# Pathogenic Lymphocytes in Lupus Nephritis

> **NIH NIH R21** · YALE UNIVERSITY · 2020 · $208,565

## Abstract

PROJECT SUMMARY
Lupus nephritis occurs in a majority of patients with systemic lupus erythematosus (SLE, lupus), and is a
leading cause of morbidity and mortality. CD4+ and CD8+ T effector cells contribute to the inflammatory
response in lupus nephritis in mice and in humans with their renal infiltration correlating with tissue damage
and disease severity. Yet, there is limited knowledge of the phenotypic characteristics of the T cells that
contribute to local tissue injury in lupus. In a like manner, autoreactive B cells with maturation to autoantibody-
producing plasma cells promote renal injury in lupus, with initiation of immune complex glomerulonephritis, a
sentinel finding of lupus in mice and humans. More recent data reveal that a subset of B cells, marked by
expression of CD11c and the transcription factor T-bet, drives pathogenic autoantibody production and
subsequent tissue injury in murine lupus nephritis, with data emerging that phenotypically similar cells arise in
normal humans and circulate in the blood of patients with SLE. Renal-infiltrating B cells and plasma cells are a
common finding in lupus nephritis in mice and humans, although such cells have not been well characterized.
Changes in the local microenvironment likely affect the phenotype and function of renal-infiltrating T and B
cells in lupus. The kidney microenvironment becomes hypoxic as a common denominator following a variety of
insults, an appropriately physiologic response analogous to that which occurs to ensure proper lymphocyte
effector function during hypoxic stress, such as in areas of pathogen replication or in and around tumors. We
have shown in preliminary studies that this response in the murine lupus kidney results in transcriptional and
phenotypic changes in tissue-infiltrating T and B cells, changes associated with their enhanced effector
capability. We now propose in this innovative grant to explore the hypothesis that hypoxic stress necessarily
shapes the phenotypes of renal-infiltrating T and B cells in lupus, with programming for activation and effector
function, a hypothesis we will explore in murine lupus using in vitro and in vivo studies, including genetic and
pharmacologic manipulation of hypoxia-induced effector pathways.

## Key facts

- **NIH application ID:** 9829537
- **Project number:** 5R21AI142145-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Joseph Edgar Craft
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $208,565
- **Award type:** 5
- **Project period:** 2018-12-01 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9829537

## Citation

> US National Institutes of Health, RePORTER application 9829537, Pathogenic Lymphocytes in Lupus Nephritis (5R21AI142145-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9829537. Licensed CC0.

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