Complement is a network of more than 50 proteins in the blood and on cell surfaces and is part of the innate immune system, in contrast to the adaptive system consisting of antibodies which can "learn" and adapt themselves on the fly to different antigens.  The complement proteins quietly cruise the blood system, keeping a low profile until triggered into action.

Once complement is summoned to sites of potential threat, its proteins form one of several variants of an enzyme called C3 convertase. In 2009, John Lambris Ph.D., the Dr. Ralph and Sallie Weaver Professor of Research Medicine, unraveled the molecular structure of the C3 enzyme in collaboration with Piet Gros’ group from Utrecht University. They also defined the structure of the C3b component with a key regulator called factor H, which helps prevent the complement system from attacking its own host. 

Lambris and the Utrecht team extended this work further the following year, detailing the structure of two more key protein complexes of the complement system, C3bB and C3bBD. The work provided crucial details of how complement functions, clues for treatments of complement-related diseases, and possible designer drugs targeting malfunctioning proteins.

In 2008, Lambris found that sometimes the complement system can impair, rather than enhance, the body's defenses.  When complement was activated in tumor tissue in mice, the C5a protein recruits myeloid-derived suppressor cells (MDSC) that blocked the action of killer T cells that normally destroy tumors. But by blocking the C5a receptor on cell surfaces, tumor cell growth was inhibited as effectively as with chemotherapy drugs. In this way, complement revealed a possible approach to cancer rather than traditional chemotherapy.

Yet the disease involvement of complement reaches far beyond cancer, and complement has been shown to contribute to a broad spectrum of immune, inflammatory and age-related diseases. In collaboration with Daniel Ricklin Ph.D., a research assistant professor in the same group, Lambris is working on developing novel therapeutic concepts to tame inappropriate complement activation and/or protect material and cell surfaces from an attack of this defense system. Using small inhibitors of the central complement component C3, engineered regulatory proteins and protective cell coatings, they could already demonstrate the benefit of therapeutic complement modulation in a variety of clinical situations ranging from implant surgery and solid organ transplantation to sepsis and hemodialysis-related complications.

One of the most prevalent conditions that can be caused by malfunctioning complement is age-related macular degeneration (AMD), in which part of the retina deteriorates, leading to impaired sight and sometimes blindness. In 2011, working on a $2 million grant from NIH, Lambris's investigated a new class of complement inhibitor drugs.  Using non-human primates, Lambris is trying to suppress the activation of the complement cascade in subretinal tissue, hoping to delay or suppress the onset and progress of AMD.            

Complement's influence also extends beyond the interior of the body to its outermost defense layer -- namely the skin and the microbial organisms that live there.  Collaborating with Penn dermatologist Elizabeth Grice, M.D., Lambris found that the skin microbiome of mice treated with a complement inhibitor contained a different population of microbes than untreated mice, implying that complement is somehow affecting the skin microbiome. This apparent symbiosis could play an important role in the development or suppression of skin diseases, some of which might be caused by an imbalance between the complement and the skin microbiome. 

In collaboration with George Hajishengallis, D.D.S., PhD, professor of Microbiology in the School of Dental Medicine at Penn, Lambris has also implicated complement in the induction of periodontal disease. Specifically, periodontal bacteria were shown to exploit complement to both evade immune clearance and to instigate inflammatory destruction of bone that supports the teeth. This collaborative research has already identified several targets of therapeutic intervention against periodontitis. Initial studies with specific complement inhibitors have produced promising results in various preclinical models of periodontitis.

Lambris and his collaborators are demonstrating that the complement system is far more complex, subtle, and important than previously believed. Despite its traditional relegation to a relatively minor role, he maintains that needs to be considered and studied as a major player as part of the immune system and in other biochemical functions.

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