# Mechanisms driving extrafollicular polyreactive B cell lineages in partial RAG deficiency

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2021 · $440,669

## Abstract

PROJECT SUMMARY
Patients with congenital immunodeficiencies, such as combined immunodeficiencies (CID) with partial
recombinase activating gene (RAG) deficiency (pRD) are highly vulnerable to chronic infections and refractory
autoimmune disorders. RAG1/2 are key to creating and censoring the B cell receptor diversity. In case of pRD,
developing B cells that are naturally autoreactive may remain reactive to self in the periphery and be unable to
mount efficient antibody responses. This results in chronic antigen exposure that can activate T and B cells.
We propose to focus on two specific cell populations: hyperactive T follicular helper (Tfh) cells and innate-like
extrafollicular polyreactive B cells, as markers of autoimmunity. The latter resemble age-associated B cells
(ABCs), which accumulate with infections and with age. Normally, ABCs are highly sensitive to innate immune
stimulation by microbes and inflammatory cytokines and play a key role in controlling viral infections by
producing protective antibodies. After the infection resolves, ABC numbers contract markedly. However, with
chronic infections, ABCs or ABC-like cells expand, persist and produce antibodies that are less protective
against microbes and more reactive to self, especially in individuals with particular genetic immunodeficiencies.
Sustained expansion of polyreactive ABCs parallels microbial/antigen load (toll-like receptor stimulation) and
expansion of Tfh cells, which secrete the inflammatory cytokines, interferon gamma (IFNand interleukin 21
(IL-21). It is unclear which stimuli and cell signaling pathways are dominant in promoting ABC autoreactivity in
pRD or other CID s. Our long-term goal is to understand how autoreactive ABCs emerge in CID in order to
develop effective immune modulatory treatments. We hypothesize that the susceptibility to infections of
patients with pRD results in increased, continual microbial/antigen presence and chronic low-grade
inflammation throughout the body. In response, Tfh cells secrete inflammatory cytokines abundantly (IFNand
IL-21), which together with chronic microbial stimulation induces ABC-like cells to expand and become
autoantibody-secreting cells and present autoantigens to Tfh cells, which sustains them. Thus, ABC-like cell
abundance and autoreactivity is perpetuated in pRD. Our specific aims are to 1) identify likely drivers of ABC-
like cells in pRD patients and 2) dissect mechanisms contributing to ABC-like cell generation and persistence
using pRD mouse models. Our innovative research strategies include studying an international cohort of pRD
patients in parallel with using novel mouse models, exposing mice to varying levels of microbes, and
correlating gene expression changes with ABC developmental characteristics and autoimmune severity of
patients. Our proposed study is significant because it will likely illuminate how dysfunctional ABC-like cells
develop in persons susceptible to chronic infections and lead to therapi...

## Key facts

- **NIH application ID:** 10367376
- **Project number:** 1R01AI153830-01A1
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Jolan Eszter Walter
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $440,669
- **Award type:** 1
- **Project period:** 2021-09-22 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367376

## Citation

> US National Institutes of Health, RePORTER application 10367376, Mechanisms driving extrafollicular polyreactive B cell lineages in partial RAG deficiency (1R01AI153830-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10367376. Licensed CC0.

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