Mechanisms by which IL-10 limits Toll-like Receptor 9 mediated Macrophage Activat

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DESCRIPTION (provided by applicant): Macrophage Activation Syndrome (MAS) is an uncommon but potentially life-threatening complication of many infectious, malignant and rheumatic diseases. It is characterized by fever, difficulty clotting and multiple organ dysfunctio in the setting of overwhelming inflammation. MAS shares features with other cytokine storm syndromes including sepsis and Hemophagocytic Lymphohistiocytosis (HLH). Patients with a primary form of HLH have genetic defects in the machinery necessary for killing by immune cells, and usually die at a young age unless they receive potent immunosuppression and bone marrow transplant. Patients with MAS, however, have no such genetic defects, and very little is known about the genetic, environmental, and/or immunologic causes of MAS. Current animal models of HLH/MAS are confounded by the use of genetic mutations and/or infection. Previous work has shown that repeated stimulation through Toll-like Receptor 9 (TLR9) leads to a syndrome very similar to MAS in wild-type mice. TLR9-driven MAS requires interferon gamma (IFN¿), and hepatitis in this model is worse in mice deficient in B and T lymphocytes. Mice repeatedly stimulated through TLR9 who are unable to signal through the interleukin 10 (IL-10) receptor develop much more severe disease, underscoring the critical role of IL-10 as a negative regulator of MAS. The overall purpose of the proposed research is to define the mechanisms by which IL-10 limits the development of severe MAS. Specifically, this study aims to expand on the finding that hepatic T cells may be important sources of IL-10, and thereby are regulators of MAS. We aim to determine whether these cells are necessary and/or sufficient for preventing severe disease. A better understanding of the regulation of TLR9-driven disease will be beneficial to knowing more about how patients develop MAS, and how best to diagnose and treat this potentially fatal condition. PUBLIC HEALTH RELEVANCE: Macrophage Activation Syndrome (MAS) is a potentially fatal complication of many inflammatory diseases that is characterized by fever, clotting problems, and multiple organ dysfunction. The current understanding of MAS is poor and thus its diagnosis and treatment are difficult and highly variable. The proposed study hopes to determine how the immune system protects itself against MAS by expanding on a newly-developed mouse model, with the goal of gaining a better understanding of how best to diagnose and treat this life-threatening disease.