Medical Therapy of Sarcoidosis

Baughman, Robert P.; Lower, Elyse E.

doi:10.1055/s-0034-1376401

Cited by 27 publications

(5 citation statements)

References 138 publications

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“…The anti-TNF agent infliximab is known to induce Treg functionality in RA [ 7 ]. Induction of Treg survival may very well contribute to its therapeutic effect as observed in patients with chronic sarcoidosis [ 5 ]. Investigation of Treg proportions present in or around the granulomas, their functional capacities, and apoptosis susceptibility during the natural course of disease and in response to therapy should further unravel the role of Tregs in the development of chronic sarcoidosis.…”

Section: Discussionmentioning

confidence: 99%

“…Failure of immune regulatory mechanisms to limit duration of inflammation has been suggested to contribute to persisting granulomatous responses in sarcoidosis [ 4 ], and may explain the need for immunosuppressive drugs. Effective immunosuppressive agents for (chronic) sarcoidosis include corticosteroids and anti-TNF agents [ 5 ]. Interestingly, these drugs can induce Th cell apoptosis, while sparing or even inducing regulatory T cell (Treg) proportions and function [ 6 – 10 ], thereby favoring an anti-inflammatory milieu.…”

Section: Introductionmentioning

confidence: 99%

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Impaired survival of regulatory T cells in pulmonary sarcoidosis

et al. 2015

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BackgroundImpaired regulatory T cell (Treg) function is thought to contribute to ongoing inflammatory responses in sarcoidosis, but underlying mechanisms remain unclear. Moreover, it is not known if increased apoptotic susceptibility of Tregs may contribute to an impaired immunosuppressive function in sarcoidosis. Therefore, the aim of this study is to analyze proportions, phenotype, survival, and apoptotic susceptibility of Tregs in sarcoidosis.MethodsPatients with pulmonary sarcoidosis (n = 58) were included at time of diagnosis. Tregs were analyzed in broncho-alveolar lavage fluid and peripheral blood of patients and healthy controls (HC).ResultsIn sarcoidosis patients no evidence was found for a relative deficit of Tregs, neither locally nor systemically. Rather, increased proportions of circulating Tregs were observed, most prominently in patients developing chronic disease. Sarcoidosis circulating Tregs displayed adequate expression of FoxP3, CD25 and CTLA4. Remarkably, in sarcoidosis enhanced CD95 expression on circulating activated CD45RO+ Tregs was observed compared with HC, and proportions of these cells were significantly increased. Specifically sarcoidosis Tregs - but not Th cells - showed impaired survival compared with HC. Finally, CD95L-mediated apoptosis was enhanced in sarcoidosis Tregs.ConclusionIn untreated patients with active pulmonary sarcoidosis, Tregs show impaired survival and enhanced apoptotic susceptibility towards CD95L. Increased apoptosis likely contributes to the insufficient immunosuppressive function of sarcoidosis Tregs. Further research into this field will help determine whether improvement of Treg survival holds a promising new therapeutic approach for chronic sarcoidosis patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0265-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Impaired survival of regulatory T cells in pulmonary sarcoidosis

et al. 2015

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“…This similarity can potentially underlie responsiveness of different types of diseases to the same type of treatment (e.g. glucocorticoids) [ 31 – 33 ] indicating the presence of shared drug targets. However, the global picture of molecular mechanisms underlying the similarities and specificities of chronic inflammatory disorders is not completely understood and is addressed in this study, using gene expression data to compare activation patterns of selected pathways in a subset of AI and AIF diseases.…”

Section: Introductionmentioning

confidence: 99%

Autoimmunity and autoinflammation: A systems view on signaling pathway dysregulation profiles

et al. 2017

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IntroductionAutoinflammatory and autoimmune disorders are characterized by aberrant changes in innate and adaptive immunity that may lead from an initial inflammatory state to an organ specific damage. These disorders possess heterogeneity in terms of affected organs and clinical phenotypes. However, despite the differences in etiology and phenotypic variations, they share genetic associations, treatment responses and clinical manifestations. The mechanisms involved in their initiation and development remain poorly understood, however the existence of some clear similarities between autoimmune and autoinflammatory disorders indicates variable degrees of interaction between immune-related mechanisms.MethodsOur study aims at contributing to a holistic, pathway-centered view on the inflammatory condition of autoimmune and autoinflammatory diseases. We have evaluated similarities and specificities of pathway activity changes in twelve autoimmune and autoinflammatory disorders by performing meta-analysis of publicly available gene expression datasets generated from peripheral blood mononuclear cells, using a bioinformatics pipeline that integrates Self Organizing Maps and Pathway Signal Flow algorithms along with KEGG pathway topologies.Results and conclusionsThe results reveal that clinically divergent disease groups share common pathway perturbation profiles. We identified pathways, similarly perturbed in all the studied diseases, such as PI3K-Akt, Toll-like receptor, and NF-kappa B signaling, that serve as integrators of signals guiding immune cell polarization, migration, growth, survival and differentiation. Further, two clusters of diseases were identified based on specifically dysregulated pathways: one gathering mostly autoimmune and the other mainly autoinflammatory diseases. Cluster separation was driven not only by apparent involvement of pathways implicated in adaptive immunity in one case, and inflammation in the other, but also by processes not explicitly related to immune response, but rather representing various events related to the formation of specific pathophysiological environment. Thus, our data suggest that while all of the studied diseases are affected by activation of common inflammatory processes, disease-specific variations in their relative balance are also identified.

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“…The use of corticosteroid-sparing agents (such as antimetabolites) has improved the treatment options available to patients, but not all benefit from this therapy and some experience adverse effects requiring cessation of therapy [12]. With the emergence of many other biologics targeting specific molecules in the inflammatory cascade, there is a burdening need to explore them as potential therapies for patients with sarcoidosis.…”

Section: Introductionmentioning

confidence: 99%

New molecular targets for the treatment of sarcoidosis

Chiarchiaro

Chen

Gibson

2016

Current Opinion in Pulmonary Medicine

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Purpose of review Sarcoidosis is a chronic granulomatous disease typically affecting the lung, lymph nodes, and other organ systems. Evidence suggests that the morbidity and mortality rates for sarcoidosis in the USA are rising, despite widespread use of anti-inflammatory therapies. In this review, we survey new therapies that target specific inflammatory pathways in other diseases (such as rheumatoid arthritis, Crohn’s disease, and psoriasis) that are similar to pathways relevant to sarcoidosis immunopathogenesis, and therefore, represent potentially new sarcoidosis therapies. Recent findings Immunopathogenesis of sarcoidosis has been well elucidated over the past few years. There is abundant evidence for T-cell activation in sarcoidosis leading to activation of both Th1 and Th17 inflammatory cascades. Therapies targeting T-cell activation, Th1 pathways (such as the interleukin-6 inhibitors), Th17 pathway mediators, and others have been Food and Drug Administration approved or under investigation to treat a variety of autoimmune inflammatory diseases, but have not been studied in sarcoidosis. Targeting the p38 mitogen-activated protein kinases and the ubiquitine proteasome system with new agents may also represent a novel therapeutic option for patients with sarcoidosis. Summary Rising morbidity and mortality rates for patients with sarcoidosis strongly support the need to develop more effective anti-inflammatory therapies to treat chronic disease.

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Medical Therapy of Sarcoidosis

Cited by 27 publications

References 138 publications

Impaired survival of regulatory T cells in pulmonary sarcoidosis

Impaired survival of regulatory T cells in pulmonary sarcoidosis

Autoimmunity and autoinflammation: A systems view on signaling pathway dysregulation profiles

New molecular targets for the treatment of sarcoidosis

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