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Our translational studies focus on uncovering biomarkers for macrophage activation syndrome (MAS) and understanding the relation of genetic differences in MAS patients to cell function. Our studies also examine the use of a novel imaging agent to assess disease in mouse models of arthritis.
After analyzing the MAS signature identified in the gene expression project, we identified several candidate biomarkers that might be useful for the early diagnosis of MAS. The clinical utility of these markers is now being explored in the clinical project funded through the NIH Multidisciplinary Clinical Research Center (MCRC).
Support: NIH P60-AR047784 MCRC Grant.
MAS bears close resemblance to a group of histiocytic disorders collectively known as hemophagocytic lymphohistiocytosis (HLH). HLH disease processes are characterized by accumulations of well-differentiated mononuclear cells with a macrophage phenotype exhibiting hemophagocytic activity.
The development of these disorders has been associated with defects in the granule dependant cytotoxic functions of lymphocytes. And in approximately 10 percent of patients with familial HLH, the development of cytolytic dysfunction is associated with mutations in the MUNC13-4 gene. The protein encoded by this gene is an important player in the intracellular transport of perforin, a molecule that is central to the ability of NK cells and cytotoxic T lymphocytes to induce lysis of target cells.
Our recent observations suggest that, as in HLH, MAS patients have profoundly depressed NK-cell function, often associated with abnormal perforin expression and 12 single-nucleotide polymorphisms (SNPs) in the MUNC13-4 gene, inherited as an extended haplotype. We seek to determine whether the observed polymorphisms in the MUNC 13-4 are associated with abnormal function or expression of the MUNC13-4 protein and, thus, directly contribute to the development of cytolytic dysfunction in patients with MAS.
Another possibility we are investigating is that the described haplotype may extend upstream or downstream of the MUNC13-4 gene, thus involving additional polymorphisms in other immunologically relevant genes. The project seeking to answer these questions is being performed in collaboration with Kejian Zhang, MD, MBA, (human genetics) and Alexandra Filipovich, MD (BMT and immunodeficiency).
Support: NIH RO1AR059049. Scientific review completed, awaiting counsel review (likely to be funded, based on historic paylines).
SapC-DOPS is a reagent that targets stressed cells. We are using it to determine if, through the addition of a fluorophore, we can image arthritis earlier in animals than can be done with macroscopic scoring. This novel technology provides the sensitivity required to assess arthritic disease onset and progression in live subjects. This line of research may eventually provide a means for targeted local delivery of therapeutic biologics. These studies are being done in conjunction with Xiaoyang Qi, PhD, (human genetics) and Matthew Flick, PhD (experimental hematology).
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