# Marginal Zone B Cell Regulation of Red Blood Cell Alloimmunization

> **NIH NIH P01** · UNIVERSITY OF VIRGINIA · 2021 · $405,254

## Abstract

Project Summary
RBC transfusion can induce alloantibodies that can make it difficult to find compatible blood for future
transfusions, increase the likelihood of incompatible transfusion reactions, and directly increase morbidity and
mortality in patients with sickle cell disease (SCD). Empirical data have shown that although antigen-matching
protocols reduce RBC alloimmunization, no currently available strategies completely prevent RBC-induced
alloantibody formation following therapeutic transfusion. This in part reflects a lack of understanding regarding
key factors responsible for initiating RBC alloimmunization. Our central hypothesis is that marginal zone (MZ)
B cells represent a central node in the initiation and orchestration of immune responses to RBC alloantigens,
and thus may be a viable immunological target for the development of novel strategies to not only predict, but
also prevent RBC alloantibody production. Our hypothesis is formulated on the basis of our recent discovery
that MZ B cells are required for the development of RBC alloantibody formation in a pre-clinical model. As MZ
B cells can traffic antigen to B cell follicles, the requirement of MZ B cells in RBC alloimmunization may reflect
the trapping and subsequent delivery of allogeneic RBCs to B cell follicles, where antigenic substrate is then
used by CD4 T follicular helper cells (TFH) to drive effective germinal center reactions responsible for
significant alloantibody formation. As antigen trapping requires B cell receptor engagement and MZ B cells
possess a restricted and distinct repertoire of antibody specificities in any given individual, these data also
suggest that differences in the precursor frequency of RBC alloantigen specific MZ B cells may predict the
likelihood that an individual will develop alloantibodies following RBC alloantigen exposure. Furthermore, as
toll-like receptor (TLR) agonists can directly increase MZ B cell activity, conditions that directly engage TLRs,
such as excess hemin released during acute chest syndrome (ACS) in patients with SCD, may increase the
likelihood of RBC alloimmunization by positively impacting MZ B cell function, and therefore may explain in part
the increased propensity of patients with SCD to develop RBC alloantibodies. These preliminary data identify
MZ B cells as key players in regulating RBC alloantibody formation, and in so doing provide a unique
opportunity to define the role of MZ B cells in predicting and preventing RBC alloimmunization. To accomplish
this, Project 2 will use a complementary approach of clinical and pre-clinical studies to weld observational data
with mechanistic studies in order to define the role of MZ B cells in the regulation of RBC alloimmunization by
testing the following specific aims: Aim 1: Define the role of MZ B cells in RBC alloimmunization. Aim 2:
Define the impact of ACS on MZ B cell and TFH activation. We believe that successful completion of these
aims not only possess the capacit...

## Key facts

- **NIH application ID:** 10192793
- **Project number:** 5P01HL132819-05
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Sean R Stowell
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $405,254
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10192793

## Citation

> US National Institutes of Health, RePORTER application 10192793, Marginal Zone B Cell Regulation of Red Blood Cell Alloimmunization (5P01HL132819-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10192793. Licensed CC0.

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