Mechanisms of Disease: the complement system and the pathogenesis of systemic lupus erythematosus

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Abstract

Complement activation is common in patients with systemic lupus erythematosus (SLE), resulting in hypocomplementemia and deposition of complement at sites of tissue damage. The availability of mice with specific deficiencies of components of the complement system has provided new insights into the mechanisms by which complement might be involved in autoimmunity and tissue injury in SLE. In humans, deficiencies of early components of the classical complement pathway are strongly associated with SLE. Mice lacking C1q or C4 are also predisposed to autoimmunity, which is associated with the failure of normal clearance of apoptotic cells bearing on their surfaces many of the autoantigens involved in SLE. Antiphospholipid syndrome is common in patients with SLE and studies in an animal model of fetal loss caused by antiphospholipid syndrome have shown that injury is dependent on activation of complement with subsequent neutrophil influx and synthesis of tumor necrosis factor. Insights from animal models might enable the design of more rational therapeutic approaches for manipulating the complement system in human SLE.

Key Points

  • Activation of the complement cascade in patients with systemic lupus erythematosus leads to hypocomplementemia and deposition of complement components at sites of tissue injury

  • Deficiencies of early components of the classical complement pathway are strongly associated with systemic lupus erythematosus in humans and autoimmunity in mice

  • Genetically manipulated mice that lack individual proteins of the complement system have provided insights into the role of complement in autoimmunity

  • In an animal model of fetal loss caused by antiphospholipid syndrome, injury is dependent on complement activation

  • Improved therapeutic approaches that manipulate the complement system in patients with systemic lupus erythematosus might soon be developed

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Figure 1: A simplified overview of the complement system.
Figure 2: Photomicrograph of a glomerulus from a mouse lacking C1q.
Figure 3: An overview of the mechanisms of fetal loss in antiphospholipid syndrome.

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Acknowledgements

The authors would like to thank the Wellcome Trust for supporting their research.

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Correspondence to H Terence Cook.

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The authors declare no competing financial interests.

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