Genetic Variation in PTPN22 Corresponds to Altered Function of T and B Lymphocytes

University of Washington Seattle, Seattle, Washington, United States
The Journal of Immunology (Impact Factor: 4.92). 11/2007; 179(7):4704-10. DOI: 10.4049/jimmunol.179.7.4704
Source: PubMed


A variant of the PTPN22 gene, 1858C/T, is associated with an increased risk for the development of a wide array of autoimmune disorders. It is known that the protein tyrosine phosphatase Lyp encoded by this gene has an inhibitory effect on the proximal TCR signaling pathways. However, the consequences of carrying this variant and the mechanism by which it contributes to the development of autoimmunity are poorly understood. In this study, we demonstrate that homozygosity for this variant results in a profound deficit in T cell responsiveness to Ag stimulation. Heterozygosity for the variant allele is associated with reduced responsiveness of CD4+ memory T cells, characterized by diminished calcium mobilization, expression of CD25, and IL-10 production upon TCR stimulation. Additionally, the presence of the variant allele is associated with an increase in circulating memory T cells. We further demonstrate that these effects are not limited to the T cell compartment. Individuals with the variant allele have fewer memory B cells and these cells display a reduced response to stimulation via the BCR indicative of a B cell intrinsic defect. By identifying an immunologic phenotype in healthy subjects which correlates with the PTPN22 1858C/T genotype, we can now explore specific hypotheses regarding pathogenesis of diseases associated with the PTPN22 1858T variant.

Download full-text


Available from: Mary Rieck, Nov 18, 2015
    • "This R620W conversion is located in protein motif thought to be required for proteineprotein interaction [44]. Elegant studies have shown that the mutant (risk) allele results in decreased TCR and BCR signalling in lymphocytes [45] (reviewed recently by Rawlings et al. and by Burn et al. [46] [47]). Interestingly, in mice, the homologous R620W variant in PTPN22 known as R619W located in Ptpn22 reduced protein levels of Ptpn22 and was shown to manifest in thymic and splenic enlargements [44] [48]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The last decade has seen a dramatic technological revolution. The characterisation of the majority of the common variations in our genetic code in 2003 precipitated the discovery of the genetic risk factors predisposing to Rheumatoid Arthritis development and progression. Prior to 2007, only a handful of genetic risk factors had been identified, HLA, PTPN22 and CTLA4. Since then, over 100 genetic risk loci have been described, with the prediction that an ever-increasing number of risk alleles with consistently decreasing effect sizes will be discovered in the years to come. Each risk locus harbours multiple candidate genes and the proof of causality of each of these candidates is as yet unknown. An enrichment of these RA-associated genes is found in three pathways: T-cell receptor signalling, JAK-STAT signalling and the NF-κB signalling cascade, and currently drugs targeting these pathways are available for the treatment of RA. However, the role that RA-associated genes have in these pathways and how they contribute to disease is not always clear. Major efforts in understanding the contribution of genetic risk factors are currently under way with studies querying the role of genetic variation in gene expression of coding and non-coding genes, epigenetic marks and other regulatory mechanisms yielding ever more valuable insights into mechanisms of disease. Recent work has suggested a possible enrichment of non-coding RNAs as well as super-enhancers in RA genetic loci indicating possible new insights into disease mechanism. This review brings together these emerging genetic data with an emphasis on the immunogenetic links these findings have provided and what we expect the future will bring. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Jul 2015 · Journal of Autoimmunity
  • Source
    • "Loss of PTPN22 on the B6 background results in accumulation of memory T cells and increased germinal centers and serum IgG although these mice do not exhibit more autoantibodies or autoimmunity, possibly due to increased Treg numbers and function, or the lack of other factors that contribute to autoimmune disease [4] [16] [17]. Studies have suggested a role for PTPN22 in B cell signaling [18] [19] [20] [21] [22], although the extent to which this may be a consequence of increased T cell help is unresolved [4] [23]. Recently a novel, non-phosphatase role for PTPN22 in myeloid cell activity has been described downstream of TLR signaling which is necessary for efficient type I IFN production [24]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A single nucleotide polymorphism in PTPN22 is linked to increased disease susceptibility in a range of autoimmune diseases including systemic lupus erythematosus (SLE). PTPN22 encodes the Lyp phosphatase that dampens TCR signaling and is necessary for signaling downstream of toll-like receptors in myeloid cells. To understand these dual functions in disease, we examined the impact of deficiency in PTPN22 on a spontaneous murine model of SLE. Male PTPN22 KO mice carrying BXSB chromosome 1 and the Yaa disease accelerating factor developed disease at a similar rate and severity as PTPN22 WT. In contrast, although female mice showed no differences in survival in the absence of PTPN22, autoantibody production was significantly increased and splenic populations associated with pathogenesis in this model were expanded in the PTPN22 KO group. These findings support the notion that when coupled with other predisposing autoimmunity genes, PTPN22 deficiency contributes to a predisposition to lupus pathogenesis.
    Full-text · Article · Nov 2014 · Clinical Immunology
  • Source
    • "PTPN22 is a negative regulator of T cell activation via its dephosphorylation of the activating tyrosines of Lck, Fyn, and ZAP-70, as well as phosphorylation sites on TCRζ, CD3ε, Vav, and valosin-containing protein [85]. The W620 variant of PTPN22 results in a dominant gain of inhibitory function in T cells [86], leading to a reduced response to TCR stimulation [87]. In addition, the W620 variant of PTPN22 impairs B cell signaling [88]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Myasthenia Gravis (MG) is a paradigm of organ-specific autoimmune disease (AID). It is mediated by antibodies that target the neuromuscular junction. The purpose of this review is to place MG in the general context of autoimmunity, to summarize the common mechanisms between MG and other AIDs, and to describe the specific mechanisms of MG. We have chosen the most common organ-specific AIDs to compare with MG: type 1 diabetes mellitus (T1DM), autoimmune thyroid diseases (AITD), multiple sclerosis (MS), some systemic AIDs (systemic lupus erythematous (SLE), rheumatoid arthritis (RA), Sjogren's syndrome (SS)), as well as inflammatory diseases of the gut and liver (celiac disease (CeD), Crohn's disease (CD), and primary biliary cirrhosis (PBC)). Several features are similar between all AIDs, suggesting that common pathogenic mechanisms lead to their development. In this review, we address the predisposing factors (genetic, epigenetic, hormones, vitamin D, microbiota), the triggering components (infections, drugs) and their interactions with the immune system 1 and 2. The dysregulation of the immune system is detailed and includes the role of B cells, Treg cells, Th17 and cytokines. We particularly focused on the role of TNF-α and interferon type I whose role in MG is very analogous to that in several other AIDS. The implication of AIRE, a key factor in central tolerance is also discussed. Finally, if MG is a prototype of AIDS, it has a clear specificity compared to the other AIDS, by the fact that the target organ, the muscle, is not the site of immune infiltration and B cell expansion, but exclusively that of antibody-mediated pathogenic mechanisms. By contrast, the thymus in the early onset subtype frequently undergoes tissue remodeling, resulting in the development of ectopic germinal centers surrounded by high endothelial venules (HEV), as observed in the target organs of many other AIDs.
    Full-text · Article · Aug 2014 · Journal of Autoimmunity
Show more