Anti-DNA antibodies cross-react with C1q

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder that involves multiple organ systems and typically presents as a chronic inflammatory disease. Antibodies to double-stranded (ds) DNA are present in approximately 70% of patients and form nucleic acid containing immune complexes which activate dendritic cells through engagement of toll-like receptors, leading to a pro-inflammatory, pro-immunogenic milieu. In addition, anti-dsDNA antibodies deposit in kidneys to initiate glomerulonephritis. Antibodies to C1q have also been implicated in lupus nephritis and are found in 30–50% of patients. C1q is a known suppressor of immune activation and C1q deficiency is the strongest risk factor for SLE. We previously identified a subset of anti-DNA antibodies that binds the N-methyl-d-aspartate receptor. We now show that both mouse and human anti-DNA antibodies with this specificity bind C1q. These antibodies bind to Clq in glomeruli and exhibit decreased glomerular deposition in the absence of C1q. We propose that this subset of anti-DNA antibodies participates in lupus pathogenesis through direct targeting of C1q on glomeruli and also through removal of soluble C1q thereby limiting the ability of C1q to mediate immune homeostasis.

Immune mediators in the brain and peripheral tissues in autism spectrum disorder

“…Interestingly, although 30–60% of individuals with SLE possess NMDAR-specific autoantibodies, each antibody clone has unique physiological effects. Some antibodies have potent co-agonist properties, leading to increased calcium influx through NMDARs and eventually neuronal death 71 , whereas other clones with slightly different epitopes are not pathogenic and yet others cross-react with C1q, a component of the complement cascade 72 . Remarkably, the effects of these anti-NMDAR antibodies are sex-specific in mice: they cause death through apoptosis of NR2A-expressing neurons, which are enriched in the brainstem of female, but not male, fetuses 73 .…”

Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity

“…An example of such cross-reactivity is antidsDNA antibodies in SLE, which have been shown to recognize antigens in the glomerular basement membrane, where these autoantibodies can deposit (44)(45)(46)(47). While the binding of some anti-dsDNA antibodies to glomeruli depends on the presence of nucleosomes containing DNA on the glomerular membrane, the contribution of cross-reactivity to renal pathology has also been demonstrated (48,49).…”

The complement system in systemic lupus erythematosus: an update

“…C1q antibodies could result in decreased C1q levels, mimicking a C1q-deficient state with impaired clearance of dying cells 45. Whether the antibodies are directed at C1q or simply cross-reacting due to antigen resemblance is a matter of debate 46. The level of C1q antibodies is a good predicative marker for LN,47 48 since the antibodies amplify the effect of C1q-containing ICs in the kidneys 49.…”