ANTIGEN-SPECIFIC DEPLETION OF PLASMA CELLS IN MYASTHENIA GRAVIS

Background: IgG4 is associated with two emerging groups of rare diseases: 1) IgG4 autoimmune diseases (IgG4-AID) and 2) IgG4-related diseases (IgG4-RLD). Anti-neuronal IgG4-AID include MuSK myasthenia gravis, LGI1- and Caspr2-encephalitis and autoimmune nodo-/paranodopathies (CNTN1 or NF155 antibodies). IgG4-RLD is a multiorgan disease hallmarked by tissue-destructive fibrotic lesions with lymphocyte and IgG4 plasma cell infiltrates and increased serum IgG4 concentrations. It is unclear, whether IgG4-AID and IgG4-RLD share relevant clinical and immunopathological features. Methods: We collected and analysed serological, clinical, and histopathological data in 50 patients with anti-neuronal IgG4-AID and 16 patients with IgG4-RLD. Results: A significantly higher proportion of IgG4-RLD patients had serum IgG4 elevation when compared to IgG4-AID patients (50% vs. 16%, p = .015). Moreover, those IgG4-AID patients with elevated IgG4 did not meet the diagnostic criteria of IgG4-RLD, and their autoantibody titres did not correlate with their serum IgG4 concentrations. In addition, patients with IgG4-RLD were negative for anti-neuronal/neuromuscular autoantibodies and among these patients, men showed a significantly higher propensity for IgG4 elevation, when compared to women (p = .041). Last, a kidney biopsy from a patient with autoimmune paranodopathy due to CNTN1/Caspr1-complex IgG4 autoantibodies and concomitant nephrotic syndrome did not show fibrosis or IgG4+ plasma cells, which are diagnostic hallmarks of IgG4-RLD. Conclusion: Our observations suggest that anti-neuronal IgG4-AID and IgG4-RLD are most likely distinct disease entities.

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Altered expression of transcription factors IRF4 and IRF8 in peripheral blood B cells is associated with clinical severity and circulating plasma cells frequency in patients with myasthenia gravis

Autoimmunity ◽

10.1080/08916934.2018.1454913 ◽

2018 ◽

Vol 51 (3) ◽

pp. 126-134 ◽

Cited By ~ 2

Author(s):

Yong Zhang ◽

Xiao Jia ◽

Yan Xia ◽

Hao Li ◽

Fei Chen ◽

...

Keyword(s):

Transcription Factors ◽

B Cells ◽

Myasthenia Gravis ◽

Peripheral Blood ◽

Plasma Cells ◽

Clinical Severity ◽

Altered Expression

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Serological Immunoglobulin-Free Light Chain Profile in Myasthenia Gravis Patients

Journal of Immunology Research ◽

10.1155/2018/9646209 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 7

Author(s):

Umberto Basile ◽

Mariapaola Marino ◽

Cecilia Napodano ◽

Krizia Pocino ◽

Paolo Emilio Alboini ◽

...

Keyword(s):

Myasthenia Gravis ◽

Disease Activity ◽

B Cell ◽

Lupus Erythematosus ◽

Cell Activation ◽

Plasma Cells ◽

Cell Activity ◽

B Cell Activation ◽

Heavy Chains ◽

Autoimmune Conditions

Background. Serological levels of free immunoglobulin light chains (FLCs), produced in excess of heavy chains during synthesis of immunoglobulins by plasma cells, can be considered a direct marker of B cell activity in different systemic inflammatory-autoimmune conditions and may represent a useful predictor of rituximab (RTX) therapeutic efficacy, as reported for rheumatoid arthritis and systemic lupus erythematosus. Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction with antibodies (abs) targeting the acetylcholine receptor (AChR) or the muscle-specific tyrosine kinase (MuSK), inducing muscle weakness and excessive fatigability. As MG course may be remarkably variable, we evaluated the possible use of FLCs as biomarkers of disease activity. Subjects and Methods. We assessed FLC levels in 34 sera from 17 AChR-MG and from 13 MuSK-MG patients, in comparison with 20 sera from patients with systemic autoimmune rheumatic diseases and 18 from healthy blood donors, along with titers of specific auto-abs and IgG subclass distribution. Results. We found a statistically significant increase in free κ chains in both AChR- and MuSK-MG patients, while free λ chain levels were increased only in AChR-MG. We also observed a significant reduction of both free κ and λ chains in 1/4 MuSK-MG patients along with specific abs titer, two months after RTX treatment. Conclusions. From our data, FLCs appear to be a sensitive marker of B cell activation in MG. Further investigations are necessary to exploit their potential as reliable biomarkers of disease activity.

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Disturbed B cell subpopulations and increased plasma cells in myasthenia gravis patients

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2013.09.006 ◽

2013 ◽

Vol 264 (1-2) ◽

pp. 114-119 ◽

Cited By ~ 17

Author(s):

Siegfried Kohler ◽

Thomas Oskar Philipp Keil ◽

Marc Swierzy ◽

Sarah Hoffmann ◽

Hanne Schaffert ◽

...

Keyword(s):

Myasthenia Gravis ◽

B Cell ◽

Plasma Cells ◽

Cell Subpopulations

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Thymus-derived B cell clones persist in the circulation after thymectomy in myasthenia gravis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2007206117 ◽

2020 ◽

Vol 117 (48) ◽

pp. 30649-30660 ◽

Cited By ~ 1

Author(s):

Ruoyi Jiang ◽

Kenneth B. Hoehn ◽

Casey S. Lee ◽

Minh C. Pham ◽

Robert J. Homer ◽

...

Keyword(s):

B Cells ◽

Myasthenia Gravis ◽

B Cell ◽

Plasma Cells ◽

Cell Repertoire ◽

B Cell Repertoire ◽

Cell Clones ◽

Autoantibody Titer ◽

Repertoire Sequencing ◽

Symptom Measures

Myasthenia gravis (MG) is a neuromuscular, autoimmune disease caused by autoantibodies that target postsynaptic proteins, primarily the acetylcholine receptor (AChR) and inhibit signaling at the neuromuscular junction. The majority of patients under 50 y with AChR autoantibody MG have thymic lymphofollicular hyperplasia. The MG thymus is a reservoir of plasma cells that secrete disease-causing AChR autoantibodies and although thymectomy improves clinical scores, many patients fail to achieve complete stable remission without additional immunosuppressive treatments. We speculate that thymus-associated B cells and plasma cells persist in the circulation after thymectomy and that their persistence could explain incomplete responses to resection. We studied patients enrolled in a randomized clinical trial and used complementary modalities of B cell repertoire sequencing to characterize the thymus B cell repertoire and identify B cell clones that resided in the thymus and circulation before and 12 mo after thymectomy. Thymus-associated B cell clones were detected in the circulation by both mRNA-based and genomic DNA-based sequencing. These antigen-experienced B cells persisted in the circulation after thymectomy. Many circulating thymus-associated B cell clones were inferred to have originated and initially matured in the thymus before emigration from the thymus to the circulation. The persistence of thymus-associated B cells correlated with less favorable changes in clinical symptom measures, steroid dose required to manage symptoms, and marginal changes in AChR autoantibody titer. This investigation indicates that the diminished clinical response to thymectomy is related to persistent circulating thymus-associated B cell clones.

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Targeting plasma cells with proteasome inhibitors: possible roles in treating myasthenia gravis?

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.2012.06824.x ◽

2012 ◽

Vol 1274 (1) ◽

pp. 48-59 ◽

Cited By ~ 24

Author(s):

Alejandro M. Gomez ◽

Nick Willcox ◽

Peter C. Molenaar ◽

Wim Buurman ◽

Pilar Martinez-Martinez ◽

...

Keyword(s):

Myasthenia Gravis ◽

Plasma Cells ◽

Proteasome Inhibitors

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Anti-Neuronal IgG4 Autoimmune Diseases and IgG4-Related Diseases May Not Be Part of the Same Spectrum: A Comparative Study

Frontiers in Immunology ◽

10.3389/fimmu.2021.785247 ◽

2022 ◽

Vol 12 ◽

Author(s):

Verena Endmayr ◽

Cansu Tunc ◽

Lara Ergin ◽

Anna De Rosa ◽

Rosa Weng ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Autoimmune Diseases ◽

Myasthenia Gravis ◽

Rare Diseases ◽

Plasma Cells ◽

Kidney Biopsy ◽

Serum Igg4 ◽

Distinct Disease ◽

Disease Entities ◽

Multiorgan Disease

BackgroundIgG4 is associated with two emerging groups of rare diseases: 1) IgG4 autoimmune diseases (IgG4-AID) and 2) IgG4-related diseases (IgG4-RLD). Anti-neuronal IgG4-AID include MuSK myasthenia gravis, LGI1- and Caspr2-encephalitis and autoimmune nodo-/paranodopathies (CNTN1/Caspr1 or NF155 antibodies). IgG4-RLD is a multiorgan disease hallmarked by tissue-destructive fibrotic lesions with lymphocyte and IgG4 plasma cell infiltrates and increased serum IgG4 concentrations. It is unclear whether IgG4-AID and IgG4-RLD share relevant clinical and immunopathological features.MethodsWe collected and analyzed clinical, serological, and histopathological data in 50 patients with anti-neuronal IgG4-AID and 19 patients with IgG4-RLD.ResultsA significantly higher proportion of IgG4-RLD patients had serum IgG4 elevation when compared to IgG4-AID patients (52.63% vs. 16%, p = .004). Moreover, those IgG4-AID patients with elevated IgG4 did not meet the diagnostic criteria of IgG4-RLD, and their autoantibody titers did not correlate with their serum IgG4 concentrations. In addition, patients with IgG4-RLD were negative for anti-neuronal/neuromuscular autoantibodies and among these patients, men showed a significantly higher propensity for IgG4 elevation, when compared to women (p = .005). Last, a kidney biopsy from a patient with autoimmune paranodopathy due to CNTN1/Caspr1-complex IgG4 autoantibodies and concomitant nephrotic syndrome did not show fibrosis or IgG4+ plasma cells, which are diagnostic hallmarks of IgG4-RLD.ConclusionOur observations suggest that anti-neuronal IgG4-AID and IgG4-RLD are most likely distinct disease entities.

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