Editors' ChoiceAutoimmunity

PTPN22: A Risky Business

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Science Translational Medicine  24 Aug 2011:
Vol. 3, Issue 97, pp. 97ec134
DOI: 10.1126/scitranslmed.3003064

Genome-wide association studies (GWASs) identify common genetic variants that alter disease risk but often leave one guessing about the causal link between these variants and disease. In multiple large GWAS analyses, the PTPN22 gene encoding protein tyrosine phosphatase nonreceptor type 22 has been associated with increased risk for several autoimmune diseases, including rheumatoid arthritis, type 1 diabetes, and systemic lupus erythematosus. Now, Menard et al. provide insight into the mechanism by which the major risk allele of PTPN22 could contribute to autoimmunity.

The major risk allele encodes an R620W amino acid change that has been shown to result in a gain-of-function in PTPN22 activity, leading to decreased signaling though both the T cell and B cell receptors. To get at the origins of disease risk, Menard and colleagues examined the impact of the PTPN22 R620W variant in healthy donors. By examining both newly emigrant and mature naïve B cell clones from healthy donors carrying one or two PTPN22 risk alleles, they found that individuals carrying even a single copy of the variant showed increased numbers of autoreactive B cells and an increase in autoantibodies to self-antigens such as insulin and double-stranded DNA. Thus, a dominant effect of the R620W variant is to impair the removal of autoreactive B cells during normal B cell development and maturation, setting the stage for the future onset of autoimmune disease. The increase in self-reactive B cells among R620W carriers was comparable with that seen in patients with type 1 diabetes and rheumatoid arthritis, suggesting a similar breakdown in the checkpoints that maintain immune tolerance and prevent autoimmune disease. Moreover, compared with the naïve B cells of healthy donors who do not carry the PTPN22 R620W variant, naïve B cells from carriers exhibited enhanced responses upon B cell activation and a gene expression profile favoring B cell activation and proliferation. Menard et al. conclude that the PTPN22 R620W variant leads to the generation and survival of autoreactive B cells that may cause autoimmunity directly through B cell activation or indirectly through presentation of antigen to T cells.

This elegant human cellular immunology study defines one mechanism for how a major PTPN22 risk variant could contribute to autoimmunity. Further investigation is needed into the direct action of the R620W variant on B cell signaling and its role in other immune cells. Because the R620W variant is relatively common in northern Europe, therapies targeting PTPN22 could have a wide impact on many autoimmune conditions and may allow earlier interventions in at-risk individuals.

L. Menard et al., The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J. Clin. Invest. 1 August 2011 (10.1172/JCI45790). [Abstract]

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