Systemic Juvenile Idiopathic Arthritis (SJIA) patients constitute about 10% of all JIA population and represent the most distinct subtype of childhood arthritis. Most peripheral blood gene expression signatures that distinguish SJIA from other JIA subtypes reflect activation of the innate immune pathways in monomyelocytoid cells. A perplexing feature of SJIA is a strong association with macrophage activation syndrome (MAS), a life-threatening condition characterized by an overwhelming inflammatory reaction driven by excessive activation and expansion of T cells and hemophagocytic macrophages. While overt MAS is relatively rare, mild subclinical MAS may be occurring in 30-50% of patients with active SJIA. Our gene expression studies suggest that these patients can be distinguished by a gene expression pattern that combines a strong signature of erythropoiesis (most likely reflecting an increased red blood cell turnover in response to subclinical hemophagocytosis) and a strong signature of the alternative pathway of macrophage differentiation. Given the highly inflammatory nature of SJIA and the presence of IFN-y, a cytokine that normally drives the classic pro-inflammatory pathway of macrophage differentiation (Ml), the absence of the IFN-induced signature and emergence of the features of alternatively activated M2 macrophages in this setting are surprising. Preliminary evidence suggests that macrophages in SJIA may show altered responsiveness to IFN-y skewing their differentiation towards the M2 pathway. As a result, these macrophages may have a unique phenotype that does not fit the M1/M2 paradigm. Since hemophagocytic macrophages in MAS strongly express GDI 63, an M2 marker, we hypothesize that the pathways associated with skewing towards the M2 pathway of macrophage differentiation may also contribute to predisposition to MAS in SJIA. To explore this further first we will confirm that the presence of a strong signature of the alternative pathway of macrophage differentiation indeed identifies patients who are more likely to develop MAS (Sp.
Aim 1). We will then further characterize the phenotype of circulating monocytes/macrophages in SJIA in terms of M1/M2 polarization (Sp.
Aim 2). Finally, in Specific Aim 3, we will determine the phenotype of the macrophages in the bone marrow in pre-clinical and full blown MAS and assess the extent of it's overlap with the phenotype of circulating monocytes/macrophages in active SJIA as determined in Sp.
Aim 2. The long-term goal of this project is to identify pathways responsible for the development of MAS predisposition in SJIA and develop biomarkers for early diagnosis of this life-threatening condition.

Public Health Relevance

Macrophage Activation Syndrome (MAS) is a life-threatening complication of Systemic Juvenile Idiopathic Arthritis (SJIA). In clinical practice, there is a strong need for biomarkers that would help with an early diagnosis of MAS. In the proposed study we will explore gene expression signatures that distinguish patients with MAS, identify pathways that put SJIA patients at risk for MAS and develop a list of potential biomarkers of this potentially fatal condition.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Special Emphasis Panel (ZAR1-HL)
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Cincinnati Children's Hospital Medical Center
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