Researchers show that IgA adjusts the body’s interactions with microbes

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A new study by researchers at Children’s Hospital of Philadelphia (CHOP) has begun to answer that question, showing that IgA acts as a “dial” that regulates the number of microbes the body sees every day, restricting the systemic immune response. to these commensal microbes. and limiting the development of systemic immune dysregulation.

“Right now, if we identify IgA deficiency in a patient through a blood test, we have no way of knowing if the patient will become symptomatic if they aren’t already, and we don’t know if or when they might go on to develop a more severe immunodeficiency,” said Sarah E. Henrickson, MD, PhD, assistant professor and attending physician in CHOP’s Division of Allergy and Immunology and co-senior author of the paper, which was published today in science immunology. “Our article lays the foundation for answering these critically important questions by providing insight into how IgA and the microbiome interact and how an imbalance in that interaction could lead to symptomatic disease.”

IgA (short for Immunoglobulin A) is an antibody protein that is part of the immune system and plays a role in fighting disease. It is found mainly in the respiratory and digestive tracts, but it can also be found in blood, saliva, tears, and breast milk. To be diagnosed with IgA deficiency, patients must be over 4 years of age and have no IgA determined by blood tests, as well as normal serum levels of IgG and IgM, with no other known causes of immunodeficiency.

Some investigators have suggested that perhaps IgM provides a “backup” function in some patients with IgA deficiency, which explains why some patients are asymptomatic. However, it is still unclear how secretory IgA and IgM function together in the mucosal system and whether their functions are redundant or distinct.

To investigate this further, the researchers analyzed samples from 19 IgA-deficient pediatric patients and 13 control pediatric patients, from 15 families, and then supplemented that analysis with studies of IgA-deficient mice. They sought to answer two questions: how mucosal antibodies such as IgA and IgM and systemic antibodies such as IgG interact with mucosal microbes, and how IgA deficiency affects the balance of the immune system.

By analyzing blood and stool samples, the researchers measured antibody levels; identified the microbial targets of IgA, IgM, and IgG antibodies; and performed an immunological profile to measure the activation of the immune system. In doing so, they demonstrated that although IgA, IgM, and IgG target overlapping sets of microbes, the role of IgA is distinct from that of IgM in restricting commensal microbes in the gut, with IgM only modestly compensating for the absence of gut IgA.

They also determined that 26% of IgA-deficient patients through blood tests had normal IgA levels in their stool. Interestingly, patients with normal fecal IgA were less likely to develop immune dysregulation and clinical disease, as demonstrated by immune assay of cytokine levels, whereas those with IgA deficiency in both blood and stool were more likely. of having elevated inflammatory cytokines and showing clinical symptoms.

To validate their findings, the researchers studied knockout mice that lacked IgA. Mirroring the findings in human patients, these mice exhibited elevated cytokines and immune dysregulation. The researchers also found live microbes in the adipose tissue of the knockout mice, which were not found in the healthy control mice, providing further evidence for the role of IgA in modulating systemic microbial exposure.

“Based on these results, we propose that IgA supports the intestinal barrier in maintaining the proper balance of commensal microbes that interact with the immune system, acting as a tuner to keep the immune system in check,” said co-lead author Michael Silverman, MD. . , PhD, assistant professor and attending physician in CHOP’s Division of Infectious Diseases. “Without IgA protecting the gut, commensal bacteria can pass through, increasing the 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 whether these findings can be used to predict disease course and outcomes.”