# Principal Project

> **NIH NIH U19** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $155,045

## Abstract

SUMMARY ACE Principal Project; PD/PI – Pascual, V.
Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by breakdown of
tolerance to nucleic acids (NAs) and widespread inflammation stemming from pathogenic innate
and adaptive immune interactions in genetically susceptible individuals. Clinical and molecular
heterogeneity represent a major challenge and contribute to the long series of failed clinical trials
in SLE. Understanding major disease pathogenic drivers, identifying biomarkers to follow them in
the clinical setting, and stratifying patients for targeted therapies are therefore highly significant
goals to advance clinical trial design and deliver personalized patient care. This is particularly
relevant to patients with childhood-onset SLE (cSLE), who present with a more aggressive
phenotype and overall poorer outcome compared to adult-onset SLE. Our studies, stemming from
three previous ACE cycles, uncovered molecular heterogeneity among cSLE patients which
allowed their stratification based on major disease pathogenic drivers. We also described the
presence in cSLE patients of a novel extra-follicular CD4+ memory T cell subset that provides B
cell help independently of IL21 and CXCL13, thus expanding the spectrum of T helper pathways
in this disease. We then extensively profiled the blood CD4+ T cells compartment of cSLE which
uncovered transcriptomic signatures associated with disease activity (DA) and/or Lupus Nephritis
(LN). Herein, we propose to deconvolute the cSLE CD4+ T cell compartment longitudinally
in patients stratified according to the presence/absence of LN and the response to therapy.
This will help elucidate how both standard of care and B-cell targeting therapies affect the
frequency and function of CD4+ T cells and what basic mechanisms lead to amplification of T
helper pathogenic pathways in SLE. Secondly, we will study functional alterations of cSLE
CD4+ T regulatory cells and their potential connection with the microbiome. Results from
the proposed studies will ultimately help stratify patients and identify therapeutic targets for a
systemic autoimmune disease with a significant track record of clinical trial failure. Completion of
the project goals will lead to a better understanding of these pathways at the phenotypic and
functional levels. Additionally, these studies will identify biomarkers to characterize distinct CD4+
T cell-compartments with unprecedented granularity in blood and tissues, as well as potential
targets to intervene therapeutically in selected patients.

## Key facts

- **NIH application ID:** 10845040
- **Project number:** 2U19AI144301-06
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Maria Virginia Pascual
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $155,045
- **Award type:** 2
- **Project period:** 2019-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10845040

## Citation

> US National Institutes of Health, RePORTER application 10845040, Principal Project (2U19AI144301-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10845040. Licensed CC0.

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