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 6

PEP-R619W expression alters B cell selection, augments BCR signaling, and partially protects immature B cells from apoptosis.

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PEP-R619W expression alters B cell selection, augments BCR signaling, an...
(A) Increased T1 B cell in 6- to 8-week-old knockin mice. Splenic B cell subsets were defined as in Figure 5. (B) Enhanced selection for M167-Id+ cells in the MZ compartment in young knockin mice. Splenocytes were stained with anti-B220, anti-CD21, anti-CD24, and anti-M167-Id–specific (where Id, indicates idiotype) antibodies. Percentage of M167-Id+ cells within the MZ gate (CD21hiCD24hiCD23lo/–) is displayed. Each symbol represents an individual mouse; horizontal bars represent mean ± SEM. *P < 0.05. (C) BCR signaling in naive and CpG prestimulated B cells. Naive B cells (top), CpG prestimulated B cells from T/C, T/T, and WT littermates (middle), and from PEP-deficient and control mice (bottom) were stimulated with anti-IgM antibody at the times indicated by arrows. Induction of Ca2+ mobilization was determined by flow cytometry. (D) PEP-R619W expression promotes enhanced phosphorylation of BCR-dependent substrates in CpG-prestimulated B cells. CpG-prestimulated B cells were stimulated with anti-IgM antibody for indicated times, and cell lysates were blotted using the indicated antibodies. (E) Proliferation of T/C, T/T, and control B cells. Purified CD43– splenic B cells were labeled with CellTrace and stimulated as indicated; proliferation was determined by CellTrace dilution. (F) Apoptosis analysis of T1 and FM B cells. Splenocytes were stained with anti-B220, anti-CD21, and anti-CD24. T1 and FM B cells were analyzed for apoptosis by TUNEL. Each symbol represents an individual mouse. *P < 0.05; **P < 0.01. Data shown are representative of 6 (A), 3 (C and E), and 2 (D) independent experiments.