CHOP Researchers Explore the Role of IgA in Immune Dysregulation

By Kate Knab

When Michael Silverman, MD, PhD, grabbed a cup of coffee with Sarah Henrickson, MD, PhD, conversation turned, as it so often does, to science. They realized they shared a similar interest in symptoms surrounding immunoglobin A (IgA) deficiency: Why do many, but not all, patients with IgA deficiency experience symptoms?

A CHOP pilot grant designed to forge new collaborative initiatives between clinical and basic researchers paired Jonathan Spergel MD, PhD and Dr. Henrickson’s expertise as attending physicians in the Division of Allergy and Immunology at CHOP with the Silverman Lab’s ability to drill down into the mechanisms of the microbiome to answer that question, provide guidance on how the disorder is diagnosed, and identify patients at a higher risk of complications.

Understanding the Role of IgA

In a study appearing in Science Immunology, the research team showed that IgA is an antibody that plays a distinct and critical role in the immune function of mucosal membranes, such as the gut barrier, by binding to bacteria (commensals) and restraining them in the gut.

When IgA is not present, that bacteria can access non-gut spaces, over stimulating the immune system and potentially triggering autoimmune diseases, allergies, and infections.

“One of our main conclusions is that IgA helps ‘tune’ how much of those commensal microbes get beyond the gut and talk to other parts of your immune system,” Dr. Silverman said. 

In patients without IgA, Dr. Silverman and his colleagues noted they had higher cytokine levels in their blood, which is important for cell signaling. Some T cells also appear more activated.

Additionally, they found more antibodies in the blood than are typically present, such as immunoglobin G antibodies that are able to bind to gut microbes. Microbes are in constant conversation with the immune system, and these findings indicate that with an increase in commensals in the wrong areas of the body, the immune system can trigger an inflammatory response to correct it.

Diagnostic and Therapeutic Implications

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 were intrigued to find that 26% of patients who were IgA deficient via blood tests had normal levels of IgA in their feces.

The patients with normal fecal IgA were less likely to develop immune dysregulation and clinical disease, as demonstrated through immune analysis of cytokine levels. Those deficient in both blood and fecal IgA were more likely to have elevated inflammatory cytokines and exhibit clinical symptoms.

“We discovered in our small cohort that patients missing IgA in both the blood and the stool were the only people affected by symptoms,” Dr. Henrickson said. “If we could reduce that anxiety for families and patients by giving them more mechanism-based advice around what one lab test tells us, I think that would hopefully help improve our families’ quality of life, as well as help us identify the patients who need to be monitored carefully.”

Many aspects of immune response are age and sex dependent, so it is important to compare disease samples or participants who are dealing with diseases to the appropriate controls. Developing appropriate controls to match the microbiome and genetics is even more difficult but crucial for more specific characterization. To address this, study participants had to be siblings living in the same home to measure shared exposures to diet, environment, and infection. Such carefully chosen controls resulted in a small cohort, but initial findings suggest potential for future studies to better test for and treat this disease.

“As we think about therapeutics and how to use microbes to modulate the immune system, understanding IgA and how it responds to microbes is going to help us figure out how to make probiotics work better,” Dr. Silverman said. “This study is an important first step towards that.”