Related Experiment Videos
C1q and systemic lupus erythematosus
M J Walport1, K A Davies, M Botto
1Department of Medicine, Imperial College School of Medicine, London, U.K.
Insights
Systemic lupus erythematosus (SLE) is linked to complement component 1q (C1q) deficiency. C1q deficiency may cause SLE through impaired immune complex processing and dysregulated apoptosis, impacting immune complex clearance and potentially leading to autoimmune responses.
Area of Science:
- Immunology
- Rheumatology
- Molecular Biology
Background:
- Complement component 1q (C1q) deficiency is associated with autoimmune diseases, particularly Systemic Lupus Erythematosus (SLE).
- Clinical observations link C1q deficiency and anti-C1q antibodies to severe SLE, kidney involvement, and hypocomplementemic urticarial vasculitis.
- Genetic deficiencies in the complement system, beyond C1q, are also implicated in lupus pathogenesis.
Purpose of the Study:
- To review the clinical associations of C1q deficiency with SLE and other autoimmune conditions.
- To explore the mechanisms by which C1q deficiency might contribute to SLE development, focusing on immune complex processing and apoptosis.
- To discuss the role of anti-C1q antibodies and findings in C1q-deficient mouse models.
Main Methods:
- Literature review of clinical associations between C1q deficiency and autoimmune diseases.
- Analysis of the relationship between C1q consumption, low molecular weight C1q, and SLE.
- Examination of anti-C1q antibodies in SLE and hypocomplementemic urticarial vasculitis.
- Discussion of C1q-deficient mouse models, including C1q knockout mice, to investigate SLE pathogenesis.
Main Results:
- C1q deficiency is associated with SLE, potentially due to impaired immune complex processing and abnormal apoptosis regulation.
- Anti-C1q antibodies correlate with severe SLE, particularly renal disease, and hypocomplementemic urticarial vasculitis.
- C1q knockout mice exhibit features of lupus, including antinuclear antibodies and glomerulonephritis, with evidence of defective apoptotic cell clearance.
Conclusions:
- C1q plays a critical role in the clearance of apoptotic cells and immune complexes, and its deficiency can predispose individuals to SLE.
- Dysregulation of apoptosis and impaired immune complex processing are key mechanisms linking C1q deficiency to SLE pathogenesis.
- Further research into C1q's function in apoptosis and immune regulation may offer insights into SLE treatment strategies.
Abstract:
In this chapter we review the association between SLE and C1q. In the first part of the chapter we discuss the clinical associations of C1q deficiency, and tabulate the available information in the literature relating to C1q deficiency and autoimmune disease. Other clinical associations of C1q deficiency are then considered, and we mention briefly the association between other genetically determined complement deficiencies and lupus. In the review we explore the relationship between C1q consumption and lupus and we discuss the occurrence of low molecular weight (7S) C1q in lupus, which raises the possibility that increased C1q turnover in the disease may result in unbalanced chain synthesis of the molecule. Anti-C1q antibodies are also strongly associated with severe SLE affecting the kidney, and with hypocomplementaemic urticarial vasculitis, and these associations are also examined. We address the question of how C1q deficiency may cause SLE, discussing the possibility that this may be due to abnormalities of immune complex processing, which have been well characterised in a umber of different human models. There is clear evidence that immune complex processing is abnormal in patients with hypocomplementaemia, and this is compatible with the hypothesis that ineffective immune complex clearance could cause tissue injury, and this may in turn stimulate an autoantibody response. We have also considered the possibility that C1q-C1q receptor interactions are critical in the regulation of apoptosis, and we explore the hypothesis that dysregulation of apoptosis could explain important features in the development of autoimmune disease associated with C1q deficiency. An abnormally high rate of apoptosis, or defective clearance of apoptotic cells, could promote the accumulation of abnormal cellular products that might drive an autoimmune response. Anti-C1q antibodies have been described in a number of murine models of lupus, and these are also briefly discussed. We focus on the recently developed C1q "knockout" mice, which have been developed in our laboratory. Amongst the C1q deficient mice of a mixed genetic background high titres of antinuclear antibodies were detected in approximately half the animals, and around 25% of the mice, aged eight months had evidence of a glomerulonephritis with immune deposits. Large numbers of apoptotic bodies were also present in diseased glomeruli, and this supports the hypothesis that C1q may have a critical role to play in the physiological clearance of apoptotic cells.