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C1 subcomponent complexes and C2 cleavage in active systemic lupus erythematosus
H Jonsson1, A G Sjöholm, U Mårtensson
1Department of Rheumatology, University Hospital, Lund, Sweden.
Insights
In active systemic lupus erythematosus (SLE), C1 dissociation and C1 inactivator (C1 IA)-containing complexes are common, suggesting C1 IA
Area of Science:
- Immunology
- Rheumatology
Background:
- Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune complex deposition and inflammation.
- The classical complement pathway plays a role in SLE pathogenesis.
- C1 inactivator (C1 IA) regulates the classical complement pathway.
Purpose of the Study:
- To investigate the activation and C1 IA-dependent dissociation of the C1 complex.
- To correlate these events with classical pathway recruitment in SLE patients during disease flares.
- To assess the relationship between complement activation and SLE clinical severity.
Main Methods:
- Studied 24 SLE patients divided into three clinical groups based on disease activity (mild, major extrarenal, renal).
- Analyzed serum concentrations of C1 IA-C1r-C1s and C1 IA-C1r-C1s-C1 IA complexes.
- Assessed C2 and C3 cleavage in EDTA plasma to indicate classical pathway activation.
Main Results:
- High concentrations of C1 IA-C1r-C1s trimers were found in most SLE patients.
- Some patients with high trimers showed no classical pathway activation, indicating C1 IA control at the C1r level.
- Formation of C1 IA-C1r-C1s-C1 IA tetramers correlated with C2/C3 cleavage and hypocomplementemia.
- Classical pathway recruitment was linked to SLE disease severity.
Conclusions:
- C1 dissociation with C1 IA-containing complexes is consistently observed in active SLE.
- C1 IA-dependent control of C1 activation is biologically significant in SLE.
- C1 IA-C1r-C1s-C1 IA tetramers may not always be a sensitive indicator of classical pathway activation.
Abstract:
We studied the activation and C1 inactivator-dependent dissociation of the first component of complement, the C1q(C1r-C1s)2 complex, in relation to recruitment of the classical activation pathway in the circulation of 24 patients with systemic lupus erythematosus (SLE). The patients were divided into three groups on a clinical basis, and were investigated during flares of disease activity. Group I had mild symptoms, group II major extrarenal manifestations, and group III manifest renal disease. High serum concentrations of trimer complexes containing C1 inactivator, activated C1r and zymogen C1s(C1 IA-C1r-C1s) were found in the majority of the patients. Some patients with high C1 IA-C1r-C1s concentrations showed no evidence of classical pathway activation, indicating that C1 activation was controlled by the action of C1 IA at the C1r level. By contrast, formation in serum of tetramer complexes in which C1 IA was firmly bound to both C1r and C1s (C1 IA-C1r-C1s-C1 IA) was associated with C2 and C3 cleavage in EDTA plasma, and with manifest hypocomplementemia. Low C1 IA-C1r-C1s-C1 IA values were observed in conjunction with substantial C2 cleavage in a few patients. Thus, C1 IA-C1r-C1s-C1 IA may not always be a sensitive indicator of classical pathway activation. Efficient recruitment of the classical pathway was related to disease severity, with some overlap between the clinical groups. In conclusion, C1 dissociation with formation of C1 IA-containing complexes was consistently found in patients with active SLE. The results suggested that C1 IA-dependent control of C1 activation was of biological significance in the disease.