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The complement fixing ability of putative circulating immune complexes in rheumatoid arthritis and its relationship
Insights
Circulating immune complexes (CIC) are common in rheumatoid arthritis (RA) but rarely activate complement. This suggests most CIC in RA patients do not cause severe extra-articular disease.
Area of Science:
- Immunology
- Rheumatology
Background:
- Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation of the joints.
- The role of circulating immune complexes (CIC) in RA pathogenicity is debated.
- Complement system activation is implicated in the inflammatory processes of RA.
Purpose of the Study:
- To investigate the hypothesis that pathogenicity of CIC in RA is linked to complement fixation.
- To assess the association between CIC, complement activation, and extra-articular manifestations in RA patients.
Main Methods:
- Employed three CIC assays: 125I C1q binding assay, C1q solid phase assay, and Raji cell assay.
- Quantified C3d levels (a complement breakdown product) using rocket immunoelectrophoresis to detect complement hypercatabolism.
- Studied 152 RA patients (54 with extra-articular disease, 98 with joint disease only) and 55 healthy controls.
Main Results:
- Elevated plasma C3d levels were significantly higher in RA patients than controls (P < 0.01), particularly in those with extra-articular disease (P < 0.05).
- 54% of RA patients had positive CIC assays, with higher prevalence in the extra-articular group (P < 0.005).
- Coincident positive CIC and elevated C3d strongly correlated with extra-articular disease (P = 10(-3)).
Conclusions:
- While CIC are frequent in RA, most do not appear to activate complement.
- This lack of complement activation by the majority of CIC may explain the relative infrequency of clinically apparent active extra-articular disease in RA patients.
Abstract:
The hypothesis that the pathogenicity of putative circulating immune complexes (CIC) in rheumatoid arthritis (RA) is related to their ability to fix complement was investigated. Three assays for CIC were employed; (a) the 125I C1q binding assay (C1q BA), (b) the C1q solid phase assay (C1q SP) and (c) the Raji cell assay (RCA). Evidence for hypercatabolism of complement was obtained by using a highly sensitive quantitative assay for C3d (a breakdown product of C3) by rocket immunoelectrophoresis. One hundred and fifty-two patients with classical or definite RA were studied; 54 had clinical evidence of extra-articular disease including vasculitis, nodules, scleritis, neuropathy and lung disease; 98 patients had clinical evidence of joint disease alone. Plasma levels of C3d were significantly elevated in the RA group as a whole 16.7 +/- 4.4 mg/l (mean +/- 1 s.d.) compared with 13.1 +/- 3.25 mg/l in a group of 55 normal controls (P less than 0.01). Elevated levels of C3d were found in 26% of all patients but occurred significantly more often in the extra-articular disease group (P less than 0.05). Fifty-four percent of patients had at least one positive assay for CIC although no individual assay was positive in more than 36% of the group as a whole. The prevalence of positive CIC was significantly greater in those patients with extra-articular disease than in those with joint disease alone (P less than 0.005). Of the total of 82 patients with putative CIC, 30 (37%) had a raised C3d level. The coincident finding of positive tests for CIC and an elevated C3d level was very significantly correlated with the presence of extra-articular disease (chi 2 = 12.7 P = 10(-3)). Whilst putative CIC are frequent in RA (54%) these findings in contrast to previous work, suggest that the majority are not associated with abnormal complement activation and may account for the relative infrequency of clinically detectable active extra-articular disease.