The immune system sustains a continuous dialogue with the endogenous microbial communities residing at the mucosal surfaces, mediated by many factors, including IgA, the most abundant antibody isotype. In PNAS, Xiong et al.(1) explore the role of a B cellspecific factor in regulation of IgA secretion in the gut. IgA is crafted and secreted by plasma cells residing mostly in the lamina propria (LP) of the intestinal villi. Once released into the gut lumen, IgA coats bacterial surfaces and regulates the maintenance and function of the microbiota (2). In turn, the microbiota primes and fine-tunes immune cell function, affecting how the host responds to environmental stimuli. The generation and maintenance of the “pool” of IgA at the mucosal surfaces is critical for immune homeostasis. IgA deficiency disturbs the composition of the gut microbiota, leading to allergies, autoimmunity, and other inflammatory diseases in mice and humans (3). Synthesis of T cell-dependent, adaptive IgA is a regulated, stepwise process requiring (i) activation of IgM+ B cells in the germinal center of Peyer’s patches to switch to IgA+, directed by activation-induced cytidine deaminase (AID);(ii) migration of IgA+ cells to the intestinal LP, directed by integrins and chemokines;(iii) differentiation of plasmablasts into IgA+ plasma cells capable of secreting large amounts of protein; and (iv) transport of IgA across the LP epithelium into the gut lumen. Humans secrete an extraordinary amount of IgA each day (40 mg/kg body weight)(3). However, T cell-independent, innate IgA can also be generated from other innatelike B cells, such as those residing in the peritoneal cavity (3). These alternative pathways are characterized by their relative speed and the polyreactivity of the resulting IgA. T cell-independent antibody appears within hours, bridging the lag time between the innate immune responses mediated by granulocytes and macrophages within minutes of antigen exposure and the acquired T cell-dependent immune responses that arrive after a week or more (4). Xiong et al.(1) unfold a new layer of complexity in gut IgA synthesis, identifying the marginal zone B and B-1 cell-specific protein (MZB1) as a molecular chaperone facilitating the formation of polymeric IgA, especially during rapid responses.

MZB1 is an endoplasmic reticulum (ER)-localized protein constitutively expressed in innatelike B cells, such as marginal zone (MZ) B cells and B1 cells, and highly up-regulated during plasma cell differentiation. In the ER, MZB1 associates with antibody heavy and light chains (HC and LC, respectively) to promote the assembly and secretion of IgM polymers (5, 6). MZB1 also regulates calcium homeostasis and integrinmediated cell adhesion in innatelike B cells (7). MZB1 is thus critical for the rapid recruitment of B cells and the secretion of polyreactive IgM antibodies during the first-line antibody response. Now, Xiong et al.(1) show that MZB1 is also involved in IgA responses. They begin with the striking observation that the amount of IgA and IgM, but not IgG, was significantly reduced in the serum of Mzb1−/− mice. Cultured Mzb1−/− splenocytes up-regulated AID, underwent class switch, and differentiated into IgA plasma cells normally, but secreted less IgA (and IgM) on a per-cell basis. These observations led the authors (1) to investigate the molecular mechanisms of MZB1 regulation of early IgA synthesis with elegant molecular cell biology techniques. To uncover how MZB1 regulates IgA secretion at the cellular level, Xiong et al.(1) inactivated Mzb1 in a plasmacytoma cell line using CRISPR/Cas9-mediated gene editing. These plasmacytomas were coerced to secrete antibodies after “Ig …