Sarcoidosis-Immunopathogenetic Concepts

Zissel, Gernot; Prasse, Antje; Müller–Quernheim, Joachim

doi:10.1055/s-2007-970329

Cited by 95 publications

(69 citation statements)

References 100 publications

(115 reference statements)

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“…30,31 Th1 immune response mediated by CD4 ϩ T-cells is activated in sarcoidosis and responsible for the initiation of granulomas formation. 7,8,19 Osteopontin is one of the most prominently expressed proteins in giant and epithelioid cells in sarcoidosis. 21 Recently it was shown that osteopontin can be cleaved by thrombin and several metalloproteinases.…”

Section: Discussionmentioning

confidence: 99%

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ApoE-Deficient Mice on Cholate-Containing High-Fat Diet Reveal a Pathology Similar to Lung Sarcoidosis

Samokhin

Bühling

Theissig

et al. 2010

The American Journal of Pathology

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Sarcoidosis is a chronic disease of unknown etiology characterized by the formation of non-necrotizing epithelioid granulomas in various organs , especially in the lungs. The lack of an adequate animal model reflecting the pathogenesis of the human disease is one of the major impediments in studying sarcoidosis. In this report , we describe ApoE ؊/؊ mice on a cholatecontaining high-fat diet that exhibit granulomatous lung inflammation similar to human sarcoidosis. Histological analysis revealed well-defined and non-necrotizing granulomas in about 40% of mice with the highest number of granulomas after 16 weeks on a cholate-containing high-fat diet. Granulomas contained CD4؉ and CD8 ؉ T cells , and the majority of the cells in granulomas showed immunoreactivity for the macrophage marker Mac-3. Cells with morphological features of epithelioid cells expressed angiotensinconverting enzyme , osteopontin , and cathepsin K, all characteristics of epithelioid and giant cells in granulomas of human sarcoidosis. Giant cells and nonspecific inclusions such as Schaumann's bodies and crystalline deposits were also detected in some lungs. Granulomatous inflammation resulted in progressive pulmonary fibrosis. Removal of cholate from the diet prevented the formation of lung granulomas. The observed similarities between the analyzed mouse lung granulomas and granulomas of human sarcoidosis , as well as the chronic disease character leading to fibrosis , suggest that this mouse model might be a useful tool to study sarcoidosis.

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Section: Discussionmentioning

confidence: 99%

“…7 In sarcoidosis, CD4 ϩ lymphocytes are predominant and a smaller number of CD8 ϩ T-cells are typically present in the periphery of granulomas. 12,17 We observed a similar distribution of CD4 ϩ and CD8 Figure 2H).…”

Section: With Characteristic Features Of Granulomas In Human Sarcoidosismentioning

confidence: 99%

ApoE-Deficient Mice on Cholate-Containing High-Fat Diet Reveal a Pathology Similar to Lung Sarcoidosis

Samokhin

Bühling

Theissig

et al. 2010

The American Journal of Pathology

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“…+ helper T-cells after exposure to an as yet elusive antigen under the regulatory influence of cytokines produced by local mononuclear phagocytes, T-cells, dendritic cells and fibroblasts [1,2]. According to the course of the disease, patients can be classified as being affected by acute or chronic sarcoidosis [3].…”

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confidence: 99%

Genome-wide association analysis reveals 12q13.3–q14.1 as new risk locus for sarcoidosis

Hofmann

Fischer

Nothnagel³

et al. 2012

Eur Respir J

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Sarcoidosis is a systemic inflammatory disease of unknown aetiology, influenced by genetic and environmental factors. However, the loci so far identified for sarcoidosis explain only a part of its assumed heritability.To identify further susceptibility loci, we performed a genome-wide association analysis using the Affymetrix 6.0 Human GeneChip followed by validation and replication stages.After quality control, 637 cases, 1233 controls and 677 619 single-nucleotide polymorphisms (SNPs) were available for an initial screening. 99 SNPs were selected for validation in an independent study panel (1664 patients, 2932 controls). SNP rs1050045 was significantly associated with sarcoidosis (corrected p50.0215) in the validation panel and yielded a p-value of 9.22610 -8 (OR 1.24) in the meta-analysis of the screening and validation stage. A meta-analysis of three populations from Germany, the Czech Republic and Sweden confirmed this finding (p50.024; OR 1.14). Fine-mapping and mRNA expression studies pointed to osteosarcoma amplified 9 (OS9) as the most likely candidate for the underlying risk factor. The OS9 protein plays an important role in endoplasmic reticulum-associated protein degradation and acts during Toll-like receptor induced activation of myeloid cells. Expression analyses of OS9 mRNA provide evidence for a functional mechanism underlying the detected association signal.

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“…Moreover, this key Th1 transcription factor, T-bet, directs Th1 lineage commitment [8]. Although sarcoidosis is a predominantly Th1 immune disease [9,10], and CXCR3 and IFN-c are implicated in its pathogenesis, there is currently no information about the involvement of the Th1 transcription factor T-bet in this disorder.…”

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confidence: 99%

T-helper cell type-1 transcription factor T-bet is upregulated in pulmonary sarcoidosis

Kriegová¹,

Fillerová²,

Tománková³

et al. 2011

Eur Respir J

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Upregulation of genes for interferon (IFN)-γ and CXC chemokine receptor (CXCR)3 expression, two crucial molecules in sarcoid inflammation and granuloma formation, is directly controlled by the T-helper (Th)1 transcription factor T-bet (T-box, expressed in T-cells). However, there is no information on T-bet expression in sarcoidosis or its relationship with “sarcoidosis-associated” genes.Therefore, we investigated expression of T-bet mRNA and, in parallel, a spectrum of genes known to be involved in sarcoidosis pathogenesis. Transcripts were determined in bronchoalveolar lavage (BAL) cells from 62 sarcoidosis patients and 25 controls by quantitative RT-PCR; T-bet protein was localised by immunohistochemistry.Patient’s BAL cells expressed higher mRNA T-bet levels than those of controls (mean±sdfold change 3.64±1.72; p=0.00006). T-bet mRNA expression did not vary between clinical phenotypes as assessed by chest radiography stage, presence/absence of Löfgren's syndrome, extrapulmonary/pulmonary involvement or progressing/remitting disease (p>0.05). T-bet mRNA expression correlated with expression of IFN-γ, CC chemokine ligand 5, CXC chemokine ligand (CXC)10, interleukin (IL)-2 receptor/IL-15 receptor β, CXCR3 and CXCR6 (p<0.01). T-bet protein was localised to alveolar macrophages and lymphocytes, tissue multinucleated giant cells, macrophages and lymphocytes.In pulmonary sarcoidosis, T-bet upregulation is associated with changes in expression of IFN-γ, CXCR3 and chemokines/receptors involved in the pathogenesis of sarcoidosis, which suggests a role for T-bet in this Th1 disease, including modulation of some sarcoidosis-associated genes.

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Sarcoidosis-Immunopathogenetic Concepts

Cited by 95 publications

References 100 publications

ApoE-Deficient Mice on Cholate-Containing High-Fat Diet Reveal a Pathology Similar to Lung Sarcoidosis

ApoE-Deficient Mice on Cholate-Containing High-Fat Diet Reveal a Pathology Similar to Lung Sarcoidosis

Genome-wide association analysis reveals 12q13.3–q14.1 as new risk locus for sarcoidosis

T-helper cell type-1 transcription factor T-bet is upregulated in pulmonary sarcoidosis

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