# Identifying immunotherapy targets against thymus B cells in AChR myasthenia gravis (MG)

> **NIH NIH F31** · YALE UNIVERSITY · 2020 · $30,330

## Abstract

Project Summary
Myasthenia gravis (MG) is an autoimmune neuromuscular disorder caused by autoantibodies that disrupt
components of neuromuscular junctions, such as the acetylcholine receptor (AChR, 90% of patients). Rituximab
(RTX) is a B cell depleting agent used in the management of an increasingly wide range of autoimmune diseases;
many AChR MG patients achieve remission after RTX but relapse following treatment cessation is common. The
thymus is a known reservoir of B cells that can produce pathogenic anti-AChR antibodies and resection of the
thymus has long been known to improve MG symptoms; however, many patients also fail to achieve complete
remission after thymectomy. In both cases, we conclude that the failed depletion of B cells relevant to disease
may be driving poor responses. Developing systemic immunotherapy to better target B cells that escape
depletion is therefore of critical importance for effective MG treatment. Characterizing the features of B cells that
re-emerge after RTX depletion in MG would further the development of more effective treatments for MG and
lead to a deeper understanding of the immuno-pathophysiology behind the disorder. The overall goal of this
project is to characterize the transcriptional features of disease-relevant B cells from patients who experienced
poor outcomes from two randomized clinical trials on the use of rituximab and thymectomy for the treatment of
AChR MG. Our laboratory recently developed a method called single cell tracing of adaptive immune repertoires
(STAIR) that allows for the unbiased identification and transcriptional characterization of autoantigen-specific B
cells that escape RTX depletion by combining high-depth bulk repertoire sequencing methods with single cell
gene expression and repertoire analysis. For this proposal, I will apply this approach to investigate the single cell
gene expression characteristics of B cells from the thymus that persist in the circulation of patients who
underwent thymectomy (Goal 1), and the characteristics of B cells associated with poor clinical responses to
RTX (Goal 2). We will test the hypothesis that B cells shared with the thymus will have a similar single cell
transcriptional identity as those that fail to be depleted by RTX: we expect that they will be clonally expanded
IgG-switched ASCs with specificity for autoantigen. This fellowship integrates a training plan that will include
invaluable learning experiences in machine learning and the latest NGS technology This training plan will
enhance the applicant's goal of becoming a physician scientist at the interface of clinical medicine and science.

## Key facts

- **NIH application ID:** 10068690
- **Project number:** 1F31AI154799-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Ruoyi Jiang
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $30,330
- **Award type:** 1
- **Project period:** 2020-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068690

## Citation

> US National Institutes of Health, RePORTER application 10068690, Identifying immunotherapy targets against thymus B cells in AChR myasthenia gravis (MG) (1F31AI154799-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10068690. Licensed CC0.

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