Reduced Number of Thymoma CTLA4-Positive Cells Is Associated With a Higher Probability of Developing Myasthenia Gravis
Álvarez-Velasco, Rodrigo (Universitat Autònoma de Barcelona. Departament de Medicina)
Dols Icardo, Oriol (Institut d'Investigació Biomèdica Sant Pau)
El Bounasri, Shaima (Institut d'Investigació Biomèdica Sant Pau)
López Vilaró, Laura (Institut d'Investigació Biomèdica Sant Pau)
Trujillo, Juan Carlos (Institut d'Investigació Biomèdica Sant Pau)
Reyes-Leiva, David (Universitat Autònoma de Barcelona. Departament de Medicina)
Suarez-Calvet, Xavier (Institut d'Investigació Biomèdica Sant Pau)
Cortés-Vicente, Elena (Institut d'Investigació Biomèdica Sant Pau)
Illa, Isabel (Institut d'Investigació Biomèdica Sant Pau)
Gallardo, Eduard (Institut d'Investigació Biomèdica Sant Pau)

Date:	2023
Abstract:	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. 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. 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/mm 2 (95% CIs: 39. 6-99. 1) vs 674. 4 (276. 0-1,024. 0) cells/mm 2 ; p = 0. 001 and vs controls (200. 74 [57. 9-343. 6] cells/mm 2 ; 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/mm 2 (95% CI: −51. 5 to 207. 5) vs 343. 3 cells/mm 2 (95% CI: 126. 2-560. 4). Reduced CTLA4 expression in thymoma may predispose to a higher risk of developing MG.
Grants:	Instituto de Salud Carlos III PI19-01774 Instituto de Salud Carlos III JR19-00037
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	CTLA-4 Antigen ; Forkhead Transcription Factors ; Myasthenia Gravis ; Probability ; Retrospective Studies ; Thymoma ; Thymus Neoplasms
Published in:	Neurology® neuroimmunology & neuroinflammation, Vol. 10 (january 2023) , ISSN 2332-7812

DOI: 10.1212/NXI.0000000000200085
PMID: 36697230

9 p, 270.5 KB

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