Lack of Gut Secretory Immunoglobulin A in Memory B-Cell Dysfunction-Associated Disorders: A Possible Gut-Spleen Axis: Frontiers in Immunology

R. Carsetti, A. Di Sabatino, M.M. Rosado, S. Cascioli, E. Piano Mortari, C. Milito, O. Grimsholm, A. Aranburu, E. Giorda, F.P. Tinozzi, F. Pulvirenti, G. Donato, F. Morini, P. Bagolan, G.R. Corazza, I. Quinti

Research output: Contribution to journalArticlepeer-review

Abstract

Background: B-1a B cells and gut secretory IgA (SIgA) are absent in asplenic mice. Human immunoglobulin M (IgM) memory B cells, which are functionally equivalent to mouse B-1a B cells, are reduced after splenectomy. Objective: To demonstrate whether IgM memory B cells are necessary for generating IgA-secreting plasma cells in the human gut. Methods: We studied intestinal SIgA in two disorders sharing the IgM memory B cell defect, namely asplenia, and common variable immune deficiency (CVID). Results: Splenectomy was associated with reduced circulating IgM memory B cells and disappearance of intestinal IgA-secreting plasma cells. CVID patients with reduced circulating IgM memory B cells had a reduced frequency of gut IgA+ plasma cells and a disrupted film of SIgA on epithelial cells. Toll-like receptor 9 (TLR9) and transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) induced IgM memory B cell differentiation into IgA+ plasma cells in vitro. In the human gut, TACI-expressing IgM memory B cells were localized under the epithelial cell layer where the TACI ligand a proliferation inducing ligand (APRIL) was extremely abundant. Conclusions: Circulating IgM memory B cell depletion was associated with a defect of intestinal IgA-secreting plasma cells in asplenia and CVID. The observation that IgM memory B cells have a distinctive role in mucosal protection suggests the existence of a functional gut-spleen axis. © Copyright © 2020 Carsetti, Di Sabatino, Rosado, Cascioli, Piano Mortari, Milito, Grimsholm, Aranburu, Giorda, Tinozzi, Pulvirenti, Donato, Morini, Bagolan, Corazza and Quinti.
Original languageEnglish
JournalFront. Immunol.
Volume10
DOIs
Publication statusPublished - 2020

Keywords

  • common variable immune deficiency
  • gut mucosal immunology
  • plasma cell
  • splenectomy
  • transmembrane activator and calcium-modulator and cyclophilin ligand interactor
  • ADP ribosyl cyclase/cyclic ADP ribose hydrolase 1
  • APRIL protein
  • CD19 antigen
  • CD24 antigen
  • immunoglobulin A
  • immunoglobulin M
  • interleukin 21
  • interleukin 4
  • Pneumococcus vaccine
  • secretory immunoglobulin
  • toll like receptor 9
  • transmembrane activator and CAML interactor
  • adult
  • Article
  • asplenia
  • B lymphocyte
  • cell differentiation
  • cell selection
  • clinical article
  • cohort analysis
  • common variable immunodeficiency
  • controlled study
  • crypt cell
  • enzyme linked immunosorbent assay
  • flow cytometry
  • gastrointestinal symptom
  • human
  • human cell
  • human tissue
  • humoral immune deficiency
  • immunoglobulin class switching
  • intestine
  • memory cell
  • mucosal immunity
  • peripheral blood mononuclear cell
  • protein expression
  • spleen
  • aged
  • epithelium cell
  • female
  • immunological memory
  • immunology
  • intestine flora
  • lymphocyte activation
  • male
  • middle aged
  • Adult
  • Aged
  • B-Lymphocytes
  • Common Variable Immunodeficiency
  • Epithelial Cells
  • Female
  • Gastrointestinal Microbiome
  • Humans
  • Immunoglobulin A, Secretory
  • Immunoglobulin M
  • Immunologic Memory
  • Lymphocyte Activation
  • Male
  • Middle Aged
  • Plasma Cells
  • Spleen
  • Toll-Like Receptor 9
  • Transmembrane Activator and CAML Interactor Protein
  • Tumor Necrosis Factor Ligand Superfamily Member 13

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