On May 19, 2021, Megan A. Cooper, MD, PhD, an associate professor of pediatrics at Washington University School of Medicine in St. Louis and colleagues announced they had identified a rare immune condition caused by a mutation in a gene known as TLR8 that plays a fundamental role in activating the immune system to fight viruses such as influenza. However, with this disorder, TLR8 is too active, causing inflammation as well as malfunctions in multiple parts of the immune system.

After dozens of high-fever infections, after excess fluid in the brain, after an enlarged spleen, after kidney and liver failures, after two bone marrow transplants, after high-dose chemotherapy and radiation, after cardiac arrest, after endless feeding tubes and breathing machines, 4-year-old Joseph Anthony Vena IV was tired. “For years, he kept going,” said his mother, Ashley Bitler. “But after Joseph’s second bone marrow transplant and rounds of chemotherapy, his body couldn’t take it. He looked at us and said he was tired.” Joseph died June 13, 2020, at age 4, in a hospital near his home in southern New Jersey.

The boy’s infections confounded doctors up and down the Eastern Seaboard. Eventually, in 2019, a physician referred the parents to Megan A. Cooper, MD, PhD, an associate professor of pediatrics at Washington University School of Medicine in St. Louis. Cooper, who treats patients at St. Louis Children’s Hospital, specializes in diagnosing and treating rare genetic diseases affecting the immune system. She collaborates with pediatric specialists worldwide to try to solve their most puzzling cases.

A few months earlier, Cooper and a postdoctoral fellow in her laboratory, Jahnavi Aluri, PhD, began to study two boys with conditions similar to Joseph’s. Such cases have helped Cooper and other researchers identify a rare immune condition caused by a mutation in a gene known as TLR8 that plays a fundamental role in activating the immune system to fight viruses such as influenza. However, with this disorder, TLR8 is too active, causing inflammation as well as malfunctions in multiple parts of the immune system.

The TLR8 discovery inspired an ongoing collaboration of scientists nationwide who had encountered children and teenagers — all boys, at this point — with inexplicable immune deficiencies believed to trigger enlarged organs, blood disorders and sometimes death. Cooper and Aluri documented the first six known cases of TLR8-associated immunodeficiency, published May 6 in the print edition of Blood, the journal of the American Society of Hematology. Recently, they identified an additional child with this disease and are actively searching for more.

The scientists dedicated the study to Joseph, whose parents helped fund the research through memorial donations to the St. Louis Children’s Hospital Foundation.

Research from the first six known cases of TLR8-associated immunodeficiency, was published in the print edition of Blood, the journal of the American Society of Hematology.