Abstract
BackgroundWhile vascular and immune abnormalities are common in juvenile and adult dermatomyositis (DM), the molecular changes that contribute to these abnormalities are not clear. Therefore, we investigated pathways that facilitate new blood vessel formation and dendritic cell migration in dermatomyositis.MethodsMuscle biopsies from subjects with DM (9 children and 6 adults) and non-myositis controls (6 children and 7 adults) were investigated by immunohistochemistry using antibodies that recognize existing (anti-CD146) and newly formed blood vessels (anti-αVβ3) and mature dendritic cells (anti-DC-LAMP). Blood vessel quantification was performed by digitalized image analysis. Additional muscle biopsies from subjects with adult DM and non-myositis controls were used for global gene expression profiling experiments.ResultsA significant increase in neovascularization was found in muscle biopsies of DM patients; neovascularization (αVβ3 positive capillaries and vessels per muscle fiber) was much higher in juvenile than in adult DM patients (control vs juvenile DM: Mean ± SE: 0.06 ± 0.01 vs 0.6 ± 0.05; p < 0.0001 and control vs adult DM: Mean ± SE: 0.60 ± 0.1 vs 0.75 ± 0.1; p = 0.051). Gene expression analysis demonstrated that genes that participate not only in angiogenesis but also in leukocyte trafficking and the complement cascade were highly up regulated in DM muscle in comparison to age matched controls. DC-LAMP positive dendritic cells were highly enriched at perivascular inflammatory sites in juvenile and adult DM patients along with molecules that facilitate dendritic cell transmigration and reverse transmigration (CD142 and CD31).ConclusionThese results suggest active neovascularization and endothelial cell activation in both juvenile and adult DM. It is likely that close association of monocytes with endothelial cells initiate rapid dendritic cell maturation and an autoimmune response in DM.
Highlights
While vascular and immune abnormalities are common in juvenile and adult dermatomyositis (DM), the molecular changes that contribute to these abnormalities are not clear
Neoangiogenesis in DM Blood vessels in normal muscle tissues weakly stained for CD146, whereas a more intense staining was observed in capillaries of adult and juvenile DM biopsies (Fig. 1)
Capillaries in normal muscle tissues were generally negative for the neoangiogenesis marker αVβ3 except for occasionally positive large vessels, whereas a significant number of capillaries and large blood vessels were strongly stained for αVβ3 in the adult and juvenile DM biopsies (Fig. 2)
Summary
While vascular and immune abnormalities are common in juvenile and adult dermatomyositis (DM), the molecular changes that contribute to these abnormalities are not clear. We investigated pathways that facilitate new blood vessel formation and dendritic cell migration in dermatomyositis. In DM, inflammatory changes occur both in muscle and in skin. In juvenile DM, intramuscular blood vessels show endothelial hyperplasia, immune complex and complement deposition, and focal loss of capillaries [1]. It is believed that in adult DM, capillary loss precedes other pathological changes in the muscle, and that the capillary endothelium is an early and possibly primary target of immune attack [2,3]. A physiologic reaction to capillary loss would be formation of new blood vessels, but the evidence for such neovascularization in DM patients has not previously been investigated
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