Article

Unraveling the functional implications of GWAS: How T cell protein tyrosine phosphatase drives autoimmune disease

Division of Rheumatology, Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, UCSF, San Francisco, California, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 11/2011; 121(12):4618-21. DOI: 10.1172/JCI60001
Source: PubMed

ABSTRACT

Genome-wide association studies (GWAS) have identified a large number of SNPs that are linked to human autoimmune diseases. However, the functional consequences of most of these genetic variations remain undefined. T cell protein tyrosine phosphatase (TCPTP, which is encoded by PTPN2) is a JAK/STAT and growth factor receptor phosphatase that has been linked to the pathogenesis of type 1 diabetes, rheumatoid arthritis, and Crohn's disease by GWAS. In this issue of the JCI, Wiede and colleagues have generated a T cell-specific deletion of TCPTP and identified a novel role for this phosphatase as a negative regulator of TCR signaling. These data provide new insight as to how noncoding PTPN2 SNPs identified in GWAS could drive human autoimmune diseases.

Download full-text

Full-text

Available from: Arthur Weiss, Jun 30, 2014
  • Source
    • "PTPN2 encodes for the ubiquitously expressed T cell protein tyrosine phosphatase (TCPTP), a JAK/STAT and growth factor receptor phosphatase that has been linked with the pathogenesis of type 1 diabetes mellitus, rheumatoid arthritis and Crohn’s disease by GWAS findings of non-coding SNP associations. Mouse and human studies have shown that reduced expression of TCPTP may drive autoimmune pathologies by enhancing signalling downstream of the T cell receptor (TCR), cytokines, or growth factors to produce a pro-inflammatory cytokine milieu [65]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction Our objective was to utilise network analysis to identify protein clusters of greatest potential functional relevance in the pathogenesis of oligoarticular and rheumatoid factor negative (RF-ve) polyarticular juvenile idiopathic arthritis (JIA). Methods JIA genetic association data were used to build an interactome network model in BioGRID 3.2.99. The top 10% of this protein:protein JIA Interactome was used to generate a minimal essential network (MEN). Reactome FI Cytoscape 2.83 Plugin and the Disease Association Protein-Protein Link Evaluator (Dapple) algorithm were used to assess the functionality of the biological pathways within the MEN and to statistically rank the proteins. JIA gene expression data were integrated with the MEN and clusters of functionally important proteins derived using MCODE. Results A JIA interactome of 2,479 proteins was built from 348 JIA associated genes. The MEN, representing the most functionally related components of the network, comprised of seven clusters, with distinct functional characteristics. Four gene expression datasets from peripheral blood mononuclear cells (PBMC), neutrophils and synovial fluid monocytes, were mapped onto the MEN and a list of genes enriched for functional significance identified. This analysis revealed the genes of greatest potential functional importance to be PTPN2 and STAT1 for oligoarticular JIA and KSR1 for RF-ve polyarticular JIA. Clusters of 23 and 14 related proteins were derived for oligoarticular and RF-ve polyarticular JIA respectively. Conclusions This first report of the application of network biology to JIA, integrating genetic association findings and gene expression data, has prioritised protein clusters for functional validation and identified new pathways for targeted pharmacological intervention.
    Full-text · Article · May 2014 · Arthritis Research & Therapy
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent genome-wide association studies identified single nucleotide polymorphisms within gene loci, encoding autophagy genes, e.g. the autophagy-related 16-like 1 (ATG16L1) and the immunity-related GTPase family M (IRGM), as an important risk factor for the onset of chronic inflammatory diseases such as Crohn's disease (CD) or rheumatoid arthritis. CD is characterized by a breakdown of the intestinal epithelial barrier function leading to an overwhelming and uncontrolled immune response to bacterial antigens. Autophagy, and therefore ATG16L1 and IRGM, are critically involved in the innate immune response to invading pathogens. Dysfunction of these molecules results in the increased survival of intracellular bacteria, defective antigen presentation and proinflammatory cytokine secretion. Interestingly, autophagy can also be regulated by other CD susceptibility genes, such as nucleotide oligomerization domain 2 or protein tyrosine phosphatase nonreceptor type 2, and the presence of the CD-associated variations within these genes results in comparable effects. ATG16L1 also plays a crucial role in maintaining Paneth cell function and morphology, while IRGM seems to be associated with mitochondrial function and apoptosis. Dysfunction of these molecules, i.e. of autophagy in vivo, is clearly associated with the increased bacterial infection and the onset of colitis. Interestingly, the phenotype of aberrant Paneth cells and dextran sodium sulphate-induced colitis in ATG16L1 hypomorphic mice closely resembles human CD. Taken together, the available data strongly suggest an important role for autophagy in maintaining intestinal homeostasis, and dysfunction of autophagy seems to be a major risk factor for the onset of chronic intestinal inflammation.
    Preview · Article · Jan 2012 · Digestive Diseases
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Autoimmune diseases represent a heterogeneous group of conditions whose incidence is increasing worldwide. This has stimulated studies on their etiopathogenesis, derived from a complex interaction between genetic and environmental factors, aimed at finally improving prevention and treatment of these diseases. In the autoimmune process, immune responses are generated against self antigens presented by Major Histocompatibility Complex (MHC) class I on the cell surface. These peptide/MHC class I complexes are generated and assembled through MHC class I antigen processing and presentation machinery. In the endoplasmic reticulum (ER), aminopeptidases ERAP1 and ERAP2 display distinct trimming activity before antigenic peptides are loaded onto MHC class I molecules. The advent of new tools such as genome-wide association studies (GWAS) has provided evidence for new susceptibility loci and candidate genes playing a role in the autoimmune process for the recognized immune function of their transcripts. Genetic linkage has been discovered with MHC antigens and various autoimmune conditions. Recent GWAS showed the importance of ERAP1 and ERAP2 in several autoimmune diseases, including ankylosing spondylitis, insulin-dependent diabetes mellitus, psoriasis, multiple sclerosis, Crohn's disease. In this review, we first provide a general overview of ERAP1 and ERAP2 genes, their biological functions and their relevancy in autoimmunity. We then discuss the importance of GWAS and the case-control studies that confirm the relevancy of ERAP single-nucleotide polymorphism associations and their linkage with particular MHC class I haplotypes, supporting a putative functional role in the autoimmune process.
    Full-text · Article · May 2012 · Autoimmunity reviews
Show more