Erasmus Medical Center, Laboratory of Medical Immunology, Department of Immunology, Dr. Molewaterplein 40, Rotterdam, 3015 GD, The Netherlands.
Department of Internal Medicine, Division of Allergy and Clinical Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
J Clin Immunol. 2024 Oct 7;45(1):22. doi: 10.1007/s10875-024-01817-3.
Granulomatous disease affects up to 20% of patients with Common Variable Immunodeficiency (CVID). Granulomas are comprised of highly activated immune cells, and emerge in response to antigenic triggers. In CVID granulomas however, the underlying pathophysiology is unclear and the specific trigger remains unknown. Granuloma formation in CVID is often compared to sarcoidosis, although clinical context and prognosis differ, suggesting a different pathogenesis. The aim of this study was to investigate if the cellular organization and proteomics of granulomas in CVID is different from other granulomatous diseases. Therefore, tissue slides from formaldehyde fixed paraffin embedded biopsies obtained from patients with CVID, sarcoidosis, tuberculosis and foreign-material induced pseudo-sarcoidosis were stained with hematoxylin and eosin and assessed for histopathological characteristics. Targeted spatial protein analysis was performed, and immune fluorescent multiplex assays were used to analyze the cellular organization. Histological analysis revealed that CVID granulomas were smaller, less circumscribed, with fewer multinucleated giant cells and minimal fibrosis compared to the other granulomatous diseases. Spatial protein analysis showed that granulomas in all diseases expressed CD68, CD11c, CD44, CD127, and PD-L1. However in CVID, reduced expression of the fibrosis-related protein fibronectin, but enrichment of CD163, CD3 and FAPα inside CVID granulomas was observed. Immunofluorescence analysis conformed a different cellular organization in CVID granulomas with increased influx of neutrophils, macrophages, T and B lymphocytes. In conclusion, granulomas in CVID display a different histological and cellular organization with increased influx of myeloid and lymphoid cells, compared to sarcoidosis, tuberculosis and pseudo-sarcoidosis, indicating a distinct pathogenesis underlying granuloma formation.
肉芽肿病影响高达 20%的普通可变免疫缺陷（CVID）患者。肉芽肿由高度活跃的免疫细胞组成，是对抗原刺激的反应而出现的。然而，在 CVID 肉芽肿中，潜在的病理生理学机制尚不清楚，具体的触发因素也尚不清楚。CVID 肉芽肿的形成常与结节病相比较，尽管临床背景和预后不同，提示发病机制不同。本研究旨在探讨 CVID 肉芽肿的细胞组织和蛋白质组学是否与其他肉芽肿性疾病不同。因此，对来自 CVID、结节病、结核病和异物诱导的假结节病患者的甲醛固定石蜡包埋活检组织切片进行苏木精和伊红染色，并评估其组织病理学特征。进行了靶向空间蛋白质分析，并使用免疫荧光多重分析来分析细胞组织。组织学分析表明，与其他肉芽肿性疾病相比，CVID 肉芽肿更小、边界不清晰，多核巨细胞更少，纤维化程度最小。空间蛋白质分析表明，所有疾病的肉芽肿均表达 CD68、CD11c、CD44、CD127 和 PD-L1。然而，在 CVID 中，纤维化相关蛋白纤连蛋白的表达减少，但 CD163、CD3 和 FAPα在 CVID 肉芽肿内富集。免疫荧光分析证实了 CVID 肉芽肿中不同的细胞组织，其中中性粒细胞、巨噬细胞、T 和 B 淋巴细胞的流入增加。总之，与结节病、结核病和假结节病相比，CVID 中的肉芽肿显示出不同的组织学和细胞组织，其中髓样和淋巴样细胞的流入增加，表明其肉芽肿形成的发病机制不同。
