# Gene-Environment Collaboration in Autoimmune Disease

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $362,250

## Abstract

Inhaled silica has been compellingly linked to several human autoimmune diseases, including systemic
lupus erythematosus and ANCA vasculitis that destroy kidneys, lungs, and other organs. However, little is
known about the mechanism of autoimmune induction or the role of genetic susceptibility. Autoantibodies
are prominent in these disorders and key mediators of tissue injury. The experiments proposed here test the
overarching hypothesis that the silica-exposed lung creates a microenvironment that alters autoimmune cell
regulation in genetically susceptible individuals. We further propose that this breach in B cell tolerance
occurs through the intermediary of pulmonary tertiary lymphoid structures or iBALT that promote survival
and activation of autoreactive lymphocytes, and that the human HLA DRB1*1501 risk allele and Toll-like
receptor ligand co-exposure contribute to this breach. This hypothesis can be tested using in vivo models
that permit complex and dynamic immune cell interactions at the environment/lung interface and that are
amenable to mechanistic dissection. We propose three Specific Aims supported by extensive preliminary
data and established cross-disciplinary collaborations. Specific Aim 1 tests the hypothesis that silica-
induced iBALT is a major site for loss of B cell tolerance, and that the extent and nature of iBALT formation
and defective tolerance varies according to genetic susceptibility. We will measure recruitment and
activation of autoreactive B cells within iBALT and secondary lymphoid organs of silica-exposed subjects
using flow cytometry, immunoassay, cell culture, and microdissection. This aim is possible using a unique
and experimentally tractable murine model system developed in our lab, in which an autoantibody
transgene serves as a reliable reporter to track autoreactive cells and monitor well-defined tolerance
phenotypes within the context of genetically distinct B6 and autoimmune MRL, NZB, and BXSB strains that
collectively mirror human lupus genetic heterogeneity. Specific Aim 2 tests the role of a potent human
autoimmune risk allele, HLA class II DRB1*1501, in silica-induced iBALT induction and proteinase 3 (PR3)-
ANCA vasculitis. This aim uses two novel humanized models that replace murine class II molecules with
human class II DR2 (DRA1/DRB1*1501). We will measure silica exposure impact on autoreactive cell
recruitment and tolerance using DR2+ B6 autoAb Tg mice, and on anti-PR3 autoreactivity and vasculitis
using dual humanized Hu-HSC mice expressing DR2 both in thymus and on human immune cells and
subject to PR3 immunization or PR3-ANCA infusion. Specific Aim 3 tests the capacity of silica to break
tolerance to myeloperoxidase (MPO) or to modify anti-MPO immunity and MPO-ANCA vasculitis. This aim
takes advantage of MPO immunoreactivity and disease-susceptibility in MRL and MPO-deficient B6 models.
Ultimately, insight into mechanisms of silica-controlled autoimmunity will identify new targets and new
route...

## Key facts

- **NIH application ID:** 10246383
- **Project number:** 5R01ES027873-05
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** MARY H. FOSTER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $362,250
- **Award type:** 5
- **Project period:** 2017-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246383

## Citation

> US National Institutes of Health, RePORTER application 10246383, Gene-Environment Collaboration in Autoimmune Disease (5R01ES027873-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10246383. Licensed CC0.

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