After infection with Epstein-Barr virus (EBV), males with the X- linked lymphorproliferative syndrome (XLP) develop fatal or life- threatening infectious mononucleosis (IM), acquired hypogammaglonbulinemia and bone marrow hypoplasias, or B cell malignant lymphomas. Mortality is 85% by 10 and 100% by 40 years of age. We seek to detect mechanisms responsible for the pathogenesis of EBV-induced immunodeficiency and steps from the premalignant state to malignant lymphoma by: 1) maintaining and updating XLP and Fatal IM Registries, 2) detecting XLP by restriction fragment length polymorphisms linkage analysis with the XLP locus and by assessing antibody responses to bacteriophage OX174 and EBV, and 3) identifying mechanisms of acquired immunodeficiency post-EBV infection and steps in conversion from the premalignant state to malignant lymphoma. Detection of chromosomal translocations by karyotying and/or genetic alterations of c-myc and c-fgr and Ig genes and presence of EBV genome will be achieved by Southern blot analyses. We will measure expression of c-myc protein in lymphoid cells using monoclonal antibodies and flow cytometry. The expression of latent membrane protein and EBV nuclear antigen will be detected in the lymphoproliferative lesions using immunoblotting. Thereby we will determine whether karyotypic and molecular changes in a proliferating B cell endow the cell with enhanced growth (i.e., due to increase c-myc expression) and resistance to cytotoxic T cells (i.e., due to decreased expression of EBV latent membrane protein). These findings will be evaluated and compared to morphological features (i.e., malignant lymphoma vs IM) and clinical behavior. Results of these studies ought to provide improved detection of XLP, prevention, and therapy for EBV-induced lymphoproliferative diseases in immune deficient patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Pathology B Study Section (PTHB)
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University of Nebraska Medical Center
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Okano, M; Thiele, G M; Purtilo, D T (1993) Variable presence of circulating cytokines in patients with sporadic or X-linked lymphoproliferative disease with fatal infectious mononucleosis. Pediatr Hematol Oncol 10:97-9
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