# The immunoregulatory role of Alveolar Macrophages in Chronic Beryllium Disease

> **NIH NIH R01** · NATIONAL JEWISH HEALTH · 2020 · $335,765

## Abstract

Project Summary/Abstract:
The goal of this study is to determine the impact of CD55 and JAK/STAT pathway dysregulation in
alveolar macrophages (AMs) on chronic beryllium disease (CBD) progression. CBD is an important
organ-specific immune-mediated disease, characterized by granulomatous lung inflammation, fibrosis, and
death, due to end-stage respiratory insufficiency. Thus, CBD remains an important public health concern.
The precursor to this disease (beryllium sensitization; BeS) progresses to CBD at a rate of approximately 6-8%
per year. Although the binding and presentation of Be via βGlu69-containing HLA-DP molecules to pathogenic
CD4+ T cells provides an explanation for the genetic linkage of DP2 to CBD and BeS, this does not explain the
progression of BeS to CBD. Furthermore, DP2 is found in up to 40% of Be-workers without evidence of BeS or
CBD. Thus, additional mechanisms must be involved in progression of BeS to CBD. Our hypothesis is that
CBD AMs downregulate the negative immunoregulatory gene CD55 and its pathway and overexpress
the positive regulatory activating JAK/STAT pathway, which augments the immune response to Be and
progression from BeS to CBD. In Aim 1, we will define if CD55 on AMs is a negative regulator in the
immune response to Be in AMs from BeS patients. Specifically, using either the overexpression of the CD55
genes using a adenovirus overexpression system and agonistic antibody or the reduction of CD55 genes using
adenovirus knockdown system and neutralizing antibody of CD55, we will determine the impact of alteration of
CD55 on consequential functional changes in TNF-α production, phenotype (CD16, CD40, CD80, CD86, HLA-
DR), JAK/STAT activation and BeLPT comparing CBD, BeS and controls. Finally, using RNA-seq, we will
investigate the regulatory networks associated with the downregulation of CD55 in CBD compared to BeS; In
Aim 2, we will determine if the JAK/STAT pathway is a positive regulator of the immune response to Be in AMs
and is increased in AMs from subjects with CBD compared to BeS. Specifically, AMs from CBD will be
compared to those from BeS and controls subjects, assessing either the overexpression of the JAK/STAT
pathway genes using a adenovirus overexpression system or the reduction of the JAK/STAT pathway genes
using adenovirus knockdown system and pharmacological JAK1- 3 inhibitors on the Be immune response. We
will evaluate the changes in TNF-α production, phenotype (CD16, CD40, CD80, CD86, HLA-DR), and BeLPT.
Finally, using RNA-seq we will define the regulatory networks associated with the overactivation of the
JAK/STAT pathway. In Aim 3, we will investigate whether the CD55 and JAK /STAT pathway are associated
with CBD and progression from BeS to CBD, compared to BeS, using a longitudinal study and validate these
findings in a larger longitudinal population to determine if these genes and pathways reveal potential novel
biomarkers of diagnosis and prognosis for CBD. At the end of this project we w...

## Key facts

- **NIH application ID:** 9993524
- **Project number:** 5R01ES025722-05
- **Recipient organization:** NATIONAL JEWISH HEALTH
- **Principal Investigator:** Li Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $335,765
- **Award type:** 5
- **Project period:** 2016-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993524

## Citation

> US National Institutes of Health, RePORTER application 9993524, The immunoregulatory role of Alveolar Macrophages in Chronic Beryllium Disease (5R01ES025722-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9993524. Licensed CC0.

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