Epstein-Barr virus (EBV) is associated with both B cell cancers (Hodgkin lymphoma, Burkitt lymphoma) and epithelial cell cancers (nasopharyngeal carcinoma, gastric carcinoma). The virus typically infects epithelial cells of the oropharynx and B cells circulating in the blood. The virus establishes a latent infection in B cells where it persists for life. Some patients who become infected with EBV develop hydroa vacciniforme lymphoproliferative disorder (HVLPD). Patients with classic HVLPD typically have high levels of EBV DNA in T cells and/or NK cells in blood, and skin lesions induced by sun exposure that are infiltrated with EBV-infected lymphocytes and heal with scaring. HVLPD is very rare in the United States and Europe, but more common in Asia and South America. The disease can progress to a systemic form which may result in fatal lymphoma. We reported our 11-year experience with 16 HVLPD patients from the United States and England and found that Caucasians were less likely to develop systemic EBV disease (1/10) than non-Caucasians (5/6). All (10/10) of the Caucasians were generally in good health at last follow-up, while two-thirds (4/6) of the non-Caucasians required hematopoietic stem cell transplantation. Non-Caucasians had later age of onset of HVLPD than Caucasians (median age 8 vs. 5 years), higher levels of EBV DNA (median 1,515,000 vs. 250,000 copies/ml), and more often had low numbers of NK cells (83% vs. 50% of patients) and T cell clones in the blood (83% vs. 30% of patients). RNA-seq analysis of an HVLPD skin lesion in a Caucasian compared with his normal skin showed increased expression of genes encoding interferon-gamma and chemokines that attract T cells and NK cells. Thus, Caucasian patients with HVLPD were less likely to have systemic disease with EBV and had a much better prognosis than non-Caucasians, and it is important to follow HVLPD patients who have no systemic symptoms conservatively. This year in collaboration with Dr. Andrew Snow at the Uniformed Services University of the Health Sciences we reported a group of patients with mutations in the CARD11 (caspase activation and recruitment domain 11) gene. CARD11 is an adapter protein that is important for transmitting signals in lymphocytes that have become activated after binding to foreign proteins. Patients with CARD11 mutations can have severe combined immune deficiency, B cell proliferation, or allergic diseases, depending on the mutation in CARD11. One of the patients with CARD11 mutations had elevated levels of EBV in the blood, low numbers of B lymphocytes, and had numerous viral skin infections. We continue to follow and study a number of patients with EBV diseases, including those with chronic active EBV, EBV hydroa vacciniforme, and EBV lymphoproliferative diseases.
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