IgA deficiency is the most common primary immune deficiency worldwide. However, its presentation is not fully understood. A new study by researchers at Children’s Hospital of Philadelphia (CHOP) has revealed that IgA acts as a “tuner” that regulates the number of microbes the body sees every day, restraining the systemic immune response to these commensal microbes and limiting the development of systemic immune dysregulation.
Their findings are published in Science Immunology in an article titled, “IgA deficiency destabilizes immune homeostasis towards intestinal microbiota and increases the risk of systemic immune dysregulation.”
“Right now, if we identify IgA deficiency in a patient through a blood test, we have no way of knowing whether the patient will become symptomatic if they aren’t already, and we don’t know whether or when they might go on to develop a more serious immune deficiency,” said Sarah E. Henrickson, MD, PhD, an assistant professor and attending physician in the division of allergy and immunology at CHOP and co-senior author of the study. “Our paper lays the groundwork for being able to answer these critically important questions by providing a lens into how IgA and the microbiome interact and how an imbalance in that interaction could lead to symptomatic disease.”
The researchers analyzed samples from 19 pediatric patients with IgA deficiency and 13 pediatric control patients, from 15 families, and they then complemented that analysis with studies of IgA-deficient mice. They sought to answer two questions: how mucosal antibodies like IgA and IgM and system antibodies like IgG interact with mucosal microbes, and how IgA deficiency affects the equilibrium of the immune system?
Analyzing both blood and fecal samples, the researchers measured antibody levels and identified the microbial targets of IgA, IgM, and IgG antibodies. They showed that although IgA, IgM, and IgG target overlapping sets of microbes, the role of IgA is distinct from IgM in restraining commensal microbes in the gut, and IgM only modestly compensates for the absence of intestinal IgA.
“Based on these results, we propose that IgA supports the intestinal barrier to keep the proper balance of commensal microbes interacting with the immune system, acting as a tuner to keep the immune system in check,” said co-senior author Michael Silverman, MD, PhD, an asistant professor and attending physician in the division of infectious diseases at CHOP. “Without IgA protecting the gut, commensal bacteria can get through, increasing a patient’s systemic exposure to these microbes and creating an inflammatory environment. Future studies with larger patient populations should investigate IgA levels in other target tissues and determine if these findings can be used to predict disease course and outcomes.”
