Cytokines in juvenile dermatomyositis pathophysiology: potential and challenge.
OBJECTIVE
Cytokines are criticalmediators of the immune response. This review focuses on cytokine-specific information from children with juvenile dermatomyositis, and includes pertinent data from adults with polymyositis and dermatomyositis.


RESULTS
Much of the new data concern the role of possible antigens and the definition of genetic control of the immune response in juvenile dermatomyositis. Gene expression profile data of DQA1*0501 (present in 85% of patients) compared with age-matched control subjects show that the initial immune response is an interferon-alpha/beta-induced cascade with secondary stimulation of interferon-gamma. Specific epitopes of group A beta-hemolytic streptococcal M protein, with sequence homology for myosin, elicit both cell-mediated cytotoxicity and tumor necrosis factor-alpha production when incubated with mononuclear cells from children with active juvenile dermatomyositis. Tumor necrosis factor-alpha synthesis is increased in juvenile dermatomyositis patients with the tumor necrosis factor-alpha-308A allele, and is associated with increased thrombospondin-1 (an antiangiogenic agent) production and small vessel occlusion in untreated juvenile dermatomyositis. Studies in adults with polymyositis and dermatomyositis implicate interleukin-1alpha, transforming growth factor-beta, and endothelial cell perturbation early in the disease course. Cultured myoblasts were found to produce interleukin-15, which impacts local T-cell activation and proliferation.


CONCLUSIONS
The limited data suggest that a possible viral/microbial antigen may elicit an interferon-alpha/beta-induced response, and that antigenic epitopes may be shared. Increased synthesis of tumor necrosis factor-alpha, more common in juvenile dermatomyositis with the tumor necrosis factor-alpha-308A polymorphism, may augment this response and is associated with a wide range of pathologic consequences, as well as disease chronicity and calcifications. The muscle fibers themselves can regulate local inflammation by production of tumor necrosis factor-alpha, interleukin-15 and interleukin-1alpha, and transforming growth factor-beta.
Uzel
Gulbu
G
Feinberg School of Medicine, Northwestern University, Department of Pediatrics, Chicago, Illinois, USA.
Pachman
Lauren M
LM
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000032:analysis / Q000378:metabolism*; D003882:Dermatomyositis / Q000209:etiology* / Q000503:physiopathology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics*; D007378:Interleukins / Q000032:analysis; D008297:Male; D011379:Prognosis; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D015415:Biomarkers; D016207:Cytokines; D016898:Interferon-alpha; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha