# Mechanisms underlying inflammation-induced alloimmunization to RBC antigens in lupus

> **NIH NIH R03** · CEDARS-SINAI MEDICAL CENTER · 2021 · $83,500

## Abstract

Abstract
Approximately 50% of patients with systemic lupus erythematosus (SLE) suffer from anemia, for which red blood
cell (RBC) transfusion is a common therapy. While RBC transfusion can be life-saving, production of
alloantibodies against non-self RBC antigens causes clinically significant hemolytic events during RBC
transfusion, pregnancy, and renal transplant. Prior human and animal studies have demonstrated that
inflammation in a transfusion recipient, including autoimmune-associated inflammation, can induce or enhance
RBC alloantibody responses. For example, while 3-5% of hospitalized patients in the United States produce RBC
alloantibodies, more than 20% of patients with SLE produce RBC alloantibodies, representing the second highest
prevalence compared to all other studied disease populations. However, mechanisms underlying autoimmune-
induced RBC alloimmunization are poorly understood. Using murine transfusion models, we previously reported
that acute viral-like stimuli and influenza infection induce pro-inflammatory type 1 interferons (IFNα/β), which
critically regulate alloimmunization to human RBC antigens expressed on mouse RBCs. Approximately two-
thirds of adults and nearly all children with SLE express an IFNα/β gene signature, defined as the production of
numerous interferon stimulated genes by innate immune cells. Thus, we hypothesized and recently reported that
IFNα/β also promotes RBC alloimmunization during acute inflammation in a lupus mouse model, prior to
development of autoimmunity. It is unclear, however, whether chronic inflammation, in the presence of
autoantibodies and lupus-like pathology, promotes RBC alloimmunization. In addition, it is unclear whether the
lupus phenotype or IFNα/β directly promotes alloimmunization in the chronic setting. In this application, we
propose to utilize lupus models with chronic inflammation to generate preliminary data for a future R01. We will
test the hypothesis that chronic inflammation in lupus promotes RBC alloantibody production by an
IFNα/β-dependent mechanism by determining the role of the lupus phenotype and IFNα/β in regulating RBC
alloantibody production (Aim1) and identifying innate immune signaling pathways that promote inflammation-
induced alloimmunization in models of chronic lupus (Aim 2). While the K08 focused on basic mechanisms of
IFNα/β production and IFNα/β-mediated alloimmunization in the absence of inflammation or disease, this
application diverges by examining mechanisms of chronic inflammation-induced alloimmunization in lupus
models. Findings will provide a potential mechanistic basis for past observations of autoimmunity-associated
alloimmunization. In addition, results may uncover novel pathways underlying inflammation-induced
alloimmunization and provide preclinical data to strengthen an R01 proposal that will include investigation of
mechanisms underlying RBC alloimmunization in patients with SLE. With mentorship from experts in RBC
alloimmunization, lup...

## Key facts

- **NIH application ID:** 10281785
- **Project number:** 1R03HL158637-01
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** David R Gibb
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $83,500
- **Award type:** 1
- **Project period:** 2021-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10281785

## Citation

> US National Institutes of Health, RePORTER application 10281785, Mechanisms underlying inflammation-induced alloimmunization to RBC antigens in lupus (1R03HL158637-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10281785. Licensed CC0.

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