Randy Cron, M.D., Ph.D., UAB, and Devin Absher, Ph.D., HudsonAlpha, grant to contribute to understanding macrophage activation syndrome.
UAB and Children’s of Alabama is the first ever clinical trial site (investigator-initiated) to study the role of blocking the pro-inflammatory cytokine, interleukin-1 (IL-1), in treating pediatric and adult patients with the frequently fatal disorder, macrophage activation syndrome (MAS). MAS shares many clinical and laboratory features with familial hemophagocytic lymphohistiocytosis (fHLH), which is a rare but fatal disease of infancy caused by homozygous (both genetic alleles) defects in a variety of genes which are all involved with the ability of natural killer (NK) cells and cytotoxic CD8 T lymphocytes to lyse/kill antigen presenting cells via the perforin mediated cytolytic pathway. The Cron lab and others have identified heterozygous (single copy mutations) defects in fHLH associated genes in the much more common disorder of MAS. In the lab, some of the mutations have been shown to contribute to disease pathology by acting as partial or complete dominant-negative mutations. Studies of MAS patients suggest that 10-40% will possess at least one heterozygous mutation in a known fHLH gene. “The funding from the Center for Genomic Medicine is highly welcome as this will allow us to explore fHLH, and novel gene, mutations that may contribute to MAS in the patients enrolled in the clinical trial assessing IL-1 blockade,” says Dr. Cron. “The ability to identify known and novel mutations (through our collaboration with Hudson-Alpha) and explore their role in the pathophysiology of MAS (in our lab at UAB), as well as correlate the mutations with outcomes in the clinical trial, will greatly contribute to a better understanding of MAS disease pathology and the genetic risk factors involved.”