Antibodies to C1q in systemic lupus erythematosus: Characteristics and relation to FcγRIIA alleles

Abstract

Autoantibodies to the collagen-like region of the first complement component (C1qAB) are found in patients with systemic lupus erythematosus (SLE), particularly those with renal disease. In a cohort of 46 SLE patients with diffuse proliferative glomerulonephritis, we found declining C1qAB titers in 77% of treatment responders and in only 38% of treatment non-responders (P < 0.03). To further characterize this autoantibody, we tested 240 SLE patients for the presence of C1qAB. Positive titers were found in 44% of patients with renal disease and 18% of patients without renal disease (chi2 P < 0.0003). Analysis of IgG subclass revealed IgG2 C1qAB alone in 34%, IgG1 C1qAB alone in 20%, and both IgG1 and IgG2 in 46% of patients. Fewer than 10% of patients had measurable titers of IgG3 or IgG4 C1qAB. The pathogenic role of these IgG2-skewed C1qAB may relate to impaired immune complex clearance by the mononuclear phagocyte system: IgG2 antibodies are efficiently recognized by only one IgG receptor, the H131 allele of Fc gamma RIIa (Fc gamma RIIa-H131). In contrast, Fc gamma RIIa-R131, which is characterized by minimal IgG2 binding, has recently been associated with lupus nephritis. In our C1qAB positive patients, the presence of Fc gamma RIIA-R131 was associated with an increased risk for renal disease. Autoantibodies to C1q may have pathogenic significance in SLE patients with genetic defects in the ability to clear IgG2 containing immune complexes.

Specificity and affinity of human Fcγ receptors and their polymorphic variants for human IgG subclasses

“…Likewise, the Fc␥RIIA H 131 R polymorphism is associated with bacterial infections 17 and nephropathy. 16 We confirm that Fc␥RIIA R131 binds IgG2 IC less efficiently than Fc␥RIIA H131 . IgG2 is a major isotype in anti-bacterial antibody responses.…”

“…15 hFc␥R polymorphisms have been linked to autoimmune and infectious diseases. hFc␥RIIA R131 has been associated with an increased prevalence of nephropathy, 16 bacterial infections, 17 and possibly systemic lupus erythematosus (SLE). 18,19 hFc␥RIIIA F158 has been linked to SLE 20 and to rheumatoid arthritis (RA).…”

Anti-C1q in systemic lupus erythematosus

“…47,51,52 On the other hand, anti-C1q titers decreased with treatment in SLE patients with proliferative lupus nephritis, with a more significant decrease noted in treatment responders compared to non-responders, 77% and 38%, respectively. 41 Serial determination of anti-C1q in SLE patients with renal flares might help to identify treatment responders and define patients remaining at risk for renal relapses. 5 The latest data from the SLICC international cohort 37 confirmed the association of anti-C1q with lupus nephritis with a prevalence of 45.5% in patients with SLE with American College of Rheumatology (ACR) renal involvement.…”

“…40 Since these original observations, the association of anti-C1q antibodies with proliferative lupus nephritis, disease activity, and anti-dsDNA antibodies has been consistently reported, both in adult and pediatric SLE patients. [41][42][43][44][45][46] In a longitudinal study that evaluated the association between relapses and plasma levels of autoantibodies, 43 patients were selected from a group of 151 SLE patients: the first 17 patients who developed a renal relapse during the study period, the first 16 patients who developed a relapse in organs other than the kidneys, and 10 randomly selected patients without a relapse of SLE. At the time of SLE flare, anti-C1q were detected by an inhouse ELISA in 12 of 17 patients with primarily a renal relapse compared with six of 16 patients whose flare was non-renal and two of 10 patients who remained clinically inactive (p < 0.005).…”

Identification of Fc Gamma Receptor Glycoforms That Produce Differential Binding Kinetics for Rituximab

“…Polymorphisms of FcγRIIa (Arg 131/His 131) exist, which also result in differences in the binding affinity for IgG with human IgG2 binding efficiently to the His 131 variant and not to the Arg 131 variant (10). Physiological effects also exist with the Arg 131 form causing increased susceptibility to bacterial infections, nephropathy and SLE (11)(12)(13).…”