MZB1 folding and unfolding the role of IgA

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 cell-specific 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 … [↵][1]1To whom correspondence may be addressed. Email: sidonia.fagarasan{at}riken.jp. [1]: #xref-corresp-1-1