Advancements in Immunology Research and Remembering Dr. Dan Kennedy II

We’re honored to share research that came directly from this community, made possible by your participation at the 2023 TBRS Summit.

We want to start by celebrating the life of Dr. Dan Kennedy. If you attended the 2023 TBRS Summit, you probably had the honor of meeting this kind and intelligent man. Meeting people with TBRS inspired Dr. Kennedy. He wanted to make a difference for our families through his work to understand immune issues in TBRS. Sadly, Dan passed away shortly before his work was published. This paper is dedicated to Dan.

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Here is a summary:

As we age, some blood stem cells acquire genetic mutations and gradually outgrow their neighbors, a phenomenon called clonal hematopoiesis. One of the most common mutations occurs in a gene called DNMT3A. People with clonal hematopoiesis are known to have a higher risk of severe infections, but scientists have not fully understood why.  

In this study, Zimmer, Kennedy, and colleagues investigated how loss of Dnmt3a affects the immune system. Using mice with Dnmt3a mutations, they infected the animals with influenza virus and examined how their immune cells responded. The researchers found that mice lacking Dnmt3a had more virus in their lungs and were less able to control the infection. [pubmed.ncb...lm.nih.gov], [exphem.org] The team focused on neutrophils, the most abundant white blood cells and one of the body's first responders to infection. Surprisingly, the mutant mice had normal numbers of neutrophils circulating in their blood. The problem was that these neutrophils had difficulty traveling to the site of infection in the lungs. As a result, fewer neutrophils reached infected tissues where they were needed most.  Further experiments showed that the neutrophils were not generally defective. They matured normally and retained many of their antimicrobial functions. Instead, the main defect was in their ability to sense and follow chemical signals that guide them toward infection, a process known as chemotaxis. The mutant cells expressed lower levels of molecules involved in migration, including the chemokine receptor CXCR1, making them less efficient at finding their destination.  To determine whether these findings might be relevant to humans, the researchers also studied blood samples from individuals with Tatton-Brown-Rahman syndrome, a rare condition caused by inherited DNMT3A mutations. These individuals showed changes in blood proteins involved in cell movement and cytoskeletal function, supporting the idea that DNMT3A helps regulate how immune cells migrate.  

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Why This Matters: This study suggests that DNMT3A mutations can weaken immune defenses not by reducing the number of neutrophils, but by impairing their ability to reach infections quickly and efficiently. These findings provide a potential explanation for why people with clonal hematopoiesis or TBRS may be more vulnerable to serious infections. The work also highlights leukocyte trafficking and migration pathways as possible targets for future therapies aimed at improving immunity in individuals with DNMT3A-mutant clonal hematopoiesis or TBRS.  Bottom line: DNMT3A-mutant neutrophils are present and functional, but they are poor navigators. They struggle to migrate to infected tissues, leading to less effective pathogen clearance and increased susceptibility to infection. [exphem.org]

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Click here to read the full paper.

With gratitude for this community, and in remembrance of those who helped make this work possible.