Comments for:
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.
Authors
Panos Stathopoulos, Aditya Kumar, Richard J. Nowak, Kevin C. O’Connor
Circulating plasmablasts in muscle-specific kinase myasthenia gravis
Submitter: Guillermo Delgado-García | guillermo.delgadogr@gmail.com
Authors: Guillermo Delgado-García and Teresa Corona-Vázquez
Clinical Laboratory of Neurodegenerative Diseases, National Institute of Neurology and Neurosurgery, Mexico City
Published October 17, 2017
We recently read with great interest the research article published by Stathopoulos et al in the Journal (1). We believe that their findings are quite relevant in the study of immunopathogenic mechanisms in muscle-specific kinase myasthenia gravis (MuSK MG). Considering the importance of this topic, we think it is pertinent to add some comments.
At the end of their discussion the authors mention that "given their modest elevation in MuSK MG [0.3-3%], plasmablast frequency distributions do not appear to be reliable markers of disease activity" (1). Here it is worth noting that of the four patients who were intially included in the study, the initial B cell flow cytometry was only performed in three who were in postinterventional exacerbation (i.e., this study was not performed in the patient who was in complete stable remission). Of these three patients, two were on prednisone treatment (10 mg daily), a therapy that effectively reduces circulating plasmoblasts (2). Samples extracted from the second patient were collected on two consecutive occasions (MuSK 2a and MuSK 2b in Table 1). In the first of these, the patient had recently been immunized and, in the second, he was already on prednisone treatment. Plasmablasts have been shown to increase post-vaccination (3). These two factors (prednisone treatment and vaccination) have already been stressed by us (4) in reference to Guptill et al's study (5), since they can alter the results and their interpretation.
In their results the authors mention that an expanded compartment of plasmablasts has been previously observed in a small subset of MG patients, and they include two references to support this assertion (5, 6). However, Guptill et al found no differences in the percentage of plasmablasts between healthy controls and MuSK MG patients not treated with rituximab. In addition, they neither found differences between immunosuppressed and nonimmunosuppressed patients (5). On the other hand, Kohler et al did not include patients with MuSK MG in their study (6).
Studies exploring MuSK MG usually have limited sample sizes (1, 5). In the future, multicentric studies through international, collaborative efforts might mitigate this limitation (4).
Conflict of interests: The authors have declared that no conflict of interest exists.
References:
1. Stathopoulos P, Kumar A, Nowak RJ, O'Connor KC. Autoantibody-producing plasmablasts after B cell depletion identified in muscle-specific kinase myasthenia gravis. JCI Insight. 2017 Sep 7;2(17). pii: 94263. doi: 10.1172/jci.insight.94263.
2. Iwata S, Saito K, Hirata S, Tanaka Y. Phenotypic changes of lymphocyte in a patient with IgG4-related disease after corticosteroid therapy. Ann Rheum Dis. 2012 Dec;71(12):2058-9. doi: 10.1136/annrheumdis-2012-201657.
3. Maecker HT, McCoy JP, Nussenblatt R. Standardizing immunophenotyping for the Human Immunology Project. Nat Rev Immunol. 2012 Feb 17;12(3):191-200. doi: 10.1038/nri3158.
4. Delgado-García G, Corona-Vázquez T. Peripheral plasmablasts in anti-MuSK myasthenia gravis. Neuroimmunol Neuroinflammation. 2017;4:0. doi:10.20517/2347-8659.2017.39.
5. Guptill JT, et al. Characterization of B cells in muscle-specific kinase antibody myasthenia gravis. Neurol Neuroimmunol Neuroinflamm. 2015 Feb 26;2(2):e77. doi: 10.1212/NXI.0000000000000077.
6. Kohler S, et al. Disturbed B cell subpopulations and increased plasma cells in myasthenia gravis patients. J Neuroimmunol. 2013 Nov 15;264(1-2):114-9. doi: 10.1016/j.jneuroim.2013.09.006.
