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To maintain Ab titers, individual plasma cells must survive for extended periods, perhaps even for the life of the host. Although it is clear that plasma cell survival requires cell extrinsic signals, the nature and source of these signals remains open for debate. It is commonly postulated that plasma cells only gain access to these signals within specialized regulatory microenvironments, or niches, in the bone marrow or in the gut. In this review we discuss current concepts and information surrounding plasma cell survival niches, and consider two opposing models to explain long-term serologic immunity.

Despite their critical role in long-term immunity, the lifespan of individual memory B cells remains poorly defined. Using a tetracycline-regulated pulse-chase system, we measured population turnover rates and individual half-lives of pre-established antigen-induced immunoglobulin (Ig) class-switched and IgM-positive memory B cells over 402 days. Our results indicate that, once established, both IgG-positive and less frequent IgM-positive memory populations are exceptionally stable, with little evidence of attrition or cellular turnover. Indeed, the vast majority of cells in both pools exhibited half-lives that appear to exceed the lifespan of the mouse, contrasting dramatically with mature naïve B cells. These results indicate that recall antibody responses are mediated by stable pools of extremely long-lived cells, and suggest that antigen-experienced B cells employ remarkably efficient survival mechanisms.

Current models hold that serum antibody titers are maintained chiefly by long-lived bone marrow (BM) plasma cells (PCs). Here we characterize the role of subpopulations of BM PCs in long-term humoral responses to T-cell dependent antigen. Surprisingly, our results indicate that 40–50% of BM PCs are recently formed cells, defined in part by rapid steady state turnover kinetics and secretion of low affinity immunoglobulin-M (IgM) antibodies. Further, for months after immunization with a hapten-protein conjugate newly formed antigen-induced IgM-secreting BM PCs were detected in parallel with longer-lived IgG-secreting cells, suggesting ongoing and parallel input to the BM PC pool from two distinct pools of activated B cells. Consistent with this interpretation, IgM and IgG antibodies secreted by cells within distinct PC subsets exhibited distinct light chain usage. We conclude that long-term antibody responses are maintained by a dynamic BM PC pool comprised of both recently formed and long-lived PCs drawn from clonally disparate precursors.

Gut educated IgA secreting plasma cells that disseminate beyond the mucosa and into systemic tissues have been described as providing beneficial effects from disease in several contexts. Several bacteria have been implicated in the induction of systemic IgA, however the mechanisms that result in differential levels of induction by each bacterial species are still unknown. Here we show, the commensal bacteria, Bacteroides fragilis ( Bf ), is an efficient inducer of systemic IgA responses. The ability of Bf to induce the production of bone marrow IgA plasma cells and high levels of serum IgA relied on high levels of gut colonization in a dose-dependent manner. Colonization induced Bf -specific IgA responses were severely diminished in the absence of Peyer's patches, but not the murine cecal patch. Colonization of mice with Bf , a natural human commensal, resulted in few changes within the microbiome and the host transcriptional profile in the gut, suggesting a commensal relationship with the host. Bf colonization did benefit the mice by inducing systemic IgA that led to increased protection in a bowel perforation model resulting in lower peritoneal abscess formation. These findings demonstrate a critical role for bacterial colonization and Peyer's patches in the induction of robust systemic IgA responses that confer protection from bacterial dissemination outside of the gut., Competing Interests: Competing Interests The authors declare no competing interests.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of the pandemic human respiratory illness COVID-19, is a global health emergency. While severe acute disease has been linked to an expansion of antibody-secreting plasmablasts, we sought to identify B cell responses that correlated with positive clinical outcomes in convalescent patients. We characterized the peripheral blood B cell immunophenotype and plasma antibody responses in 40 recovered non-hospitalized COVID-19 subjects that were enrolled as donors in a convalescent plasma treatment study. We observed a significant negative correlation between the frequency of peripheral blood memory B cells and the duration of symptoms for convalescent subjects. Memory B cell subsets in convalescent subjects were composed of classical CD24+ class-switched memory B cells, but also activated CD24-negative and natural unswitched CD27+ IgD+ IgM+ subsets. Memory B cell frequency was significantly correlated with both IgG1 and IgM responses to the SARS-CoV-2 spike protein receptor binding domain (RBD). IgM+ memory, but not switched memory, directly correlated with virus-specific antibody responses, and remained stable over time. Our findings suggest that the frequency of memory B cells is a critical indicator of disease resolution, and that IgM+ memory B cells play an important role in SARS-CoV-2 immunity.