New study uncovers a key immune mechanism that modulates the diversity of the gut microbiota

Previous research has found that the gut microbiome modulates both immune system development and gut homeostasis through its interaction with the host immune cells. Although both innate and adaptive humoral responses target distinct commensal bacteria via mucosal secretory immunoglobulin A (SIgA), little is known about whether secretory immunoglobulin M (SIgM) is also involved.

A new study, led by Dr. Andrea Cerutti from the Hospital del Mar Medical Research Institute (IMIM) (Barcelona, Spain) and the Department of Medicine at Icahn School of Medicine at Mount Sinai (New York, USA), has found for the first time that immunoglobulin M secreted by the human intestine interacts with the gut microbiome to maintain its diversity.

Analyses were undertaken using both mouse and human ileum and colon tissue samples.

The researchers found that the gut mucosa IgM-secreting plasma cells -which account for about 20% of all gut plasma cells- were more abundant in humans than in mice gut and coexisted with a large but previously unrecognized repertoire of gut-specific memory IgM+ B cells that emerged early in life and were clonally related to IgM-secreting plasma cells as well as some memory IgA+ B cells and IgA-secreting plasma cells. According to the authors, “Our identification of clonally related memory IgM+ cells and IgM-secreting plasma cells extends evidence from mouse systemic immunization models indicating that humoral memory is not merely comprised of memory IgG+ and memory IgA+ B cells, but further extends to memory IgM+ B cells”.

Human gut memory IgM+ B cells underwent proliferation, plasma cell differentiation, IgM secretion, and IgA class switching in response to T cell-dependent and T cell-independent signals. First, human memory IgM+ B cells disseminated in both the ileum and the colon, and afterwards they differentiated to IgM-secreting plasma cells and class-switched IgA-secreting plasma cells by entering germinal centres or progressing through extra-germinal centre pathways. Besides this, memory IgM+ B cells secreted IgM that targeted mucus-embedded commensals, similar to SIgM from IgM-secreting plasma cells. Human SIgM recognized bacteria dually coated by SIgA that exhibited higher diversity when compared to SIgA-only-coated or uncoated bacteria. However, murine SIgM could not bind a highly diverse microbiota dually coated by SIgA. On the whole, these data show that human secretory IgM emerges from pre-existing gut memory B cells and plays a role in helping SIgA to anchor highly diverse commensal communities to mucus.

“We have discovered that, in addition to immunoglobulin A (IgA), immunoglobulin M (IgM), secreted by the human intestine, interacts with the intestinal microbiota and actively participates in maintaining its diversity. In addition, we have demonstrated that this immunoglobulin is part of an immunological memory system through which our organism is able to recognise and adapt to its microbial environment”, say the first authors of the article, Giuliana Magri and Laura Comerma.

In conclusion, this study demonstrates that IgM has a fundamental role in the regulation of the gut microbiota. Therefore, SIgM may have a role in enhancing host-microbiota symbiosis, similar to SIgA.

Reference:

Magri G, Comerma L, Pybus M, et al. Human secretory IgM emerges from plasma cells clonally related to gut memory B cells and targets highly diverse commensals. Immunity. 2017; 47(1):1-17. doi: 10.1016/j.immuni.2017.06.013.