Autoimmunity; Cell Metabolism; Gene Expression; Immunology; Inflammation; Intrinsic Immunity; Metabolism; Molecular and Cellular Biology; Molecular Basis of Disease; Neurobiology; Neuroimmunology; Neuroscience; Pathophysiology; Transgenic organisms
Complement: Its nuances in health and disease:
The lab has 2 ongoing projects: The first one is to study the role of the complement (C) system in the kidney and brain in normal and disease settings. C discovered by Jules Bordet in the 1800s is one of the critical mechanisms involved in human defense. The exciting work in the last decade has revealed that in addition to the established function of host defense, C also participates in several novel non-canonical functions, and has functional specificities at different locations, that have led to a rapidly expanding C therapeutics arena. C regulators strictly modulate the C system, preventing injury to host tissue. The absence of C factor H (FH), a critical regulator of the alternative C pathway causes loss of kidney function in men and mice. The goal of the kidney arm of the work is to understand the role of FH in glomerular inflammation, using the immune complex-mediated glomerulonephritis (ICGN) mouse model. Bone marrow and kidney transplant studies in the lab revealed that ICs were transported by FH on platelets in mice and processed by FH on kidney podocytes. In addition, our results showed that circulating FH played a critical role in causing kidney disease pathology. Since significant macrophage (MØs) infiltration occurred in the kidneys in this disease setting, and depletion of MØs in mice alleviated the pathology we are determining the role of these cells and the underlying mechanisms involved. We are studying the role of extrinsic and intrinsic C on MØs in this setting and the mechanisms at play in the regulation of trafficking and polarization of MØs by FH. Another observation in this disease setting is the subendothelial deposits. The endothelial layer is an integral part of the kidney filtration unit. Using cultured endothelial cells isolated from wildtype and FH knockout mice, our recent studies revealed for the first time that intrinsic endothelial C is of significance in maintaining kidney endothelial layer integrity. The translatability of the results was established using human endothelial cells transfected with FH SiRNA. The molecular pathways involved are the focus of ongoing studies. One of the commonalities between the brain and the kidney is that both organs filter the blood passing through. We study the role of C in the brain focusing on the systemic lupus erythematosus (lupus) model and 2D cell culture systems. Our results show that C inhibition protected the blood-brain barrier (BBB) integrity, reduced the severity of the disease, and improved behavior in lupus. C5a generated during C activation alters the structural integrity of the BBB by signaling through the G-coupled receptor, C3aR. We are currently studying the C-dependent pathways involved in brain endothelial cells.
The second project that is currently ongoing is to study the role of the microbiome and the C connection in different inflammatory diseases such as lupus in men and mice. The collection of samples to determine how the microbiome impacts the disease in lupus patients in India was initiated through a Fulbright scholarship. We are grateful for the support of the Community of Excellence for Global Health Equity and the Office of the Vice President of Research, UB that has allowed us to begin processing and analysis of these samples. With the support of Genome, Environment, and Microbiome (GEM, UB), we have accrued the microbiome samples from mice, and the sequencing and analysis are currently ongoing.