# Antibody quality and germinal center requirements for peroxisomal function in lymphocytes

> **NIH NIH R21** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $259,500

## Abstract

Project Summary
Generating antibodies, refining their qualities, and creating durable humoral memory are crucial parts of adaptive
immunity. Protecting against microbes and maintaining commensal relationships with them draw on each facet of
antibody regulation. As such, it is vital to decipher key cellular and molecular processes that affect antibody (Ab)
qualities. In developing a means of mapping the distributions of nutrients and products of metabolism relative to
micro-anatomic features of lymphoid organs, we performed unbiased lipidomic analyses using IMS (imaging mass
spectrometry). This study revealed that an interconnected set of phospholipids characterized by non-acyl linkages
- i.e., ether-linked and plasmalogen species – that were enriched in germinal centers (GC). Of note, de novo
synthesis of ether and plasmalogen lipids and phospholipids requires several enzymes localized exclusively to
peroxisomes. One such enzyme is PexRAP, encoded by the gene Dhrs7b, which encodes a late step in ether lipid
synthesis. In parallel, recent work of others provided evidence that peroxisomes and fatty acid oxidation (FAO)
executed by them are increased in both activated and GC B cells. However, there is as yet no direct evidence of a
functional impact of peroxisomes or their FAO in vivo on GC B cells or on Ab responses. So are peroxisomal
functions important in any limb of humoral response? A first goal of this exploratory / developmental program
application is to test the high-risk hypothesis that the local cell-intrinsic generation of these species is
functionally important in GC B cells in addition to a broader role in Ab responses, i.e., rather than the alternate
model in which incorporation of circulating plasmalogens and other ether lipids is sufficient. Specific hypotheses
connected to this goal include (1) B cell type-restricted depletion of PexRAP will reduce not only IgG2c and IgA
output but also germinal centers. Preliminary findings with widespread loss-of-function for Dhrs7b (the gene
encoding PexRAP) support an impact on Ab responses and GC but might reflect B cell extrinsic functions or
biochemical steps independent from maintenance of GC. (2) Conditional disruption of Dhrs7b within GC B cells
and/or Tfh cells will undermine the formation of high-affinity, somatically hyper-mutated Ab as well as humoral
memory; (3) that the lack of this peroxisomal biosynthetic function will reduce not only the specific ether lipids most
prominent in our lipidomic results, but also germ line transcript induction and Ig class switching. Functions of ether
lipids in lymphocytes have not previously been studied. Accordingly, a second objective is to test the possibility
that these ether lipids promote GC in part because they enhance BCR signal transduction, and in part because
they assist in detoxifying reactive oxygen species (ROS) to protect the B cells from lipid peroxidation. Expected
outcomes & impact of the proposed studies are that we will (i) provi...

## Key facts

- **NIH application ID:** 10318012
- **Project number:** 1R21AI164760-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Mark R Boothby
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $259,500
- **Award type:** 1
- **Project period:** 2021-08-16 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10318012

## Citation

> US National Institutes of Health, RePORTER application 10318012, Antibody quality and germinal center requirements for peroxisomal function in lymphocytes (1R21AI164760-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10318012. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*