Mechanisms underlying B cell immune dysregulation and autoantibody production in MuSK myasthenia gravis

Document Type

Article

Abstract

Pathogenic autoantibodies to muscle-specific tyrosine kinase (MuSK) can be found in patients with myasthenia gravis (MG) who do not have detectable antibodies to the acetylcholine receptor. Although the autoantibody-mediated pathology is well understood, much remains to be learned about the cellular immunology that contributes to autoantibody production. To that end, our laboratory has investigated particular components associated with the cellular immunopathology of MuSK MG. First, we found that B cell tolerance defects contribute to the abnormal development of the naive repertoire, which indicates that dysregulation occurs before the production of autoantibodies. Second, both the naive and antigen-experienced memory B cell repertoire, which we examined through the application of high-throughput adaptive immune receptor repertoire sequencing, include abnormalities not found in healthy controls. This highlights a broad immune dysregulation. Third, using complementary approaches, including production of human monoclonal antibodies, we determined that circulating plasmablasts directly contribute to the production of MuSK-specific autoantibodies in patients experiencing relapse following B cell depletion therapy. These collective findings contribute to defining a mechanistic model that describes MuSK MG immunopathogenesis.

Medical Subject Headings

Autoantibodies (biosynthesis); B-Lymphocyte Subsets (immunology); Central Tolerance; Humans; Immunoglobulin Variable Region (genetics); Immunologic Memory; Lymphocyte Depletion; Models, Immunological; Myasthenia Gravis (etiology, immunology, therapy); Receptor Protein-Tyrosine Kinases (immunology); Receptors, Cholinergic (immunology); Rituximab (therapeutic use)

Publication Date

1-1-2018

Publication Title

Annals of the New York Academy of Sciences

E-ISSN

1749-6632

Volume

1412

Issue

1

First Page

154

Last Page

165

PubMed ID

29381221

Digital Object Identifier (DOI)

10.1111/nyas.13535

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