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IRF4 and its regulators: evolving insights into the pathogenesis of inflammatory arthritis?

ABSTRACT: Accumulating evidence from murine and human studies supports a key role for interleukin-17 (IL-17) and IL-21 in the pathogenesis of inflammatory arthritis. The pathways and molecular mechanisms that underlie the production of IL-17 and IL-21 are being rapidly elucidated. This review focuses on interferon regulatory factor 4 (IRF4), a member of the IRF family of transcription factors, which has emerged as a crucial controller of both IL-17 and IL-21 production. We first outline the complex role of IRF4 in the function of CD4(+) T cells and then discuss recent studies from our laboratory that have revealed a surprising role for components of Rho GTPase-mediated pathways in controlling the activity of IRF4. A better understanding of these novel pathways will hopefully provide new insights into mechanisms responsible for the development of inflammatory arthritis and potentially guide the design of novel therapeutic approaches.

SUBMITTER: Biswas PS

PROVIDER: S-EPMC2920730 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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IRF4 and its regulators: evolving insights into the pathogenesis of inflammatory arthritis?

Biswas Partha S PS Bhagat Govind G Pernis Alessandra B AB

Immunological reviews 20100101 1

Accumulating evidence from murine and human studies supports a key role for interleukin-17 (IL-17) and IL-21 in the pathogenesis of inflammatory arthritis. The pathways and molecular mechanisms that underlie the production of IL-17 and IL-21 are being rapidly elucidated. This review focuses on interferon regulatory factor 4 (IRF4), a member of the IRF family of transcription factors, which has emerged as a crucial controller of both IL-17 and IL-21 production. We first outline the complex role o ...[more]

PMID: 20192994

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Project description:BackgroundJuvenile idiopathic arthritis (JIA) is an autoimmune joint disease that frequently co-occurs with other complex phenotypes, including cancers and other autoimmune diseases. Despite the identification of numerous risk variants through genome-wide association studies (GWAS), the affected genes, their connection to JIA pathogenesis, and their role in the development of associated traits remain unclear. This study aims to address these gaps by elucidating the gene-regulatory mechanisms underlying JIA pathogenesis and exploring its potential role in the emergence of associated traits.MethodsA two-sample Mendelian Randomization (MR) analysis was conducted to identify blood-expressed genes causally linked to JIA. A curated protein interaction network was subsequently used to identify sets of single-nucleotide polymorphisms (i.e., spatial eQTL SNPs) that regulate the expression of JIA causal genes and their protein interaction partners. These SNPs were cross-referenced against the GWAS catalog to identify statistically enriched traits associated with JIA.ResultsThe two-sample MR analysis identified 52 genes whose expression changes in the blood are putatively causal for JIA. These genes (e.g., HLA, LTA, LTB, IL6ST) participate in a range of immune-related pathways (e.g., antigen presentation, cytokine signalling) and demonstrate cell type-specific regulatory patterns across different immune cell types (e.g., PPP1R11 in CD4+ T cells). The spatial eQTLs that regulate JIA causal genes and their interaction partners were statistically enriched for GWAS SNPs linked with 95 other traits, including both known and novel JIA-associated traits. This integrative analysis identified genes whose dysregulation may explain the links between JIA and associated traits, such as autoimmune/inflammatory diseases (genes at 6p22.1 locus), Hodgkin lymphoma (genes at 6p21.3 [FKBPL, PBX2, AGER]), and chronic lymphocytic leukemia (BAK1).ConclusionOur approach provides a significant advance in understanding the genetic architecture of JIA and associated traits. The results suggest that the burden of associated traits may differ among JIA patients, influenced by their combined genetic risk across different clusters of traits. Future experimental validation of the identified connections could pave the way for refined patient stratification, the discovery of new biomarkers, and shared therapeutic targets.

Project description:BackgroundThe Trial of Early Aggressive Therapy in Juvenile Idiopathic Arthritis (TREAT trial) was accompanied by a once-in-a-generation sample collection for translational research. In this paper, we report the results of whole blood gene expression analyses and genomic data-mining designed to cast light on the immunopathogenesis of polyarticular juvenile idiopathic arthritis (JIA).MethodsTREAT samples and samples from an independent cohort were analyzed on Affymetrix microarrays and compared to healthy controls. Data from the independent cohort were used to validate the TREAT data. Pathways analysis was used to characterize gene expression profiles. Furthermore, we correlated differential gene expression with new information about functional regulatory elements within the genome to develop models of aberrant gene expression in JIA.ResultsThere was a strong concordance in gene expression between TREAT samples and the independent cohort. In addition, rheumatoid factor (RF)-positive and RF-negative patients showed only small differences on whole blood expression profiles. Analysis of the combined samples showed 158 genes represented by 176 probes that showed differential expression between TREAT subjects at baseline and healthy controls. None of the differentially expressed genes were encoded within linkage disequilibrium blocks containing single nucleotide polymorphisms known to be associated with risk for JIA. Functional analysis of these genes showed functional associations with multiple processes associated with innate and adaptive immunity, and appeared to reflect overall suppression of STAT1-3/interferon response factor-mediated pathways.ConclusionsDespite their limitations, whole blood expression profiles clearly distinguish children with polyarticular JIA from healthy controls. Whole blood expression profiles identify several immunologic pathways of biologic relevance that will need to be pursued in homogeneous cell populations in order to clarify mechanisms of pathogenesis.Trial registrationClinicalTrials.gov registry #NCT00443430 , originally registered 2 March 2007 and last updated 30 May 2013.

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IRF4 and its regulators: evolving insights into the pathogenesis of inflammatory arthritis?

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IRF4 and its regulators: evolving insights into the pathogenesis of inflammatory arthritis?

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