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Shiv Pillai, MD, PhDProfessor of MedicineHarvard Medical School
Associate GeneticistCenter for Cancer Research
The Pillai laboratory asks basic questions about the biology of the immune system and human genetics for two reasons: 1) Can we manipulate the immune system to treat cancer and to increase immunological memory; and 2) Can this information be used to better understand and develop new therapies for chronic inflammatory human diseases such as arthritis, lupus and Crohn’s disease? Our discovery of the role of an enzyme called Btk in the activation of B cells has contributed to the generation of Btk inhibitors that are effective in B cell malignancies and in trials of autoimmunity. One of the pathways we are currently studying suggests new approaches for the treatment of autoimmune disorders. We have also found a novel way to strengthen immune responses and enhance helper T cell memory that provides hope for developing more effective personalized immune-system based treatments for cancer.
Shiv Pillai MD, PhDPrincipal Investigator
B cell lineage commitment and B cell memoryWe are interested in cell fate decisions during B cell development and memory B cell generation. We seek to understand how BCR signal strength, Notch2, NFκB p50 and the Hippo pathway contribute to lineage commitment events in B cell development. We are also currently studying the molecular basis of B cell memory and the role of DNA methylation in this process.
Studies on the genesis of plasmacytoid dendritic cellsThe origins of plasmacytoid dendritic cells have long been controversial. We have identified unique bone marrow progenitors that exclusively give rise to plasmacytoid dendritic cells without differentiating into conventional dendritic cells. This work is generating new insights as to the nature of the myeloid versus lymphoid split during hematopoietic cell development.
B cell tolerance and the role of the SIAE/Siglec pathway in CD4+T cell memoryWe are particularly interested in a novel pathway in which sialic acid acetylesterase (SIAE) and inhibitory receptors of the Siglec family regulate peripheral B cell tolerance. In particular, we are examining the mechanism of tolerance mediated by this pathway and the mechanism by which this pathway regulates CD4+ T cell memory and T follicular helper cell generation.
Genetic variants and human autoimmunity A major area of interest for this lab is the genetic basis of human autoimmunity, especially the role of rare variants in genes that regulate B cell tolerance. The major approaches we are pursuing include exome sequencing and the detailed functional analyses of human B cells. Somatic changes in B cell malignanciesWe have long been interested in the biochemical and in vivo biological roles of B cell signaling pathways, and have extended this interest to the study of somatic changes in B cell signaling pathways that occur in follicular lymphomas as identified by exome sequencing studies. Most recently, we have undertaken detailed analyses to discriminate between driver and passenger mutations.
Negative regulators in conventional and plasmacytoid dendritic cells and enhancing immune responses to HIV and cancerOur studies on SIAE and inhibitory Siglecs in B cells have led us to explore how similar pathways function in regulating signaling in murine and human dendritic cells. We 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 design of personalized immunotherapy in cancer by combining exome sequencing and the regulation of dendritic cell activation.
Studies on RIPK4 and the NFKB pathway in human cancers RIPK4 is a kinase that we identified many years ago as an NFκB activating kinase. We have studied the mechanism by which mutations of this kinase contribute to an inherited ectodermal developmental defect known as popliteal pterygium syndrome. We are also involved in studies of this kinase in the context of human malignancy.
View a list of publications by researchers at the Pillai Laboratory
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