. Macrophage activation syndrome (MAS) is characterized by an overwhelming inflammatory reaction driven by excessive expansion of T cells and hemophagocytic macrophages. MAS has been strongly associated with systemic Juvenile Idiopathic Arthritis (sJIA). It is a potentially fatal condition, but the diagnosis is difficult due to the lack of diagnostic criteria. In clinically similar genetic diseases, the exaggerated immune response has been linked to defective cytolytic function. We have preliminary data indicating the presence of single-nucleotide polymorphisms (SNP) in the MUNC13-4 gene whose product is involved in the secretion of cytolytic granules. These SNP alleles appear to be inherited as an extended haplotype in the majority of MAS patients. Therefore, the main question in Specific Aim 1 is whether genetic polymorphisms in the MUNC 13-4 gene are associated with MAS in sJIA and thus, may help identify patients at a long-term risk for MAS. In this part of the study, banked DMA samples from a large cohort of sJIA patients (including those with MAS) and controls will be examined for the presence of the MUNC13-4 haplotype by targeted genetic analysis of a limited number of SNPs. The SNP data will then be linked to the clinical phenotypes of the patients determined in Specific Aims 2 and 3. We have preliminary evidence that serum levels of soluble IL2 receptor a chain (slL2Ra) and soluble CD163 (sCD163) may reflect the degree of activation and expansion of T cells and macrophages in MAS, and thus serve as early diagnostic markers. The main question in Specific Aim 2 is whether elevated levels of slL2Ra and sCD163 will distinguish patients with overt and subclinical MAS from patients with conventional sJIA flare. The main question in Specific Aim 3 is whether sJIA patients at risk for MAS represent a distinct subtype of sJIA with a distinct course, and these patients can be distinguished at onset of sJIA. The longterm goal of this proposal is to understand the pathways leading to the increased incidence of MAS in sJIA, define the MAS risk group, and to develop guidelines for monitoring and treatment of such patients.
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