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

• Main Authors: Rita Carsetti, Antonio Di Sabatino, Maria Manuela Rosado, Simona Cascioli, Eva Piano Mortari, Cinzia Milito, Ola Grimsholm, Alaitz Aranburu, Ezio Giorda, Francesco Paolo Tinozzi, Federica Pulvirenti, Giuseppe Donato, Francesco Morini, Pietro Bagolan, Gino Roberto Corazza, Isabella Quinti
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2020-01-01
• Series: Frontiers in Immunology
• Subjects: common variable immune deficiency; gut mucosal immunology; plasma cell; splenectomy; transmembrane activator and calcium-modulator and cyclophilin ligand interactor
• Online Access: https://www.frontiersin.org/article/10.3389/fimmu.2019.02937/full

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.