# Project 1

> **NIH NIH P01** · EMORY UNIVERSITY · 2022 · $550,191

## Abstract

Antibodies, which are produced following infection and vaccination, promote rapid pathogen clearance and, if
made for extended periods of time, can provide protection following re-exposure to the same or related
pathogens. However, antibodies can also be detrimental and, if directed against the wrong antigen or epitopes,
can cause, rather than prevent, disease. Pathologic antibodies are most often observed in the setting of chronic
inflammatory diseases such as autoimmunity, allergy and organ transplantation. Given the importance of
antibodies in promoting both health and disease there is a need to better understand the development and
maintenance of the antibody secreting cells (ASCs). ASCs are the terminally differentiated effector progeny of
the mature naïve and memory B cell pools. While we have made great gains in our understanding of the signals
and transcription factors that control ASC development from the parent naïve and memory B cells, we know
remarkably little about the factors, both intrinsic and extrinsic, that control the lifespan of ASCs. In our preliminary
studies we show that the capacity of particular B cell subsets to differentiate into ASCs with a long survival
potential appeared to be hardwired and limited to the memory B cell compartment rather than the naïve B cell
pool. We identified several discrete subsets of memory B cells and showed that these memory B cells differed
in their transcriptional, epigenetic and metabolic programs and exhibited distinct functional capabilities. We
identified a subset of memory B cells (referred to as effector memory B cells), that were more similar to ASCs in
their metabolic potential and expression of epigenetic modifiers like the methylase EZH2 and NAD-dependent
deacetylase SIRT1. We showed that effector memory B cells differentiated into ASCs more rapidly than other
memory subsets. Moreover, the ASCs derived from the effector memory B cells were uniquely capable of
surviving for weeks when cultured in a supportive microenvironment. Finally, we showed that ASC survival is
highly dependent on new NAD metabolism and that drugs which block vitamin B3-directed NAD biosynthesis
will ablate ASCs in autoimmune and chronically infected animals. The central hypothesis tested in the Specific
Aims is that the effector memory B cells, which have undergone specific epigenetic and metabolic programming
steps, are licensed to give rise to ASCs with superior survival potential. The immediate objectives of this proposal
are to: (i) identify the transcriptional and epigenetic changes controlling Bmem differentiation into long-lived
ASCs; (ii) determine the role for EZH2 and SIRT1 in ASC survival; and (iii) assess the role of NAD metabolism
in the survival of long-lived ASCs. We believe that these studies are important as they will advance our
fundamental knowledge of the factors that control ASC lifespan and may in the future lead to new therapeutic
approaches to dampen ASC responses to control antibody m...

## Key facts

- **NIH application ID:** 10428167
- **Project number:** 2P01AI125180-06
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Ignacio E. Sanz
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $550,191
- **Award type:** 2
- **Project period:** 2016-06-25 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428167

## Citation

> US National Institutes of Health, RePORTER application 10428167, Project 1 (2P01AI125180-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10428167. Licensed CC0.

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