Research Abstract: Complement is an ancient host defense system. It that also is an integral player in both contemporary innate and adaptive immunity. The complement system guards the intracellular space from bacterial and viral infections. Most sStriking is that it works in seconds, being particularly noted for serving as a first responder to an invasion of the circulation. By releasing small peptides to activate local proinflammatory cell responses and by attaching large opsonic fragments to a target, complement provides protection against pathogens and instructs (nature’s adjuvant) the adaptive immune response. The cell-bound activation fragments promote immune adherence, phagocytosis, lysis, antigen processing and presentation and lymphocyte responsiveness. Several decades ago this laboratory identified a multigene family of receptor and regulatory proteins that inhibit complement activation and serve as receptors for complement-opsonized antigens. Structure-function relationships, cell signaling, microbial interactions and disease associations of these complement inhibitors and receptors have been a center piececentral focus of the laboratory’s efforts. Many pathogens, including multiple viruses (measles, pox, adeno and flavi), bacteria (Nneisseria, Sstreptococci, Ccoliforms) and parasites (malaria), abuse the complement system by 1) employing them an inhibitor as a receptor for cellular attachment, 2) hijacking a host regulator to protect against complement attack or 3) synthesizing a homologous inhibitory replicate. Relative to the last point, a recent focus of the laboratory has been to characterize the poxviral mimics of complement regulators and to define interactions with flaviviruses (Ddengue and West Nile). Many human diseases feature autoantibodies that form complement-fixing immune complexes such as in systemic lupus erythematosus. Since the Ccomplement system is activated by the autoantibody to a host antigen, it is and commonly is responsible for much of the ensuing cell/tissue damage. A related, more recently recognized function of the complement system is the safe (minimal or no adaptive immune response) clearance of “altered self” including host antigens in extracellular debris such as found inproduced by apoptotic and necrotic cells. During the aging process, oxidized lipids (atherosclerosis), amyloid proteins (Alzheimer’s Disease), lipofuscin pigments (age-related macular degeneration - AMD) and urate crystals (gout) accumulate and cause substantial morbidity and mortality. The complement system facilitates the handling of this so-called cellular “garbage”. As an example of thisThis is an exciting and emerging paradigmarea of complement research. As an example of this new paradigm, common and rare variants in the complement inhibitors factor H and factor I account for approximately 50% of the genetic risk of AMD, the most common cause of blindness in the developed world. A second genetic highlight the past decade has been the identification of heterozygous mutations in complement inhibitors that predispose to human diseases in which thrombi develop in the microvasculature (for example, atypical hemolytic uremic syndrome). Along this line, we are employing next- generation targeted gene sequencing technology to identify disease-causing mutations associated with the complement system in thrombomicroangiopathies, C3 glomerulopathies, and the pregnancy-related disorder, preeclampsia. Although a therapeutic agent that blocks C5 is now FDA approved to treat several diseases featuring excessive complement activation, it is also the costliest drug in the world (~ $600,000/year). Additional agents are under study and will soon be entering the market place. Lastly, work over the past three years partially driven by our laboratory has led to the discovery of an intracellular complement system to autoactivate cells and to influence metabolic pathways. . Much of the initial was carried out in human peripheral blood CD4+ T cells but multiple cell types can synthesize complement components and, remarkably, or take up and process blood C3. These emerging areas may ultimately lead to the development of new complement-based therapeutic targets.