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You are here: Home / Articles / Complement Polymorphism Plays Role in RA Pathology

Complement Polymorphism Plays Role in RA Pathology

April 13, 2015 • By Lara C. Pullen, PhD

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Complement plays an important role in the innate immune response, and complement polymorphisms and mutations are known to contribute to the risk of acquiring several different diseases. Specifically, complement appears to play a role in the pathology of rheumatoid arthritis (RA), as evidenced by the fact that patients with RA have elevated levels of complement activation products in their plasma, synovial fluid and synovial tissues. Moreover, genome-wide association studies have revealed an association between complement polymorphism, particularly polymorphism in C5 and RA.

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A new study proposes a mechanism by which a polymorphism in C5 is linked to RA pathology. The researchers explain that while C5 is typically cleaved in vivo by proteases, a single nucleotide polymorphism in C5 may predispose it to being cleaved by elastase found in rheumatoid joints. This results in increased generation of active C5a, which then recruits neutrophils to the arthritic joints, thereby maintaining inflammation.

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Joanna L. Giles, MD, an Arthritis Research–United Kingdom Foundation Fellow at the Cardiff Institute of Infection & Immunity and colleagues published the results of their complement analysis in the Journal of Immunology.1 They focused their study on the single nucleotide polymorphism (SNP) rs17611 that encodes a V802 polymorphism in C5. The researchers began by measuring plasma levels of C5, C5a and terminal complement complex, as well as allele frequency of the rs17611 SNP, in 111 healthy donors and 80 patients with RA. They found that the “risk” allele, rs17611, was positively associated with elevated levels of C5a and decreased levels of C5. By comparison, there was no association between the risk allele and levels of C3a. This result suggested that there was increased turnover of C5 V802 relative to more common C5 polymorphisms.

The investigators then evaluated the relationship between the SNP and C5 functionality. They asked whether the elevated C5a levels and decreased C5 levels in individuals expressing rs17611 alleles were the result of higher turnover of C5 by the convertase enzyme. To answer the question, they performed functional assays on different C5v8021 variants. When they tested the variants in a cobra venom factor (CVF) C3/C5 convertase assay, they found no significant differences in lytic activity between the C5 variants. This result suggested to them that the V802 turnover was not mediated by complement convertase enzymes. The team then searched for an alternative explanation for differences in turnover between the two risk alleles.

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Although C5 is typically cleaved by proteases, it can also be cleaved by human neutrophil elastase (HNE), which, in the presence of C6, generates a C5b6-like hemolytic complex. HNE is released from activated neutrophils at inflammatory sites. The investigators found that the C5 V802 variant was, indeed, preferentially cleaved by elastase, thereby generating a “C5a” that was biologically active. The C5a-like fragment generated by HNE migrated at a slightly higher molecular mass when compared with recombinant C5a and C5a generated by the cleavage of C5 by the CVFBb convertase.

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Filed Under: Research Reviews Tagged With: inflammation, neutrophil, pathology, Polymorphism, Research, rheumatoid arthrtitisIssue: June 2015

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