# B cell costimulatory signals in the pathogenesis of SLE

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2020 · $87,892

## Abstract

Project abstract
Despite modern immunosuppressive therapies, patients with systemic lupus erythematosus (SLE) remain at
high risk for progressive organ damage, emphasizing the need for better, targeted treatments for this disease.
In addition to the production of pathogenic autoantibodies, recent studies have demonstrated that B cells can
promote lupus pathogenesis by initiating immune tolerance breaks and facilitating the generation of
spontaneous germinal centers (GC). In this context, distinct costimulatory receptor families have been linked
with the pathogenesis of autoimmunity. However, despite compelling preclinical data in SLE and clinical benefit
in other autoimmune diseases, costimulatory blockade with CTLA4-Ig (Abatacept) failed to control disease in
lupus clinical trials. These data emphasize that our understanding of the cell-intrinsic mechanisms whereby
B7:CD28 costimulatory signals impact autoreactive B cell activation in lupus is incomplete. In this project, we
will use well-characterized murine lupus models and the novel application of chimeric antigen receptor (CAR) T
cell technology to dissect the immune mechanisms underlying the initiation, propagation and cellular output of
extra-follicular (EF) vs. GC B cell activation pathways in SLE. In Aim 1, we will study whether pathogenic
autoantibodies can be generated via an EF B cell activation pathway in a T cell-dependent, but CD28
independent, manner. In Aim 2, we will test whether B cell costimulatory signals promote the initiation or
maintenance of autoimmune GC responses. Finally, in Aim 3, we will test whether another costimulatory
receptor pair, ICOS:ICOS ligand, compensates for loss of CD28 signals during lupus pathogenesis. Together,
these studies promise to advance our understanding of lupus pathogenesis and may inform the design of
future human clinical trials of costimulatory blockade in SLE and other humoral autoimmune diseases.

## Key facts

- **NIH application ID:** 10169781
- **Project number:** 3R01AR073938-02S1
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Shaun William Jackson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $87,892
- **Award type:** 3
- **Project period:** 2019-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169781

## Citation

> US National Institutes of Health, RePORTER application 10169781, B cell costimulatory signals in the pathogenesis of SLE (3R01AR073938-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10169781. Licensed CC0.

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