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Immune mechanisms in fibrotic pulmonary sarcoidosis.

ABSTRACT: Sarcoidosis is an immune-mediated disorder. Its immunopathology has been steadily mapped out over the past few decades. Despite this, the underpinning mechanisms for progressive fibrotic sarcoidosis is an almost uncharted area. Consequently, there has been little change in the clinical management of fibrotic sarcoidosis over the decades and an unfocused search for new therapeutics. In this review, we provide a comprehensive examination of the relevant immune findings in fibrotic and/or progressive pulmonary sarcoidosis and propose a unifying mechanism for the pathobiology of fibrosis in sarcoidosis.

SUBMITTER: Weeratunga P

PROVIDER: S-EPMC9879330 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Immune mechanisms in fibrotic pulmonary sarcoidosis.

Weeratunga Praveen P Moller David R DR Ho Ling-Pei LP

European respiratory review : an official journal of the European Respiratory Society 20221221 166

Sarcoidosis is an immune-mediated disorder. Its immunopathology has been steadily mapped out over the past few decades. Despite this, the underpinning mechanisms for progressive fibrotic sarcoidosis is an almost uncharted area. Consequently, there has been little change in the clinical management of fibrotic sarcoidosis over the decades and an unfocused search for new therapeutics. In this review, we provide a comprehensive examination of the relevant immune findings in fibrotic and/or progressi ...[more]

PMID: 36543347

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Project description:PurposeReduced physical activity in many chronic diseases is consistently associated with increased morbidity. Little is known about physical activity in sarcoidosis. The aim of this study was to objectively assess physical activity in patients with pulmonary sarcoidosis and investigate its relationship with lung function, exercise capacity, symptom burden, and health status.MethodsPhysical activity was assessed over one week in 15 patients with pulmonary sarcoidosis and 14 age-matched healthy controls with a tri-axial accelerometer (ActivPal™) and the International Physical Activity Questionnaire (IPAQ). All participants underwent pulmonary function tests, 6-min walk test (6MWT) and completed the Fatigue Assessment Scale (FAS), Medical Research Council (MRC) Dyspnoea Scale and the King's Sarcoidosis Questionnaire (KSQ).ResultsPatients with sarcoidosis had significantly lower daily step counts than healthy controls; mean (SD) 5624 (1875) versus 10,429 (2942) steps (p?<?0.01) and a trend towards fewer sit-to-stand transitions each day (p?=?0.095). Only two patients (13%) self-reported undertaking vigorous physical activity (IPAQ) compared to half of healthy individuals (p?<?0.01). Daily step count was significantly associated with 6MWT distance in sarcoidosis (r?=?0.634, p?=?0.01), but not with forced vital capacity (r?=?0.290), fatigue (r?=?0.041), dyspnoea (r?=?-0.466) or KSQ health status (r?=?0.099-0.484). Time spent upright was associated with fatigue (r?=?-0.630, p?=?0.012) and health status (KSQ Lung scores r?=?0.524, p?=?0.045), and there was a significant correlation between the number of sit-to-stand transitions and MRC dyspnoea score (r?=?-0.527, p?=?0.044).ConclusionPhysical activity is significantly reduced in sarcoidosis and is associated with reduced functional exercise capacity (6MWD). Fatigue, exertional symptoms and health status were more closely associated with time spent upright and the number of bouts of physical activity, as compared to step counts. Further studies are warranted to identify the factors that determine different physical activity profiles in sarcoidosis.

Project description:BackgroundMacrophages are pivotal cells in sarcoidosis. Monocytes-derived (MD) macrophages have recently been demonstrated to play a major role especially in pulmonary sarcoidosis. From inflammatory tissues to granulomas, they may be exposed to low oxygen tension environments. As hypoxia impact on sarcoidosis immune cells has never been addressed, we designed the present study to investigate MD-macrophages from sarcoidosis patients in this context. We hypothesized that hypoxia may induce functional changes on MD-macrophages which could have a potential impact on the course of sarcoidosis.MethodsWe studied MD-macrophages, from high active sarcoidosis (AS) (n=26), low active or inactive sarcoidosis (IS) (n=24) and healthy controls (n=34) exposed 24 hours to normoxia (21% O2) or hypoxia (1.5% O2). Different macrophage functions were explored: hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-kappa B (NF-κB) activation, cytokines secretion, phagocytosis, CD80/CD86/HLA-DR expression, profibrotic response.ResultsWe observed that hypoxia, with a significantly more pronounced effect in AS compared with controls and IS, increased the HIF-1α trans-activity, promoted a proinflammatory response (TNFα, IL1ß) without activating NF-κB pathway and a profibrotic response (TGFß1, PDGF-BB) with PAI-1 secretion associated with human lung fibroblast migration inhibition. These results were confirmed by immunodetection of HIF-1α and PAI-1 in granulomas observed in pulmonary biopsies from patients with sarcoidosis. Hypoxia also decreased the expression of CD80/CD86 and HLA-DR on MD-macrophages in the three groups while it did not impair phagocytosis and the expression of CD36 expression on cells in AS and IS at variance with controls.ConclusionsHypoxia had a significant impact on MD-macrophages from sarcoidosis patients, with the strongest effect seen in patients with high active disease. Therefore, hypoxia could play a significant role in sarcoidosis pathogenesis by increasing the macrophage proinflammatory response, maintaining phagocytosis and reducing antigen presentation, leading to a deficient T cell response. In addition, hypoxia could favor fibrosis by promoting profibrotic cytokines response and by sequestering fibroblasts in the vicinity of granulomas.

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Immune mechanisms in fibrotic pulmonary sarcoidosis.

Publications

Immune mechanisms in fibrotic pulmonary sarcoidosis.

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