25 research outputs found
Maternal microchimerism in muscle biopsies from children with juvenile dermatomyositis
Objective. Recent advances in molecular techniques have revealed that there is bi-directional transfer of cells between mother and child during pregnancy, and the presence of a mother's cells in her child has been termed maternal microchimerism (MMc). There is the potential for maternal cells to provoke inappropriate immune responses in the child, which could be a factor in autoimmunity including JDM. The aim of this study was to determine whether maternal (female) cells could be detected in frozen muscle sections from seven males (age range 3â13 years) with JDM participating in the Juvenile Dermatomyositis National (UK and Ireland) Cohort Biomarker Study and Repository for Idiopathic Inflammatory Myopathies and sections of muscle controls (age range 2â12 years)
Genetic association study of NF-ÎșB genes in UK caucasian adult and juvenile onset idiopathic inflammatory myopathy
Objective. Treatment-resistant muscle wasting is an increasingly recognized problem in idiopathic inflammatory myopathy (IIM). TNF-α is thought to induce muscle catabolism via activation of nuclear factor-kappa B (NF-ÎșB). Several genes share homology with the NF-ÎșB family of proteins. This study investigated the role of NF-ÎșB-related genes in disease susceptibility in UK Caucasian IIM. Methods. Data from 362 IIM cases [274 adults, 49 (±14.0) years, 72% female; 88 juveniles, 6 (±3.6) years, 73% female) were compared with 307 randomly selected Caucasian controls. DNA was genotyped for 63 single nucleotide polymorphisms (SNPs) from NF-ÎșB-related genes. Data were stratified by IIM subgroup/serotype. Results. A significant allele association was observed in the overall IIM group vs controls for the IKBL-62T allele (rs2071592, odds ratio 1.5, 95% CI 1.21, 1.89, corrected Pâ=â0.0086), which strengthened after stratification by anti-Jo-1 or -PM-Scl antibodies. Genotype analysis revealed an increase for the AT genotype in cases under a dominant model. No other SNP was associated in the overall IIM group. Strong pairwise linkage disequilibrium was noted between IKBL-62T, TNF-308A and HLA-B*08 (DâČâ=â1). Using multivariate regression, the IKBL-62T IIM association was lost after adjustment for TNF-308A or HLA-B*08. Conclusion. An association was noted between IKBL-62T and IIM, with increased risk noted in anti-Jo-1- and -PM-Scl antibody-positive patients. However, the IKBL-62T association is dependent on TNF-308A and HLA-B*08, due to strong shared linkage disequilibrium between these alleles. After adjustment of the 8.1 HLA haplotype, NF-ÎșB genes therefore do not independently confer susceptibility in IIM
CD4+FOXP3+ regulatory T cells are abundantly present in inflamed muscle of patients with juvenile dermatomyositis
Validation of a score tool for measurement of histological severity in juvenile dermatomyositis and association with clinical severity of disease.
OBJECTIVES: To study muscle biopsy tissue from patients with juvenile dermatomyositis (JDM) in order to test the reliability of a score tool designed to quantify the severity of histological abnormalities when applied to biceps humeri in addition to quadriceps femoris. Additionally, to evaluate whether elements of the tool correlate with clinical measures of disease severity. METHODS: 55 patients with JDM with muscle biopsy tissue and clinical data available were included. Biopsy samples (33 quadriceps, 22 biceps) were prepared and stained using standardised protocols. A Latin square design was used by the International Juvenile Dermatomyositis Biopsy Consensus Group to score cases using our previously published score tool. Reliability was assessed by intraclass correlation coefficient (ICC) and scorer agreement (α) by assessing variation in scorers' ratings. Scores from the most reliable tool items correlated with clinical measures of disease activity at the time of biopsy. RESULTS: Inter- and intraobserver agreement was good or high for many tool items, including overall assessment of severity using a Visual Analogue Scale. The tool functioned equally well on biceps and quadriceps samples. A modified tool using the most reliable score items showed good correlation with measures of disease activity. CONCLUSIONS: The JDM biopsy score tool has high inter- and intraobserver agreement and can be used on both biceps and quadriceps muscle tissue. Importantly, the modified tool correlates well with clinical measures of disease activity. We propose that standardised assessment of muscle biopsy tissue should be considered in diagnostic investigation and clinical trials in JDM
Muscle biopsy in combination with myositis-specific autoantibodies aids prediction of outcomes in juvenile dermatomyositis
ObjectiveJuvenile dermatomyositis (DM) is a rare and severe autoimmune condition characterized by rash and proximal muscle weakness. While some patients respond to standard treatment, others do not. This study was carried out to investigate whether histopathologic findings and myositisâspecific autoantibodies (MSAs) have prognostic significance in juvenile DM.MethodsMuscle biopsy samples (nâ=â101) from patients in the UK Juvenile Dermatomyositis Cohort and Biomarker Study were stained, analyzed, and scored for severity of histopathologic features. In addition, autoantibodies were measured in the serum or plasma of patients (nâ=â90) and longitudinal clinical data were collected (median duration of followâup 4.9 years). Longâterm treatment status (on or off medication over time) was modeled using generalized estimating equations.ResultsMuscle biopsy scores differed according to MSA subgroup. When the effects of MSA subgroup were accounted for, increased severity of muscle histopathologic features was predictive of an increased risk of remaining on treatment over time: for the global pathology score (histopathologist's visual analog scale [hVAS] score), 1.48âfold higher odds (95% confidence interval [95% CI] 1.12â1.96; Pâ=â0.0058), and for the total biopsy score (determined with the standardized score tool), 1.10âfold higher odds (95% CI 1.01â1.21; Pâ=â0.038). A protective effect was identified in patients with antiâMiâ2 autoantibodies, in whom the odds of remaining on treatment were 7.06âfold lower (95% CI 1.41â35.36; Pâ=â0.018) despite muscle biopsy scores indicating more severe disease. In patients with antiânuclear matrix protein 2 autoantibodies, antiâtranscription intermediary factor 1Îł autoantibodies, or no detectable autoantibody, increased histopathologic severity alone, without adjustment for the effect of MSA subtype, was predictive of the risk of remaining on treatment: for the hVAS global pathology score, 1.61âfold higher odds (95% CI 1.16â2.22; Pâ= 0.004), and for the total biopsy score, 1.13âfold higher odds (95% CI 1.03â1.24; Pâ=â0.013).ConclusionHistopathologic severity, in combination with MSA subtype, is predictive of the risk of remaining on treatment in patients with juvenile DM and may be useful for discussing probable treatment length with parents and patients. Understanding these associations may identify patients at greater risk of severe disease
Divergence in the degree of clonal expansions in inflammatory T cell subpopulations mirrors HLA-associated risk alleles in genetically and clinically distinct subtypes of childhood arthritis
Selective recruitment of polarized T cells expressing CCR5 and CXCR3 to the inflamed joints of children with juvenile idiopathic arthritis
Morphometric analyses of normal pediatric brachial biceps and quadriceps muscle tissue
Pediatric normal brachial biceps (14
specimens) and quadriceps muscles (14 specimens) were
studied by immunohistochemistry to quantify fiber-type,
diameter and distribution, capillary density, presence of
inflammatory cells (CD3, CD20, CD68) and expression
of neonatal myosin and MHC class 1 proteins. Brachial
biceps showed more fast-twitch fibers and lower
capillary/fiber ratio than quadriceps. The mean diameter
of both fiber types was smaller in biceps than
quadriceps. Fast-fibers were smaller than slow-fibers,
and capillary/fiber ratio was <1.0 in both muscles. Fiber
size and capillary / fiber ratio increased with age.
Normal limits for infiltrating haematopoietic cells were
<4 T lymphocytes, or CD68+ cells, very few B cells, <6
neonatal myosin positive fibers, and no fibers MHC
class 1 positive in one x20 field, for both muscles. The
present comparison of quantitative findings between
brachial biceps and quadriceps may allow
standardization of the assessment of pathological
changes in both pediatric muscles
Human dendritic cells infected with an adenoviral vector suppress proliferation of autologous and allogeneic T cells
Dendritic cells (DCs) play a key role in the type and course of an immune response. The manipulation of human DCs to produce therapeutic agents by transduction with viral vectors is a growing area of research. We present an investigation into the effects of adenoviral vector infection on human DCs and other cell types, and on their subsequent ability to induce T-cell proliferation. We show that infection with replication-deficient adenovirus results in impaired proliferation of T cells in a mixed lymphocyte reaction (MLR). We show this to be an active suppression rather than a defect in the DCs as T cells also fail to proliferate in response to phytohaemagglutinin in the presence of adenoviral vector-infected DCs. This suppression is not attributable to phenotypic changes, death or inability of the DCs to produce cytokines on stimulation. By separation of DCs from T cells, and addition of conditioned supernatants, we show that suppression is mediated by a soluble factor. Blocking of interleukin (IL)-10 but not transforming growth factor (TGF)-ÎČ could overcome the suppressive effect in some donors, and the source of the suppressive IL-10 was lymphocytes exposed to conditioned supernatant. Together our data suggest that infection of DCs by adenoviral vectors leads to suppression of the resulting immune response