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

Translational Research Program, Benaroya Research Institute, Virginia Mason, Seattle, WA 98101, USA.
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.

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    • "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]. "
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    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.
    Clinical Immunology 11/2014; 156(1). DOI:10.1016/j.clim.2014.11.003 · 3.67 Impact Factor
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    • "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]. "
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    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.
    Journal of Autoimmunity 08/2014; 52. DOI:10.1016/j.jaut.2014.05.001 · 8.41 Impact Factor
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    • "Our results also revealed that the production of IL-10 from individuals carrying the rs2488457 CC genotype was significantly decreased compared to CG and GG carriers. A similar association of the 1858C/T polymorphism with a decreased IL-10 production has been demonstrated in a previous study [41]. The report showed that IL-10 gene knockout mice develop autoimmune disease which indicated that IL-10 played a critical role in autoimmunity [42]. "
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    ABSTRACT: Protein tyrosine phosphatase non-receptor 22 (PTPN22) is a key negative regulator of T lymphocytes and has emerged as an important candidate susceptibility factor for a number of immune-related diseases. This study aimed to examine the predisposition of PTPN22 SNPs to Vogt-Koyanagi-Harada (VKH) syndrome and acute anterior uveitis (AAU) associated with ankylosing spondylitis (AS). A total of 1005 VKH syndrome, 302 AAU+AS+ patients and 2010 normal controls among the Chinese Han population were enrolled in the study. Genotyping, PTPN22 expression, cell proliferation, cytokine production and cell activation were examined by PCR-RFLP, Real-time PCR, CCK8, ELISA and Flow cytometry. The results showed significantly increased frequencies of the rs2488457 CC genotype and C allele but a decreased frequency of the GG genotype in VKH syndrome patients (PBonferroni correction (Pc) = 3.47×10-7, OR = 1.54; Pc = 3.83×10-8, OR = 1.40; Pc = 6.35×10-4, OR = 0.62; respectively). No significant association of the tested SNPs with AAU+AS+ patients was observed. Functional studies showed a decreased PTPN22 expression, impaired cell proliferation and lower production of IL-10 in rs2488457 CC cases compared to GG cases (Pc = 0.009, Pc = 0.015 and Pc = 0.048 respectively). No significant association was observed concerning T cell activation and rs2488457 genotype. The study showed that a functional variant of PTPN22 confers risk for VKH syndrome but not for AAU+AS+ in a Chinese Han population, which may be due to a modulation of the PTPN22 expression, PBMC proliferation and IL-10 production.
    PLoS ONE 05/2014; 9(5):e96943. DOI:10.1371/journal.pone.0096943 · 3.23 Impact Factor
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