# Mapping the genes that predispose to murine lupus

> **NIH NIH R21** · HENRY M. JACKSON FDN FOR THE ADV MIL/MED · 2020 · $228,744

## Abstract

Summary)
 )To elucidate the T cell – B cell mechanisms involved lupus pathogenesis, the PI has
used an induced model of murine lupus, the parent-into-F1 model of graft-vs.-host
disease (GVHD). Using B6D2F1 mice as hosts, DBA/2 (DBA) parental T cell transfers
result in lupus specific autoantibodies and lupus nephritis (chronic GVHD) whereas B6
parental T cell donors cause elimination of host B cells and no lupus specific
autoantibodies (acute GVHD). The PI has demonstrated that these two divergent
outcomes are strongly associated with differential parental CD4 IL-2 production e.g. B6
CD4 T cells are strong IL-2 producers and promote a donor cytotoxic T cell response
whereas DBA CD4 T cell IL-2 production is profoundly impaired resulting in skewing
towards T follicular helper cells, host B cell activation and autoantibody formation.
 The BXD Recombinant Inbred (BXDRI) lines are > 100 lines of backcrosses of the
B6 and DBA parents that have been successfully used in gene mapping. In an earlier
study, the PI and collaborators used a limited number of BXD strains and demonstrated
the feasibility of using BXD splenocytes as donors into B6D2F1 mice to induce acute or
chronic GVHD. Genetic analysis and mapping tools have advanced significantly since
then and the number of BXD strains has nearly tripled. Using the PàF1 model, we
propose to:
Aim 1. Map the gene variants that predispose to lupus-like cGVHD phenotype. In
collaboration with Dr. Robert Williams who has developed many of the new BXDRI lines
we will test a larger number of BXD strains as donors into B6D2 mice and map the
genes important in chronic GVHD lupus phenotype.
Aim 2. Map the sequence variants involved in defective CD4 IL-2 production and
determine their linkage to lupus-like cGVHD. In vitro IL-2 production by BXD CD4 T
cells will be tested and the genes for the IL-2 defect mapped as well as the concordance
between BXD strains that exhibit both defective CD4 IL-2 production in vitro and chronic
cGVHD in vivo. These results will address the hypothesis that a primary asymptomatic
defect in CD4 IL-2 production in humans could predispose to lupus.
 Successful mapping of the gene variants that modulate lupus-like GVHD will define
new molecular mechanisms, complex networks of interactions among cells and tissues,
and define homologous mechanisms with potential applicability to human lupus.

## Key facts

- **NIH application ID:** 9975984
- **Project number:** 1R21AI146633-01A1
- **Recipient organization:** HENRY M. JACKSON FDN FOR THE ADV MIL/MED
- **Principal Investigator:** Charles S. Via
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $228,744
- **Award type:** 1
- **Project period:** 2020-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975984

## Citation

> US National Institutes of Health, RePORTER application 9975984, Mapping the genes that predispose to murine lupus (1R21AI146633-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9975984. Licensed CC0.

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