating immune-complex mediated DC activation, which is believed to be involved in disease initiation and perpetuation. Methods Bone-marrow-derived myeloid DCs were stimulated with ICs composed of IgG-autoantibody-chromatin or IgG-autoantibody-RNA. Outcome was evaluated based on production of inflammatory cytokines by ELISA, and expression of co-stimulatory molecules, which are markers of DC activation, by flow cytometry. MAPK activation was evaluated by phospho-flow and immunofluorescence microscopy. Results Anti-AC NAb IgM dose-dependently suppressed both DNA- and RNA-IC-induced IL-6 and DNA-IC-induced TNF-α production, as well as RNA-IC-induced upregulation of CD86 and CD40 on DCs. NAb IgM-mediated inhibition was associated with suppression of IC-mediated p38-MAPK activation and nuclear localization. Conclusions We demonstrated a direct in vitro inhibitory effect of the NAb IgM on inflammatory responses induced by IgG-nucleic acid ICs. These findings contribute to emerging evidence that regulatory NAbs to apoptotic-cell determinants may oppose the influence of pathogenic lupus autoantibody-ICs and thereby play roles in the maintenance of immune homeostasis.

MAPK phosphatase-1 is required for regulatory natural autoantibody-mediated inhibition of TLR responses

“…Importantly, inhibition of antichromatin IgG immune complex-induced DC activation by anti-AC IgM/complement factor also correlated with MKP-1 induction (Fig. S5) and, as previously reported, with the inhibition of P-p38 (16).…”

“…After cell stimulation, the cells were centrifuged and resuspended in Cytofix/Cytoperm solution (Becton Dickinson), followed by PermWash solution (Becton Dickinson) as per manufacturer's protocol. Cells were stained for P-p38, MKP-1 and costained with anti-MHCII to identify high-TLR-responsive cells as described (16). Statistical analysis used the two-tailed t test using Welsh correction when appropriate; P < 0.05 was considered significant (Instat; GraphPad).…”

“…Such anti-AC NAbs also have a direct inhibitory effect on inflammatory responses induced in vitro by lupus-associated IgG-nucleic acid immune complexes (16). In addition, infusions of AC-reactive IgM markedly reduced clinical disease activity and synovial leukocytic infiltrates in the collagen-induced arthritis model (9) and in responses to pathogenic anticollagen IgG autoantibodies (9).…”

T cell–independent B cell activation induces immunosuppressive sialylated IgG antibodies

“…have suppressive feedback effects, as was previously suggested for IgM Abs in a different context (1,41,(49)(50)(51)(52)(53). In the present study, a desialylated monoclonal anti-TNP IgM Ab enhanced TNP-Ficollinduced B cell activation in vivo.…”

Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity

“…IgM and IgG autoantibodies are the most abundant. IgM autoantibodies are also present in healthy individuals and are therefore often considered to be less pathogenic (85). IgM is a potent activator of the complement component 1, q subcomponent (C1q), which has recently been shown to inhibit TLR activation by acting as a ligand for the inhibitory leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), suggesting that IgM might inhibit immune effector responses (86).…”