A Complement Renaissance
More than 600 million years ago, primitive components of the complement system likely fashioned the first humoral immune system. The modern complement system comprises more than 30 proteins that react in a dizzying array of interconnectedness to identify and quell invading pathogens. Within seconds of activation, millions of fragments may be released into the milieu to trigger a local inflammatory reaction.
Because of its proinflammatory, immune-enhancing, and destructive capabilities, tight regulation is critical. It should come as no surprise, then, that nearly half of complement's components act to mitigate its effects. Host tissues normally express such inhibitors and are protected. And recent work from our lab and others has shown how pathogens such as smallpox and monkeypox have co-opted this regulation. The monkeypox inhibitor of complement enzymes (MOPICE) serves as a virulence factor because it is closely related to human proteins (such as factor H and CD46) in both structure and function.1 Thus, at some point in the past the virus likely hijacked the gene.
If we too can learn to better use the systems in place to regulate complement, we may be able to reverse the pathologic progression for a growing number of diseases. New evidence suggests that complement disposes of cellular waste, removing large numbers of apoptotic and effete cells and their products every day. This garbage, if improperly handled, can accumulate and become a source of chronic inflammation. Such self-debris are associated with some of the most common illnesses in the developed world including atherosclerosis (lipids), Alzheimer disease (amyloid), gout (urate crystals), and age-related macular degeneration (drusen).
Four separate research teams recently discovered the genetic link between age-related macular degeneration (AMD) development and polymorphic variants of a plasma complement regulatory protein known as factor H.2-5 Although normal aging may lead to some accumulation of the lipid-rich waste known as drusen, in AMD large amounts deposit and interact with the complement system. This is hypothesized to occur especially in the setting of factor H anomalies.
Abnormalities of factor H and closely related complement-control proteins have also been associated with an uncommon disease called hemolytic uremic syndrome (HUS). Characterized by an acute onset of hemolytic anemia, a low platelet count, and renal failure, "typical" HUS most commonly follows an infection by a Shiga toxin-producing Escherichia coli. A rarer familial form of HUS (atypical HUS) is more insidious and often does not have an identifiable trigger. It tends to be recurrent and frequently leads to permanent kidney failure.
Genetic screenings of individuals with atypical HUS have identified heterozygous mutations in one of three complement regulators in roughly 50% of patients (factor H, factor I, or CD46).6 If regulators synthesized in the liver are deficient (factors H and I), a renal transplant usually fails because the transplant does not restore the deficient protein. However, if a membrane protein (e.g., CD46) is deficient, transplantation of a normal kidney can correct the cellular deficiency. Thus genetic screening becomes critical for managing these patients.
These and other equally exciting observations are helping to refocus interest on this ancient system and its role in modern maladies. Understanding the mechanisms by which these develop will enhance our understanding of the activation and regulation of the complement system, and may help reveal whether anti-complement drugs can regulate the specific inflammatory responses. In the future, it's likely that genetic screening will be important for those deemed at high risk for AMD, as it is becoming for the diagnosis of atypical HUS.
M. Kathryn Liszewski is a research scientist and John P. Atkinson is a professor of medicine and professor of molecular microbiology in the Division of Rheumatology at Washington University School of Medicine, St. Louis.
1. M.K. Liszewski et al., "Structure and regulatory profile of the monkeypox inhibitor of complement: comparison to homologs in vaccinia and variola and evidence for dimer formation," J Immunol, 176:3725-34, 2006.
2. J.L. Haines et al., "Complement factor H variant increases the risk of age-related macular degeneration," Science, 308:419-21, 2005.
3. A.O. Edwards et al., "Complement factor H polymorphism and age-related macular degeneration," Science, 308:421-4, 2005.
4. R.J. Klein et al., "Complement factor H polymorphism in age-related macular degeneration," Science, 308:385-9, 2005.
5. G.S. Hageman et al., "A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration," Proc Natl Acad Sci, 102:7227-32, 2005.
6. M.A. Dragon-Durey, V. Fremeaux-Bacchi, "Atypical haemolytic uraemic syndrome and mutations in complement regulator genes," Springer Semin Immunopathol, 27:359-74, 2005.