Dr. Schwartzberg's laboratory studies signal transduction in T lymphocytes, with a particular focus on signaling molecules that affect T lymphocyte function and their ability to respond to infection. Her group generates mouse models that lack genes affecting a variety of signaling molecules to see how the loss of a particular gene affects the immune system.
They have generated mouse models that "knockout" genes involved in or related to several primary human immunodeficiency syndromes, including X-linked lymphoproliferative syndrome and X-linked agammaglobulinemia. They challenge these knockout mouse models with a wide array of infectious agents, including parasites, to study the effect of the loss of gene function on the overall immune system in vivo and to analyze cells from the animals in vitro to examine what has happened at both a biochemical and a cellular level. Studies such as these not only can help explain what is going wrong in human immune diseases but also can advance basic scientific understanding of immune system function in general and often identify likely pathways for therapeutic research.
X-linked lymphoproliferative syndrome is a severe (and usually fatal) immune disorder characterized by a hyperactive response to viral infection, low serum antibodies, and, frequently, lymphoma. It is caused by mutations in the SH2D1A gene, which encodes a small signaling molecule called SLAM-associated protein, or SAP. Dr. Schwartzberg's laboratory has found that mutations affecting SAP in mice cripple long-term serum antibody production. Specifically, mutations in SAP prevent T cells from signaling B cells- the antibody-forming cells of the immune system- to differentiate and form a persistent defense against infectious agents. Dr. Schwartzberg's group has further demonstrated that SAP-deficient T cells show abnormal activation of nuclear factor NF?B1, a transcription factor that plays a key role in the regulation of cellular genes involved in immune and inflammatory responses. In addition to pointing toward new lines of research for treating the disease, these insights may aid in the development of vaccines, because the generation of long-term persisting antibodies against a particular infectious agent is a crucial requirement for successful vaccine development.
X-linked agammaglobulinemia is a severe immunodeficiency characterized by very low serum antibodies and defective B cell development and function. It is caused by mutations in a Tec family tyrosine kinase called Btk, which is a key signaling molecule in B lymphocyte development. Dr. Schwartzberg's laboratory is investigating whether the Tec kinases play equivalent roles in T lymphocytes. They have generated mice carrying mutations that affect the major Tec kinases expressed in T cells to answer this question. One of these -Itk- appears to be the major Tec kinase involved in T-cell function; it is required for proper intracellular calcium signaling, activation of the regulation of T-cell actin cytoskeleton, activation of downstream transcription pathways, and activation of T helper 2 cell responses against parasites and allergens. Itk, therefore, is a highly promising target for research into treatments for asthma and hypersensitivity.
Another Tec- family kinase member, Rlk, may be important for T helper 1 (TH1) cell responses and is a potential target for developing therapies for TH1-mediated diseases, including autoimmune disorders.
Finally, Dr. Schwartzberg's group investigates the genetics of Wiskott-Aldrich syndrome, a severe immunodeficiency syndrome marked by increased susceptibility to infections, eczema, and autoimmune disorders. It is caused by mutations in a gene known as WASP (for Wiskott-Aldrich syndrome protein). The WASP protein appears to play an important role in the T cell's actin cytoskeleton, which is required for organizing signaling molecules to permit effective T-cell function. Dr. Schwartzberg's laboratory found that WASP fails to be activated properly in T cells from Itk-deficient mice. They are now investigating the responses of WASP-deficient mice to parasitic challenges in vivo to determine whether some of the observed phenotypes can be understood in the context of what is known about Itk.
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Last Reviewed: August 16, 2012