# alpha v integrin regulation of B cell tolerance

> **NIH NIH R56** · BENAROYA RESEARCH INST AT VIRGINIA MASON · 2021 · $200,000

## Abstract

PROJECT SUMMARY
There is a fundamental need to understand how the immune system discriminates self-antigens and regulates
potentially harmful autoimmune responses. Increasing evidence from genetics and functional studies indicate
that innate immune signaling in response to products caused by cell death is a major etiological factor in
autoimmune and chronic inflammatory disease. Our long-term goal is to better understand how immune
tolerance to antigens derived from apoptotic cells and other self-antigens is maintained and how this can break
down in autoimmune diseases. The objective in this application is to understand how av integrins and
components of the autophagy pathway contribute to B cell tolerance. Our central hypothesis is that av-
mediated activation of autophagy components regulates TLR signaling in B cells, limiting cell proliferation,
differentiation and production of autoantibodies. The rationale for this grant is that the proposed work will
define the role of av-mediated autophagy in B cell tolerance, and develop better models for autoimmune
disease. Furthermore, this work has the potential to translate into new therapeutic approaches through the use
of existing compounds that target av and autophagy. Based on strong preliminary data, our hypothesis will be
tested in three specific aims: (1) Determine how av regulates development of autoreactive B cells and lupus-
like autoimmunity in mice. av-knockout mice crossed with an autoreactive BCR heavy chain transgenic mouse
strain will be used to follow development of autoreactive B cells, and understand how av regulates tolerance
and response to self-antigen. (2) Determine how av-mediated regulation of type I-IFNs regulates B cell
tolerance. We will test how increased type I IFN production by B cells and plasmacyotid DCs contribute to B
cell activation. (3) Test the hypothesis that non-canonical autophagy regulates B cell TLR signaling to promote
tolerance. We will analyze the role of Rubicon in autoreactive B cell activation, and evaluate a potential new
component of non-canonical autophagy, Atg16l2 Our approach is innovative as it focuses on a novel role for
integrins and autophagy components in regulating immune signaling in B cells. The proposed work is
significant because it will establish a new paradigm for B cell recognition of potential self-antigens in immune
tolerance and provide a mechanism by which this occurs. Ultimately this has the potential to change our
understanding of how immune tolerance is maintained and how autoreactive B cells may escape control to
promote autoimmunity.

## Key facts

- **NIH application ID:** 10294130
- **Project number:** 1R56AI148785-01A1
- **Recipient organization:** BENAROYA RESEARCH INST AT VIRGINIA MASON
- **Principal Investigator:** Adam Lacy-Hulbert
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $200,000
- **Award type:** 1
- **Project period:** 2020-12-16 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10294130

## Citation

> US National Institutes of Health, RePORTER application 10294130, alpha v integrin regulation of B cell tolerance (1R56AI148785-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10294130. Licensed CC0.

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