IgA Described as "Tuner" in Microbe Interaction Regulation

Throughout the world, IgA deficiency is considered to be the most common primary immune deficiency, but its presentation has continued to confuse researchers and physicians.

IgA Described as "Tuner" in Microbe Interaction Regulation

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Few people with the disorder exhibit symptoms consistent with autoimmune disease, recurrent infections, or allergies, whereas others have no symptoms at all and only turn out to be aware of their IgA-deficient status via an incidental finding on a blood test.

This variability has increased the question among scientists: why are not several of those with IgA deficiency sicker?

At the Children’s Hospital of Philadelphia (CHOP), a new study performed by scientists has started to answer that question, illustrating that IgA serves as a “tuner” that controls various microbes the body notices every day. This restrains the systemic immune response to such commensal microbes and thereby restricting 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 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.”

Sarah E. Henrickson, M.D., Ph.D., Assistant Professor and Attending Physician, Division of Allergy and Immunology, Children’s Hospital of Philadelphia

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.”

Henrickson is the co-senior author of the study, which was reported currently in the journal Science Immunology.

IgA (short for Immunoglobulin A) is known as an antibody protein that is part of the immune system and plays a crucial role in fighting disease. It is discovered primarily in the respiratory and digestive tracts, but it can also be found in tears, saliva, blood, and breast milk.

To be identified with IgA deficiency, patients should be more than four years of age and have no IgA as identified via a blood test, and also normal serum levels of IgG and IgM, without other notable causes of immune deficiency.

Few scientists have proposed that potential IgM offers a “backup” role in some patients with IgA deficiency, describing why few patients are asymptomatic. But how secretory IgA and IgM work collaboratively in the mucosal system and if their roles were unnecessary or clear remained obscure.

For this to be analyzed further, the researchers examined samples from 19 pediatric patients with IgA deficiency and 13 pediatric control patients, from 15 families, and they further complemented that analysis with studies of IgA-deficient mice.

They aimed to answer two questions: how mucosal antibodies like IgM and IgA and system antibodies like IgG interact with mucosal microbes, and how IgA deficiency impacts the equilibrium of the immune system.

Examining both blood and fecal samples, the scientists quantified antibody levels; determined the microbial targets of IgM, IgA, and IgG antibodies; and executed immune profiling to gauge the activation of the immune system.

By doing so, they displayed that even though IgM, IgA, and IgG target overlapping sets of microbes, the role of IgA is clear from IgM in confining commensal microbes in the gut, and IgM only humbly compensates for the lack of intestinal IgA.

Also, they identified that 26% of patients who were IgA deficient through blood tests consisted of normal levels of IgA in their feces.

Interestingly, the patients with normal fecal IgA were less probably to develop immune dysregulation and clinical disease, as illustrated via immune analysis of cytokine levels. In contrast, those deficient in both fecal IgA and blood were more probably to have elevated inflammatory cytokines and display clinical symptoms.

For their findings to be validated, the scientists learned knockout mice who lacked IgA. Mirroring the outcomes in human patients, mice displayed elevated cytokines and immune dysregulation.

Also, the scientists discovered live microbes in the fat tissue of the knockout mice, which was not found in healthy control mice, thereby offering additional proof for the role of IgA in controlling systemic microbial exposure.

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.

Michael Silverman, M.D., Ph.D., Study Co-Senior Author and Assistant Professor, Attending Physician, Division of Infectious Diseases, Children’s Hospital of Philadelphia

Silverman added, “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.”

Source:
Journal reference:

Conrey, P. E., et al. (2023) IgA deficiency destabilizes homeostasis toward intestinal microbes and increases systemic immune dysregulation. Science Immunology. doi.org/10.1126/sciimmunol.ade2335

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