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1.
Pediatr Rheumatol Online J ; 14(1): 7, 2016 Feb 09.
Article in English | MEDLINE | ID: mdl-26861863

ABSTRACT

BACKGROUND: Various pathways involved in the pathogenesis of sJIA have been identified through gene expression profiling in peripheral blood mononuclear cells (PBMC), but not in neutrophils. Since neutrophils are important in tissue damage during inflammation, and are elevated as part of the acute phase response, we hypothesised that neutrophil pathways could also be important in the pathogenesis of sJIA. We therefore studied the gene profile in both PBMC and neutrophils of sJIA patients treated with tocilizumab. METHODS: We studied the transcriptomes of peripheral blood mononuclear cells (PBMC) and neutrophils from eight paired samples obtained from 4 sJIA patients taken before and after treatment, selected on the basis that they achieved ACR90 responses within 12 weeks of therapy initiation with tocilizumab. RNA was extracted and gene expression profiling was performed using Affymetrix GeneChip Human Genome U133 Plus 2.0 microarray platform. A longitudinal analysis using paired t-test (p < 0.05 and FC ≥ 1.5) was applied to identify differentially expressed genes (DEGs) between the two time points followed by ingenuity pathway analysis. Gene Set Enrichment Analysis (GSEA) and quantitative real-time PCR were then performed to verify the microarray results. RESULTS: Gene ontology analysis in neutrophils revealed that response to tocilizumab significantly altered genes regulating mitochondrial dysfunction and oxidative stress (p = 4.6E-05). This was independently verified with GSEA, by identifying a set of oxidative genes whose expression correlated with response to tocilizumab. In PBMC, treatment of sJIA with tocilizumab appeared to affect genes in Oncostatin M signalling and B cell pathways. CONCLUSIONS: For the first time we demonstrate that neutrophils from sJIA patients responding to tocilizumab showed significantly different changes in gene expression. These data could highlight the importance of mitochondrial genes that modulate oxidative stress in the pathogenesis of sJIA.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Arthritis, Juvenile/genetics , Cytokines/genetics , Gene Expression Regulation/drug effects , Microarray Analysis/methods , Neutrophils/metabolism , Oxidative Stress/genetics , RNA/analysis , Adolescent , Arthritis, Juvenile/drug therapy , Arthritis, Juvenile/metabolism , Child , Child, Preschool , Cytokines/biosynthesis , Female , Humans , Male , Pilot Projects , Real-Time Polymerase Chain Reaction
2.
PLoS One ; 7(10): e47673, 2012.
Article in English | MEDLINE | ID: mdl-23094074

ABSTRACT

BACKGROUND: The cytokine IL-10 and its family members have been implicated in autoimmune diseases and we have previously reported that genetic variants in IL-10 were associated with a rare group of diseases called juvenile idiopathic arthritis (JIA). The aim of this study was to fine map genetic variants within the IL-10 cytokine family cluster on chromosome 1 using linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (tSNPs) approach with imputation and conditional analysis to test for disease associations. METHODOLOGY/PRINCIPAL FINDINGS: Fifty-three tSNPs were tested for association between Caucasian paediatric cohorts [219 systemic JIA (sJIA), 187 persistent oligoarticular JIA (pOJIA), and 139 extended OJIA (eOJIA) patients], and controls (Wellcome Trust control cohort, WTCCC2). Significant association with sJIA was detected at rs1400986 in the promoter of IL-20 (odds ratio 1.53; 95% CI 1.21-1.93; p = 0.0004), but in no other subtypes. Imputation analysis identified additional associated SNPs for pOJIA at IL-20 and IL-24, including a rare, functional, missense variant at IL-24 with a p = 0.0002. Penalised logistic regression analysis with HyperLasso and conditional analysis identified several further associations with JIA subtypes. In particular, haplotype analysis refined the sJIA association, with a joint effect at rs1400986 and rs4129024 in intron 1 of MAPKAPK2 (p = 3.2E-5). For pOJIA, a 3-SNP haplotype including rs1878672 in intron 3 of IL-10 showed evidence for association (p = 0.0018). In eOJIA, rs10863962 (3'UTR of FCAMR) and rs12409577 (intron of IL-19) haplotype showed some evidence of association (p = 0.0003). CONCLUSIONS: This study supports previous association of IL-20 with sJIA. Haplotype analyses provided stronger association signals than single point analyses, while a penalised logistic regression approach also suggested multiple independent association signals. Replication studies are required to confirm or refute these findings. The results indicate that combined effects with unknown/rare variants remain to be characterised in JIA, and represent a possible example of synthetic association in this region.


Subject(s)
Arthritis, Juvenile/genetics , Chromosomes, Human, Pair 1 , Haplotypes , Interleukin-10/genetics , Interleukins/genetics , Polymorphism, Single Nucleotide , Arthritis, Juvenile/pathology , Case-Control Studies , Child , Genetic Loci , Humans , Intracellular Signaling Peptides and Proteins/genetics , Introns , Linkage Disequilibrium , Promoter Regions, Genetic , Protein Serine-Threonine Kinases/genetics , Regression Analysis
3.
Rheumatology (Oxford) ; 51(10): 1881-6, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22772320

ABSTRACT

OBJECTIVE: The role of the adaptive immune system has not been explored in detail compared with the innate immune system in systemic JIA (sJIA) pathogenesis. The aim of this study was to examine the phenotype of circulating peripheral blood CD4(+) T-cell subpopulations in a cross-sectional study of sJIA patients during disease remission on medication and during acute flare of the disease. METHODS: Flow cytometry was used to examine the phenotype and cytokine production of IFNγ-, IL-4- and IL-17-producing CD4(+) T cells in the peripheral blood of 10 sJIA patients with active disease, 9 sJIA with inactive disease, 14 JIA patients with oligoarticular onset, 10 adult control subjects and 10 age-matched control subjects. In parallel, we examined the proportion of FoxP3(+) Tregs. RESULTS: IFNγ- and IL-17-producing CD4(+) T cells and IL-17-producing CD3(+)CD4(-) T cells were present at higher proportions in the peripheral blood of sJIA patients, irrespective of their disease status. Our data also confirm the known increase of the proportions of IFNγ-producing Th1 cells with increasing age and suggest an increase with age in the IL-17-producing CD4(+) T-cell population. CONCLUSION: This study is the first to describe significantly higher proportions of Th1 and Th17 T helper cell subsets in the peripheral blood of sJIA patients. These proinflammatory cells may play a pathogenic role in sJIA. Our data also emphasize the importance of using paediatric age-matched control subjects when evaluating the T-cell cytokine profile in JIA.


Subject(s)
Arthritis, Juvenile/immunology , Th1 Cells/pathology , Th17 Cells/pathology , Adolescent , Arthritis, Juvenile/blood , Arthritis, Juvenile/pathology , Child , Child, Preschool , Cross-Sectional Studies , Cytokines/biosynthesis , Female , Flow Cytometry , Humans , Immunophenotyping , Lymphocyte Count , Male , Th1 Cells/immunology , Th17 Cells/immunology
4.
Tunis Med ; 85(12): 999-1003, 2007 Dec.
Article in English | MEDLINE | ID: mdl-19170376

ABSTRACT

UNLABELLED: Over the last twenty years, the progress made in molecular biology have led to the identification of many transcription factor genes, whose mutations has been reported as causes of familial hypopituitarism. AIM: Based on a literature review, this study is intending to highlight the role of some transcription factors in the development of the anterior pituitary gland and to analyse the involvement of their dysfunction in some cases of congenital hypopituitarism. METHODS: Litterature review. RESULTS: These transcription factors are nuclear proteins expressed specifically in certain target cells, in order to control genes expression. Their role is fundamental in embryonic and foetal development, and particularly in pituitary ontogenesis. Together, they direct the formation of anterior pituitary gland, the differentiation, the expansion and the definitive function of the five pituitary cell types. In this report, after introducing the different stages of anterior pituitary development and differentiation of its cell lines, we will briefly highlight the clinical phenotypes associated with alterations of different transcription factor genes in both murine models and humans.


Subject(s)
Hypopituitarism/congenital , Hypopituitarism/genetics , Animals , Cell Lineage , Disease Models, Animal , Gene Expression , Humans , Hypopituitarism/embryology , Infant , Infant, Newborn , Mice , Mice, Knockout , Mutation , Phenotype , Pituitary Gland, Anterior/cytology , Pituitary Gland, Anterior/embryology , Pituitary Gland, Anterior/growth & development , Transcription Factor Pit-1/genetics , Transcription Factors/genetics
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