# Impact of Loss-of-function NADPH Oxidase Variants on B cell Activation in SLE

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2022 · $531,189

## Abstract

Project abstract
Genome-wide association studies (GWAS) have identified immune pathways linked to the pathogenesis of
systemic lupus erythematosus (SLE). However, despite these insights, our understanding of how individual
genetic variants promote autoimmunity remains poor. Loss-of-function mutations in genes of the phagocytic
NADPH oxidase complex (NOX2), including NCF1 and NCF2, have been linked with the pathogenesis of SLE
and other humoral autoimmune diseases. The current model for how reduced NOX2 activity promotes lupus
development focuses on defects in the clearance of apoptotic material by phagocytic myeloid lineages. While
myeloid defects likely contribute to disease risk, we hypothesize that a parallel B cell-intrinsic mechanism
underlies the profound increase risk of SLE in human carriers of NCF1 and NCF2 variants. In addition to the
production of pathogenic autoantibodies, recent studies have demonstrated that B cells can promote lupus
pathogenesis by initiating immune tolerance breaks and facilitating the generation of spontaneous germinal
centers (GC). The activation of autoreactive B cells in SLE requires B cell-intrinsic expression of the endosomal
toll-like receptors TLR7 and TLR9, and our published and preliminary data show that reduced NOX2 activity
results in dysregulated endosomal TLR signaling by impacting non-canonical autophagy pathways. Based on
these data, we hypothesize that a B cell-specific reduction in NOX2 activity will result in enhanced TLR-
dependent GC formation and the development of humoral autoimmunity. We will test this idea via parallel in vivo
and in vitro mechanistic studies. In Aim 1, we will test whether B cell-intrinsic deletion NOX2 component genes
results in enhanced TLR-dependent GC responses using a well-characterized model of viral infection. In Aim 2,
we will study whether reduced NOX2 activity promotes autoantibody production and humoral autoimmunity in
murine SLE. Finally, in Aim 3, we will use biochemical and cell imaging approaches to test whether NAPDH
oxidase activity impacts B cell TLR signaling and non-canonical autophagy pathways using both murine genetic
models and gene-edited human B cells. Together, these studies promise to advance our understanding of lupus
pathogenesis and may inform the design of future targeted therapies for human SLE.

## Key facts

- **NIH application ID:** 10336533
- **Project number:** 5R01AR075813-02
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Shaun William Jackson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $531,189
- **Award type:** 5
- **Project period:** 2021-02-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10336533

## Citation

> US National Institutes of Health, RePORTER application 10336533, Impact of Loss-of-function NADPH Oxidase Variants on B cell Activation in SLE (5R01AR075813-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10336533. Licensed CC0.

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