Lab Research Focus
The focus of ongoing research in the laboratory is directed towards understanding the molecular processes that are involved in B lymphocyte activation. By delineating the molecular events that take place during lymphocyte activation, it should be possible to develop more effective strategies for regulating the immune response. The development of immunotherapeutic regimens will in turn have significant implications for potentiation of the immune response in order to fight viral and bacterial infections or cancer. Similar strategies can also be used to facilitate the development of better approaches to suppress the immune system in order to control autoimmune disease.
B lymphocytes express receptors for antigen on their surface that enable them to discriminate between self and non-self (i.e. expression of these receptors confers the ability to detect and respond to foreign viruses and bacteria). In the B cell, membrane immunoglobulin functions as the antigen recognition unit and is part of a larger multi-subunit complex, referred to as the B cell antigen receptor complex (BCR), that includes the CD79a and CD79b polypeptides. The CD79a/CD79b heterodimer functions as a transport/transducer structure that couples membrane immunoglobulin to intracellular effector proteins that mediate signal transduction leading to alterations in gene transcription.
In immature B cells, the BCR plays an important role in determining the fate of the cell in a process referred to as tolerance induction. B cells that express receptors with a high affinity for self antigen are eliminated from the system either through clonal deletion, induction of clonal anergy or actuation of receptor editing. Cells that express receptors specific for foreign antigen, which survive the process of tolerance induction exit into the periphery where they contribute to the effective B cell repertoire. When a mature, quiescent B cell encounters antigen it responds by increasing gene transcription, undergoing clonal expansion and differentiating into an antibody-secreting plasma cell.
Because the BCR serves a critical role in determining the biological response to antigen and thus in regulating B cell immune function, it is of great importance to delineate the molecular processes that transduce a signal from the external environment to the nucleus of the cell.
Studies have clearly demonstrated that B cell activation (as well as tolerance induction) is regulated by reversible tyrosine phosphorylation of multiple signal transducing effector proteins. Indeed, increased tyrosine phosphorylation of intracellular substrates is the earliest detectable consequence of antigen binding to the B cell. At the most basic level, reversible tyrosine phosphorylation is regulated by specific protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTP) in the B cell. These effector molecules regulate signaling via the BCR either through a direct association with the CD79a/CD79b heterodimer or indirectly via their association with accessory proteins such as CD19 or CD22. Because the net balance between phosphorylation and dephosphorylation in cells is tightly controlled and involves an extensive, interactive network of kinases and phosphatases, it is of interest to delineate the role that specific PTKs and PTPs play in the context of this larger network. Towards this goal, studies in the laboratory focus on: 1) understanding the molecular mechanisms by which PTK and PTP function is regulated, 2) identifying substrates for these effector molecules and 3) elucidating the consequence that reversible tyrosine phosphorylation of specific effector molecules has on their ability to regulate B cell immune function. The laboratory examines these questions on a molecular level using structure/function analysis and ultimately tests the findings from molecular studies in cell lines and whole animal models including transgenic and gene targeted mice.
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