Department of Pathology, Faculty of Medicine, University of Sao Paulo, São Paulo, 01246-903, Brazil.
Rheumatology Division, Faculty of Medicine, University of Sao Paulo, São Paulo, 01246-903, Brazil.
Hum Pathol. 2018 May;75:104-115. doi: 10.1016/j.humpath.2018.01.018. Epub 2018 Apr 16.
This study analyzed the type 1 and type 2T helper (Th1/Th2) cytokines (including interleukins), immune cellular, matrix profile, and pathogens in granulomas with unexplained etiology compared to those with infectious and noninfectious etiology. Surgical lung biopsies from 108 patients were retrospectively reviewed. Histochemistry, immunohistochemistry, immunofluorescence, morphometry and polymerase chain reaction were used, respectively, to evaluate total collagen and elastin fibers, collagen I and III, immune cells, cytokines, matrix metalloproteinase-9, myofibroblasts, and multiple usual and unusual pathogens. No relevant polymerase chain reaction expression was found in unexplained granulomas. A significant difference was found between the absolute number of eosinophils, macrophages, and lymphocytes within granulomas compared to uninvolved lung tissue. Granulomas with unexplained etiology (UEG) presented increased number of eosinophils and high expression of interleukins (ILs) IL-4/IL-5 and transforming growth factor-β. In sarcoidosis, CD4/CD8 cell number was significantly higher within and outside granulomas, respectively; the opposite was detected in hypersensitivity pneumonitis. Again, a significant difference was found between the high number of myofibroblasts and matrix metalloproteinase-9 in UEG, hypersensitivity pneumonitis, and sarcoidosis compared to granulomas of tuberculosis. Granulomas of paracoccidioisis exhibited increased type I collagen and elastic fibers. Th1 immune cellular profile was similar among granulomas with unexplained, infectious, and noninfectious etiology. In contrast, modulation of Th2 and matrix remodeling was associated with more fibroelastogenesis and scarring of lung tissue in UEG compared to infectious and noninfectious. We concluded that IL-4/IL-5 and transforming growth factor-β might be used as surrogate markers of early fibrosis, reducing the need for genotyping, and promise therapeutic target in unexplained granulomas.
本研究分析了原因不明与感染性及非感染性病因的肉芽肿中 1 型和 2 型辅助性 T 细胞（Th1/Th2）细胞因子（包括白细胞介素）、免疫细胞、基质谱和病原体。回顾性分析了 108 例患者的外科肺活检。分别采用组织化学、免疫组织化学、免疫荧光、形态计量学和聚合酶链反应评估总胶原和弹性纤维、胶原 I 和 III、免疫细胞、细胞因子、基质金属蛋白酶-9、肌成纤维细胞和多种常见和不常见的病原体。在原因不明的肉芽肿中未发现相关的聚合酶链反应表达。与未受累的肺组织相比，肉芽肿内的嗜酸性粒细胞、巨噬细胞和淋巴细胞的绝对数量存在显著差异。原因不明的肉芽肿（UEG）表现为嗜酸性粒细胞数量增加，白细胞介素（IL）IL-4/IL-5 和转化生长因子-β表达升高。结节病中，肉芽肿内和肉芽肿外的 CD4/CD8 细胞数量分别显著升高；过敏性肺炎则相反。同样，UEG、过敏性肺炎和结节病中肌成纤维细胞和基质金属蛋白酶-9的数量明显高于结核性肉芽肿。副球孢子菌病的肉芽肿表现为 I 型胶原和弹性纤维增加。原因不明、感染性和非感染性病因的肉芽肿中 Th1 免疫细胞谱相似。相比之下，Th2 和基质重塑的调节与 UEG 中更多的纤维弹性生成和肺组织瘢痕形成相关，与感染性和非感染性病因相比。我们得出结论，IL-4/IL-5 和转化生长因子-β可能作为早期纤维化的替代标志物，减少基因分型的需要，并为原因不明的肉芽肿提供治疗靶点。
