# Investigating the role of B cells in pulmonary fibrosis resulting from STING gain-of-function autoinflammation

> **NIH NIH F30** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $48,333

## Abstract

PROJECT SUMMARY/ABSTRACT
Pulmonary fibrosis is a poorly understood process that is thought to involve a preceding stage of immune
infiltration and inflammation. Bleomycin, a DNA damage inducing agent, is often used to experimentally induce
pulmonary fibrosis in mice, indicating that immune sensing of nucleic acids may be tied to the etiology of
fibrotic lung disease. cGAS-STING is a cytosolic dsDNA sensing pathway, which is tightly regulated to
preserve immune homeostasis by discriminating immune response to danger signals like pathogens or
genotoxic stress and immune tolerance to inert physiologic signals. This regulation is broken by constitutively
active STING mutations, which cause an autoinflammatory syndrome known as STING Associated
Vasculopathy with onset in Infancy (SAVI), in which patients develop immune abnormalities. Consistent with
the notion that dysregulated nucleic acid sensing promotes pulmonary fibrosis; SAVI patients rapidly succumb
to treatment resistant inflammatory lung fibrosis. To address the urgent need for SAVI lung disease therapy,
we have developed gene-targeted mice that express the SAVI mutation STINGV154M(VM) and found that these
mice recapitulate aspects of human disease including inflammatory lung fibrosis. The utility of studying our
SAVI mouse model lies not only in its impact on studying SAVI disease, but broadly for understanding the
immune defects that drive pulmonary fibrosis, a topic that has thus far been constrained by the limitations of
current fibrotic lung disease models. Our central hypothesis is that the acquisition of SAVI fibrotic lung disease
is mediated by autoreactive B cells. The following key findings support this hypothesis: (i) VM mice possess
severe immune abnormalities of lymphocytes characterized by lymphopenia with concomitant hyperactivation
of remaining lymphocytes, a feature also seen in SAVI patients. (ii) Using genetic ablation of B and T
lymphocytes by Rag1 deficiency, we found that lymphocytes are required for lung disease in VM mice;
however, when we specifically ablated αβ T cells by TCRβ deficiency in VM mice, we found that these mice
persisted in developing fulminant lung disease. (iii) Additionally, our preliminary data indicates that VM B cells
accumulate in the lung extravascular space and become activated independent of αβ T cells. In this proposal,
Aim 1 will determine the contribution of B cells to VM SAVI fibrotic lung inflammation using mouse genetic
models of B cell deficiency and pharmacologic depletion of B cells by targeted antibody treatment. Aim 2 will
determine whether VM SAVI lung B cells promote disease through autoreactivity using mouse models that
restrain the BCR repertoire to foreign antigens and by characterizing the BCR repertoire and antibody reactivity
in VM mice. The approach includes: survival studies, lung histopathologic analysis, pulmonary function testing,
flow cytometry, BCR repertoire sequencing, and antibody staining of mouse lung sections. Ou...

## Key facts

- **NIH application ID:** 10480899
- **Project number:** 5F30HL154674-03
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Kevin MingJie Gao
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $48,333
- **Award type:** 5
- **Project period:** 2020-09-04 → 2023-09-03

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10480899

## Citation

> US National Institutes of Health, RePORTER application 10480899, Investigating the role of B cells in pulmonary fibrosis resulting from STING gain-of-function autoinflammation (5F30HL154674-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10480899. Licensed CC0.

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