The PTPN22gain-of-function+1858T(+) genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis

Chuang, Wen-Yu; Ströbel, Philipp; Belharazem, Djeda; Rieckmann, Peter; Kv, Toyka; W, Nix; Schalke, Berthold; Gold, Ralf; Kiefer, Reinhard; Klinker, Erdwine; Opitz, Andreas; Inoue, Masayoshi; Tt, Kuo; Hk, Müller-Hermelink; Marx, Alexander

doi:10.1038/gene.2009.64

Cited by 37 publications

(29 citation statements)

References 27 publications

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“…Finally, polymorphisms of non-HLA genes that affect T cell receptor signaling (e.g. CTLA4, PTPN22) [86] appear to correlate with TAMG, possibly by impairing negative selection in thymomas [87][88][89]. The first next generation sequencing study of thymomas was not sufficiently powered to reveal MG-associated genetic alterations [90].…”

Section: Genetic Alterations In Thymomas and Genetic Associations In mentioning

confidence: 94%

Thymoma related myasthenia gravis in humans and potential animal models

Marx

Porubský

Belharazem

et al. 2015

Experimental Neurology

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Section: Genetic Alterations In Thymomas and Genetic Associations In mentioning

confidence: 94%

Thymoma related myasthenia gravis in humans and potential animal models

Marx

Porubský

Belharazem

et al. 2015

Experimental Neurology

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“…114 Case-control studies have also identified a strong association between PTPN22 C1858T and myasthenia gravis (MG). Metaanalysis of five studies 23,45,115,116 showed a significant association between the T allele and MG (OR ¼ 1.53; 95% CI ¼ 1.31-1.80, P ¼ 1.09 Â 10 À 07 ) ( Figure 2i). …”

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confidence: 99%

Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue

et al. 2012

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Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a strong susceptibility gene shared by many autoimmune diseases. The aim of this study was to explore the mechanisms underlying this relationship. We performed a comprehensive analysis of the association between PTPN22 polymorphism C1858T and autoimmune diseases. The results showed a remarkable pattern; PTPN22 C1858T was strongly associated with type I diabetes, rheumatoid arthritis, immune thrombocytopenia, generalized vitiligo with concomitant autoimmune diseases, idiopathic inflammatory myopathies, Graves' disease, juvenile idiopathic arthritis, myasthenia gravis, systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody-associated vasculitis and Addison's disease. By contrast, PTPN22 C1858T showed a negligible association with systemic sclerosis, celiac disease, multiple sclerosis, psoriasis, ankylosing spondylitis, pemphigus vulgaris, ulcerative colitis, primary sclerosing cholangitis, primary biliary cirrhosis, Crohn's disease and acute anterior uveitis. Further analysis revealed a clear distinction between the two groups of diseases with regard to their targeted tissues: most autoimmune diseases showing an insignificant association with PTPN22 C1858T manifest in skin, the gastrointestinal tract or in immune privileged sites. These results showed that the association of PTPN22 polymorphism with autoimmune diseases depends on the localization of the affected tissue, suggesting a role of targeted organ variation in the disease manifestations.

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“…Additionally, it could explain the unusual association of higher numbers of naive T cells in the periphery (4,52) with the development of thymoma-related autoimmune conditions such as myasthenia gravis (47) and giant cell myocarditis (1,2). A possible mechanism could be the failure of the negative selection, as suggested by observations in cases of a genetically determined T cell hyporesponsiveness due to the PTPN22 gain-of-function +1858T(+) genotypes (53). In summary, a CD247 defect, probably induced in the neoplastic thymic microenvironment, leads to the accumulation of naive, hyporesponsive gd and ab T cells in thymoma patient resulting in a novel type of acquired T cell immunodeficiency and immune dysregulation of clinical significance.…”

Section: Discussionmentioning

confidence: 99%

A Novel Thymoma-Associated Immunodeficiency with Increased Naive T Cells and Reduced CD247 Expression

Christopoulos

Dopfer

Malkovsky

et al. 2015

The Journal of Immunology

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The mechanisms underlying thymoma-associated immunodeficiency are largely unknown, and the significance of increased blood γδ Τ cells often remains elusive. In this study we address these questions based on an index patient with thymoma, chronic visceral leishmaniasis, myasthenia gravis, and a marked increase of rare γδ T cell subsets in the peripheral blood. This patient showed cutaneous anergy, even though he had normal numbers of peripheral blood total lymphocytes as well as CD4+ and CD8+ T cells. Despite his chronic infection, analyses of immunophenotypes and spectratyping of his lymphocytes revealed an unusual accumulation of naive γδ and αβ T cells, suggesting a generalized T cell activation defect. Functional studies in vitro demonstrated substantially diminished IL-2 and IFN-γ production following TCR stimulation of his “untouched” naive CD4+ T cells. Biochemical analysis revealed that his γδ and αβ T cells carried an altered TCR complex with reduced amounts of the ζ-chain (CD247). No mutations were found in the CD247 gene that encodes the homodimeric ζ protein. The diminished presence of CD247 and increased numbers of γδ T cells were also observed in thymocyte populations obtained from three other thymoma patients. Thus, our findings describe a novel type of a clinically relevant acquired T cell immunodeficiency in thymoma patients that is distinct from Good’s syndrome. Its characteristics are an accumulation of CD247-deficient, hyporresponsive naive γδ and αβ T cells and an increased susceptibility to infections.

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The PTPN22gain-of-function+1858T(+) genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis

Cited by 37 publications

References 27 publications

Thymoma related myasthenia gravis in humans and potential animal models

Thymoma related myasthenia gravis in humans and potential animal models

Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue

A Novel Thymoma-Associated Immunodeficiency with Increased Naive T Cells and Reduced CD247 Expression

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