Mount Sinai researcher Charlotte Cunningham-Rundles, MD, PhD, and her team have discovered that an inhibitor of Bruton’s tyrosine kinase (BTK), an important mediator of B-cell receptor signaling, could be used to shut off inflammation in cells of patients with primary immunodeficiency diseases.

There are more than 450 of these diseases, and unraveling their puzzles involves confronting surprises and innovating responses. Part of the puzzle is the heterogeneity of immunodeficiency diseases: All components of the immune system can experience defects.

Among these defects are failures in lymphocytes called B cells, which mature into plasma cells that last for years in bone marrow. B cells are responsible for making proteins called antibodies. The most common immunodeficiency is when a patient’s B cells don’t make an antibody they need, which can lead to infections.

“The other side of the coin, however, is that the B cells may do something other than make a needed antibody—for example, make an antibody against platelets, or red blood cells, or the GI tract, or maybe the skin,” Dr. Cunningham-Rundles explains. “So patients come through my door with autoimmunity almost as often as they do with infections.”

But Dr. Cunningham-Rundles, who is the Director of the Immunodeficiency Clinic, is undaunted by the complexity of the research. Rather, she finds it invigorating.

The Complicated Genetics

Genetics clearly influences the pathophysiology of immune deficiency diseases. Dr. Cunningham-Rundles, who is the David S. Gottesman Professor of Immunology at the Icahn School of Medicine at Mount Sinai and heads an eponymous research lab, authored a 2020 report in Blood that identified a number of genes affecting the process of generating antibodies.

“For the first 20 to 30 years that I worked on B cell issues, people thought there must be something wrong with the B cell,” she says. “So, perhaps that antibody-making cell has a malformation in the plasma cell or antibody recognition from a lymphocyte—but that turns out not to be true in most cases. It turns out there are a great number of additional genes that are not unique to B cells that, when they don’t work, gives that person what looks like a B-cell problem.”

With colleagues in Stockholm, Sweden, and Tehran, Iran, the researchers studied the genetics of more than 500 patients with common variable immunodeficiency (CVID), a primary immunodeficiency disease. The 65 genes in the patients from the United States were predominantly autosomal dominant, whereas at the other two locations the result was an approximately equal mix of dominant and recessive genes—further proof of the complexity of B cell research.

Dr. Cunningham-Rundles is quick to point out that this finding is far from the final word. She found culprit genes in only about 30 percent of the patients tested, meaning another 70 percent or so are out there waiting to be discovered. “There are many more to unpack, which is why we have been doing a lot of whole exome sequencing, with colleagues at Rockefeller University, and we may need to move on to whole-genome sequencing.”

Inflammatory Pathway Identified

For Dr. Cunningham-Rundles, the endeavor to unravel the mystery is both “confounding” and inspiring, and the ultimate beneficiaries of her work—her patients—are never far from her mind.

“I have patients who don’t make antibodies and I give them gamma globulin, so no problem. About 50 percent of those patients do fantastically. Some of them I’ve seen for decades,” she says. “But the other 50 percent develop interstitial lung disease, liver fibrosis, rampant autoimmune disease, granulomatous disease, and inflammatory diseases. So that’s the conundrum.”

Dr. Cunningham-Rundles and her team found there are about 120 genetic indicators that show markers of inflammation. Using a novel assay developed in her lab, she found that those patients with an extreme inflammatory phenotype have larger amounts of bacterial DNA from gastrointestinal organisms in their blood. This DNA activated a number of inflammatory pathways that could incite the conditions found in these patients. “We were pretty floored by this finding, but it is associated with a lack of isotype-switched B cells, which make immunoglobulin A [IgA]. What we found suggests these patients have a mucosal-barrier defect.”

Unable to replace the IgA, Dr. Cunningham-Rundles and team found that an inhibitor of BTK could shut down inflammation in cells of patients with immunodeficiency disorders. The primary immunodeficiency disease known as X-linked agammaglobulinemia is caused by mutations in the BTK gene, and patients with this disorder do not commonly have the inflammatory pathway disorders that are seen in CVID patients.

“It is counterintuitive to take someone who is immune deficient and say, OK, I will make you even more immune deficient. But we have been using rituximab with some CVID patients for years, and we’ve known that wiping out B cells helps for some conditions in these patients. This is not permanent, since the cells then come back in some months—it’s like mowing a lawn,” Dr. Cunningham-Rundles explains. “But BTK is in a lot of cells that lead to inflammation in humans and a BTK inhibitor could actually shut down the inflammation pathway.”

Dr. Cunningham-Rundles maintains an inventive approach to research and clinical care. For example, the mucosal-barrier defect mentioned above might be mitigated with the use of a small amino acid compound used in patients with celiac disease. She is looking into it.
“We are very enthusiastic about what we do,” she explains. “One door opens up to another all the time.”