The complement system and systemic lupus erythematosus (SLE) have been intertwined for nearly 70 years. Complement consumption secondary to increased turnover was an early salient observation. Autoantibodies to nuclear materials forming immune complexes were likely mediating tissue damage. A second and fascinating observation was that a complete deficiency of C1q, C4 or C2 predisposed to SLE. These two key findings have been the heart of lupus-related complement research over the next 50 years.
Complement as a biomarker A major more recent goal here has been to explore complement’s activating fragments; namely, fluid phase split products and cell-bound complement activation products (CB-CAPS). The hope here was to provide more sensitive and specific biomarkers to monitor disease activity. A thorough review of these data was recently published.1 While both split products and CB-CAPS show promise, there remain issues in demonstrating clinical superiority to standard serum C4 and C3. Limitations that commonly arise relate to the complex methodology, availability and interpretation.
Complement in etiopathogenesis The underlying hypothesis has been that complement is required for the proper handling of nuclear debris and thereby prevent an inappropriate autoimmune response. This arena remains a work in progress, but several informative studies have recently been published:2–5 In my comments, I will highlight several issues: A) the deficiency story; B) C3b instructing how the opsonic material is processed; C) Evidence that the C4A gene regulates autoreactive B cells in murine lupus; D) C4A gene as a major player in sex-biased vulnerability in SLE; and E) Discovery of an intracellular complement system.
Complement therapeutics Rare genetic variants in complement regulators have been identified in aHUS and C3G and successfully treated with anti-C5 mAbs. This therapeutic development along with the discovery of rare variants in age-related macular degeneration have ignited the field of complement therapeutics.
Describe the long history of the complement system’s interactions with lupus for the lupologist
Advances in defining the role of ‘complement’ as a biomarker for lupus
Discuss recent advances understanding how complement deficiency predisposes to SLE
Weinstein A, Alexander RV, Zack DJ. A review of complement activation in SLE. Curr Rheumatol Rep. 2021;23(3):16.
Kamitaki N, Sekar A, Handsaker RE, et al. Complement genes contribute sex-biased vulnerability in diverse disorders. Nature. 2020;582(7813):577–81.
Simoni L, Presumey J, van der Poel CE, et al. Complement C4A regulates autoreactive B cells in murine lupus. Cell Rep. 2020;33(5):108330.
Sorbara MT, Foerster EG, Tsalikis J, et al. Complement C3 drives autophagy-dependent restriction of cyto-invasive bacteria. Cell Host Microbe. 2018;23(5):644–52 e5.
Baudino L, Sardini A, Ruseva MM, et al. C3 opsonization regulates endocytic handling of apoptotic cells resulting in enhanced T-cell responses to cargo-derived antigens. Proc Natl Acad Sci U S A. 2014;111(4):1503–8.
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