Abstract
B cell dysfunction is a well-studied complication of HIV infection in adults. Data on B cell differentiation in normal and HIV-infected children are lacking. We show the distribution of B cell subsets and immunoglobulin levels in HIV-infected children compared with controls. Furthermore, we observe the long-term B cell reconstitution of vaccine-specific immunity after antiretroviral therapy (ART). Phenotype of B cells (naive, non-switched memory, switched memory) was analyzed in 48 infected children and 62 controls. In nine HIV-infected children, functional reconstitution was quantified by tetanus-specific antibodies and by performing a lymphocyte transformation test (LTT) in a longitudinal approach. Switched memory B cells are significantly reduced in HIV-infected children. Vaccine-specific antibodies and response to LTT increase after initiation of ART. Our data indicate a significant dysfunction in the B cell system, despite effective ART. Partial reconstitution of humoral immunity may have therapeutic implications in a subset of HIV-infected children.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- ARP:
-
age-related percentage
- ART:
-
antiretroviral therapy
- LTT:
-
lymphocyte transformation test
- tp:
-
time point
References
Amadori A, Zamarchi R, Ciminale V, Del Mistro A, Siervo S, Alberti A, Colombatti M, Chieco-Bianchi L 1989 HIV-1-specific B cell activation. A major constituent of spontaneous B cell activation during HIV-1 infection. J Immunol 143: 2146–2152
Zamarchi R, Barelli A, Borri A, Petralia G, Ometto L, Masiero S, Chieco-Bianchi L, Amadori A 2002 B cell activation in peripheral blood and lymph nodes during HIV infection. AIDS 16: 1217–1226
Shirai A, Cosentino M, Leitman-Klinman SF, Klinman DM 1992 Human immunodeficiency virus infection induces both polyclonal and virus-specific B cell activation. J Clin Invest 89: 561–566
Martinez-Maza O, Breen EC 2002 B-cell activation and lymphoma in patients with HIV. Curr Opin Oncol 14: 528–532
Grulich AE, Wan X, Law MG, Milliken ST, Lewis CR, Garsia RJ, Gold J, Finlayson RJ, Cooper DA, Kaldor JM 2000 B-cell stimulation and prolonged immune deficiency are risk factors for non-Hodgkin's lymphoma in people with AIDS. AIDS 14: 133–140
De Milito A, Morch C, Sonnerborg A, Chiodi F 2001 Loss of memory (CD27) B lymphocytes in HIV-1 infection. AIDS 15: 957–964
Chong Y, Ikematsu H, Kikuchi K, Yamamoto M, Murata M, Nishimura M, Nabeshima S, Kashiwagi S, Hayashi J 2004 Selective CD27+ (memory) B cell reduction and characteristic B cell alteration in drug-naive and HAART-treated HIV type 1-infected patients. AIDS Res Hum Retroviruses 20: 219–226
Miedema F, Petit AJ, Terpstra FG, Schattenkerk JK, de Wolf F, Al BJ, Roos M, Lange JM, Danner SA, Goudsmit J, Schellekens PT 1988 Immunological abnormalities in human immunodeficiency virus (HIV)-infected asymptomatic homosexual men. HIV affects the immune system before CD4+ T helper cell depletion occurs. J Clin Invest 82: 1908–1914
Conge AM, Tarte K, Reynes J, Segondy M, Gerfaux J, Zembala M, Vendrell JP 1998 Impairment of B-lymphocyte differentiation induced by dual triggering of the B-cell antigen receptor and CD40 in advanced HIV-1-disease. AIDS 12: 1437–1449
IRHIC 2004 Combined antiretroviral therapy reduces hyperimmunoglobulinemia in HIV-1 infected children. AIDS 18: 1423–1428
Shearer WT, Easley KA, Goldfarb J, Rosenblatt HM, Jenson HB, Kovacs A, McIntosh K 2000 Prospective 5-year study of peripheral blood CD4, CD8, and CD19/CD20 lymphocytes and serum Igs in children born to HIV-1 women. The P(2)C(2) HIV Study Group. J Allergy Clin Immunol 106: 559–566
Ibegbu C, Spira TJ, Nesheim S, Mendez H, Lee F, Polliotti B, Caba J, Nahmias A 1994 Subpopulations of T and B cells in perinatally HIV-infected and noninfected age-matched children compared with those in adults. Clin Immunol Immunopathol 71: 27–32
CDC 1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR Morb Mortal Wkly Rep 43: 1–10
RKI 2008 Recommendation of the Standing Vaccination Commission at Robert Koch Institute. Epidemiol Bull 30: 235–254
Niehues T, Reichenbach J, Neubert J, Gudowius S, Puel A, Horneff G, Lainka E, Dirksen U, Schroten H, Doffinger R, Casanova JL, Wahn V 2004 Nuclear factor kappaB essential modulator-deficient child with immunodeficiency yet without anhidrotic ectodermal dysplasia. J Allergy Clin Immunol 114: 1456–1462
Johnson AM, Whicher JT 2001 Effect of certified reference material 470 (CRM 470) on national quality assurance programs for serum proteins in Europe. Clin Chem Lab Med 39: 1123–1128
Niehues T, Rocha V, Filipovich AH, Chan KW, Porcher R, Michel G, Ortega JJ, Wernet P, Gobel U, Gluckman E, Locatelli F 2001 Factors affecting lymphocyte subset reconstitution after either related or unrelated cord blood transplantation in children—a Eurocord analysis. Br J Haematol 114: 42–48
Shearer WT, Rosenblatt HM, Gelman RS, Oyomopito R, Plaeger S, Stiehm ER, Wara DW, Douglas SD, Luzuriaga K, McFarland EJ, Yogev R, Rathore MH, Levy W, Graham BL, Spector SA 2003 Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol 112: 973–980
Kam KM, Leung WL, Wong KH, Lee SS, Hung MY, Kwok MY 2001 Maturational changes in peripheral lymphocyte subsets pertinent to monitoring human immunodeficiency virus-infected Chinese pediatric patients. Clin Diagn Lab Immunol 8: 926–931
Rodriguez C, Thomas JK, O'Rourke S, Stiehm ER, Plaeger S 1996 HIV disease in children is associated with a selective decrease in CD23+ and CD62L+ B cells. Clin Immunol Immunopathol 81: 191–199
Kansas GS, Dailey MO 1989 Expression of adhesion structures during B cell development in man. J Immunol 142: 3058–3062
LeBien TW 2000 Fates of human B-cell precursors. Blood 96: 9–23
Malaspina A, Moir S, Nickle DC, Donoghue ET, Ogwaro KM, Ehler LA, Liu S, Mican JA, Dybul M, Chun TW, Mullins JI, Fauci AS 2002 Human immunodeficiency virus type 1 bound to B cells: relationship to virus replicating in CD4+ T cells and circulating in plasma. J Virol 76: 8855–8863
Forster R, Schweigard G, Johann S, Emrich T, Kremmer E, Nerl C, Lipp M 1997 Abnormal expression of the B-cell homing chemokine receptor BLR1 during the progression of acquired immunodeficiency syndrome. Blood 90: 520–525
Jinquan T, Moller B, Storgaard M, Mukaida N, Bonde J, Grunnet N, Black FT, Larsen CG, Matsushima K, Thestrup-Pedersen K 1997 Chemotaxis and IL-8 receptor expression in B cells from normal and HIV-infected subjects. J Immunol 158: 475–484
Nagase H, Agematsu K, Kitano K, Takamoto M, Okubo Y, Komiyama A, Sugane K 2001 Mechanism of hypergammaglobulinemia by HIV infection: circulating memory B-cell reduction with plasmacytosis. Clin Immunol 100: 250–259
D'Orsogna LJ, Krueger RG, McKinnon EJ, French MA 2007 Circulating memory B-cell subpopulations are affected differently by HIV infection and antiretroviral therapy. AIDS 21: 1747–1752
Nagumo H, Agematsu K, Shinozaki K, Hokibara S, Ito S, Takamoto M, Nikaido T, Yasui K, Uehara Y, Yachie A, Komiyama A 1998 CD27/CD70 interaction augments IgE secretion by promoting the differentiation of memory B cells into plasma cells. J Immunol 161: 6496–6502
de Martino M, Tovo PA, Galli L, Gabiano C, Cozzani S, Gotta C, Scarlatti G, Fiocchi A, Cocchi P, Marchisio P, Canino R, Mautone A, Chiappe F, Campelli A, Consolini R, Izzi G, Laverda A, Alberti S, Tozzi AE, Duse M 1991 Prognostic significance of immunologic changes in 675 infants perinatally exposed to human immunodeficiency virus. The Italian Register for Human Immunodeficiency Virus Infection in Children. J Pediatr 119: 702–709
Moir S, Malaspina A, Pickeral OK, Donoghue ET, Vasquez J, Miller NJ, Krishnan SR, Planta MA, Turney JF, Justement JS, Kottilil S, Dybul M, Mican JM, Kovacs C, Chun TW, Birse CE, Fauci AS 2004 Decreased survival of B cells of HIV-viremic patients mediated by altered expression of receptors of the TNF superfamily. J Exp Med 200: 587–599
Samuelsson A, Sonnerborg A, Heuts N, Coster J, Chiodi F 1997 Progressive B cell apoptosis and expression of Fas ligand during human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses 13: 1031–1038
Titanji K, Chiodi F, Bellocco R, Schepis D, Osorio L, Tassandin C, Tambussi G, Grutzmeier S, Lopalco L, De Milito A 2005 Primary HIV-1 infection sets the stage for important B lymphocyte dysfunctions. AIDS 19: 1947–1955
Malaspina A, Moir S, Ho J, Wang W, Howell ML, O'Shea MA, Roby GA, Rehm CA, Mican JM, Chun TW, Fauci AS 2006 Appearance of immature/transitional B cells in HIV-infected individuals with advanced disease: correlation with increased IL-7. Proc Natl Acad Sci USA 103: 2262–2267
Malaspina A, Moir S, Chaitt DG, Rehm CA, Kottilil S, Falloon J, Fauci AS 2007 Idiopathic CD4+ T lymphocytopenia is associated with increases in immature/transitional B cells and serum levels of IL-7. Blood 109: 2086–2088
Moir S, Fauci AS 2008 Pathogenic mechanisms of B-lymphocyte dysfunction in HIV disease. J Allergy Clin Immunol 122: 12–19; quiz 20–21.
Moir S, Ho J, Malaspina A, Wang W, DiPoto AC, O'Shea MA, Roby G, Kottilil S, Arthos J, Proschan MA, Chun TW, Fauci AS 2008 Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals. J Exp Med 205: 1797–1805
Moir S, Malaspina A, Ho J, Wang W, Dipoto AC, O'Shea MA, Roby G, Mican JM, Kottilil S, Chun TW, Proschan MA, Fauci AS 2008 Normalization of B cell counts and subpopulations after antiretroviral therapy in chronic HIV disease. J Infect Dis 197: 572–579
Zaccarelli-Filho CA, Ono E, Machado DM, Brunialti M, Succi RC, Salomao R, Kallas EG, de Moraes-Pinto MI 2007 HIV-1-infected children on HAART: immunologic features of three different levels of viral suppression. Cytometry B Clin Cytom 72: 14–21
Rosenblatt HM, Song LY, Nachman SA, Stanley KE, Krogstad PA, Johnson GM, Wiznia AA 2005 Tetanus immunity after diphtheria, tetanus toxoids, and acellular pertussis vaccination in children with clinically stable HIV infection. J Allergy Clin Immunol 116: 698–703
Arpadi SM, Markowitz LE, Baughman AL, Shah K, Adam H, Wiznia A, Lambert G, Dobroszycki J, Heath JL, Bellini WJ 1996 Measles antibody in vaccinated human immunodeficiency virus type 1-infected children. Pediatrics 97: 653–657
Berkelhamer S, Borock E, Elsen C, Englund J, Johnson D 2001 Effect of highly active antiretroviral therapy on the serological response to additional measles vaccinations in human immunodeficiency virus-infected children. Clin Infect Dis 32: 1090–1094
Levin MJ, Gershon AA, Weinberg A, Blanchard S, Nowak B, Palumbo P, Chan CY 2001 Immunization of HIV-infected children with varicella vaccine. J Pediatr 139: 305–310
Lima M, De Menezes Succi RC, Nunes Dos Santos AM, Weckx LY, De Moraes-Pinto MI 2004 Rubella immunization in human immunodeficiency virus type 1-infected children: cause for concern in vaccination strategies. Pediatr Infect Dis J 23: 604–607
Melvin AJ, Mohan KM 2003 Response to immunization with measles, tetanus, and Haemophilus influenzae type b vaccines in children who have human immunodeficiency virus type 1 infection and are treated with highly active antiretroviral therapy. Pediatrics 111: e641–e644
Acknowledgements
We thank Sven Bellert and the members of the Laboratory of Pediatric Immunology at the University Hospital of Düsseldorf for their excellent technical assistance.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.pedresearch.org).
Rights and permissions
About this article
Cite this article
Ghosh, S., Feyen, O., Jebran, A. et al. Memory B Cell Function in HIV-Infected Children—Decreased Memory B Cells Despite ART. Pediatr Res 66, 185–190 (2009). https://doi.org/10.1203/PDR.0b013e3181aa057d
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/PDR.0b013e3181aa057d
This article is cited by
-
Impfen bei Immundefizienz
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz (2018)
