title: Defective anti-polysaccharide response and splenic marginal zone disorganization in ALPS patients.
abstract: Autoimmune lymphoproliferative syndrome (ALPS) caused by impaired FAS-mediated apoptosis of lymphocytes is characterized by lymphoproliferation, autoimmunity, but also an increased risk of invasive bacterial infection, notably following splenectomy. We surveyed a cohort of 100 ALPS patients (including 33 splenectomized) and found that 12 (10 splenectomized) had experienced 23 invasive bacterial infections mainly caused by Streptococcus pneumoniae. This vulnerability was associated with evidence of defective B-cell function characterized by low serum immunoglobulin (Ig) M, low IgM antibody production in response to S pneumoniae following nonconjugated immunization, and low blood memory B-cells counts (including marginal zone [MZ] B-cell counts). This immunodeficiency strongly correlated with intensity of lymphoproliferation. Spleen sections from 9 ALPS patients revealed double-negative T-cell (DN-T) infiltration of the MZ, which was depleted of B cells. MZ in ALPS patients contained an abnormally thick layer of MAdCAM-1((+)) stromal cells and an excess of DN-Ts. DN-Ts were shown to express MAdCAM-1 ligand, the α4β7 integrin. These observations suggest that accumulating DN-Ts are trapped within stromal cell meshwork and interfere with correct localization of MZ B cells. Similar observations were made in spleens of fas-deficient mice. Our data revealed an unexpected mechanism by which ALPS results in anti-polysaccharide IgM antibody production-specific defect. Splenectomy should be avoided.
authors: Unité d'immuno-hématologie pédiatrique, Hôpital Necker-Enfant Malades, Assistance Publique des Hôpitaux de Paris, Paris, France; Développement normal et pathologique du système immunitaire, Unité INSERM U768, Université Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France;
authors: Bénédicte
authors: B
authors: Neven
authors: Cytokines, hématopoïèse et réponses immunes, CNRS-UMR 8147, Université Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France; Service d'anatomopathologie, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors: Julie
authors: J
authors: Bruneau
authors: Développement normal et pathologique du système immunitaire, Unité INSERM U768, Université Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France;
authors: Marie-Claude
authors: MC
authors: Stolzenberg
authors: Department of Pediatrics and.
authors: Isabelle
authors: I
authors: Meyts
authors: Développement normal et pathologique du système immunitaire, Unité INSERM U768, Université Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France;
authors: Aude
authors: A
authors: Magerus-Chatinet
authors: Laboratory Medicine, University Hospitals Leuven, Department of Microbiology and Immunology, Catholic University of Leuven, Belgium;
authors: Leen
authors: L
authors: Moens
authors: Développement normal et pathologique du système immunitaire, Unité INSERM U768, Université Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France;
authors: Nina
authors: N
authors: Lanzarotti
authors: Facuté de Médecine, Site Necker-Enfants-Malades, INSERM U783 "Développement du système immunitaire", Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors: Sandra
authors: S
authors: Weller
authors: Etablissement Francais du Sang, Hôpital Necker-enfants malades, Paris, France;
authors: Denise
authors: D
authors: Amiranoff
authors: Service d'hématologie-oncologie pédiatrique, Hôpital de la Citadelle, Liege, Belgique;
authors: Benoit
authors: B
authors: Florkin
authors: Unité d'immuno-hématologie pédiatrique, Hôpital Necker-Enfant Malades, Assistance Publique des Hôpitaux de Paris, Paris, France; Développement normal et pathologique du système immunitaire, Unité INSERM U768, Université Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France;
authors: Brigitte
authors: B
authors: Bader-Meunier
authors: Service d'immuno-hématolo-oncologie pédiatrique, Hôpital Armand Trousseau, Paris, France;
authors: Guy
authors: G
authors: Leverger
authors: Service d'hématologie-Oncologie pédiatrique, Hôpital des Enfants Reine Fabiola, Bruxelles, Belgique;
authors: Alice
authors: A
authors: Ferster
authors: Hématologie Oncologie Pédiatrique, Département de Pédiatrie, Centre Hospitalier Chrétien (CHC) - Clinique de l'Espérance, Montegnée, Belgique;
authors: Christophe
authors: C
authors: Chantrain
authors: Unité d'immuno-hématologie pédiatrique, Hôpital Necker-Enfant Malades, Assistance Publique des Hôpitaux de Paris, Paris, France;
authors: Stéphane
authors: S
authors: Blanche
authors: Unité d'immuno-hématologie pédiatrique, Hôpital Necker-Enfant Malades, Assistance Publique des Hôpitaux de Paris, Paris, France; Centre d'Etude des Déficits Immunitaires, Assistance Publique des Hôpitaux de Paris, Paris, France; Laboratoire de génétique humaine des maladies infectieuses, INSERM U980, Faculté Necker, Université Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France;
authors: Capucine
authors: C
authors: Picard
authors: Service d'anatomopathologie, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors: Thierry Jo
authors: TJ
authors: Molina
authors: Service d'anatomopathologie, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors: Nicole
authors: N
authors: Brousse
authors: Développement normal et pathologique du système immunitaire, Unité INSERM U768, Université Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France;
authors: Anne
authors: A
authors: Durandy
authors: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Germany; and.
authors: Marta
authors: M
authors: Rizzi
authors: Facuté de Médecine, Site Necker-Enfants-Malades, INSERM U783 "Développement du système immunitaire", Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors: Xavier
authors: X
authors: Bossuyt
authors: Unité d'immuno-hématologie pédiatrique, Hôpital Necker-Enfant Malades, Assistance Publique des Hôpitaux de Paris, Paris, France; Développement normal et pathologique du système immunitaire, Unité INSERM U768, Université Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France; Collège de France, Paris, France.
authors: Alain
authors: A
authors: Fischer
authors: Développement normal et pathologique du système immunitaire, Unité INSERM U768, Université Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France;
authors: Frederic
authors: F
authors: Rieux-Laucat
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000917:Antibody Formation; D056735:Autoimmune Lymphoproliferative Syndrome / Q000453:epidemiology / Q000276:immunology* / Q000473:pathology* / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D013154:Spleen / Q000276:immunology* / Q000473:pathology* / Q000601:surgery; D013156:Splenectomy / Q000009:adverse effects / Q000706:statistics & numerical data; D013290:Streptococcal Infections / Q000453:epidemiology / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000254:growth & development / Q000276:immunology; D055815:Young Adult
chemical_list: D008070:Lipopolysaccharides