Elsevier

Seminars in Immunology

Volume 18, Issue 4, August 2006, Pages 207-213
Seminars in Immunology

Review
Role of PTPN22 in type 1 diabetes and other autoimmune diseases

https://doi.org/10.1016/j.smim.2006.03.008Get rights and content

Abstract

We recently discovered that a single-nucleotide polymorphism (SNP) in the lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene on chromosome 1p13, correlates strongly with the incidence of type 1 diabetes (T1D) in two independent populations. This findings has now been verified by numerous studies and it has been expanded to rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, Graves’ disease, generalized vitiligo and other autoimmune disease. Here we review the genetics of the SNP and its association with autoimmunity, discuss the function of the phosphatase in signaling, the biochemistry of the disease-predisposing allele, and the possible mechanisms by which PTPN22 contributes to the development of human disease.

Introduction

Type 1 diabetes (T1D) is a common autoimmune disease of complex etiology, characterized by an autoimmune attack against insulin-producing pancreatic β-cells [1]. The disease is more likely to occur in relatives of an affected person and shows a rapid fall-off in risk with decreased genetic relatedness to affected individuals. Still, the empirical risk for a monozygotic twin of an affected patient is about 50%, thus considerably less than 100%. All together, these data, and the increasing incidence of the disease in many countries over the last 40 years, indicate that disease risk depends on the complex interplay between several co-inherited susceptibility alleles interspersed throughout the genome as well as unknown environmental factors. Indeed, the strong and polygenic component of T1D has been supported by the identification of susceptibility alleles in the HLA class II, insulin (INS), CTLA-4, and PTPN22 loci, and many as yet unidentified variants are also required to completely explain disease inheritance [2], [3].

T cells of both CD4 and CD8 subpopulations play key roles in the autoimmune destruction of β-islet cells in T1D [4]. The development and differentiation of T cells, as well as their effector functions, are finely controlled by the activation of several intracellular signaling pathways in response to triggering of the T cell receptor (TCR) and receptors for co-stimulatory molecules [5], [6]. Anomalies in TCR signaling pathways can result in autoimmunity, trough effects on T cell proliferation, apoptosis, cytoskeletal changes, cytokine production, differentiation, or anergy, to mention only few of the processes regulated by the TCR in thymic and peripheral T cells [7]. TCR signaling is therefore the object of much investigation in T1D and other autoimmune diseases. In the non-obese diabetic (NOD) mouse model of T1D several investigators have reported that peripheral T cells are hyporesponsive to TCR engagement [8], [9], [10], [11]. This phenotype appears early in the course of the disease, and appears to have pathogenic relevance. Anomalies in TCR signaling in peripheral T cells from human patients with T1D have been also reported [12], [13], although this kind of studies in humans are complicated by the different genetic background of different individuals, which tends to increase the noise-to-signal ratio. Genetic studies of human diabetes also point to an important role of T cell signaling in the etio-pathogenesis of T1D. For example, the gene for the inhibitory T cell molecule CTLA-4 has been isolated as a candidate gene for T1D and other organ-specific autoimmunity [14].

Section snippets

The association of PTPN22 with autoimmune disease

We recently discovered that a single-nucleotide polymorphism (SNP) in the lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene on chromosome 1p13, correlates strongly with the incidence of type 1 diabetes (T1D) in two independent populations [15]. Within a year of our paper, other studies had confirmed our finding in additional large population samples [16], [17], [18], [19]. An association of the same SNP in PTPN22 was also discovered with rheumatoid arthritis (RA) [20] in the North

Structure and function of PTPN22

PTPN22 is located on chromosome 1p13.3–13.1 and encodes a 807-amino acid residue protein referred to as the lymphoid tyrosine phosphatase (LYP) [40]. The mouse ortholog was isolated in 1992 under the name PEST-enriched phosphatase (PEP) [41] and was given the genomic designation PTPN8. The designation of the human and mouse orthologs as different genes was based on uncertainty whether they were orthologs or not, because they display a lower degree of identity than what signaling molecules

Biochemistry of the disease-predisposing LYP*W620

The autoimmunity-predisposing allele of PTPN22 is a missense C–T mutation at position 1858, which changes amino acid residue 620 from Arg (R) to Trp (W) in the encoded LYP protein. We became interested in this SNP because R620 is a critical residue in the Pro-rich motif in LYP that binds the SH3 domain of Csk [42], [43]. Indeed, the LYP*W620 protein fails to bind Csk [15]. Since both LYP and Csk are crucial gatekeepers of T cell antigen receptor (TCR) signaling, we had expect that the threshold

Possible mechanisms by which LYP*W620 may produce autoimmunity

Based on the observation that LYP*W620 is a gain-of-function variant, our working hypothesis postulates that LYP*W620 predisposes to autoimmune disease because it suppresses TCR signaling more efficiently during thymic development, resulting in the survival of autoreactive T cells that would have been deleted by negative selection in individuals of C1858/C1858 (*R620/*R620) genotype (Fig. 2). This would explain why the susceptibility variant is dominant and not recessive, i.e. heterozygous

Acknowledgements

This work was supported by a fellowship from the Norwegian Cancer Society (to TV) and by grants from the Juvenile Diabetes Research Foundation (1-2005-342 to NB), Telethon-JDRF (GJT 030477 to FC), and the US National Institutes of Health (AI53585 to TM).

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