Commensal Microbes Induce Serum IgA Responses that Protect against Polymicrobial Sepsis

Abstract

Serum immunoglobulin A (IgA) antibodies are readily detected in mice and people, but the mechanisms underlying the induction of serum IgA and its role in host protection remain uncertain. We report that select commensal bacteria induce several facets of systemic IgA-mediated immunity. Exposing conventional mice to a unique but natural microflora that included several members of the Proteobacteria phylum led to T cell-dependent increases in serum IgA levels and the induction of large numbers of IgA-secreting plasma cells in the bone marrow. The resulting serum IgA bound to a restricted collection of bacterial taxa, and antigen-specific serum IgA antibodies were readily induced after intestinal colonization with the commensal bacterium Helicobacter muridarum. Finally, movement to a Proteobacteria-rich microbiota led to serum IgA-mediated resistance to polymicrobial sepsis. We conclude that commensal microbes overtly influence the serum IgA repertoire, resulting in constitutive protection against bacterial sepsis.

The continuing story of T‐cell independent antibodies

“…Surprisingly, this work revealed that while the vast majority of plasma cells arise coincident with the GC reaction, most memory B cells appear to arise much earlier including before GCs were detected 40. 42 Therefore, while IgG-secreting plasma cells clearly dominate responses to immunization with exogenous T-dependent antigens, other pathways may also be at play.Interestingly, we recently reported that, in mice that were not intentionally immunized, upwards of 40% of bone marrow plasma cells secrete IgM, with another 40% or more actively secreting IgA 47. This observation is consistent with the other work showing that long-lived IgM + memory B cells can form via a GCindependent pathway.…”

“…63 Here we return to the layered immune system hypothesis. 47 Together these observations suggest that the IgA repertoire consists of multiple stable layers that collectively target and continuously regulate the composition of the bacterial microbiota. 72 Remarkably, 70% of these antibodies bound a diverse pool of commensal bacteria derived from the small intestine, suggesting that a large fraction of the IgA repertoire targets conserved molecular structures common to a variety of bacterial taxa.…”

Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis

“…3C). In light of the tremendous impact of altered microbiota on the outcome of CLP sepsis (Wilmore et al, 2018), it will be interesting to examine whether Gpx4 deficiency causes microbiome variation in independent studies.…”

The microbiome and immune memory formation

“…highlight the capacity of the mucosal immune interaction to affect systemic antibody response during homeostasis. The ability of the mucosal immune system to co‐operate with systemic immunity in a homeostatic context is further highlighted by increased levels of T‐dependent serum IgA in response to certain commensals in the gut and induction of IgA‐secreting plasma cells in the bone marrow . Furthermore, clonal relationships between gut IgA plasma cells and memory cells in the spleen as well as splenic IgM memory subsets with antibacterial specificities sustained from persistent mucosal responses have been described .…”