Autoimmune Lymphoproliferative Syndrome is associated with deficiency in anti-polysaccharide antibodies production and a disorganisation of the spleen marginal zone

Neven, Bénédicte; Bruneau, Julie; Stolzenberg, Marie-Claude; Meyts, Isabelle; Magerus-Chatinet, Aude; Moens, Leen; Lanzarotti, Nina; Weller, Sandra; Amiranoff, Denise; Florkin, Benoit; Bader-Meunier, Brigitte; Leverger, Guy; Ferster, Alice; Chantrain, Christophe; Blanche, Stéphane; Picard, Capucine; Molina, Thierry Jo; Brousse, Nicole; Durandy, Anne; Rizzi, Marta; Bossuyt, Xavier; Fischer, Alain; Rieux-Laucat, Frederic

Autoimmune Lymphoproliferative Syndrome is associated with deficiency in anti-polysaccharide antibodies production and a disorganisation of the spleen marginal zone

Author:

Neven, Bénédicte

Bruneau, Julie ; Stolzenberg, Marie-Claude ; Meyts, Isabelle ; Magerus-Chatinet, Aude ; Moens, Leen ; Lanzarotti, Nina ; Weller, Sandra ; Amiranoff, Denise ; Florkin, Benoit ; Bader-Meunier, Brigitte ; Leverger, Guy ; Ferster, Alice ; Chantrain, Christophe ; Blanche, Stéphane ; Picard, Capucine ; Molina, Thierry Jo ; Brousse, Nicole ; Durandy, Anne ; Rizzi, Marta ; Bossuyt, Xavier ; Fischer, Alain ; Rieux-Laucat, Frederic

Keywords:

1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, 1114 Paediatrics and Reproductive Medicine, Immunology, 3101 Biochemistry and cell biology, 3201 Cardiovascular medicine and haematology, 3213 Paediatrics

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 IgM, low IgM antibody production in response to S.pneumoniae following non-conjugated 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 nine 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-T cells. DN-T were shown to express MAdCAM-1 ligand, alpha4-beta7 integrin. These observations suggest that accumulating DN T-cells are trapped within stromal cell meshwork and interfere with correct localization of MZ B-cells. Similar observations were made in spleen of fas-deficient mice. Our data revealed an unexpected mechanism by which ALPS results in antipolysaccharide IgM antibody production specific defect. Splenectomy should be avoided.