Antibodies Produced by CLL Phenotype B Cells in Patients With Myasthenia Gravis Are Not Directed Against Neuromuscular Endplates

Abstract

Background and ObjectivesMyasthenia gravis (MG) can in rare cases be an autoimmune phenomenon associated with hematologic malignancies such as chronic lymphocytic leukemia (CLL). It is unclear whether in patients with MG and CLL, the leukemic B cells are the ones directly driving the autoimmune response against neuromuscular endplates.MethodsWe identified patients with acetylcholine receptor antibody–positive (AChR+) MG and CLL or monoclonal B-cell lymphocytosis (MBL), a precursor to CLL, and described their clinical features, including treatment responses. We generated recombinant monoclonal antibodies (mAbs) corresponding to the B-cell receptors of the CLL phenotype B cells and screened them for autoantigen binding.ResultsA computational immune cell screen revealed a subgroup of 5/38 patients with MG and 0/21 healthy controls who displayed a CLL-like B-cell phenotype. In follow-up hematologic flow cytometry, 2 of these 5 patients were diagnosed with an MBL. An additional patient with AChR+MG as a complication of manifest CLL presented at our neuromuscular clinic and was successfully treated with the anti-CD20 therapy obinutuzumab plus chlorambucil. We investigated the specificities of expanding CLL-like B-cell clones to assess a direct causal link between the 2 diseases. However, we observed no reactivity of the clones against the AChR, antigens at the neuromuscular junction, or other common autoantigens.DiscussionOur study suggests that AChR autoantibodies are produced by nonmalignant, polyclonal B cells The new anti-CD20 treatment obinutuzumab might be considered in effectively treating AChR+MG.Classification of EvidenceThis is a single case study and provides Class IV evidence that obinutuzumab is safe to use in patients with MG.

Registered trials on novel therapies for myasthenia gravis: a cross-sectional study on ClinicalTrials.gov

“…Obinutuzumab provides a distinct mechanism of action from rituximab through primarily direct cell death rather than complement-mediated cytotoxicity. It may be worth considering as an effective treatment for AChR MG 48 .…”

An angel or a devil? Current view on the role of CD8+ T cells in the pathogenesis of myasthenia gravis

“…Anti-CD20 mAbs is a potential therapy for both antibody-mediated and T cell-mediated autoimmune diseases [108], such as MS [109][110][111][112], rheumatoid arthritis (RA) [113][114][115], systemic lupus erythematosus [115][116][117], antineutrophil cytoplasmic antibody-associated vasculitis [117,118], polymyositis/dermatomyositis [119,120], primary Sjögren's syndrome [121,122], idiopathic autoimmune thrombocytopenia and neutropenia [123], and MG [119,124,125]. Two mechanisms might explain the effect of rituximab on T cells: one is the indirect effect on B cell depletion that could influence T cell function, while the other, which might be more important, is the direct depletion of CD20 + T cells [126].…”