Autoantibody-producing plasmablasts after B cell depletion identified in muscle-specific kinase myasthenia gravis
Document Type
Article
Abstract
Myasthenia gravis (MG) is a B cell-mediated autoimmune disorder of neuromuscular transmission. Pathogenic 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). MuSK MG includes immunological and clinical features that are generally distinct from AChR MG, particularly regarding responsiveness to therapy. B cell depletion has been shown to affect a decline in serum autoantibodies and to induce sustained clinical improvement in the majority of MuSK MG patients. However, the duration of this benefit may be limited, as we observed disease relapse in MuSK MG patients who had achieved rituximab-induced remission. We investigated the mechanisms of such relapses by exploring autoantibody production in the reemerging B cell compartment. Autoantibody-expressing CD27+ B cells were observed within the reconstituted repertoire during relapse but not during remission or in controls. Using two complementary approaches, which included production of 108 unique human monoclonal recombinant immunoglobulins, we demonstrated that antibody-secreting CD27hiCD38hi B cells (plasmablasts) contribute to the production of MuSK autoantibodies during relapse. The autoantibodies displayed hallmarks of antigen-driven affinity maturation. These collective findings introduce potential mechanisms for understanding both MuSK autoantibody production and disease relapse following B cell depletion.
Medical Subject Headings
Adult; Aged; Aged, 80 and over; Animals; Autoantibodies (biosynthesis); B-Lymphocytes (immunology); Cohort Studies; Female; Humans; Immunologic Factors (therapeutic use); Lymphocyte Depletion; Male; Mice; Middle Aged; Myasthenia Gravis (drug therapy, immunology); Receptor Protein-Tyrosine Kinases (immunology); Receptors, Cholinergic (immunology); Recurrence; Remission Induction; Rituximab (therapeutic use); Tumor Necrosis Factor Receptor Superfamily, Member 7 (immunology)
Publication Date
9-7-2017
Publication Title
JCI insight
E-ISSN
2379-3708
Volume
2
Issue
17
PubMed ID
28878127
Digital Object Identifier (DOI)
10.1172/jci.insight.94263
Recommended Citation
Stathopoulos, Panos; Kumar, Aditya; Nowak, Richard J.; and O'Connor, Kevin C., "Autoantibody-producing plasmablasts after B cell depletion identified in muscle-specific kinase myasthenia gravis" (2017). Neurology. 1663.
https://scholar.barrowneuro.org/neurology/1663