# The Genetics of Silica-Induced Autoimmunity

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $435,375

## Abstract

Silica exposure is associated with different disorders including pulmonary silicosis and autoimmune diseases
such as progressive systemic sclerosis (Pss), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA),
and dermatomyositis (DM). Although a number of studies have noted the association of silica exposure with
nephropathy, particularly in the setting of silica-induced autoimmunity, nothing is known about the genetics of
silica-induced renal disease. This identifies a critical barrier to progress in understanding how silica exposure
leads to autoimmune pathology. Kidney disease is a common feature in autoimmunity particularly in SLE where
30–60% of adults may have lupus nephritis. A number of features appear to be implicated including inflammation
initiated by deposition of autoantibody containing immune complexes, leading to production of inflammatory
mediators involving the innate and adaptive immune responses which results in cellular infiltrates, particularly of
macrophages, progression to tissue damage, aberrant tissue repair and fibrosis. Studies, predominantly in
animal models, have identified numerous molecular mediators that affect glomerulonephritis (GN). However,
most play roles in innate and/or adaptive immunity and do not primarily dictate renal disease. Moreover, genetic
studies in mice have identified a number of GN susceptibility loci, but many of these also associate with
autoantibody production arguing against a primary role in nephritis. Studies of silica-induced autoimmunity and
related pathology have been hampered by the lack of suitable animal models. To address this deficiency, we
have begun to characterize the spectrum of immunological responses leading to autoimmunity in Diversity
Outbred (DO) mice. We have examined the immunological responses to silica including the inflammatory
response in the lung and associated protein biomarkers in the BAL fluid, the spectrum of serum autoantibodies
and tissue pathology in the kidney. These findings have revealed significant development of silicosis,
autoimmunity and glomerulonephritis (GN). Quantitative trait locus (QTL) analysis determined the latter to be
linked with a region on chromosome 15. Significantly, this locus (called Smgn1) is associated with susceptibility
and resistance to silica-induced GN. None of the DO mice carrying the A/J allele at the locus developed GN
suggesting a dominant inheritance trait. We proposed two distinct but interrelated aims to further characterize
the genetic elements involved in the development of GN.
 Aim 1: Identification of the mode of resistance to silica-induced glomerulonephritis.
 Aim 2: Identification of the mode of susceptibility to silica-induced glomerulonephritis.
These studies are of considerable importance because they will allow insight into the molecular and cellular
pathways leading to glomerulonephritis following silica exposure. Such information will be essential for
identification of potential therapeutic targets a...

## Key facts

- **NIH application ID:** 9963252
- **Project number:** 5R01ES029581-03
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Kenneth Michael Pollard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $435,375
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963252

## Citation

> US National Institutes of Health, RePORTER application 9963252, The Genetics of Silica-Induced Autoimmunity (5R01ES029581-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9963252. Licensed CC0.

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