Cells

Research

11 pages, 926 KiB

Open AccessArticle

ANXA11 rs1049550 Associates with Löfgren’s Syndrome and Chronic Sarcoidosis

by Bekir Karakaya, Joanne J. van der Vis, Marcel Veltkamp, Douwe H. Biesma, Jan C. Grutters and Coline H. M. van Moorsel

Cells 2022, 11(9), 1557; https://doi.org/10.3390/cells11091557 - 05 May 2022

Cited by 6 | Viewed by 1751

Abstract

Sarcoidosis is an immune mediated granulomatous disease commonly affecting the lungs. Genome wide association studies identified many genomic regions that are shared among multiple immune mediated diseases. However, ANXA11 gene polymorphism rs1049550 is exclusively associated with sarcoidosis, making it a key gene of [...] Read more.

Sarcoidosis is an immune mediated granulomatous disease commonly affecting the lungs. Genome wide association studies identified many genomic regions that are shared among multiple immune mediated diseases. However, ANXA11 gene polymorphism rs1049550 is exclusively associated with sarcoidosis, making it a key gene of interest for sarcoidosis disease pathogenesis. However, sarcoidosis is a heterogeneous disease and contradictory findings for ANXA11 have been reported for disease phenotypes. We performed a case–control association study to investigate if ANXA11 associates with benign (Löfgren’s syndrome (LS)) or chronic sarcoidosis and performed a meta-analysis on previously reported findings. A total of 262 sarcoidosis patients, of which 149 had LS and 113 chronic sarcoidosis, and 363 controls were genotyped for rs1049550. Meta-analysis included allele findings for rs1049550 from 6 additional studies. We found a significantly lower T allele frequency in sarcoidosis patients than in healthy controls (0.30 vs. 0.41, respectively, odds ratio (OR) 0.61, 95% confidence interval (CI) 0.48–0.77, p = 3 × 10⁻⁵). In LS the T allele frequency of 0.33, and in chronic sarcoidosis the T allele frequency of 0.26 were significantly lower than in healthy controls (OR 0.69, 95% CI 0.52–0.92, p = 0.01 and OR 0.51, 95% CI 0.36–0.70, p = 4 × 10⁻⁵, respectively). Meta-analysis including previously published European, African American and Asian cohorts confirmed the association of rs1049550 with sarcoidosis and resulted in a pooled OR of 0.70 (CI 0.66–0.75, p = 3.58 × 10⁻²⁹). Presence of the T allele of rs1049550 in ANXA11 is protective for sarcoidosis, including benign and chronic phenotypes of the disease. Full article

(This article belongs to the Special Issue Sarcoidosis and Granulomatous Diseases: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)

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10 pages, 1033 KiB

Open AccessArticle

Findings and Graduation of Sarcoidosis-Related Uveitis: A Single-Center Study

by Lynn S. zur Bonsen, Dominika Pohlmann, Anne Rübsam and Uwe Pleyer

Cells 2022, 11(1), 89; https://doi.org/10.3390/cells11010089 - 29 Dec 2021

Cited by 5 | Viewed by 2108

Abstract

Ocular involvement is present in up to 79% of sarcoid patients. Uveitis is the main ocular manifestation and presents as a chronic intraocular inflammatory condition with potentially detrimental effects on visual acuity and quality of life. This retrospective study was conducted to explore [...] Read more.

Ocular involvement is present in up to 79% of sarcoid patients. Uveitis is the main ocular manifestation and presents as a chronic intraocular inflammatory condition with potentially detrimental effects on visual acuity and quality of life. This retrospective study was conducted to explore the incidence and characteristics of ocular sarcoidosis in a single tertiary ophthalmology center. Medical records of 84 patients presenting between June 2007 and March 2021 were analyzed. Based on the “International Workshop on Ocular Sarcoidosis” (IWOS) criteria, ocular sarcoidosis was determined as: definite (n = 24; 28.6%), presumed (n = 33; 39.3%), probable (n = 10; 11.9%), and indefinite (n = 17; 20.2%) in our study population. In 43.9% of the definite and presumed cases, the eye was primarily affected. In addition to specific ocular findings, the diagnosis was supported by biopsy (28.6%) and chest x-ray or computer tomography (66.7%). Moreover, an increased soluble interleukin-2 receptor (sIL-2R) expression (76.2%), elevated angiotensin-converting enzyme (ACE) levels (34.8%), and lymphocytopenia (35.1%) were valuable laboratory findings. Co-affected organs were lungs (60.7%), skin (15.5%), and central nervous system (8.3%). Our findings support the prominent role of the eye in the early detection of sarcoidosis. In addition to the IWOS criteria, sIL-2R, in particular, was shown to be relevant in establishing the diagnosis. Full article

(This article belongs to the Special Issue Sarcoidosis and Granulomatous Diseases: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)

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9 pages, 2395 KiB

Open AccessArticle

Activation of Downstream mTORC1 Target Ribosomal Protein S6 Kinase (S6K) Can Be Found in a Subgroup of Dutch Patients with Granulomatous Pulmonary Disease

by Raisa Kraaijvanger, Kees Seldenrijk, Els Beijer, Jan Damen, Jayne Louise Wilson, Thomas Weichhart, Jan C. Grutters and Marcel Veltkamp

Cells 2021, 10(12), 3545; https://doi.org/10.3390/cells10123545 - 15 Dec 2021

Cited by 2 | Viewed by 2254

Abstract

Mechanistic target of rapamycin complex 1 (mTORC1) has been linked to different diseases. The mTORC1 signaling pathway is suggested to play a role in the granuloma formation of sarcoidosis. Recent studies demonstrated conflicting data on mTORC1 activation in patients with sarcoidosis by measuring [...] Read more.

Mechanistic target of rapamycin complex 1 (mTORC1) has been linked to different diseases. The mTORC1 signaling pathway is suggested to play a role in the granuloma formation of sarcoidosis. Recent studies demonstrated conflicting data on mTORC1 activation in patients with sarcoidosis by measuring activation of its downstream target S6 kinase (S6K) with either 33% or 100% of patients. Therefore, the aim of our study was to reevaluate the percentage of S6K activation in sarcoidosis patients in a Dutch cohort. To investigate whether this activation is specific for sarcoid granulomas, we also included Dutch patients with other granulomatous diseases of the lung. The activation of the S6K signaling pathway was evaluated by immunohistochemical staining of its downstream effector phospho-S6 in tissue sections. Active S6K signaling was detected in 32 (43%) of the sarcoidosis patients. Twelve (31%) of the patients with another granulomatous disorder also showed activated S6K signaling, demonstrating that the mTORC1 pathway may be activated in a range for different granulomatous diseases (p = 0.628). Activation of S6K can only be found in a subgroup of patients with sarcoidosis, as well as in patients with other granulomatous pulmonary diseases, such as hypersensitivity pneumonitis or vasculitis. No association between different clinical phenotypes and S6K activation can be found in sarcoidosis. Full article

(This article belongs to the Special Issue Sarcoidosis and Granulomatous Diseases: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)

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11 pages, 2178 KiB

Open AccessArticle

T Lymphocyte Maturation Profile in the EBUS-TBNA Lymph Node Depending on the DLCO Parameter in Patients with Pulmonary Sarcoidosis

by Elżbieta Rutkowska, Iwona Kwiecień, Joanna Bednarek, Rafał Sokołowski, Agata Raniszewska, Karina Jahnz- Różyk and Piotr Rzepecki

Cells 2021, 10(12), 3404; https://doi.org/10.3390/cells10123404 - 02 Dec 2021

Cited by 1 | Viewed by 1772

Abstract

Sarcoidosis (SA) is a systemic granulomatous disorder of unknown etiology with lung and mediastinal lymph nodes (LNs) as the main location. T lymphocytes play important role in the formation of granulomas in SA, but still little is known about the role of maturation [...] Read more.

Sarcoidosis (SA) is a systemic granulomatous disorder of unknown etiology with lung and mediastinal lymph nodes (LNs) as the main location. T lymphocytes play important role in the formation of granulomas in SA, but still little is known about the role of maturation profile in the development of inflammatory changes. The aim of this study was to determine the CD4+ and CD8+ T cells maturation profile in LNs and in peripheral blood (PB) and its relation to disease severity expressed by diffusing capacity of the lung for carbon monoxide (DLCO). 29 patients with newly pulmonary SA were studied. Flow cytometry was used for cells evaluation in EBUS-TBNA samples. We observed lower median proportion of T lymphocytes, CD4+ T and CD8+ T cells in patients with DLCO< 80% than in patients with normal diffusion (DLCO > 80%). Patients with DLCO < 80% had lower median proportion of effector and higher median proportion of central memory CD4+ and CD8+ T cells than patients with DLCO > 80%. We reported for the first time that LNs CD4+ and CD8+ T cells maturation differs depending on the DLCO value in sarcoidosis. Lymphocytes profiles in LNs may reflect the immune status of patients with SA and can be analysed by flow cytometry of EBUS-TBNA samples. Full article

(This article belongs to the Special Issue Sarcoidosis and Granulomatous Diseases: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)

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29 pages, 8763 KiB

Open AccessArticle

Autophagy and Mitophagy-Related Pathways at the Crossroads of Genetic Pathways Involved in Familial Sarcoidosis and Host-Pathogen Interactions Induced by Coronaviruses

by Yves Pacheco, Dominique Valeyre, Thomas El Jammal, Maxime Vallee, Fabien Chevalier, Jérôme Lamartine, Dominique Sigaudo-Roussel, Bernard Verrier, Dominique Israel-Biet, Nathalie Freymond, Vincent Cottin and Alain Calender

Cells 2021, 10(8), 1995; https://doi.org/10.3390/cells10081995 - 05 Aug 2021

Cited by 9 | Viewed by 3293

Abstract

Sarcoidosis is a multisystem disease characterized by the development and accumulation of granulomas, the hallmark of an inflammatory process induced by environmental and/or infectious and or genetic factors. This auto-inflammatory disease mainly affects the lungs, the gateway to environmental aggressions and viral infections. [...] Read more.

Sarcoidosis is a multisystem disease characterized by the development and accumulation of granulomas, the hallmark of an inflammatory process induced by environmental and/or infectious and or genetic factors. This auto-inflammatory disease mainly affects the lungs, the gateway to environmental aggressions and viral infections. We have shown previously that genetic predisposition to sarcoidosis occurring in familial cases is related to a large spectrum of pathogenic variants with, however, a clustering around mTOR (mammalian Target Of Rapamycin)-related pathways and autophagy regulation. The context of the COVID-19 pandemic led us to evaluate whether such genetic defects may increase the risk of a severe course of SARS-CoV2 infection in patients with sarcoidosis. We extended a whole exome screening to 13 families predisposed to sarcoidosis and crossed the genes sharing mutations with the list of genes involved in the SARS-CoV2 host-pathogen protein-protein interactome. A similar analysis protocol was applied to a series of 100 healthy individuals. Using ENRICH.R, a comprehensive gene set enrichment web server, we identified the functional pathways represented in the set of genes carrying deleterious mutations and confirmed the overrepresentation of autophagy- and mitophagy-related functions in familial cases of sarcoidosis. The same protocol was applied to the set of genes common to sarcoidosis and the SARS-CoV2-host interactome and found a significant enrichment of genes related to mitochondrial factors involved in autophagy, mitophagy, and RIG-I-like (Retinoic Acid Inducible Gene 1) Receptor antiviral response signaling. From these results, we discuss the hypothesis according to which sarcoidosis is a model for studying genetic abnormalities associated with host response to viral infections as a consequence of defects in autophagy and mitophagy processes. Full article

(This article belongs to the Special Issue Sarcoidosis and Granulomatous Diseases: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)

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12 pages, 1018 KiB

Open AccessArticle

A Polymorphism in C-C Chemokine Receptor 5 (CCR5) Associates with Löfgren’s Syndrome and Alters Receptor Expression as well as Functional Response

by Bekir Karakaya, Coline H. M. van Moorsel, Marcel Veltkamp, Claudia Roodenburg-Benschop, Karin M. Kazemier, Annette H. M. van der Helm-van Mil, Tom W. J. Huizinga, Jan C. Grutters and Ger T. Rijkers

Cells 2021, 10(8), 1967; https://doi.org/10.3390/cells10081967 - 03 Aug 2021

Cited by 3 | Viewed by 1818

Abstract

C-C chemokine receptor 5 (CCR5) and polymorphisms in CCR5 gene are associated with sarcoidosis and Löfgren’s syndrome. Löfgren’s syndrome is an acute and usually self-remitting phenotype of sarcoidosis. We investigated whether the single nucleotide polymorphism (SNP) rs1799987 is associated with susceptibility for Löfgren’s [...] Read more.

C-C chemokine receptor 5 (CCR5) and polymorphisms in CCR5 gene are associated with sarcoidosis and Löfgren’s syndrome. Löfgren’s syndrome is an acute and usually self-remitting phenotype of sarcoidosis. We investigated whether the single nucleotide polymorphism (SNP) rs1799987 is associated with susceptibility for Löfgren’s syndrome and has an effect on CCR5 expression on monocytes and function of CCR5. A total of 106 patients with Löfgren’s syndrome and 257 controls were genotyped for rs1799987. Expression of CCR5 on monocytes was measured by flowcytometry. We evaluated calcium influx kinetics following stimulation upon N-formylmethionyl-leucyl-phenylalanine (fMLP) and macrophage inflammatory protein-1α (MIP-1α) on monocytes by measuring the median fluorescence intensity (MFI). The frequency of the G allele of rs1799987 was significantly higher in Löfgren’s syndrome than in healthy controls (p = 0.0015, confidence interval (CI) 1.22–2.32, odds ratio (OR) 1.680). Patients with a GG genotype showed higher CCR5 expression on monocytes than patients with the AA genotype (p = 0.026). A significantly (p = 0.027) lower count of patients with the GG genotype showed a calcium influx reaction to simulation upon MIP-1 α, compared with patients with the AA genotype. The rs1799987 G allele in CCR5 gene is associated with susceptibility to Löfgren’s syndrome and with quantitative and qualitative changes in CCR5, potentially effecting the inflammatory response. Full article

(This article belongs to the Special Issue Sarcoidosis and Granulomatous Diseases: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)

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11 pages, 931 KiB

Open AccessArticle

Elevated Serum Amyloid a Levels Are not Specific for Sarcoidosis but Associate with a Fibrotic Pulmonary Phenotype

by Els Beijer, Claudia Roodenburg-Benschop, Milou C. Schimmelpennink, Jan C. Grutters, Bob Meek and Marcel Veltkamp

Cells 2021, 10(3), 585; https://doi.org/10.3390/cells10030585 - 07 Mar 2021

Cited by 18 | Viewed by 2487

Abstract

Elevated Serum Amyloid A (SAA) levels have been found in several inflammatory diseases, including sarcoidosis. SAA is suggested to be involved in sarcoidosis pathogenesis by involvement in granuloma formation and maintenance. We hypothesized that SAA serum levels would be higher in sarcoidosis compared [...] Read more.

Elevated Serum Amyloid A (SAA) levels have been found in several inflammatory diseases, including sarcoidosis. SAA is suggested to be involved in sarcoidosis pathogenesis by involvement in granuloma formation and maintenance. We hypothesized that SAA serum levels would be higher in sarcoidosis compared to other non-infectious granulomatous and non-granulomatous diseases. SAA levels were measured in serum from sarcoidosis, Hypersensitivity pneumonitis (HP), and (eosinophilic) granulomatosis with polyangiitis ((E)GPA) patients. Idiopathic pulmonary fibrosis (IPF) patients were included as non-granulomatous disease group. SAA levels of patients with sarcoidosis (31.0 µg/mL), HP (23.4 µg/mL), (E)GPA (36.9 µg/mL), and IPF (22.1 µg/mL) were all higher than SAA levels of healthy controls (10.1 µg/mL). SAA levels did not differ between the diagnostic groups. When SAA serum levels were analyzed in sarcoidosis subgroups, fibrotic sarcoidosis patients showed higher SAA levels than sarcoidosis patients without fibrosis (47.8 µg/mL vs. 29.4 µg/mL, p = 0.005). To conclude, the observation that fibrotic sarcoidosis patients have higher SAA levels, together with our finding that SAA levels were also increased in IPF patients, suggests that SAA may next to granulomatous processes also reflect the process of fibrogenesis. Further studies should clarify the exact role of SAA in fibrosis and the underlying mechanisms involved. Full article

(This article belongs to the Special Issue Sarcoidosis and Granulomatous Diseases: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)

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8 pages, 242 KiB

Open AccessArticle

Switching to an Infliximab Biosimilar Was Safe and Effective in Dutch Sarcoidosis Patients

by Bas J. M. Peters, Anish Bhatoe, Adriane D. M. Vorselaars and Marcel Veltkamp

Cells 2021, 10(2), 441; https://doi.org/10.3390/cells10020441 - 19 Feb 2021

Cited by 4 | Viewed by 2476

Abstract

The effect of switching from originator infliximab to biosimilar infliximab in patients with sarcoidosis is unknown. The objective of this study is to investigate the effect of switching from Remicade^® or Inflectra^® to Flixabi^® in patients with severe refractory sarcoidosis. [...] Read more.

The effect of switching from originator infliximab to biosimilar infliximab in patients with sarcoidosis is unknown. The objective of this study is to investigate the effect of switching from Remicade^® or Inflectra^® to Flixabi^® in patients with severe refractory sarcoidosis. This single center retrospective cohort study was performed at St Antonius Hospital Nieuwegein, The Netherlands. All patients diagnosed with severe refractory sarcoidosis receiving Remicade^® or Inflectra^® switched to Flixabi^®. The primary outcome was infliximab discontinuation within 6 months of switching. Secondary endpoints included adverse events and loss of clinical, functional, or inflammatory response. Out of 86 patients who switched to Flixabi^®, 79 patients had complete data. None of the 79 patients discontinued infliximab during the first 6 months after switching. Five patients reported an adverse event related to Flixabi^® treatment. We found no change from baseline in FVC, FEV1, DLCOc, 6MWT, and infliximab trough levels 26 weeks after switching. An improvement in physical functioning of 7.3 ± 13.4 points (p = 0.002) with RAND/SF36 and in biomarker sIL-2R (−475.58 ± 1452.39; p = 0.005) was observed. Switching from originator infliximab Remicade^® or biosimilar infliximab Inflectra^® to biosimilar infliximab Flixabi^® did not result in treatment discontinuation or loss of clinical/functional/inflammatory remission. Full article

(This article belongs to the Special Issue Sarcoidosis and Granulomatous Diseases: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)

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16 pages, 2849 KiB

Open AccessFeature PaperReview

Clinical Features, Histopathology and Differential Diagnosis of Sarcoidosis

by Claudio Tana, Iginio Donatiello, Alessandro Caputo, Marco Tana, Teresa Naccarelli, Cesare Mantini, Fabrizio Ricci, Andrea Ticinesi, Tiziana Meschi, Francesco Cipollone and Maria Adele Giamberardino

Cells 2022, 11(1), 59; https://doi.org/10.3390/cells11010059 - 26 Dec 2021

Cited by 28 | Viewed by 8468

Abstract

Sarcoidosis is a chameleon disease of unknown etiology, characterized by the growth of non-necrotizing and non-caseating granulomas and manifesting with clinical pictures that vary on the basis of the organs that are mainly affected. Lungs and intrathoracic lymph nodes are the sites that [...] Read more.

Sarcoidosis is a chameleon disease of unknown etiology, characterized by the growth of non-necrotizing and non-caseating granulomas and manifesting with clinical pictures that vary on the basis of the organs that are mainly affected. Lungs and intrathoracic lymph nodes are the sites that are most often involved, but virtually no organ is spared from this disease. Histopathology is distinctive but not pathognomonic, since the findings can be found also in other granulomatous disorders. The knowledge of these findings is important because it could be helpful to differentiate sarcoidosis from the other granulomatous-related diseases. This review aims at illustrating the main clinical and histopathological findings that could help clinicians in their routine clinical practice. Full article

(This article belongs to the Special Issue Sarcoidosis and Granulomatous Diseases: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)

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33 pages, 3074 KiB

Open AccessFeature PaperReview

Sarcoidosis: A Clinical Overview from Symptoms to Diagnosis

by Pascal Sève, Yves Pacheco, François Durupt, Yvan Jamilloux, Mathieu Gerfaud-Valentin, Sylvie Isaac, Loïc Boussel, Alain Calender, Géraldine Androdias, Dominique Valeyre and Thomas El Jammal

Cells 2021, 10(4), 766; https://doi.org/10.3390/cells10040766 - 31 Mar 2021

Cited by 151 | Viewed by 30800

Abstract

Sarcoidosis is a multi-system disease of unknown etiology characterized by the formation of granulomas in various organs. It affects people of all ethnic backgrounds and occurs at any time of life but is more frequent in African Americans and Scandinavians and in adults [...] Read more.

Sarcoidosis is a multi-system disease of unknown etiology characterized by the formation of granulomas in various organs. It affects people of all ethnic backgrounds and occurs at any time of life but is more frequent in African Americans and Scandinavians and in adults between 30 and 50 years of age. Sarcoidosis can affect any organ with a frequency varying according to ethnicity, sex and age. Intrathoracic involvement occurs in 90% of patients with symmetrical bilateral hilar adenopathy and/or diffuse lung micronodules, mainly along the lymphatic structures which are the most affected system. Among extrapulmonary manifestations, skin lesions, uveitis, liver or splenic involvement, peripheral and abdominal lymphadenopathy and peripheral arthritis are the most frequent with a prevalence of 25–50%. Finally, cardiac and neurological manifestations which can be the initial manifestation of sarcoidosis, as can be bilateral parotitis, nasosinusal or laryngeal signs, hypercalcemia and renal dysfunction, affect less than 10% of patients. The diagnosis is not standardized but is based on three major criteria: a compatible clinical and/or radiological presentation, the histological evidence of non-necrotizing granulomatous inflammation in one or more tissues and the exclusion of alternative causes of granulomatous disease. Certain clinical features are considered to be highly specific of the disease (e.g., Löfgren’s syndrome, lupus pernio, Heerfordt’s syndrome) and do not require histological confirmation. New diagnostic guidelines were recently published. Specific clinical criteria have been developed for the diagnosis of cardiac, neurological and ocular sarcoidosis. This article focuses on the clinical presentation and the common differentials that need to be considered when appropriate. Full article

(This article belongs to the Special Issue Sarcoidosis and Granulomatous Diseases: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)

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23 pages, 36065 KiB

Open AccessSystematic Review

Assessment of Experimental Techniques That Facilitate Human Granuloma Formation in an In Vitro System: A Systematic Review

by Nirosha Ganesan, Steven Ronsmans, Jeroen Vanoirbeek and Peter H. M. Hoet

Cells 2022, 11(5), 864; https://doi.org/10.3390/cells11050864 - 02 Mar 2022

Cited by 3 | Viewed by 6388

Abstract

The process of granuloma formation is complex, and due to species differences, the validity of animal studies is somewhat questioned. Moreover, the large number of animals needed to observe the different stages of development also raises ethical questions. Therefore, researchers have explored the [...] Read more.

The process of granuloma formation is complex, and due to species differences, the validity of animal studies is somewhat questioned. Moreover, the large number of animals needed to observe the different stages of development also raises ethical questions. Therefore, researchers have explored the use of human peripheral blood mononuclear cells (PBMCs), a heterogeneous population of immune cells, in an in vitro model. This review included in vitro studies that focused on exposing PBMCs—from healthy, sensitized, or diseased individuals—to antigens derived from infectious agents—such as mycobacteria or Schistosoma spp.—or inorganic antigens—such as beryllium. The reviewed studies mainly explored how human in vitro granuloma models can contribute towards understanding the pathogenesis of granulomatous diseases, especially during the early stages of granuloma formation. The feasibility of granuloma modelling was thus largely assessed via experimental techniques including (1) granuloma scoring indices (GI), (2) cell surface markers and (3) cytokine secretion profiling. While granuloma scoring showed some similarities between studies, a large variability of culture conditions and endpoints measured have been identified. The lack of any standardization currently impedes the success of a human in vitro granuloma model. Full article

(This article belongs to the Special Issue Sarcoidosis and Granulomatous Diseases: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)

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