Elsevier

Seminars in Immunology

Volume 18, Issue 4, August 2006, Pages 214-223
Seminars in Immunology

Review
PTPN22: Setting thresholds for autoimmunity

https://doi.org/10.1016/j.smim.2006.03.009Get rights and content

Abstract

The 620W allelic variant of the intracellular tyrosine phosphatase, PTPN22, is associated with a number of different autoimmune disorders, and this provides direct evidence for common mechanisms underlying many of these diseases. The associated allele appears to influence thresholds for T cell receptor signaling, and a variety of disease models involving both central and peripheral tolerance can be proposed. However, given the fact that PTPN22 is expressed in a variety of immunologically relevant cell types, the precise mechanisms for these associations remain unclear. In general, the PTPN22 620W allele appears to play a role in autoimmune disorders that have a prominent humoral component, suggesting that further investigation of PTPN22 activity in B cells will be useful. From a genetic perspective, the data highlights the genetic heterogeneity underlying autoimmunity in different ethnic groups.

Introduction

In their clinical heterogeneity and complexity of pathogenesis, autoimmune disorders present a challenging and fascinating problem for clinicians, immunologists, geneticists, and molecular and cellular biologists. Despite the diversity of phenotypes, the prevailing view holds that abnormalities of self-non-self discrimination constitute a common underlying feature of autoimmune diseases. While this is a useful and apparently simple conceptual paradigm, it reassuringly disguises the fact that we still have a very incomplete understanding of the complex mechanisms that exist at multiple levels for fine-tuning immune responses and controlling self-reactivity. Autoimmune phenomena per se are clearly not abnormal, as they can be observed in all normal subjects. Autoantibodies can be present without obvious clinical disease, and although they may precede clinical autoimmunity, the events that are responsible for the transition to clinical disease do not always occur, and their nature remains murky. This is consistent with a multistage process of disease development, and suggests that quantitative as well as qualitative differences in the immune response are an important feature of autoimmune disease pathogenesis.

Studies in the mouse have led to many conceptual advances in understanding immune regulation, and murine disease models have provided an essential tool for testing these concepts as they may apply to human disease phenotypes. Immunological studies in humans have tended to be much more descriptive, where cause and effect usually cannot be directly tested. One exception to this is the study of the genetic basis of human autoimmunity, since genetic effects must necessarily be “upstream” of the biology. In addition, while various “knock out” and “knock in” genetic effects can be explored in animal models to examine disease pathways, it is often difficult to assess their relevance to human conditions. In this respect, the study of human genetics, difficult as it is, may present a more direct line to understanding the molecular basis of autoimmunity. The discovery of the association of a missense SNP in the hematopoietic-specific protein tyrosine phosphastase, PTPN22, with multiple human autoimmune diseases exemplifies the potential for human genetics to provide focus and direction toward understanding the underlying mechanisms of these complex disorders.

Section snippets

The PTPN22 620W allele is associated with multiple autoimmune disorders

The many PTPN22 associations with human autoimmune diseases are striking in their reproducibility and their restriction to certain disorders. Taking a candidate gene approach, Bottini et al. were the first to publish an association of the PTPN22 620W allele with type 1 diabetes in two populations [1]. Working independently, and using a more exploratory approach based in part on previous linkage information [2], Begovich et al. followed with a report showing a similar association with rheumatoid

Ethnic diversity of PTPN22 allelic variation and the search for additional risk alleles

An interesting feature of the PTPN22 R620W (C1856T) polymorphism is the wide variation of allele frequency among different populations. First, as shown in Fig. 1, there is a gradient of increasing frequency in white European populations. The 1858T allele is found in 2–3% of Italian and Sardinian populations, 7–8% of Western Europeans, and typically >10% of Scandinavians reaching 15% in Finns. In most European–American population samples, allele frequencies in the range of 8–9% are typical,

PTPN22 biochemistry and regulation of T cell receptor signaling

It is now well established that one function of PTPN22 is negative regulation of T cell receptor signaling [31], [32]. This activity appears to reflect in part the result of PTPN22 phosphatase activity directed at removing the activating phosphate at tyrosine 394 of the tyrosine kinase, Lck. Knockout of PEP (the murine homolog of PTPN22) in a C57/Bl6 background results in increased phosphorylation of Lck in T cells, and leads to a phenotype of chronic T cell proliferation and expansion,

Increased thresholds for TCR signaling and modeling risk for autoimmunity

The first direct demonstration of clonal deletion in the thymus by Kappler and Marrack [36] has ushered in an era of elegant experiments in the mouse that clearly demonstrate the importance of quantitative parameters on the outcome of thymic selection of the peripheral T cell repertoire. Furthermore, it is now clear that tolerance to tissue-specific antigens is regulated centrally as well as peripherally, and these tolerance mechanisms depend on the level of expression of these self-antigens

PTPN22 expression and function in non-T cells

The expression and distribution of PTPN22 in subsets of hematopoietic cells is somewhat variable. Begovich et al. reported increased amounts of PTPN22 in both neutrophils and NK cells compared with T and B lymphocytes [3]. We have recently confirmed the increased expression of PTPN22 in NK cells compared with T cells by RNAse protection assays, using probes in the catalytic domain as well as the 3′ region of PTPN22 (data not shown). There is one report of Lyp-2, a splice variant of PTPN22

Conclusion

The discovery of the PTPN22 associations with multiple human autoimmune disorders is a gratifying validation of the hypothesis that common genes, and common pathways, underlie many autoimmune disorders, even though the specific clinical phenotypes are quite diverse. The effects of the PTPN22 620W variant on signaling thresholds in T cells is clearly an important mechanism, but it seems likely that this allele will have effects on other cell types as well, and these may also contribute to

Acknowledgements

PKG is supported by the National Institute of Arthritis Musculoskeletal and Skin Diseases (NAIMS) RO1-AR-44422 and NO1-AR2-2263 and by the National Arthritis Foundation. Support has also been generously provided by the Eileen Ludwig Greenland Center for Rheumatoid Arthritis.

References (62)

  • S. Cohen et al.

    Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase

    Lyp Blood

    (1999)
  • R.M. Plenge et al.

    Replication of putative candidate-gene associations with rheumatoid arthritis in >4000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4

    Am J Hum Genet

    (2005)
  • B. Rueda et al.

    C1858T functional variant of PTPN22 gene is not associated with celiac disease genetic predisposition

    Hum Immunol

    (2005)
  • I. Nistor et al.

    Protein tyrosine phosphatase gene PTPN22 polymorphism in psoriasis: lack of evidence for association

    J Invest Dermatol

    (2005)
  • M.B. Ladner et al.

    Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes

    Hum Immunol

    (2005)
  • N. Bottini et al.

    A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes

    Nat Genet

    (2004)
  • D. Jawaheer et al.

    Screening the genome for rheumatoid arthritis susceptibility genes: a replication study and combined analysis of 512 multicase families

    Arthritis Rheum

    (2003)
  • M.R. Velaga et al.

    The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves’ disease

    J Clin Endocrinol Metab

    (2004)
  • D. Smyth et al.

    Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus

    Diabetes

    (2004)
  • A. Skorka et al.

    Lymphoid tyrosine phosphatase (PTPN22/LYP) variant and Graves’ disease in a Polish population: association and gene dose-dependent correlation with age of onset

    Clin Endocrinol (Oxf)

    (2005)
  • C. Vandiedonck et al.

    Association of the PTPN22*R620W polymorphism with autoimmune myasthenia gravis

    Ann Neurol

    (2006)
  • F. Matesanz et al.

    Protein tyrosine phosphatase gene (PTPN22) polymorphism in multiple sclerosis

    J Neurol

    (2005)
  • P.L. De Jager et al.

    Evaluating the role of the 620W allele of protein tyrosine phosphatase PTPN22 in Crohn's disease and multiple sclerosis

    Eur J Hum Genet

    (2006)
  • M. van Oene et al.

    Association of the lymphoid tyrosine phosphatase R620W variant with rheumatoid arthritis, but not Crohn's disease, in Canadian populations

    Arthritis Rheum

    (1993-)
  • A. Zhernakova et al.

    Differential association of the PTPN22 coding variant with autoimmune diseases in a Dutch population

    Genes Immun

    (2005)
  • M.C. Martin et al.

    The functional genetic variation in the PTPN22 gene has a negligible effect on the susceptibility to develop inflammatory bowel disease

    Tissue Antigens

    (2005)
  • N.J. Prescott et al.

    A general autoimmunity gene (PTPN22) is not associated with inflammatory bowel disease in a British population

    Tissue Antigens

    (2005)
  • A. Hinks et al.

    Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthritis in a UK population: further support that PTPN22 is an autoimmunity gene

    Arthritis Rheum

    (2005)
  • I. Canton et al.

    A single-nucleotide polymorphism in the gene encoding lymphoid protein tyrosine phosphatase (PTPN22) confers susceptibility to generalised vitiligo

    Genes Immun

    (2005)
  • H. Kahles et al.

    Sex-specific association of PTPN22 1858T with type 1 diabetes but not with Hashimoto's thyroiditis or Addison's disease in the German population

    Eur J Endocrinol

    (2005)
  • M.F. Seldin et al.

    Finnish case–control and family studies support PTPN22 R620W polymorphism as a risk factor in rheumatoid arthritis, but suggest only minimal or no effect in juvenile idiopathic arthritis

    Genes Immun

    (2005)
  • Cited by (210)

    • Systemic Lupus Erythematosus

      2017, The Heart in Rheumatic, Autoimmune and Inflammatory Diseases: Pathophysiology, Clinical Aspects and Therapeutic Approaches
    • Genetics of Rheumatic Diseases

      2016, Kelley and Firestein's Textbook of Rheumatology: Volumes 1-2, Tenth Edition
    View all citing articles on Scopus
    View full text