Shiv Subramaniam Pillai
Professor of Medicine
Sialic acid O-acetylation, Siglecs and the regulation of hematopoiesis and immunity We are particularly interested in a novel set of pathways in which Sialic acid acetyl esterase (SIAE) and inhibitory receptors of the Siglec family regulate adaptive immunity. The O-acetylation of sialic acid marks hematopoietic progenitors and has helped us define the pathway of plasmacytoid dendritic cell development. We have identified the presence of two different 9-O acetyl transferases and have created a knockout model for one of these two molecules.
Regulation of CD4+ and CD8+ T cell effector and effector/memory responses by SIAE The absence of SIAE results in a spontaneous increase in CD4+ and CD8+ effector and effector/memory phenotype cells. There is a many-fold increase in CD4+ memory T cell responses in response to antigenic challenge, as well as an increase in T follicular helper cell generation. As a result increased germinal center B cells and a marked increase in somatic hypermutation is observed.
Small molecules to enhance immune responses in cancer and HIV Since the absence of SIAE leads to an enhancement of somatic hypermutation as well as a marked increase in CD4+ and CD8+ memory phenotype cells, this pathways offers opportunities for therapeutic manipulation. In the absence of this enzyme there is a fairly striking increase in the affinity of B cells that recognize HIV gp140. In studies in collaboration with Dr. Ben Cravatt at The Scripps Research Institute we have developed a small molecule inhibitor of this enzyme. We seek to use our increasing knowledge of negative regulatory pathways in immune cells to develop novel protocols for immunization that may be applied to the generation of neutralizing antibodies against HIVgp140 trimers, and also to the design of immunotherapy in cancer.
Epigenetic regulation of human autoimmunity A clear causal explanation for autoimmunity is currently lacking. Although genetics and the environment, especially the microbiome, certainly play a role, our studies have revealed a robust epigenetic phenomenon that may be of central relevance in lupus and rheumatoid arthritis.
Studies on the role of T cells in fibrotic human diseases especially IgG4-related disease We have used Next Generation Sequencing and expression profiling to identify a novel human CD4 +T cell subset that may drive IgG4-related disease. Using single cell cloning and sequencing of disease plasmablasts we have been able to generate recombinant human monoclonal antibodies from disease subjects in order to identify an auto-antigen. The relationship of self antigens to the activation of disease causing T cells is currently being explored.
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