# Metabolic Control of Systemic Autoimmunity

> **NIH NIH R01** · UPSTATE MEDICAL UNIVERSITY · 2024 · $486,000

## Abstract

ABSTRACT
Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. The pathogenesis is
partly attributed to compartmentalized oxidative stress inside and outside the immune system. The proposed
studies will focus on a critical gap in knowledge - how metabolic pathways that neutralize oxidative stress control
autoimmunity in SLE. The central hypothesis for this project is based on comprehensive metabolome studies
that have showed a dominant impact of SLE on the pentose phosphate pathway (PPP) in lymphocytes of
patients and T cells of lupus-prone mice undergoing lineage polarization; the results of which mimic the
deficiency of transaldolase (TAL), a rate-limiting enzyme of the PPP. Lupus-prone mice exhibit activation of the
mechanistic target of rapamycin (mTOR) and mitochondrial oxidative stress in the liver and antiphospholipid
antibody (aPL) production prior to the onset of nephritis. Similar to lupus-prone strains, mice lacking TAL exhibit
mTOR activation and overexpression of NDUFS3, a subunit of complex I in the mitochondrial electron transport
chain (ETC) that triggers the production of reactive oxygen intermediates (ROI) and aPL, both of which respond
to rapamycin treatment. TAL deficiency blocks the glycosylation and secretion of PON1 by the liver. This is
attributed to carbon trapping in the PPP and depletion of UDP-GlcNAc which are also detectable in SLE patients
and mice. Although PON1 loss in the plasma has been connected to aPL production and demonstrated in SLE,
antiphospholipid syndrome (APS), and liver diseases, the underlying mechanisms remain unknown. Therefore,
the Specific Aims will test our working hypothesis that TAL inactivation i) elicits cell type-specific carbon
sequestration in the PPP and limits substrates for NADPH and GSH production and metabolism through the
ETC and thus triggers a compensatory accumulation of oxidative stress-generating mitochondria, mTOR
pathway activation and pro-inflammatory lineage skewing in the immune system; and ii) limits the availability of
UDP-GlcNAc for glycosylation and secretion of PON1 by the liver, which in turn trigger aPL production in SLE
and TAL deficiency. Under Aim 1, we will test the hypothesis that TAL-regulated carbon flux through the PPP
causes cell-type specific accumulation of sedoheptulose 7-phosphate, depletion of NADPH and GSH, and
redox-mediated mTOR activation to promote the expansion Th17, Tfh, and DN T cells and constriction of CD8
EMT cells and Tregs in SLE patients. Under Aim 2, we will delineate T-cell intrinsic metabolic checkpoints that
control systemic autoimmunity in lupus-prone mice. Under Aim 3, we will determine the role of hepatocyte-
derived oxidative stress in aPL production, pro-inflammatory lineage skewing in the immune system and lupus
pathogenesis. The proposed research is significant because it will establish new, compartmentally defined
metabolic checkpoints of autoimmunity with broad translational relevance for the pathoge...

## Key facts

- **NIH application ID:** 10782467
- **Project number:** 5R01AI072648-15
- **Recipient organization:** UPSTATE MEDICAL UNIVERSITY
- **Principal Investigator:** Andras Perl
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $486,000
- **Award type:** 5
- **Project period:** 2008-02-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10782467

## Citation

> US National Institutes of Health, RePORTER application 10782467, Metabolic Control of Systemic Autoimmunity (5R01AI072648-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10782467. Licensed CC0.

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