The Arepally-Khandelwal laboratory investigates the role of complement in health and disease, with a particular focus on immune-mediated disorders. The long-term goal of our work is to advance knowledge of complement biology, provide insights into disease mechanisms and identify complement targets for therapeutic inhibition. As described below, active projects in the laboratory are centered on heparin-induced thrombocytopenia (HIT), a life-threatening clotting disorder caused by antibodies to platelet factor 4 (PF4) and heparin, systemic lupus erythematosus (SLE), an autoimmune disease caused by anti-nuclear antibodies, and fundamental studies of complement-immune complex interactions.
Active Projects
Complement Activation in HIT Thrombosis
Recent studies from our laboratory have shown that complement is essential for the clot promoting properties of anti-PF4/heparin antibodies that cause HIT. In collaboration with Dr. Doug Cines at the University of Pennsylvania and Dr. Lubica Rauova at the Children’s Hospital of Philadelphia, our studies are examining the contributions of complement to endothelial injury and thrombosis using in vitro assays and in vivo models.
Complement Activation in SLE
Although there is significant evidence for complement activation in SLE, little is known about the complement activating properties of anti-nuclear antibodies. With assistance from collaborators in Duke Rheumatology, Dr. Jennifer Rogers and Dr. David Pisetsky, this project seeks to identify complement-activating antibodies in patients with SLE and identify complement-dependent pathways of cellular activation and inflammation.
Complement and Immune Complex Interactions
Our recent studies indicate that physiologic levels of complement are critical for interactions of immune complexes (ICs) with CRs and FcgRs. Using model ICs, complement inhibitors and whole blood, we are investigating the complex interplay of complement, ICs, complement receptors and Fcg receptors. In collaboration with Duke evolutionary biologists Drs. V. Louise Roth and John Mercer, we are additionally performing comparative studies of complement responses to ICs in humans and rodents.
Role of Complement Activation in the HIT immune response
Studies from our laboratory identified complement activation as an early event in the host’s encounter with PF4/heparin antigenic complexes. Using in vitro and ex vivo human samples and mouse models, this project seeks to establish the contributions of complement to anti-PF4/heparin antibody formation and risk factors for heparin sensitization.
