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: Bénédicte Neven, Julie Bruneau, Marie-Claude Stolzenberg, Isabelle Meyts, Aude Magerus-Chatinet, Leen Moens, Nina Lanzarotti, Sandra Weller, Denise Amiranoff, Benoit Florkin, Brigitte Bader-Meunier, Guy Leverger, Alice Ferster, Christophe Chantrain, Stéphane Blanche, Capucine Picard, Thierry Jo Molina, Nicole Brousse, Anne Durandy, Marta Rizzi, Xavier Bossuyt, Alain Fischer, Frederic Rieux-Laucat
• Journal: Blood (Blood) Vol. 124 Issue 10 Pg. 1597-609 (Sep 04 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 24970930 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society of Hematology.

Chemical References

• Lipopolysaccharides

Topics

• Adolescent
• Adult
• Animals
• Antibody Formation
• Autoimmune Lymphoproliferative Syndrome (epidemiology, immunology, pathology, surgery)
• Child
• Child, Preschool
• Humans
• Infant
• Infant, Newborn
• Lipopolysaccharides (immunology)
• Mice
• Mice, Transgenic
• Spleen (immunology, pathology, surgery)
• Splenectomy (adverse effects, statistics & numerical data)
• Streptococcal Infections (epidemiology, immunology)
• Streptococcus pneumoniae (growth & development, immunology)
• Young Adult