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

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• The protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene encodes LYP, and its allelic variant is associated with multiple autoimmune diseases.
• These diseases include type 1 diabetes, rheumatoid arthritis, Graves disease, and systemic lupus erythematosus.

Purpose of the Study:

• To model the human disease-linked LYP-R620W variant by creating knockin mice with the analogous mutation (R619W) in the murine PEST domain phosphatase (PEP) gene.
• To investigate the functional consequences of the PEP-R619W variant on lymphocyte function and autoimmunity.

Main Methods:

• Generation of knockin mice expressing the PEP-R619W mutation.
• Analysis of lymphocyte populations (T cells and B cells) in aged knockin mice.
• Assessment of autoantibody development and systemic autoimmunity.
• Evaluation of lymphocyte hyperresponsiveness to antigen-receptor engagement and tyrosine phosphorylation profiles.

Main Results:

• The PEP-R619W variant exhibits normal protein stability but significantly alters lymphocyte function.
• Aged knockin mice showed expansion of effector T cells and various B cell subsets (transitional, germinal center, age-related).
• Development of autoantibodies and systemic autoimmunity was observed in knockin mice.
• PEP-R619W affected B cell selection and B lineage-restricted variant expression, promoting autoimmunity.
• PEP-R619W lymphocytes displayed hyperresponsiveness to antigen-receptor engagement with altered tyrosine phosphorylation.

Conclusions:

• The PEP-R619W variant uniquely modulates T and B cell homeostasis.
• This modulation leads to a loss of self-tolerance and the development of systemic autoimmunity.
• The study provides a valuable mouse model for investigating PTPN22-associated autoimmunity.