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.
Neurol Neuroimmunol Neuroinflamm. 2023 Jan 25;10(2). doi: 10.1212/NXI.0000000000200085. Print 2023 Mar.
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 (95% CIs: 39.6-99.1) vs 674.4 (276.0-1,024.0) cells/mm; = 0.001 and vs controls (200.74 [57.9-343.6] cells/mm; = 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 (95% CI: -51.5 to 207.5) vs 343.3 cells/mm (95% CI: 126.2-560.4).
Reduced CTLA4 expression in thymoma may predispose to a higher risk of developing MG.
重症肌无力（MG）是一种自身免疫性疾病，约 10%-15%的病例与胸腺瘤合并存在。T 细胞表达的细胞毒性 T 淋巴细胞相关抗原 4（CTLA4）可下调 T 细胞介导的免疫反应。CTLA4 基因的多态性与 MG 的发生有关。在这种情况下，我们旨在确定 CTLA4 在胸腺瘤中的表达是否在伴有和不伴有 MG 的患者之间存在差异，以及 CTLA4 基因多态性是否与这些差异相关。
这是一项回顾性研究，纳入了 2010 年 1 月至 2020 年 12 月在我院因胸腺瘤接受手术治疗的所有伴有和不伴有 MG 的患者。10 例正常胸腺组织标本作为对照。通过免疫组织化学检测石蜡包埋胸腺瘤标本中 CTLA4 阳性细胞的数量。通过免疫组织化学（B 细胞淋巴瘤[BCL]-6 表达）和 CD4-FOXP3 的双免疫荧光染色分别确定滤泡中心和调节性 T 细胞淋巴细胞的存在。我们评估了 CTLA4 在胸腺中的表达与 MG 发生之间的相关性。我们还评估了 CTLA4 表达与 MG 的各种临床和预后特征之间的相关性。我们对 CTLA4 基因进行了测序，并评估了 CTLA4 多态性与胸腺 CTLA4 表达之间的可能关联。最后，我们评估了这些多态性与 MG 风险之间的潜在关联。
共纳入 41 例胸腺瘤患者。其中 23 例合并 MG（56.1%）。平均而言，伴有 MG 的患者胸腺瘤中 CTLA4 阳性细胞数少于非 MG 患者：69.3 个细胞/mm（95%CI：39.6-99.1）vs 674.4（276.0-1024.0）个细胞/mm；=0.001 和 vs 对照组（200.74[57.9-343.6]个细胞/mm；=0.02）。BCL6 或 CD4-FOXP3 阳性细胞数在 MG 组与非 MG 组之间无差异。CTLA4 表达与 MG 结局或治疗抵抗无相关性。在 CTLA4 基因中检测到两个多态性，rs231770（n=30 例）和 rs231775（n=17 例）。所有基因型的 MG 患者比例相似。然而，与非携带者相比，rs231775 多态性携带者的 CTLA4 阳性细胞计数有降低的趋势，但无统计学意义：77.9 个细胞/mm（95%CI：-51.5 至 207.5）vs 343.3 个细胞/mm（95%CI：126.2 至 560.4）。
胸腺瘤中 CTLA4 表达减少可能导致发生 MG 的风险增加。
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