# Leukocyte NADPH Oxidase Variants in Lupus

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2022 · $523,001

## Abstract

This project will examine the connection between variants in the superoxide-generating
leukocyte NADPH oxidase 2 (NOX2), genetic susceptibility and pathogenesis of SLE to follow
up on our exciting discovery linking leukocyte NADPH oxidase NCF2 H389Q and R395W
mutations to human SLE. Our central hypothesis is that SLE is not a single disease entity, but
rather represents distinct subtypes based on combination of some of the genetic risk factors.
Thus, we hypothesize that lupus linked to reduced NADPH oxidase activity as a consequence of
NOX2 functional variants represent a distinct subtype of SLE with specific pathways regulating
pathogenesis, unique biomarkers and therefore responsive to specific therapies.
In the present study we will determine the overall prevalence of functionally important NADPH
oxidase variants in lupus subjects using next generation sequencing (NGS) technologies to
detect and validate important new variants in 9 NADPH oxidase genes and determine the extent
of the contribution of the NADPH oxidase complex to the genetic predisposition to human SLE
(aim 1) and will further analyze the identified and functionally promising H389Q and R395W
NCF2 variants (subaims 1.3 and 1.4). In specific aim 2 we will investigate mechanisms by which
reduced NADPH oxidase activity promotes lupus pathogenesis using newly created mouse
models of lupus with genetic defects in the NADPH oxidase, including partial deficiency
(haploinsufficient NCF2, hypomorphic NCF2) and with deletion of NADPH oxidase in selected
myeloid lineages. These mechanistic analyses will be done on several levels: gene expression
studies (subaim 2.1) to define biological markers and pathways regulating NOX2 associated
lupus; role of type I IFNs in driving pathogenesis (subaim 2.2); role of different cell subsets in
driving the process (subaim 2.3); role of NETosis in the pathogenesis (subaim 2.4) and finally
assessing potential NOX2 agonists as likely specific treatment modality to this subset of lupus
(subaim 2.5).

## Key facts

- **NIH application ID:** 10396966
- **Project number:** 5R01AR072212-05
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** CHAIM O. JACOB
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $523,001
- **Award type:** 5
- **Project period:** 2017-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10396966

## Citation

> US National Institutes of Health, RePORTER application 10396966, Leukocyte NADPH Oxidase Variants in Lupus (5R01AR072212-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10396966. Licensed CC0.

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