Fleming Lab Research
The Fleming lab's long term research goal is to understand the mechanisms underlying the damaging effects of an excessive innate autoimmune response. Innate autoimmunity instigates many diverse conditions including stroke, heart attack, intestinal ischemia/reperfusion, organ transplantation, miscarriage and systemic erythematosus lupus. Current therapeutics for these diseases attempt to decrease the inflammatory response. To prevent the initial response, we must understand the regulatory mechanisms and interactions occurring prior to and during disease.
We are investigating the initiation, regulation and crosstalk between complement and other inflammatory components which instigate or amplify these diseases. Our research centers on three innate immune mechanisms involved in tissue damage : 1) the interactions of naturally occurring antibodies and complement activation in intestinal damage 2) the interactions of toll-like receptors and complement activation in intestinal damage and 3) the role of complement in multiple other forms of ischemic damage. To determine the mechanisms of intestinal damage caused by decreased blood flow, in vivo mouse studies, cell culture and molecular analysis are used. The hypothetical model is indicated in Figure 1 with CR2+ B cells (A) producing natural antibodies which bind neo-antigens expressed on the tissue (B). Complement is activated via the classical and/or lectin pathways (C). The release of anaphylatoxins recruit inflammatory cells (D)and results in the production of cytokines and PGE2 (E).
The first project within the lab is identifying the role of naturally occurring antibodies in ischemia/reperfusion induced intestinal damage (Fig. 2). In this NIH funded project, our lab examines cellular and protein initiators of tissue damage and the molecular requirements for production of pathogenic antibodies. We recently identified cellular changes in the intestinal lipids which appear to initiate the innate immune response after abdominal trauma (Fig. 2). We also demonstrated that the serum protein, B2-glycoprotein I, binds to the altered lipids. Importantly, in a mouse model, peptides from this serum protein prevent the intestinal damage and inflammation. Finally, the Fleming lab established that pathogenic antibodies are not only produced by B1 B cells but also by CR2+ marginal zone B cells which do not require the expected C3 ligand.
The second project is determining the role of toll-like receptors in ischemia/ reperfusion-induced epithelial and endothelial damage (Fig. 3). This project recently demonstrated the interaction of two components of the immune response (toll-like receptors and complement activation). As most studies examine either component individually, examining the crosstalk between the 2 pathways will provide improved, unique therapeutics for multiple inflammatory diseases.
The final facet is an undergraduate project, studying complement inhibition of multiple forms of ischemic tissue damage. These projects examine the mechanism of hemorrhage induced injury, preeclampsia, kidney damage and myocardial infarction. We hope to understand the damage and identifiy possible therapeutics.
