title: Defective B-cell proliferation and maintenance of long-term memory in patients with chronic granulomatous disease.
abstract: BACKGROUND
  Chronic granulomatous disease (CGD) is a primary immune deficiency characterized by a defect in reactive oxygen species production. Although the effect of CGD mainly reflects on the phagocytic compartment, B-cell responses are also impaired in patients with CGD.
  
  
  OBJECTIVE
  We sought to investigate how defective gp91(phox) expression in patients with CGD and CGD carriers might affect the B-cell compartment and maintenance of long-term memory.
  
  
  METHODS
  We studied the B-cell compartment of patients with CGD in terms of phenotype and ability to produce reactive oxygen species and proliferate on stimuli differently directed to the B-cell receptor and Toll-like receptor 9. We further studied their capacity to maintain long-term memory by measuring cellular and serologic responses to measles.
  
  
  RESULTS
  We show that the memory B-cell compartment is impaired among patients with CGD, as indicated by reduced total (CD19(+)CD27(+)) and resting (CD19(+)CD27(+)CD21(+)) memory B cells in parallel to increased naive (CD19(+)CD27(-)IgD(+)) B-cell frequencies. Data on CGD carriers reveal that such alterations are related to gp91(phox) expression. Moreover, proliferative capabilities of B cells on selective in vitro stimulation of B-cell receptor or Toll-like receptor 9 pathways were reduced in patients with CGD compared with those seen in age-matched healthy control subjects. Significantly lower measles-specific antibody levels and antibody-secreting cell numbers were also observed, indicating a poor ability to maintain long-term memory in these patients.
  
  
  CONCLUSIONS
  Altogether, our data suggest that patients with CGD present a defective B-cell compartment in terms of frequencies of memory B cells, response to in vitro stimulation, and maintenance of long-term antigen-specific memory.
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Children's Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Cotugno
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Children's Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Finocchi
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Children's Hospital Bambino Gesù, Rome, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Cagigi
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Children's Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Gigliola
authors.initials: G
authors.lastname: Di Matteo
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Children's Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Chiriaco
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Children's Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Di Cesare
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Children's Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Rossi
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Children's Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy; TIGET, Scientific Institute San Raffaele, Milan, Italy. Electronic address: aaiuti@gmail.com.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Children's Hospital Bambino Gesù, Rome, Italy. Electronic address: paolo.palma@opbg.net.
authors.forename: Paolo
authors.initials: P
authors.lastname: Palma
authors.affiliation: Center for Hematology and Regenerative Medicine (HERM), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. Electronic address: iyadh.douagi@ki.se.
authors.forename: Iyadh
authors.initials: I
authors.lastname: Douagi
mesh_terms: D000293:Adolescent; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression; D006105:Granulomatous Disease, Chronic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects*; D016130:Immunophenotyping; D007223:Infant; D008297:Male; D008457:Measles / Q000276:immunology / Q000517:prevention & control*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000276:immunology*; D010641:Phenotype; D011043:Pokeweed Mitogens / Q000494:pharmacology; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology; D014611:Vaccination; D014765:Viral Vaccines / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D008562:Membrane Glycoproteins; D011043:Pokeweed Mitogens; D017382:Reactive Oxygen Species; D011947:Receptors, Antigen, B-Cell; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D014765:Viral Vaccines; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: B cell; Chronic granulomatous disease; long-term memory; measles; memory B-cell compartment; proliferation; reactive oxygen species deficiency