VASCULOPATHY OF JUVENILE DERMATOMYOSITIS

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DESCRIPTION (Taken from the application): Juvenile dermatomyositis (JDMS), the most common pediatric inflammatory myopathy affecting 3/1,000,000 children/year with a mortality of over 2%, is a genetically associated (DQAI *0501) systemic vasculopathy affecting capillaries and arterioles, in which there are no laboratory predictors of disease course or severity. The hypothesis of this proposal is that pathological damage to vascular structures involves activation of the cellular immune system, T cells and macrophages, and is correlated with elevated concentrations of circulating mediators reflecting alterations of angiogenesis and hemostasis. This proposal will provide a comprehensive assessment of structural findings at three levels-physical examination, nailfold capillary morphology, and muscle biopsy--which will allow comparisons with laboratory evidence of mediators characteristic of specific T cells subsets (Thl, Th2) and circulating factors reflecting alterations in thrombosis and hemostasis. The first Specific Aim is to develop disease activity and chronicity scores (ACSs) in a cross- sectional study of 40 JDMS of 1 ) clinical findings, 2) nailfold capillaroscopy, and 3) histological change on muscle biopsy and determine the relationship between them using Pearson correlation coefficients. In Specific Aim #2, a longitudinal study, the diagnostic muscle biopsy will be assessed for mRNA characteristic of Th1 (IL2, INFgamma) and Th2 cells (IL-4, IL-1O) as well as localization of these products by immunohistochemistry. The relationship of Th1 to Th2 associated cytokines may be relative to disease progression in JDMS and will be reevaluated in 20 new onset JDMS by needle biopsy 6 months after initiation of therapy using analysis of variance. The concentration of circulating macrophage (IL-8, TNF-alpha) or lymphocyte derived (bFGF, TGFbeta) factors affecting angiogenesis and hemostasis will be measured in Specific Aim #3, as well markers of coagulation, d-dimer fibrin cleavage product, prothrombin activation peptide, F 1.2, vWF:Ag and thrombomodulin, using a paired t-test for samples at onset and follow- up, and the levels correlated with the three ACSs. In Specific Aim #4, circulating factors--plasma derived serum, unfractionated peripheral blood mononuclear cells, and isolated CD4+ and CD8+ T cells--and their tissue culture supernatant will be tested on in vitro models of endothelial proliferation, migration, tube formation and smooth muscle proliferation and migration. Specific Aim #5 will compare those children with and without the Class lI antigen, DQAI *0501, with ACSs and levels of the specific vasoactive mediators using 2 sample t-tests.