title: Granulomas are a source of interleukin-33 expression in pulmonary and extrapulmonary sarcoidosis.
abstract: Sarcoidosis is a chronic inflammatory disease characterized by noncaseating epithelioid granulomas. These granulomas consist of highly differentiated mononuclear phagocytes--epithelioid cells and multinucleated giant cells (MNGCs)--surrounded by a proinflammatory infiltrate. Interleukin-33 (IL-33) is an inflammatory cytokine that is constitutively expressed in barrier tissues such as skin and lung and up-regulated in inflammation. Because sarcoidosis occurs most frequently in lung and skin, we studied the expression of this cytokine by immunohistochemistry in these tissues from patients with sarcoidosis, with foreign body granulomas, with other granulomatous diseases, and in corresponding normal tissues. We identified nuclear IL-33 staining of epithelioid cells and MNGCs in biopsies of skin (18/25 patients, 72%) and lung (10/19 patients, 53%) sarcoidosis. In contrast, sarcoidal granulomas in lymph nodes did not show IL-33 expression. Other granulomatous diseases showed only occasional and weak IL-33 expression. In sarcoidosis, we found a strong correlation between IL-33 expression and systemic disease, presence of MNGCs, and an M2-like macrophage phenotype as assessed by CD163 staining. Therefore, we propose that IL-33 plays a critical role in pathogenesis and disease progression of sarcoidosis. Because IL-33 is less commonly and only weakly expressed in other granulomatous diseases, the detection of IL-33 might serve as an adjunctive diagnostic marker. IL-33 expression in sarcoidosis seems to be dependent on the specific tissue microenvironment of sarcoidal granulomas and represents a novel biomarker for systemic involvement.
authors.affiliation: Kempf und Pfaltz Histologische Diagnostik, Research Unit, 8057 Zürich, Switzerland.
authors.forename: Werner
authors.initials: W
authors.lastname: Kempf
authors.affiliation: Kempf und Pfaltz Histologische Diagnostik, Research Unit, 8057 Zürich, Switzerland.
authors.forename: Therese
authors.initials: T
authors.lastname: Zollinger
authors.affiliation: Cantonal Hospital Baselland, Institute of Pathology Liestal, 4410 Liestal, Switzerland.
authors.forename: Melanie
authors.initials: M
authors.lastname: Sachs
authors.affiliation: Cantonal Hospital Baselland, Department of Internal Medicine, Division of Pulmonary Diseases, 4410 Liestal, Switzerland.
authors.forename: Elke
authors.initials: E
authors.lastname: Ullmer
authors.affiliation: Cantonal Hospital Baselland, Institute of Pathology Liestal, 4410 Liestal, Switzerland.
authors.forename: Gieri
authors.initials: G
authors.lastname: Cathomas
authors.affiliation: University Hospital Basel, Institute of Pathology, 4031 Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Dirnhofer
authors.affiliation: Cantonal Hospital Baselland, Institute of Pathology Liestal, 4410 Liestal, Switzerland; University Hospital Zürich, Institute of Surgical Pathology, 8091 Zürich, Switzerland. Electronic address: KirstenDiana.Mertz@usz.ch.
authors.forename: Kirsten D
authors.initials: KD
authors.lastname: Mertz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D006099:Granuloma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012507:Sarcoidosis / Q000378:metabolism* / Q000473:pathology; D017565:Sarcoidosis, Pulmonary / Q000378:metabolism* / Q000473:pathology; D012871:Skin Diseases / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
chemical_list: D015415:Biomarkers; C506536:IL33 protein, human; D000067596:Interleukin-33; D007378:Interleukins
keywords: Biomarker; Granuloma; Immunohistochemistry; Interleukin-33; Macrophage; Sarcoidosis