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.
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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

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Figure 2

Expression of the PEP variant promotes autoimmunity in a mixed genetic background.

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Expression of the PEP variant promotes autoimmunity in a mixed genetic b...
(A) Increased spleen size and cellularity in 6-month-old T/C and T/T mice. Error bars represent SD based on 8 animals/genotype. **P < 0.01. (B) Infiltration of thymus with B cells in aged T/C and T/T animals. Analysis of total thymocytes (top) and double-negative (CD4–CD8–) thymocytes (bottom) are shown with numbers indicating percentages within total live or double-negative cells. Data in A and B are representative of 8 independent analyses. (C) Anti-dsDNA IgG ELISA was performed using sera from T/C, T/T, and WT littermates and control autoimmune Wiskott-Aldrich syndrome (WAS) knockout mice. Each symbol represents an individual 6-month-old animal; horizontal bars represent mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. (D) H&E-stained tissue sections showing spectrum of histologic lesions in aged knockin mice compared with WT littermates. Original magnification, ×4 (lung, top panel); ×20 (salivary gland, bile duct); ×40 (lung [second panel], mesentery, and base of aorta). (E) Anti-insulin autoantibodies were determined by ELISA using sera from T/C, T/T, and WT littermates. Each symbol represents an individual 6- to 10-month-old animal; horizontal bars represent mean ± SEM. *P < 0.05 (F) STZ-induced diabetes in 6- to 8-week-old male T/C, T/T, and WT littermates. Mice (7/genotype) were treated with 40 mg/kg STZ for 4 consecutive days and blood glucose levels measured twice weekly. Diabetes was defined as glucose levels above 250 mg/dl for 2 consecutive assays. Data are representative of 2 independent experiments.