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

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.

Depletion of circulating IgM memory B cells predicts unfavourable outcome in COVID-19

“…We also found an increased infectious risk in our 63-patient cohort, in the majority of cases sustained by bacteria spreading from the gastrointestinal tract. This is in keeping with the evidence that subjects who have IgM memory B cell depletion are characterised by lack of mucosal IgA-secreting plasma-cells, an important factor of innate immunity that prevents gut-borne infections and contributes to the normal immunosurveillance function of the gut 36 . Although overwhelming post-splenectomy infections are more frequently caused by encapsulated bacteria, such as S. pneumoniae, H. influenzae, and N. meningitidis , other pathogens may be cause of this condition.…”

Differential Expression of IgM and IgD Discriminates Two Subpopulations of Human Circulating IgM+IgD+CD27+ B Cells That Differ Phenotypically, Functionally, and Genetically

“…In line with this hypothesis, IgM + IgD + CD27 + B cells from GALT had relatively high expression of CD80, compared with the same subset in spleen and tonsils (24), and CD80 is among the 78 genes that differed between both IgM subpopulations (Figure 2A) and highly expressed in IgM hi B cells. Also in support of this hypothesis, a relationship has been found between IgM + IgD + CD27 + B cells and the number of IgA secretory plasma cells and secretory IgA in gut (62). Studies to evaluate the expression of homing receptors (63) on the different B cells subsets studied here may be useful to test this hypothesis.…”

Different Innate and Adaptive Immune Responses to SARS-CoV-2 Infection of Asymptomatic, Mild, and Severe Cases

“…Innate MBCs produce natural antibodies in response to TLR stimulation (60,96) but are also able to enter the GC where they remodel their antibodies to increase their affinity (58,97). IgM + MBCs are the precursors of most IgA + and IgG + switched MBCs (97) and give rise to IgA + plasma cells at mucosal site (98). 'Natural antibodies', produced by innate MBCs, are antibodies that have a protective role in the early phases of the response independently of any previous encounter with antigen (96,99,100).…”