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SP0071 Complement gene mutations
  1. M Botto,
  2. MC Pickering,
  3. MJ Walport
  1. Rheumatology Section, Imperial College School of Medicine, Hammersmith Campus, London, UK

Abstract

Homozygous complement protein deficiencies are rare. However, the study of inherited deficiencies of complement proteins in vivo offer insights into the physiological activities of the complement system that are not readily available from in vitro analysis. The phenotype of complement deficiency varies according to the position of the missing component within the complement activation pathways. This demonstrates that different parts of the complement system subserve particular functions. For example, terminal complement component deficiency predisposes to recurrent Neisserial infections. Furthermore, individuals with classical pathway component deficiencies develop SLE. These observations have led to the hypothesis that the classical pathway protects against the development of SLE. However, the mechanism underlying this association has not been fully established. Recent findings obtained using animal models of complement deficiencies, suggest that the classical pathway plays an important role in promoting the physiological clearance of apoptotic cells. The discovery that apoptotic cells may be the source of autoantigens in SLE has lead to the hypothesis that complement deficiency may promote autoimmunity by impairing the clearance of apoptotic cells.

To prevent host tissue injury and depletion of complement components, the complement system is tightly regulated by a series of proteins circulating in plasma and present on cell membranes. The major inhibitory protein of the alternative pathway is factor H (FH). Deficiency of this protein results in secondary depletion of C3 due to uncontrolled alternative pathway (AP) activation. This occurs commonly in individuals with C3 nephritic factor, an IgG autoantibody that stabilises the alternative pathway C3 convertase. Both individuals deficient in FH and those with C3 nephritic factor develop membranoproliferative glomerulonephritis (MPGN). To explore the mechanisms by which uncontrolled C3 activation predisposes to MPGN, we have developed an in vivo model of factor H deficiency. FH deficient mice have secondary C3 deficiency, show large amounts of C3 deposited preferentially on the glomerular basement membrane and develop MPGN. Both partial and complete FH deficiencies have been associated with haemolytic uraemic syndrome (HUS) and the pathogenesis is poorly understood. This animal model will allow us to investigate the mechanisms by which C3 dysregulation predisposes to glomerulonephritis and HUS.

In conclusion, individuals and experimental models of complement deficiency prove to be an invaluable tool to investigate the role of the complement system in health and in disease.

Reference

  1. Pickering MC, Botto M, Taylor PR, Lachmann PJ, Walport MJ. Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol. 2001;76:227–324

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