A disease-associated PTPN22 variant promotes systemic autoimmunity in murine models
Xuezhi Dai, … , Jane H. Buckner, David J. Rawlings
Xuezhi Dai, … , Jane H. Buckner, David J. Rawlings
Published April 24, 2013
Citation Information: J Clin Invest. 2013;123(5):2024-2036. https://doi.org/10.1172/JCI66963.
View: Text | PDF
Research Article

A disease-associated PTPN22 variant promotes systemic autoimmunity in murine models

Abstract

Multiple autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, Graves disease, and systemic lupus erythematosus, are associated with an allelic variant of protein tyrosine phosphatase nonreceptor 22 (PTPN22), which encodes the protein LYP. To model the human disease-linked variant LYP-R620W, we generated knockin mice expressing the analogous mutation, R619W, in the murine ortholog PEST domain phosphatase (PEP). In contrast with a previous report, we found that this variant exhibits normal protein stability, but significantly alters lymphocyte function. Aged knockin mice exhibited effector T cell expansion and transitional, germinal center, and age-related B cell expansion as well as the development of autoantibodies and systemic autoimmunity. Further, PEP-R619W affected B cell selection and B lineage–restricted variant expression and was sufficient to promote autoimmunity. Consistent with these features, PEP-R619W lymphocytes were hyperresponsive to antigen-receptor engagement with a distinct profile of tyrosine-phosphorylated substrates. Thus, PEP-R619W uniquely modulates T and B cell homeostasis, leading to a loss in tolerance and autoimmunity.

Authors

Xuezhi Dai, Richard G. James, Tania Habib, Swati Singh, Shaun Jackson, Socheath Khim, Randall T. Moon, Denny Liggitt, Alejandro Wolf-Yadlin, Jane H. Buckner, David J. Rawlings

×

Figure 7

B lineage–restricted expression of PEP-R619W is sufficient to trigger autoimmunity in a mixed genetic background.

Options: View larger image (or click on image) Download as PowerPoint
B lineage–restricted expression of PEP-R619W is sufficient to trigger au...
(A) Schematic representation of the Rosa26-targeting strategy. Cre-mediated deletion of the STOP cassette (Neo-tpA) induces coexpression of HA-tagged PEP-R619W and cis-linked GFP. (B) Expression of cis-linked GFP solely in B lineage cells in Rosa-PEP-R619W/CD19-Cre mice. Splenocytes were analyzed by FACS for GFP, B220, and Thy1.2 expression. Purified splenic B lysates were subjected to Western blot with anti-HA, anti–PEP-P2, and anti-actin antibodies. Numbers denote PEP/actin ratio. (C) Increased spleen size and splenic cellularity in 10-month-old Rosa-PEP-R619W/CD19 Cre mice. Error bars depict SD (4 mice/genotype). *P < 0.05. (D) Histology analysis of kidneys from Rosa-PEP-R619W/CD19-Cre mice and CD19-Cre control mice. Three of 4 Rosa-PEP-R619W/CD19-Cre mice evaluated exhibited significant renal abnormalities compared with control animals. Scale bars: 50 μm. (E) Anti-dsDNA ELISA using sera from 10-month-old Rosa-PEP-R619W/CD19-Cre mice and CD19-Cre littermates. Each symbol represents an individual mouse. *P < 0.05. (F) Increased GC B cell percentage and absolute numbers in Rosa-PEP-R619W/CD19-Cre mice. Splenocytes analyzed by FACS for B220, CD38, and FAS expression. (G) Increased ABC percentage and absolute numbers in Rosa-PEP-R619W/CD19-Cre mice. Splenocytes were analyzed for B220, CD11b, and CD11c expression. Each symbol represents an individual animal, horizontal bars represent mean ± SEM, and error bars represent SD (4 animals/genotype). *P < 0.05; **P < 0.01.