Expression of TNFα by Muscle Fibers in Biopsies from Children with Untreated Juvenile Dermatomyositis: Association with the TNFα-308A Allele

Fedczyna, Tamara O.; Lutz, Jennica; Pachman, Lauren M.

doi:10.1006/clim.2001.5063

Cited by 63 publications

(33 citation statements)

References 13 publications

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“…Although the etiology is unknown, proinflammatory cytokines are implicated in the pathogenesis of inflammatory myopathies (1). Specifically in juvenile DM, tumor necrosis factor ␣ (TNF␣) was expressed in the muscle fibers of children with untreated disease (2). The finding that the TNF␣-308A polymorphism was associated with dystrophic calcifications (3) was the impetus for this study.…”

Section: Introductionmentioning

confidence: 94%

Pilot Study of Etanercept in Patients With Refractory Juvenile Dermatomyositis

Rouster‐Stevens

Ferguson

Morgan

et al. 2014

Arthritis Care & Research

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Section: Introductionmentioning

confidence: 94%

Pilot Study of Etanercept in Patients With Refractory Juvenile Dermatomyositis

Rouster‐Stevens

Ferguson

Morgan

et al. 2014

Arthritis Care & Research

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“…This selection was done to ensure that all four of these children probably shared the same DQA-matched disease characteristics. Two patients were heterozygous for TNF-␣-308 GA (the A allele is associated with greater production of TNF-␣ by JDM PBMCs) (19) as well as JDM muscle fibers (21) and had a short disease course (mean of 0.5 years from disease onset to muscle biopsy), and two of the children were homozygous for TNF-␣-308 GG with a long period (1.3 years) of untreated disease before a diagnostic muscle biopsy was obtained (Table I). Immediately before anesthesia for the muscle biopsy, blood was taken from each child for subsequent analysis of sera and Ficoll-Hypaque isolation of PBMCs.…”

Section: Jdm Patientsmentioning

confidence: 99%

Gene Expression Profiling in DQA1*0501+ Children with Untreated Dermatomyositis: A Novel Model of Pathogenesis

Težak

Hoffman

Lutz³

et al. 2002

The Journal of Immunology

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222

143

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Juvenile dermatomyositis (JDM), the most common pediatric inflammatory myopathy, is a systemic vasculopathy affecting young children. Epidemiology studies documenting an antecedent illness in the 3 mo before the first definite symptom (rash and/or weakness) of JDM are supported by immunologic data that suggest that the disease pathophysiology is Ag driven. The purpose of this study was to compare the gene expression profiles in muscle biopsies of four untreated DQA1*0501+ JDM children with profiles from children with a known necrotizing myopathy (Duchenne muscular dystrophy), as well as an in vitro antiviral model (NF90), and healthy pediatric controls. Nearly half (47%) of the dysregulated genes in JDM were associated with the immune response. In particular, increased expression of IFN-αβ-inducible genes 6-16, myxovirus resistance protein p78, latent cytosolic transcription factor, LMP2, and TAP1 was observed. This profile is consistent with an IFN-αβ transcription cascade seen in the in vitro viral resistance model. The IFN-αβ-inducible profile was superimposed on transcription profiles reflective of myofiber necrosis and regeneration shared with Duchenne muscular dystrophy. Expressed genes were confirmed by quantitative real-time PCR (6-16), immunofluorescence (thrombospondin 4), and immunolocalization (IFN-γ, p21). We hypothesize that these data support a model of Ag (?viral) induction of an apparent autoimmune disease based on dynamic interaction between the muscle, vascular, and immune systems in the genetically susceptible (DQA1*0501+) child.

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“…We then observed that a substitution of A for G at the Ϫ308 position of the TNF␣ promoter was associated with an increased frequency of vascular occlusion in muscle biopsies from children with JDM prior to therapy (6). The TNF␣-308A allele is also overrepresented in children with definite JDM (7) and is associated with increased production of TNF␣ both in vitro (8) and in vivo (7) and a disease course that is more resistant to immunosuppressive therapy, which may be complicated by a higher frequency of pathological calcification (7). The identification of the TNF␣-308A allele substitution in children with an unremitting course of JDM suggests that this allele might be linked to factors that alter the vascular bed in children with JDM.…”

Section: Introductionmentioning

confidence: 99%