Immunoglobulin A (IgA), an antibody produced by plasma cells that plays a pivotal role in adaptive immunity, is the most abundant mammalian antibody. It is often found at barrier surfaces, such as the intestinal mucosa, where it serves as a first line of defense against enteric pathogens. IgA responses are continually active under normal homeostatic conditions, containing and neutralizing the high volume of microbiota passing through the gastrointestinal tract. Despite the prevalence of IgA, however, we know very little about its specificity for microbes and function in these steady state conditions.
In this study (J. J. Bunker et al., Science 358, eaan6619 (2017)) researchers sought to profile and better characterize IgA binding specificity. They performed unbiased cloning of monoclonal antibodies, isolated from multiple B cell lineages, and then used flow cytometry and RNA sequencing to study their microbiota reactivity. This large-scale and unprecedented analysis of IgA binding led to several important observations. First, IgA proved to be particularly polyreactive in nature, binding a broad but definable subset of microbiota. While microbiota-reactive and polyreactive antibodies arose in all B cell populations, they were significantly enriched among IgA-secreting plasma cells. Second, circulation into Peyer’s Patches (collections of lymphoid tissue found in the small intestine) played a key role in selecting naive B cells to become IgA-secreting plasma cells. This occurred independently of T cell activation or somatic hypermutation. Finally, researchers studied IgA production and reactivity in germ-free mice, and found that differentiation of IgAs occurred independent of exposure to microbiota or exogenous dietary antigens. This final insight showed that, while derived from the adaptive immune system, IgAs possess innate specificity for microbiota. Together, these findings illustrate a natural defense mechanism derived from endogenous IgA development with polyreactive properties.
While we know that IgA responses are enhanced in pathologic conditions such as Inflammatory Bowel Disease and enteric infections, the extent to which these responses deviate from homeostatic conditions is unclear. This study enhances our understanding of innate IgA functions, providing an important foundation to better understand aberrant mechanisms in disease states and potentially inform future therapeutic interventions.