Epstein Barr virus (EBV) is a cause of infectious mononucleosis and is associated with a number of cancers including Burkitt lymphoma and lymphoma in transplant recipients. Chronic active EBV (CAEBV) disease is an often fatal disease in which patients have markedly elevated levels of antibody to EBV or EBV DNA in the blood, and infiltration of tissues with EBV-infected lymphocytes. Last year, in collaboration with Michael Lenardo in the Laboratory of Immunology, NIAID, we found that one of our patients with CAEBV disease who died of an EBV-positive lymphoma had a mutation in a gene important for magnesium transport (MagT1). The patient's T cells have reduced baseline levels of free magnesium and defective magnesium and calcium influx when they are stimulated with a potent T cell stimulus (an antibody to the T cell receptor). The patient's peripheral blood cells are impaired for activating several proteins in signaling pathways (NF-Kappa B, NFAT, PLC-gamma-1, PKC-theta), Since T lymphocytes are important for killing EBV-infected cells, the impaired activation of T lymphocytes in the patient associated with the mutation in MagT1 was likely responsible for his severe CAEBV disease. This year in collaboration with Dr. Lenardo, we showed that patients with mutations in MagT1 have reduced expression of a protein (NKG2D) present on natural killer (NK) and cytotoxic (CD8) T cells that is important for activation of the cells and their ability to kill target cells. Cells from patients that have mutations in MagT1 are impaired for killing Epstein-Barr virus-infected cells. These patients have a high rate of Epstein-Barr virus B cell lymphomas. Addition of magnesium to the cells in culture increased the level of the NKG2D protein on the surface of the cells and improved killing of Epstein-Barr virus-infected cells. Intravenous or oral magnesium supplements given to patients with mutations in MagT1 increased the level of magnesium inside their cells, increased expression of the NKG2D on the surface of their cells, and reduced the number of copies of EBV DNA in their cells. These findings indicate that mutations in the MagT1 magnesium transporter gene, that predispose patients to uncontrolled EBV infection and B cell lymphomas, are associated with reduced levels of a cell surface protein (NKG2D) that is important for killing virus-infected cells. Magnesium supplements given to patients can enhance expression of the cell surface protein (NKG2D) and reduce the level of EBV copies in their cells. This year we also identified another patient who is unable to control EBV infection and showed that he has a mutation in MagT1. This year we also identified a patient with chronic active Epstein-Barr virus infection and lymphocytic variant hyperosinophilia;the latter is a disease manifested by cytokine production by T cells which results in increased numbers of eosinophils in the blood and tissues. The patient was found to have a T cell clone that was infected with a clonal form of Epstein-Barr virus, and the T cell clone produced cytokines (IL-4, IL-5) that stimulated production of eosinophils. Thus, uncontrolled EBV infection can in rare cases be the cause of lymphocytic variant hyperosinophilia.
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