# Novel Approaches for Investigating the Pathology of Myasthenia Gravis Autoantibodies

> **NIH NIH R21** · YALE UNIVERSITY · 2020 · $171,386

## Abstract

Project Summary. Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission.
Autoantibodies to muscle specific tyrosine kinase (MuSK) can be found in patients with MG who do not have
detectable antibodies to the acetylcholine receptor (AChR). Passive transfer and active immunization studies in
animals have shown that MuSK serum autoantibodies are clearly pathogenic. Among the features distinguishing
MuSK MG from the AChR-specific subtype is a predominantly IgG4 subclass-driven immunopathology and
unique responsiveness to immunotherapy. B cells are critical in driving many aspects of MuSK MG including
production of pathogenic autoantibodies. Yet their identity, specificity, function, and fate remain very poorly
defined. It is well-recognized in the field of B cell-mediated autoimmunity that finding a means to isolate and
study the specific autoreactive B cells is an important unsolved problem of high impact. Thus, it follows that the
reason for lack of progress is not lack of interest, but rather that the problem is difficult: isolating and
characterizing autoantibody-producing B cells is non-trivial.
To this end, we applied novel technology for direct, ex-vivo isolation of individual MuSK autoantibody-producing
B cells, which relies on flow cytometry-based separation and a fluorescent MuSK antigen. We have recently
isolated a large set of memory B cells and antibody-secreting cells from patients with MuSK MG. From these
cells, we have produced more than 50 unique monoclonal antibodies (mAbs) and further demonstrated their
specificity to human MuSK. This important finding represents the first isolation of B lineage cells (and human
mAbs) that produce autoantibodies targeting the MuSK antigen.
We now wish to apply this unique approach to further describe the important biological and pathogenic
characteristics of these MG autoantibodies. We propose to investigate paradigm-changing features of MuSK MG
pathology that were previously not possible to study with antibodies derived from heterogeneous human serum.
We will demonstrate that MuSK autoantibodies can utilize IgG subclasses other than IgG4 and that they
recognize novel epitopes on MuSK. We anticipate that these findings will modify the widely accepted view of the
molecular pathology. We will then explore how different MuSK autoantibody mAbs, encoding different IgG
subclasses and different epitope recognition, contribute to immunopathology using both established in-vitro and
in-vivo models.
This study leverages an exceptionally unique approach applied to patient-derived specimens to first investigate
fundamental disease mechanisms that have the potential to change the understanding of the immunopathology
and second to develop clinically relevant disease models that will directly impact patient care.

## Key facts

- **NIH application ID:** 9830016
- **Project number:** 5R21AI142198-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Kevin C O'Connor
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $171,386
- **Award type:** 5
- **Project period:** 2018-11-28 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830016

## Citation

> US National Institutes of Health, RePORTER application 9830016, Novel Approaches for Investigating the Pathology of Myasthenia Gravis Autoantibodies (5R21AI142198-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9830016. Licensed CC0.

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