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Hum Pathol. 2018 May;75:104-115. doi: 10.1016/j.humpath.2018.01.018. Epub 2018 Apr 16.

Comprehensive analysis of immune, extracellular matrices and pathogens profile in lung granulomatosis of unexplained etiology.

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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.
Division of Respiratory Diseases of Hospital do Servidor Público Estadual, São Paulo, 04029-000, Brazil.
Department of Translational Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
Department of Pathology, Faculty of Medicine, University of Sao Paulo, São Paulo, 01246-903, Brazil. Electronic address:


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.


Collagens; Granuloma; Immune cells; Immunofluorescence; Immunohistochemistry; Morphometry; PCR

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