# Identification of novel Inhibitory receptors Involved In B cell tolerance

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2020 · $226,993

## Abstract

Project Summary
Both genetic and environmental factors conspire during early stages of autoimmune disease to break immune
tolerance. Several risk alleles associated with an increased risk of developing systemic lupus erythematosus
(SLE), and other autoimmune diseases, target the function of the Src-family tyrosine kinase Lyn. Lyn plays an
important role in immune tolerance by initiating inhibitory signaling in autoreactive B cells, leading to a state of
unresponsiveness or anergy. Important downstream phosphatases that mediate this inhibitory signaling are
SHIP-1 and SHP-1. It is still unclear how Lyn facilitates the activation of SHIP-1 and SHP-1 in anergic B cells.
Lyn phosphorylates specific motifs on inhibitory receptors (ITIM or ITSM) that enables these receptors to
recruit and activate phosphatases. The aims of this proposal are to identify the Lyn-dependent inhibitory
receptors required to activate SHIP-1 (Aim 1) and SHP-1 (Aim 2) in anergic B cells. We will use a novel
technique, Inhibitory Receptor Trap (IRT), to identify these inhibitory receptors. IRT uses SH2 domains from
SHIP-1 or SHP-1 to specifically isolate phosphorylated inhibitory receptors (indicating that the receptors are
active). Isolated receptors will be identified by mass spectrometry. We will evaluate the relevance of identified
receptors in anergic B cells from man and mouse. Understanding the molecular pathways by which inhibitory
signaling circuits are activated in autoreactive B cells is important. Many risk alleles associated with an
increased risk to develop autoimmune disease affect these inhibitory circuits. Delineating pathway
relationships will allow for more accurate predictions of which risk alleles will act synergistically. This will
enable us to identify individuals at heightened risk and will allow for earlier intervention and possible preventive
care. Identified receptors are also potential novel targets for therapeutic intervention which may allow us to
restore B cell tolerance.

## Key facts

- **NIH application ID:** 10056152
- **Project number:** 1R21AI149019-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Andrew Getahun
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $226,993
- **Award type:** 1
- **Project period:** 2020-06-09 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10056152

## Citation

> US National Institutes of Health, RePORTER application 10056152, Identification of novel Inhibitory receptors Involved In B cell tolerance (1R21AI149019-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10056152. Licensed CC0.

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