{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T09:13:28Z","timestamp":1791278008777,"version":"4.1.0"},"reference-count":29,"publisher":"American Society of Hematology","issue":"5","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Detailed longitudinal studies of patients with X-linked lymphoproliferative disease (XLP) may increase our understanding of the immunologic defects that contribute to the development of lymphoma and hypogammaglobulinemia in XLP. We describe progressive changes observed in immunoglobulin concentrations, lymphocyte subsets, and Epstein-Barr virus (EBV) loads occurring in a 2-year period in a newly infected, but otherwise healthy, carrier (patient 9). We compare these findings with those observed in the patient's brother, who had hypogammaglobulinemia and XLP (patient 4). Immunoglobulin G (IgG), IgM, and IgA concentrations increased in patient 9 during acute EBV infection, but thereafter they decreased steadily to concentrations consistent with hypogammaglobulinemia, reaching a plateau 5 months after infection. In both patients, CD19+ B-lymphocyte rates remained lower than 3%, with a contraction of the B-cell memory compartment (CD27+ CD19+\/CD19+) to 20% (normal range, 32%-56%). T-lymphocyte subpopulations showed a reduction in CD4+ T-cell counts and a permanent CD8+ T-cell expansion. Interestingly, CXCR3 memory TH1 cells were expanded and CCR4+ TH2 lymphocytes were reduced, suggesting that abnormal skewing of memory T-cell subsets might contribute to reduced antibody synthesis. Despite an expanded number of CD3+CD8+ lymphocytes, increased EBV loads occurred in both patients without overt clinical symptoms of mononucleosis, lymphoproliferative disease, or lymphoma.<\/jats:p>","DOI":"10.1182\/blood-2003-07-2525","type":"journal-article","created":{"date-parts":[[2003,11,11]],"date-time":"2003-11-11T01:13:36Z","timestamp":1068513216000},"page":"1625-1631","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":45,"title":["Loss of circulating CD27+ memory B cells and CCR4+ T cells occurring in association with elevated EBV loads in XLP patients surviving primary EBV infection"],"prefix":"10.1182","volume":"103","author":[{"given":"Alejandro","family":"Malbran","sequence":"first","affiliation":[{"name":"From the Departamento de Alergia e Inmunologi\u0301a, Hospital Brita\u0301nico, Buenos Aires; Divisio\u0301n Inmunologi\u0301a, Instituto de Investigaciones Hematolo\u0301gicas, Academia Nacional de Medicina, Buenos Aires, Argentina; and Division of Pediatric Oncology, Children's Hospital of Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Belmonte","sequence":"additional","affiliation":[{"name":"From the Departamento de Alergia e Inmunologi\u0301a, Hospital Brita\u0301nico, Buenos Aires; Divisio\u0301n Inmunologi\u0301a, Instituto de Investigaciones Hematolo\u0301gicas, Academia Nacional de Medicina, Buenos Aires, Argentina; and Division of Pediatric Oncology, Children's Hospital of Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Ruibal-Ares","sequence":"additional","affiliation":[{"name":"From the Departamento de Alergia e Inmunologi\u0301a, Hospital Brita\u0301nico, Buenos Aires; Divisio\u0301n Inmunologi\u0301a, Instituto de Investigaciones Hematolo\u0301gicas, Academia Nacional de Medicina, Buenos Aires, Argentina; and Division of Pediatric Oncology, Children's Hospital of Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Bare\u0301","sequence":"additional","affiliation":[{"name":"From the Departamento de Alergia e Inmunologi\u0301a, Hospital Brita\u0301nico, Buenos Aires; Divisio\u0301n Inmunologi\u0301a, Instituto de Investigaciones Hematolo\u0301gicas, Academia Nacional de Medicina, Buenos Aires, Argentina; and Division of Pediatric Oncology, Children's Hospital of Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Massud","sequence":"additional","affiliation":[{"name":"From the Departamento de Alergia e Inmunologi\u0301a, Hospital Brita\u0301nico, Buenos Aires; Divisio\u0301n Inmunologi\u0301a, Instituto de Investigaciones Hematolo\u0301gicas, Academia Nacional de Medicina, Buenos Aires, Argentina; and Division of Pediatric Oncology, Children's Hospital of Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Parodi","sequence":"additional","affiliation":[{"name":"From the Departamento de Alergia e Inmunologi\u0301a, Hospital Brita\u0301nico, Buenos Aires; Divisio\u0301n Inmunologi\u0301a, Instituto de Investigaciones Hematolo\u0301gicas, Academia Nacional de Medicina, Buenos Aires, Argentina; and Division of Pediatric Oncology, Children's Hospital of Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Felippo","sequence":"additional","affiliation":[{"name":"From the Departamento de Alergia e Inmunologi\u0301a, Hospital Brita\u0301nico, Buenos Aires; Divisio\u0301n Inmunologi\u0301a, Instituto de Investigaciones Hematolo\u0301gicas, Academia Nacional de Medicina, Buenos Aires, Argentina; and Division of Pediatric Oncology, Children's Hospital of Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Hodinka","sequence":"additional","affiliation":[{"name":"From the Departamento de Alergia e Inmunologi\u0301a, Hospital Brita\u0301nico, Buenos Aires; Divisio\u0301n Inmunologi\u0301a, Instituto de Investigaciones Hematolo\u0301gicas, Academia Nacional de Medicina, Buenos Aires, Argentina; and Division of Pediatric Oncology, Children's Hospital of Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Haines","sequence":"additional","affiliation":[{"name":"From the Departamento de Alergia e Inmunologi\u0301a, Hospital Brita\u0301nico, Buenos Aires; Divisio\u0301n Inmunologi\u0301a, Instituto de Investigaciones Hematolo\u0301gicas, Academia Nacional de Medicina, Buenos Aires, Argentina; and Division of Pediatric Oncology, Children's Hospital of Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim E.","family":"Nichols","sequence":"additional","affiliation":[{"name":"From the Departamento de Alergia e Inmunologi\u0301a, Hospital Brita\u0301nico, Buenos Aires; Divisio\u0301n Inmunologi\u0301a, Instituto de Investigaciones Hematolo\u0301gicas, Academia Nacional de Medicina, Buenos Aires, Argentina; and Division of Pediatric Oncology, Children's Hospital of Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari\u0301a M.","family":"de Bracco","sequence":"additional","affiliation":[{"name":"From the Departamento de Alergia e Inmunologi\u0301a, Hospital Brita\u0301nico, Buenos Aires; Divisio\u0301n Inmunologi\u0301a, Instituto de Investigaciones Hematolo\u0301gicas, Academia Nacional de Medicina, Buenos Aires, Argentina; 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X-linked recessive progressive combined variable immunodeficiency (Duncan's disease). Lancet. 1975;1: 935-941.","DOI":"10.1016\/S0140-6736(75)92004-8"},{"key":"2020021218320508700_REF2","doi-asserted-by":"crossref","unstructured":"Morra M, Howie D, Grande MS, et al. X-linked lymphoproliferative disease: a progressive immunodeficiency. Annu Rev Immunol.2001;19: 657-682.","DOI":"10.1146\/annurev.immunol.19.1.657"},{"key":"2020021218320508700_REF3","doi-asserted-by":"crossref","unstructured":"Seemayer TA, Gross TG, Maarten-Egeler R, et al J. X-linked lymphoproliferative disease: twenty-five years after discovery. Pediatr Res.1995;38: 471-478.","DOI":"10.1203\/00006450-199510000-00001"},{"key":"2020021218320508700_REF4","unstructured":"Malbran A, Belmonte L, Ruibal-Ares B, Bare P, de Bracco MME. X-linked lymphoproliferative syndrome, EBV infection and impaired regulation of cell-mediated cytotoxicity. Medicina (Buenos Aires). 2003;63: 70-76."},{"key":"2020021218320508700_REF5","doi-asserted-by":"crossref","unstructured":"Sayos J, Wu C, Morra M, et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals through the co-receptor SLAM. Nature. 1998;395: 462-469.","DOI":"10.1038\/26683"},{"key":"2020021218320508700_REF6","doi-asserted-by":"crossref","unstructured":"Coffey AJ, Brooksbank RA, Brandau O, et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in the SH2 domain encoding gene. Nat Genet.1998;20: 120-135.","DOI":"10.1038\/2424"},{"key":"2020021218320508700_REF7","doi-asserted-by":"crossref","unstructured":"Nichols KE, Harkin DP, Levitz S, et al. Inactivating mutations in a SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proc Natl Acad Sci U S A. 1998;95: 13765-13770.","DOI":"10.1073\/pnas.95.23.13765"},{"key":"2020021218320508700_REF8","unstructured":"Sumegi J, Huang D, Lanyi A, et al. Correlation of mutations of the SH2D1A gene and Epstein-Barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease. Blood. 2000;96: 3118-3125."},{"key":"2020021218320508700_REF9","doi-asserted-by":"crossref","unstructured":"Sullivan JL, Byron KS, Brewster FE, Purtilo DT. Deficient natural killer cell activity in X-linked lymphoproliferative syndrome. Science. 1980; 210: 543-545.","DOI":"10.1126\/science.6158759"},{"key":"2020021218320508700_REF10","doi-asserted-by":"crossref","unstructured":"Seeley J, Sakamoto K, Ip SH, Hansen PW, Purtilo DT. Abnormal lymphocyte subsets in X-linked lymphoproliferative syndrome. J Immunol.1981; 127: 2618-2627.","DOI":"10.4049\/jimmunol.127.6.2618"},{"key":"2020021218320508700_REF11","doi-asserted-by":"crossref","unstructured":"Czar MJ, Kersh EN, Mijares LA, et al.Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A\/DSHP\/SAP. 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Washington DC: American Society of Microbiology; 1986;38: 712-715."},{"key":"2020021218320508700_REF15","doi-asserted-by":"crossref","unstructured":"Niesters HGM, van Esser J, Fries E, Wolthers KC, Cornelissen J, Osterhaus ADME. Development of a real-time quantitative assay for detection of Epstein-Barr virus. J Clin Microbiol. 2000; 38: 712-715.","DOI":"10.1128\/JCM.38.2.712-715.2000"},{"key":"2020021218320508700_REF16","doi-asserted-by":"crossref","unstructured":"McLaughlin P, Grillo-Lo\u0301pez A, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsing indolent lymphoma: half of patients respond to a four dose treatment program. J Clin Oncol. 1998;16: 2825-2833.","DOI":"10.1200\/JCO.1998.16.8.2825"},{"key":"2020021218320508700_REF17","doi-asserted-by":"crossref","unstructured":"Klein U, Rajewsky K, Kuppers R. 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Nature. 2003;421: 282-287.","DOI":"10.1038\/nature01318"},{"key":"2020021218320508700_REF24","doi-asserted-by":"crossref","unstructured":"Howie D, Okamoto S, Rietdjik S, et al. The role of SAP in murine CD150 (SLAM)\u2013mediated T-cell proliferation and interferon \u03b3 production. Blood. 2002;100: 2899-2907.","DOI":"10.1182\/blood-2002-02-0445"},{"key":"2020021218320508700_REF25","doi-asserted-by":"crossref","unstructured":"Okano M, Thiele GM, Purtilo DT. Variable presence of circulating cytokines in patients with sporadic or X-linked lymphoproliferative disease with fatal infectious mononucleosis. Pediatr Hematol Oncol. 1993;10: 97-99.","DOI":"10.3109\/08880019309016535"},{"key":"2020021218320508700_REF26","doi-asserted-by":"crossref","unstructured":"Wu C, Nguyen KB, Pien GC, et al. SAP controls T cell responses to virus and terminal differentiation of TH2 cells. 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