# PTPN22 R619W in NOD mice

> **NIH NIH U01** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $745,163

## Abstract

Project Summary:
Type 1 diabetes (T1D) results from a breakdown in immune tolerance that progresses to the destruction of the
insulin producing beta cells of the pancreatic islets. A large number of genetic and environmental factors
contribute to the incidence of disease. One of the strongest non-MHC genetic risk factors is a single nucleotide
polymorphism in the gene that encodes the tyrosine phosphatase non-receptor type 22, PTPN22, that results
in a single amino acid change in the protein, R620W. PTPN22 is expressed in many bone marrow derived
cells, including lymphocytes and myeloid derived cells. Although R620W increases the risk of many
autoimmune diseases associated with production of autoantibodies, including T1D, rheumatoid arthritis,
systemic lupus erythematosus, Graves disease, vitiligo, and others, little is know about how it enhances
disease. In part, this is because it functions in many different types of cells that affect the immune system. In
order to produce a mouse model that can be used to identify its mechanism of action, we used Crispr/Cas9
genome editing to introduce the mouse ortholog of the pro-autoimmune allele of PTPN22 (619W) into the non-
obese diabetes (NOD) mouse that spontaneously develops T1D. NOD mice harboring this mutation
demonstrate accelerated production of anti-insulin antibodies and accelerated T1D of higher penetrance, which
is the same phenotype exhibited by humans expressing R620W. This proposal will use the 619W NOD model
to reveal the mechanism responsible for enhanced disease by pursuing the following specific aims:
Aim1 will identify immune cells in which endogenous expression of 619W enhances IAA production and T1D.
This entails adoptive transfer experiments to produce mice expressing the 619W mutation of PTPN22 in key
immune cells.
Aim 2 will explore the mechanistic basis for enhanced IAA and T1D in 619W mice. The types of immune cells
identified under Aim 1 will be probed to identify genes affected in their level of expression by allelic difference
at 619. Genes and pathways will be identified by either RNAseq or by analyzing gene expression at the single
cell level. Candidate genes will be tested for function by altering level of expression with shRNAs delivered by
retroviral vectors.
Aim 3 will examine tolerance of insulin specific B lymphocytes in R619W mice.
Aim 4 will use TCR transgenic mice and single cell expression analysis to examine the fate of islet antigen
specific T cells as they become activated in either 619W or 619R expressing mice.
Successful completion of these studies will have relevance to development of treatments that may prevent the
many different autoimmune disease associated with PTPN22.

## Key facts

- **NIH application ID:** 10183146
- **Project number:** 5U01AI130842-05
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** LINDA A SHERMAN
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $745,163
- **Award type:** 5
- **Project period:** 2017-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183146

## Citation

> US National Institutes of Health, RePORTER application 10183146, PTPN22 R619W in NOD mice (5U01AI130842-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10183146. Licensed CC0.

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