DESCRIPTION Of RESEARCH
We investigate molecular mechanisms of B cell activation that regulate humoral immunity and pathogenesis of B cell-mediated diseases. Dynamic remodeling of the B cell membrane and the actin cytoskeleton facilitates subcellular organization of key signaling proteins, enabling B cells to accomplish their various functions. We employ high resolution live cell imaging, quantitative systems biology methods and genetic knockouts in mice to investigate the role of membrane-cytoskeleton remodeling proteins in regulating B cell function. We have discovered that Ezrin, a member of the Ezrin-Radixin-Moesin (ERM) family of membrane-cytoskeleton linkers, regulates multiple facets of B cell function, and plays an important role in regulating B cell autoimmunity, inflammation and cancer.
In additon to investigating basic mechanisms underlying B cell activation, proliferation and differentiation, we have established a new Center of Excellence in Lymphoid Malignancies Research (Lymphocenter) at the Cleveland Clinic that is actively engaged in understanding the basis of resistance and relapse in B cell lymphoma and developing novel small molecule and cellular immunotherapies for treatment of lymphoma patients. We utilize primary patient specimens to investigate causes of treatment success/failure in order to translate our finding to improve and customize patient care.
Brian Hill, MD, PhD, Hematology and Medical Oncology, CCF
Eric Hsi, MD, Clinical Pathology, CCF
Kewal Asosingh, PhD, Inflammation & Immunity, CCF
Clark Distelhorst, MD, Case Western Reserve University
In other words ...
B lymphocytes are a type of blood cell that perform a very important task, which is to make antibodies that clear infections. In my lab we study how activation signals are transmitted inside B cells, so that we can design better ways to protect ourselves. Under certain circumstances, B cells either grow too much or make antibodies against our self proteins. This can lead to B cell cancers and diseases such as lupus. We are also exploring aspects of B cell function that can be targeted to develop new treatment strategies against these diseases.
Selected Recent Publications
Pore, D., Huang, E., Dejanovic, D., Parameswaran, N., Cheung, M. and Gupta, N. 2018. Deletion of Ezrin in B cells of Lyn-deficient mice downregulates lupus pathology. J. Immuol. Cutting Edge, 201(5):1353-1358.
Enyindah-Asonye, G., Li, Y., Xin, W., Singer, N.G., Gupta, N., Fung, J., and Lin., F. 2017. CD6 receptor regulates intestinal ischemia/reperfusion-induced injury by modulating natural IgM-producing B1a cell self-renewal. J. Biol. Chem. 292(2):661-671.
Pore, D., Matsui, K., Parameswaran, N. and Gupta, N. 2016. Ezrin regulates inflammation by limiting B cell interleukin-10 production. J. Immunol. Cutting Edge,, 196(2):558-62
Pore, D., Bodo, J., Danda, A., Yan, D., Phillips, J.G., Lindner D.L., Smith, M.R., Hill, B.T., Hsi, E., and Gupta, N. 2015. Identification of Ezrin-Radixin-Moesin proteins as novel regulators of pathogenic B cell receptor signaling and tumor growth in diffuse large B cell lymphoma. Leukemia, 29:1857-1867.
Pore, D. and Gupta, N. 2014. The ezrin-radixin-moesin family of proteins in the regulation of B-cell immune response. Crit. Rev. Immunol. 35:15-31.
Parameswaran, N. and Gupta, N. 2013. Re-defining ERM function in lymphocyte activation and migration. Immunol. Rev. (Special Issue: The Cytoskeleton), 256:63-79.
Pore, D., Parameswaran, N., Matsui, K., Stone, M.B., Saotome, I., McClatchey, A.I., Veatch, S.L., and Gupta, N. 2013. Ezrin tunes the strength of humoral immunity. J. Immunol., 191:4048-4058.
Parameswaran, N., Enyindah-Asonye, G., Liggett, L., Shah, N., Bagheri, N., and Gupta, N. 2013. Spatial coupling of JNK activation to the B cell antigen receptor by tyrosine-phosphorylated ezrin. J. Immunol. 190:2017-2026.
Kish, D.D., Gorbachev, A.V., Parameswaran, N., Gupta, N., and Fairchild, R.F. 2012. Neutrophil expression of FasL and perforin directs effector CD8 T cell infiltration into antigen-challenged skin. J. Immunol. 189:2191-2202.
Matsui, K., Parameswaran, N., Bagheri, N., Willard, B., and Gupta, N. 2011. Proteomics analysis of the ezrin interactome in B cells reveals a novel association with Myo18aa. J. Proteome Res. 10:3983-3992.
Parameswaran, N., Matsui, K., and Gupta, N. 2011. Conformational switching in ezrin regulates chemokine-induced morphological and cytoskeletal changes required for B cell migration. J. Immunol. 186:4088-4097.