# Autoimmunity risk alleles compromising B cell anergy

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $457,386

## Abstract

Autoimmunity is caused by conspiring effects of genetic predisposition and environmental factors such as
injury, infection and microbiome constitution. While multiple genetic loci affect susceptibility, in most cases
each in isolation has only a small effect, suggesting that disease develops only when multiple risk-conferring
alleles that function in concert are inherited by a single individual. We hypothesize that such a situation exists
in autoreactive B cells where multiple SLE risk alleles encode molecules that appear to function in signaling
pathways that function normally to limit/terminate antigen receptor signaling. In this application we propose to
test this hypothesis, analyzing the functional interplay of this set of genes/protein and their risk conferring
alleles. Future development and implementation of “precision” medical approaches for treatment of
autoimmunity will require an understanding of the mechanisms by which genetic variations conspire to
increase disease risk, and research proposed here represents a critical first step to enable these efforts.
A number of autoimmunity risk alleles encode molecules previously proposed to function as intermediaries in
signaling pathways involved in regulation of B cell activation. As such they may be important in keeping
autoreactive B cells from becoming activated and contributing to autoimmunity. In this application we request
support to define the functions and functional interactions of proteins encoded by six genes, variants of which
confer increased risk of autoimmunity. Previous reports indicate that B cell-targeted deletion of genes encoding
SHIP-1, PTEN, SHP-1 or LYN, expression of PTPN22 (PEP-R619W), or increased expression of CSK,
promote the development of autoimmunity. However the mechanism by which this occurs is unknown. We
hypothesize that these proteins function as intermediaries in a bifurcating pathway in which final effectors are
the inositol lipid phosphatases SHIP-1 and the tyrosine phosphatase SHP-1. Further, we suggest that both
terminal effectors are required for maintenance of antigen unresponsiveness of anergic B cells. The studies will
employ reductionist genetic models in which risk allele mimetic changes in expression/function of the proteins
can be induced acutely in anergic B cells, and subsequent cell activation, proliferation, differentiation and
autoantibody production monitored. Aim 1 will test the hypothesis that PTPN22, CSK and LYN act in linear
pathways upstream of SHIP-1 and SHP-1, and that genetic variations that confer risk compromise anergy by
undermining their regulatory function. Aim 2 will define the downstream consequences of acute introduction of
risk allele mimetic conditions in terms of development of autoimmune disease, and will test candidate
therapeutic kinase inhibitors. Aim 3 will translate findings, examining the role of SHIP-1 and SHP-1
phosphatases in maintenance anergy of human B cells. Proposed studies will provide important new in...

## Key facts

- **NIH application ID:** 9870785
- **Project number:** 5R01AI124487-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** John C Cambier
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $457,386
- **Award type:** 5
- **Project period:** 2016-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870785

## Citation

> US National Institutes of Health, RePORTER application 9870785, Autoimmunity risk alleles compromising B cell anergy (5R01AI124487-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9870785. Licensed CC0.

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