ReviewPTPN22: Setting thresholds for autoimmunity
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.
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