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March 2023; 10 (2) Research ArticleOpen Access

Reduced Number of Thymoma CTLA4-Positive Cells Is Associated With a Higher Probability of Developing Myasthenia Gravis

Rodrigo Álvarez-Velasco, Oriol Dols-Icardo, Shaima El Bounasri, Laura López-Vilaró, Juan Carlos Trujillo, David Reyes-Leiva, Xavier Suárez-Calvet, Elena Cortés-Vicente, Isabel Illa, Eduard Gallardo
First published January 25, 2023, DOI: https://doi.org/10.1212/NXI.0000000000200085
Rodrigo Álvarez-Velasco
From the Neuromuscular Diseases Unit (R.Á.-V., D.R.-L., E.C.-V., I.I.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona; Department of Medicine (R.Á.-V., D.R.-L.), Universitat Autónoma de Barcelona; Memory Unit (O.D.-I., S.E.B.), Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (O.D.-I., S.E.B.), Madrid; Departments of Pathology (L.L.-V.) and Thoracic Surgery (J.C.T.), Hospital de la Santa Creu i Sant Pau, Barcelona; Neuromuscular Diseases Group (X.S.-C., E.G.), Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Barcelona; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (E.G.), Instituto de Salud Carlos III, Madrid.
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Oriol Dols-Icardo
From the Neuromuscular Diseases Unit (R.Á.-V., D.R.-L., E.C.-V., I.I.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona; Department of Medicine (R.Á.-V., D.R.-L.), Universitat Autónoma de Barcelona; Memory Unit (O.D.-I., S.E.B.), Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (O.D.-I., S.E.B.), Madrid; Departments of Pathology (L.L.-V.) and Thoracic Surgery (J.C.T.), Hospital de la Santa Creu i Sant Pau, Barcelona; Neuromuscular Diseases Group (X.S.-C., E.G.), Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Barcelona; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (E.G.), Instituto de Salud Carlos III, Madrid.
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Shaima El Bounasri
From the Neuromuscular Diseases Unit (R.Á.-V., D.R.-L., E.C.-V., I.I.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona; Department of Medicine (R.Á.-V., D.R.-L.), Universitat Autónoma de Barcelona; Memory Unit (O.D.-I., S.E.B.), Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (O.D.-I., S.E.B.), Madrid; Departments of Pathology (L.L.-V.) and Thoracic Surgery (J.C.T.), Hospital de la Santa Creu i Sant Pau, Barcelona; Neuromuscular Diseases Group (X.S.-C., E.G.), Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Barcelona; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (E.G.), Instituto de Salud Carlos III, Madrid.
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Laura López-Vilaró
From the Neuromuscular Diseases Unit (R.Á.-V., D.R.-L., E.C.-V., I.I.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona; Department of Medicine (R.Á.-V., D.R.-L.), Universitat Autónoma de Barcelona; Memory Unit (O.D.-I., S.E.B.), Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (O.D.-I., S.E.B.), Madrid; Departments of Pathology (L.L.-V.) and Thoracic Surgery (J.C.T.), Hospital de la Santa Creu i Sant Pau, Barcelona; Neuromuscular Diseases Group (X.S.-C., E.G.), Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Barcelona; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (E.G.), Instituto de Salud Carlos III, Madrid.
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Juan Carlos Trujillo
From the Neuromuscular Diseases Unit (R.Á.-V., D.R.-L., E.C.-V., I.I.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona; Department of Medicine (R.Á.-V., D.R.-L.), Universitat Autónoma de Barcelona; Memory Unit (O.D.-I., S.E.B.), Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (O.D.-I., S.E.B.), Madrid; Departments of Pathology (L.L.-V.) and Thoracic Surgery (J.C.T.), Hospital de la Santa Creu i Sant Pau, Barcelona; Neuromuscular Diseases Group (X.S.-C., E.G.), Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Barcelona; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (E.G.), Instituto de Salud Carlos III, Madrid.
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David Reyes-Leiva
From the Neuromuscular Diseases Unit (R.Á.-V., D.R.-L., E.C.-V., I.I.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona; Department of Medicine (R.Á.-V., D.R.-L.), Universitat Autónoma de Barcelona; Memory Unit (O.D.-I., S.E.B.), Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (O.D.-I., S.E.B.), Madrid; Departments of Pathology (L.L.-V.) and Thoracic Surgery (J.C.T.), Hospital de la Santa Creu i Sant Pau, Barcelona; Neuromuscular Diseases Group (X.S.-C., E.G.), Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Barcelona; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (E.G.), Instituto de Salud Carlos III, Madrid.
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Xavier Suárez-Calvet
From the Neuromuscular Diseases Unit (R.Á.-V., D.R.-L., E.C.-V., I.I.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona; Department of Medicine (R.Á.-V., D.R.-L.), Universitat Autónoma de Barcelona; Memory Unit (O.D.-I., S.E.B.), Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (O.D.-I., S.E.B.), Madrid; Departments of Pathology (L.L.-V.) and Thoracic Surgery (J.C.T.), Hospital de la Santa Creu i Sant Pau, Barcelona; Neuromuscular Diseases Group (X.S.-C., E.G.), Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Barcelona; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (E.G.), Instituto de Salud Carlos III, Madrid.
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Elena Cortés-Vicente
From the Neuromuscular Diseases Unit (R.Á.-V., D.R.-L., E.C.-V., I.I.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona; Department of Medicine (R.Á.-V., D.R.-L.), Universitat Autónoma de Barcelona; Memory Unit (O.D.-I., S.E.B.), Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (O.D.-I., S.E.B.), Madrid; Departments of Pathology (L.L.-V.) and Thoracic Surgery (J.C.T.), Hospital de la Santa Creu i Sant Pau, Barcelona; Neuromuscular Diseases Group (X.S.-C., E.G.), Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Barcelona; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (E.G.), Instituto de Salud Carlos III, Madrid.
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Isabel Illa
From the Neuromuscular Diseases Unit (R.Á.-V., D.R.-L., E.C.-V., I.I.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona; Department of Medicine (R.Á.-V., D.R.-L.), Universitat Autónoma de Barcelona; Memory Unit (O.D.-I., S.E.B.), Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (O.D.-I., S.E.B.), Madrid; Departments of Pathology (L.L.-V.) and Thoracic Surgery (J.C.T.), Hospital de la Santa Creu i Sant Pau, Barcelona; Neuromuscular Diseases Group (X.S.-C., E.G.), Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Barcelona; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (E.G.), Instituto de Salud Carlos III, Madrid.
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Eduard Gallardo
From the Neuromuscular Diseases Unit (R.Á.-V., D.R.-L., E.C.-V., I.I.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona; Department of Medicine (R.Á.-V., D.R.-L.), Universitat Autónoma de Barcelona; Memory Unit (O.D.-I., S.E.B.), Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (O.D.-I., S.E.B.), Madrid; Departments of Pathology (L.L.-V.) and Thoracic Surgery (J.C.T.), Hospital de la Santa Creu i Sant Pau, Barcelona; Neuromuscular Diseases Group (X.S.-C., E.G.), Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Barcelona; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (E.G.), Instituto de Salud Carlos III, Madrid.
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Citation
Reduced Number of Thymoma CTLA4-Positive Cells Is Associated With a Higher Probability of Developing Myasthenia Gravis
Rodrigo Álvarez-Velasco, Oriol Dols-Icardo, Shaima El Bounasri, Laura López-Vilaró, Juan Carlos Trujillo, David Reyes-Leiva, Xavier Suárez-Calvet, Elena Cortés-Vicente, Isabel Illa, Eduard Gallardo
Neurol Neuroimmunol Neuroinflamm Mar 2023, 10 (2) e200085; DOI: 10.1212/NXI.0000000000200085

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Abstract

Background and Objectives Myasthenia gravis (MG) is an autoimmune disease associated with comorbid thymoma in 10%–15% of cases. Cytotoxic T lymphocyte–associated antigen 4 (CTLA4) expressed by T cells downregulates T-cell–mediated immune response. Polymorphisms in the CTLA4 gene have been associated with the development of MG. In this context, we aimed to determine whether CTLA4 expression in the thymoma differs between patients with and without MG and whether CTLA4 gene polymorphisms are associated with these differences.

Methods This is a retrospective study of all patients, with and without MG, surgically treated at our institution for thymoma between January 2010 and December 2020. Ten samples were obtained from normal thymuses as controls. The number of CTLA4-positive cells in paraffin-embedded thymoma samples was determined by immunohistochemistry. The presence of follicular-center and regulatory T-cell lymphocytes was determined by immunohistochemistry (B-cell lymphoma [BCL]-6 expression) and double immunofluorescence–based staining of CD4-FOXP3, respectively. We evaluated the association between thymic expression of CTLA4 and the development of MG. We also determined the association between CTLA4 expression and various clinical and prognostic characteristics of MG. We sequenced the CTLA4 gene and evaluated possible associations between CTLA4 polymorphisms and thymic CTLA4 expression. Finally, we assessed the potential association between these polymorphisms and the risk of MG.

Results Forty-one patients with thymoma were included. Of them, 23 had comorbid MG (56.1%). On average, patients with MG had fewer CTLA4-positive cells in the thymoma than non-MG patients: 69.3 cells/mm2 (95% CIs: 39.6–99.1) vs 674.4 (276.0–1,024.0) cells/mm2; p = 0.001 and vs controls (200.74 [57.9–343.6] cells/mm2; p = 0.02). No between-group differences (MG vs non-MG) were observed in the number of cells positive for BCL6 or CD4-FOXP3. CTLA4 expression was not associated with differences in MG outcome or treatment refractoriness. Two polymorphisms were detected in the CTLA4 gene, rs231770 (n = 30 patients) and rs231775 (n = 17). MG was present in a similar proportion of patients for all genotypes. However, a nonsignificant trend toward a lower CTLA4-positive cell count was observed among carriers of the rs231775 polymorphism vs noncarriers: 77.9 cells/mm2 (95% CI: −51.5 to 207.5) vs 343.3 cells/mm2 (95% CI: 126.2–560.4).

Discussion Reduced CTLA4 expression in thymoma may predispose to a higher risk of developing MG.

Glossary

AChR=
acetylcholine receptors;
BCL=
B-cell lymphoma;
CTLA4=
cytotoxic T lymphocyte–associated antigen 4;
EDTA=
ethylene diamine tetraacetic acid;
GWAS=
genome-wide association study;
IgG=
immunoglobulin G;
MG=
myasthenia gravis;
MGFA-PIS=
MG Foundation of America postintervention status;
PBS=
phosphate buffer solution;
Treg=
T regulatory;
WHO=
World Health Organization

Footnotes

  • Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

  • The Article Processing Charge was funded by the authors.

  • Submitted and externally peer reviewed. The handling editor was Associate Editor Marinos C. Dalakas, MD, FAAN.

  • Received September 7, 2022.
  • Accepted in final form November 23, 2022.
  • © 2023 American Academy of Neurology

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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