# Project 4

> **NIH NIH P01** · EMORY UNIVERSITY · 2024 · $516,450

## Abstract

Antibody Secreting Cells (ASC), are the source of pathogenic autoantibodies in Systemic Lupus
Erythematosus (SLE). Despite ample evidence documenting profound abnormalities in the
generation of ASC in SLE and their correlation with active disease, little is still known regarding
their diversity, mechanisms of generation and regulatory programs. Our previous studies
document great phenotypic, functional, and molecular heterogeneity in human ASC and have
provided original insight into the contribution of different B cell precursors to the generation of
pathogenic ASC. Specifically, we described a large contribution of activated naïve B cells to
pathogenic ASC in severe SLE and COVID19 infection through extra-follicular differentiation.
Initial single cell (SC), studies provide an initial atlas of blood and bone marrow SLE B cell and
ASC and a roadmap to decipher the pathogenic and therapeutic implications of ASC diversity in
human disease. In this Project we will test the over-arching hypothesis that in order to fulfill
protective functions in primary and memory responses a healthy immune system has evolved
specialized differentiation pathways that determine the intensity, kinetics and longevity of diverse
ASC populations. Such precise regulation is subverted in SLE owing to intrinsic programs
(epigenetic) and extrinsic cues (microenvironment), determined by tissue-specific factors for local
and systemic responses (nephritis and BM , respectively). A central corollary is that the different
ASC populations will be differentially sensitive to therapies targeting separate B cell precursor
and their ASC progeny. These postulates will be addressed in a synergistic fashion with the other
PPG projects and Core B through 3 Aims: 1) Heterogeneity, origin, and fate of SLE ASC; 2)
Molecular Regulation of tissue-specific and systemic pathogenic ASC in SLE; and 3) Using B cell
targeting therapies to probe the origin, longevity and function of human ASC. Our studies will
greatly enhance our knowledge of human ASC biology and their dysregulation in SLE. The
information gained will also improve our ability to design safer and more effective therapies for
SLE and multiple antibody-mediated diseases and modulatory strategies to optimize protective
vaccine responses.

## Key facts

- **NIH application ID:** 10835937
- **Project number:** 5P01AI125180-08
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Ignacio E. Sanz
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $516,450
- **Award type:** 5
- **Project period:** 2016-06-25 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10835937

## Citation

> US National Institutes of Health, RePORTER application 10835937, Project 4 (5P01AI125180-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10835937. Licensed CC0.

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