# Role of Ptpn2 in B cells during development of autoimmunity

> **NIH NIH R03** · UNIVERSITY OF COLORADO DENVER · 2024 · $117,000

## Abstract

Project Summary
 This R03 proposal is to follow-up on recent findings from my SERCA K01 award, which focuses on
elucidating the role of the type 1 diabetes (T1D) PTPN2 risk allele in loss of B cell anergy. Previously B cells
bearing antigen receptors with high affinity for insulin were found only in the anergic B cell compartment of
healthy individuals. Importantly, these cells leave this compartment in a proportion of first-degree relatives
(FDRs), and in all autoantibody positive pre-diabetics and recent onset T1D individuals. Departure of these
autoreactive anergic B cells in FDRs was shown to be associated with the high risk non-HLA allele, PTPN2
(rs1893217). PTPN2 has been previously shown to be a negative regulator of T cell signaling, but has not been
studied in B cells. Recently we demonstrated that mice that lack Ptpn2 specifically in their B cells
(Mb1Cre.Ptpn2fl/fl.C57BL/6) have a decrease in anergic B cells, similar to our findings in humans, an increase in
autoimmune associated B cells (ABCs), increase in production of autoreactive antibodies, and a hyperresponsive
phenotype. Despite these findings, these mice did not develop overt autoimmunity, likely driven by the fact these
mice are on the autoimmune resistant genetic background, C57BL/6. Hence, in this study we aim to determine
the effect of B cell specific deletion of Ptpn2 in the NOD mouse, which develops spontaneous diabetes by about
20 weeks of age. Specifically, we aim to study whether B cell deletion of Ptpn2 increases the rate and penetrance
of diabetes incidence, the effect on frequency and activation status of insulin-reactive and non-reactive B cells,
as well as its effect on B cell antigen presentation to T cells and the differentiation of pathogenic T cells. The
potential impact of these studies will lie in understanding how risk alleles conspire to undermine maintenance of
immune tolerance to autoantigens in T1D.

## Key facts

- **NIH application ID:** 10869775
- **Project number:** 1R03OD036470-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Mia Smith
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $117,000
- **Award type:** 1
- **Project period:** 2024-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10869775

## Citation

> US National Institutes of Health, RePORTER application 10869775, Role of Ptpn2 in B cells during development of autoimmunity (1R03OD036470-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10869775. Licensed CC0.

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