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Cutting Edge: The PTPN22 Allelic Variant Associated with Autoimmunity Impairs B Cell Signaling¹

Adrian F. Arechiga^2,*, Tania Habib^2,*, Yantao He, Xian Zhang, Zhong-Yin Zhang, Andrew Funk^* and Jane H. Buckner^3,*

^* Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101; and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis IN 46202

PTPN22 is a gene encoding the protein tyrosine phosphatase Lyp. A missense mutation changing residue 1858 from cytosine to thymidine (1858C/T) is associated with multiple autoimmune disorders. Studies have demonstrated that Lyp has an inhibitory effect on TCR signaling; however, the presence of autoantibodies in all of the diseases associated with the 1858T variant and recent evidence that Ca²⁺ flux is altered in B cells of 1858T carriers indicate a role for Lyp in B cell signaling. In this study we show that B cell signal transduction is impaired in individuals who express the variant. This defect in signaling is characterized by a deficit in proliferation, a decrease in phosphorylation of key signaling proteins, and is reversed by inhibition of Lyp. These findings suggest that the PTPN22 1858T variant alters BCR signaling and implicate B cells in the mechanism by which the PTPN22 1858T variant contributes to autoimmunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by funds from the Juvenile Diabetes Research Foundation (to the Center for Translational Research at Benaroya Research Institute). Y.H., X.Z., and Z.-Y.Z. were supported by National Institutes of Health Grant CA69202.

² A.F.A. and T.H. contributed equally to this manuscript.

³ Address correspondence and reprint requests to Dr. Jane H. Buckner, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101. E-mail address: jbuckner{at}benaroyaresearch.org

⁴ Abbreviations used in this paper: SNP, single nucleotide polymorphism; PLC, phospholipase C.