New concepts in the pathogenesis of sarcoidosis

Bennett, David; Bargagli, Elena; Refini, Rosa Metella; Rottoli, Paola

doi:10.1080/17476348.2019.1655401

Cited by 40 publications

(25 citation statements)

References 115 publications

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“…The balance between Th17 and Treg cells is thought to be disrupted in sarcoidosis [71] and is an important factor in its prognosis [72]. The regulation of antigen processing, antigen presentation to the APCs, and cytokine release are all controlled through genetic elements and may link the various causal factors of sarcoidosis together [73][74][75].…”

Section: Immunopathogenesismentioning

confidence: 99%

Sarcoidosis: Causes, Diagnosis, Clinical Features, and Treatments

Jain

Yadav

Puranik

et al. 2020

JCM

119

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Sarcoidosis is a multisystem granulomatous disease with nonspecific clinical manifestations that commonly affects the pulmonary system and other organs including the eyes, skin, liver, spleen, and lymph nodes. Sarcoidosis usually presents with persistent dry cough, eye and skin manifestations, weight loss, fatigue, night sweats, and erythema nodosum. Sarcoidosis is not influenced by sex or age, although it is more common in adults (< 50 years) of African-American or Scandinavians decent. Diagnosis can be difficult because of nonspecific symptoms and can only be verified following histopathological examination. Various factors, including infection, genetic predisposition, and environmental factors, are involved in the pathology of sarcoidosis. Exposures to insecticides, herbicides, bioaerosols, and agricultural employment are also associated with an increased risk for sarcoidosis. Due to its unknown etiology, early diagnosis and detection are difficult; however, the advent of advanced technologies, such as endobronchial ultrasound-guided biopsy, high-resolution computed tomography, magnetic resonance imaging, and 18F-fluorodeoxyglucose positron emission tomography has improved our ability to reliably diagnose this condition and accurately forecast its prognosis. This review discusses the causes and clinical features of sarcoidosis, and the improvements made in its prognosis, therapeutic management, and the recent discovery of potential biomarkers associated with the diagnostic assay used for sarcoidosis confirmation.

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Section: Immunopathogenesismentioning

confidence: 99%

Sarcoidosis: Causes, Diagnosis, Clinical Features, and Treatments

Jain

Yadav

Puranik

et al. 2020

JCM

119

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“…Treg cells normally suppress immune responses by the host immune system against self and foreign antigens. In the case of sarcoidosis, it is hypothesized that Tregs are functionally defective or exhausted, making them unable to fully suppress the immune responses ( 89 ). The dysfunction of Tregs in sarcoidosis, resulting in impaired self-tolerance and failed immune homeostasis, could be an important element in the pathogenesis of sarcoidosis ( 90 ).…”

Section: Bronchoalveolar Lavage Fluidmentioning

confidence: 99%

“…A focus of interest could be whether absence of mTORC1 activation can predict treatment response with rapamycin. Rapamycin has been successfully used to treat a patient suffering from sarcoidosis ( 89 ).…”

Section: Future Biomarkersmentioning

confidence: 99%

Biomarkers in the Diagnosis and Prognosis of Sarcoidosis: Current Use and Future Prospects

et al. 2020

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Sarcoidosis is a heterogeneous disease in terms of presentation, duration, and severity. Due to this heterogeneity, it is difficult to align treatment decisions. Biomarkers have proved to be useful for the diagnosis and prognosis of many diseases, and over the years, many biomarkers have been proposed to facilitate diagnosis, prognosis, and treatment decisions. Unfortunately, the ideal biomarker for sarcoidosis has not yet been discovered. The most commonly used biomarkers are serum and bronchoalveolar lavage biomarkers, but these lack the necessary specificity and sensitivity. In sarcoidosis, therefore, a combination of these biomarkers is often used to establish a proper diagnosis or detect possible progression. Other potential biomarkers include imaging tools and cell signaling pathways. Fluor-18-deoxyglucose positron emission tomography and high-resolution computed tomography have been proven to be more sensitive for the diagnosis and prognosis of both pulmonary and cardiac sarcoidosis than the serum biomarkers ACE and sIL-2R. There is an upcoming role for exploration of signaling pathways in sarcoidosis pathogenesis. The JAK/STAT and mTOR pathways in particular have been investigated because of their role in granuloma formation. The activation of these signaling pathways also proved to be a specific biomarker for the prognosis of sarcoidosis. Furthermore, both imaging and cell signaling biomarkers also enable patients who might benefit from a particular type of treatment to be distinguished from those who will not. In conclusion, the diagnostic and prognostic path of sarcoidosis involves many different types of existing and new biomarker. Research addressing biomarkers and disease pathology is ongoing in order to find the ideal sensitive and specific biomarker for this disease.

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“…This finding in the in vitro granuloma model links macrophage antimicrobial activities with abnormally sustained mTORc1 signaling shown to lead to unchecked granuloma formation in the Tsc2 knockout mouse model and raises the speculation that evolution of sarcoidosis involves unchecked development of a granulomatous response as a result of enhanced microbial killing. The abnormal immune response in sarcoidosis featuring enhanced intracellular microbial killing via phagolysosomes is unlikely to be confined to M.tb and its antigens produced, as other intracellular pathogens, such as Histoplasmosis capsulatum and P. acnes have been incriminated in the pathogenesis of sarcoidosis (39).…”

Section: Modeling Divergent Mechanisms Of Granuloma Formation Betweenmentioning

confidence: 99%

“…IL-13 signaling is associated with a Th2-biased immune response and is a known promoter of alternative or M2-like macrophage activation ( 46 , 47 ). Furthermore, characteristic features of sarcoidosis such as multinucleated giant cell formation ( 48 , 49 ) and fibrotic tissue changes ( 8 , 39 ) associated with severe disease phenotypes are signature behaviors of M2-like macrophages.…”

Section: Modeling Macrophage Responses In Sarcoidosismentioning

confidence: 99%

Current Sarcoidosis Models and the Importance of Focusing on the Granuloma

2020

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The inability to effectively model sarcoidosis in the laboratory or in animals continues to hinder the discovery and translation of new, targeted treatments. The granuloma is the signature pathological hallmark of sarcoidosis, yet there are significant knowledge gaps that exist with regard to how granulomas form. Significant progress toward improved therapeutic and prognostic strategies in sarcoidosis hinges on tractable experimental models that recapitulate the process of granuloma formation in sarcoidosis and allow for mechanistic insights into the molecular events involved. Through its inherent representation of the complex genetics underpinning immune cell dysregulation in sarcoidosis, a recently developed in vitro human granuloma model holds promise in providing detailed mechanistic insight into sarcoidosis-specific disease regulating pathways at play during early stages of granuloma formation. The purpose of this review is to critically evaluate current sarcoidosis models and assess their potential to progress the field toward the goal of improved therapies in this disease. We conclude with the potential integrated use of preclinical models to accelerate progress toward identifying and testing new drugs and drug combinations that can be rapidly brought to clinical trials.

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New concepts in the pathogenesis of sarcoidosis

Cited by 40 publications

References 115 publications

Sarcoidosis: Causes, Diagnosis, Clinical Features, and Treatments

Sarcoidosis: Causes, Diagnosis, Clinical Features, and Treatments

Biomarkers in the Diagnosis and Prognosis of Sarcoidosis: Current Use and Future Prospects

Current Sarcoidosis Models and the Importance of Focusing on the Granuloma

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