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  • Review Article
  • Published:

PTPN22: the archetypal non-HLA autoimmunity gene

Nature Reviews Rheumatology volume 10, pages 602–611 (2014)Cite this article

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This article has been updated

Key Points

  • PTPN22 encodes a protein tyrosine phosphatase that inhibits antigen-receptor signalling in T cells and promotes pattern-recognition receptor-induced type I interferon production by myeloid cells

  • PTPN22 1858C>T is a risk factor for connective tissue autoimmune diseases, including rheumatoid arthritis (RA), juvenile idiopathic arthritis, psoriatic arthritis, systemic lupus erythematosus, systemic sclerosis and some forms of vasculitis

  • In white populations, PTPN22 1858C>T is the most important non-HLA genetic risk factor for RA and the second most important for juvenile idiopathic arthritis

  • Individuals with PTPN22 1858T are more likely to develop RA with seropositivity for anti-citrullinated protein antibodies or rheumatoid factor, and have this disease at an earlier age than those without the variant

  • Interactions between the protein encoded by PTPN22 1858T and tyrosine-protein kinase CSK are impaired, the functional consequences of which are still under investigation

  • Autoimmune pathogenesis promoted by PTPN22 1858C>T probably involves the differentiation of T-cell subsets, the B-cell repertoire and the balance between immunoregulatory and proinflammatory cytokine production

Abstract

PTPN22 encodes a tyrosine phosphatase that is expressed by haematopoietic cells and functions as a key regulator of immune homeostasis by inhibiting T-cell receptor signalling and by selectively promoting type I interferon responses after activation of myeloid-cell pattern-recognition receptors. A single nucleotide polymorphism of PTPN22, 1858C>T (rs2476601), disrupts an interaction motif in the protein, and is the most important non-HLA genetic risk factor for rheumatoid arthritis and the second most important for juvenile idiopathic arthritis. PTPN22 exemplifies a shared autoimmunity gene, affecting the pathogenesis of systemic lupus erythematosus, vasculitis and other autoimmune diseases. In this Review, we explore the role of PTPN22 in autoimmune connective tissue disease, with particular emphasis on candidate-gene and genome-wide association studies and clinical variability of disease. We also propose a number of PTPN22-dependent functional models of the pathogenesis of autoimmune diseases.

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Figure 1: Variants of human PTPN22.
Figure 2: PTPN22 regulation of cell signalling.
Figure 3: Models of PTPN22-regulated autoimmune disease.

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Change history

  • 22 July 2014

    In the original version of this article published online, the text for the section entitled 'Psoriatic arthritis' was missing. This omission has now been corrected in the HTML and PDF versions of the article.

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Acknowledgements

N.B. is supported by an NIH grant (NIH R01AI070544). S.M.S. is supported by a postdoctoral fellowship from the Juvenile Diabetes Research Foundation. The authors are grateful to M. Bottini for help with image preparation. This is manuscript #1684 from the La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.

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  1. Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, 92037, CA, USA

    Stephanie M. Stanford & Nunzio Bottini

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N.B. and S.M.S. contributed equally to researching data for the article, discussing its content, writing the article and to the review and/or editing of the manuscript before submission.

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Correspondence to Nunzio Bottini.

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Stanford, S., Bottini, N. PTPN22: the archetypal non-HLA autoimmunity gene. Nat Rev Rheumatol 10, 602–611 (2014). https://doi.org/10.1038/nrrheum.2014.109

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