IgA-Producing Plasma Cells Originate From Germinal Centers That Are Induced by B-Cell Receptor Engagement in Humans

Abstract

IgA-producing plasma cells appear to be derived from GALT germinal centers in humans. B-cell receptor engagement promotes formation of germinal centers of GALT, with no more evidence for innate immune receptor activation in the mucosa than nonintestinal immune compartments. Germinal centers in GALT should be targets of mucosal vaccinations because they are the source of human intestinal IgA response.

The Regulation of IgA Production

“…However, selective IgA deficiency has a mild phenotype in humans and experimental animals; thus it can be reasonably compensated by mucosal IgM and other innate and adaptive responses. The IgA repertoire is progressively affinity matured during aging (Rogosch et al, 2012;Lindner et al, 2012), probably mainly as a direct response to antigenic stimulation from the intestinal lumen (Barone et al, 2011;Benckert et al, 2011). This supports the idea that conventional GC reactions in PP are generating much of the IgA repertoire.…”

“…Although most plasma cells in adult mice and humans are SHM-IgAs (Barone et al, 2011;Benckert et al, 2011), likely largely generated in PP GCs, neonatal humans and mice have a relatively undiversified IgA repertoire (Bergqvist et al, 2010;Rogosch et al, 2012). Moreover, mice lacking PPs and/or GCs contain almost normal numbers of IgA plasma cells in their gut LP (Renshaw et al, 1994;Bergqvist et al, 2006;Tsuji et al, 2008;Yamamoto et al, 2000;Bergqvist et al, 2010).…”

Analysis of Celiac Disease Autoreactive Gut Plasma Cells and Their Corresponding Memory Compartment in Peripheral Blood Using High-Throughput Sequencing

“…Intestinal IgA responses against T cell-dependent Ags usually evolve in germinal centers in gut-inductive sites and result in the formation of highly selected, affinity-matured PCs and long-lived memory cells (18,41,42). TG2-specific PCs likely develop with the help of T cells (12).…”

Characterization of proposed human B-1 cells reveals pre-plasmablast phenotype

“…20 In mice, many of the IgA 1 plasma cells in the mucosa are believed to be derived from B-1 cells. 28 However, this does not hold true for humans, in which intestinal IgA 1 plasmablast are generated in germinal centers 29 and carry a number of somatic hypermutations in their Ig variable regions (a hallmark of selection of follicular B-2 cells through germinal center reactions), comparable to IgG 1 plasmablasts. 30 The results of spontaneous antibody secretion by the proposed B-1 cells are at odds with the phenotype of murine B-1 cells, for which IgM is expected to be the dominant isotype produced.…”