Cellular mechanisms of macrophage activation syndrome - ABSTRACT Macrophage activation syndrome (MAS) or secondary hemophagocytic lymphohistiocytosis (sHLH) is a dysfunctional, potentially fatal, hyperinflammatory response that is characterized by abnormal activation of lymphocytes and phagocytes leading to an overproduction of inflammatory cytokines and damage of host tissues. In rheumatic disease, MAS most often occurs in patients with systemic juvenile idiopathic arthritis (sJIA) or Adult-onset Still’s Disease although it can also occur as a complication of other rheumatic diseases, including systemic lupus erythematosus, infection, or malignancy. Myeloid cells such as circulating monocytes play a crucial role in the pathogenesis of MAS. I have discovered evidence of a type I interferon signature in monocytes from subjects with MAS secondary to sJIA, suggesting shared pathogenic features with lupus. Although data from mouse models have implicated TLRs 7 and 9 as critical to driving MAS, human monocytes express TLR7 and TLR8, but not TLR9, suggesting that TLR7 and TLR8 are likely the relevant nucleic acid sensing TLRs in human monocytes during MAS. These data highlight the importance of studying MAS in humans. I have defined specific transcriptional changes in MAS monocytes including upregulation of the homotypic cell surface receptor SLAMF7 and found that SLAMF7 and cytokines important to MAS pathogenesis, such as IL-15 and IL-18, are induced by TLR8 signaling in monocytes. The bone marrow is a key location for immune cell development and a frequent site to identify characteristic hemophagocytes during MAS; novel spatial biology approaches render this an accessible tissue for analysis from historical samples. This project will address the following aims: (1) define the cellular and molecular landscape in bone marrow during MAS and define shared and unique features between sJIA and lupus-driven MAS; (2) test the hypothesis that gene expression changes in the peripheral circulation will reflect changes in the bone marrow; (3) test the hypothesis that TLR8 signaling shapes monocyte immune responses during MAS; and (4) test the hypothesis that TLR8-induced SLAMF7 and IL-15 drive monocyte-CD8+ T cell interactions during MAS. The long-term objective of the proposed research is to elucidate the role of cell extrinsic and cell intrinsic signals in shaping monocyte differentiation and cellular interactions during MAS to better understand the pathogenesis of this potentially life-threatening complication. A K08 award will allow me to capitalize on the rich scientific environment of the University of Washington, Benaroya Research Institute, and Seattle Children’s Research Institute to successfully transition to scientific independence. The proposed research and career development plan will provide me with critical training and mentorship in human immunology, translational research, and transcriptomic data analysis, to further my career goal of enhancing knowledge of mechanisms of MAS/sHLH pathogenesis with the ultimate goal of improving the diagnosis and treatment of patients with MAS/sHLH.
