Metabolism-driven glycosylation represents therapeutic opportunities in interstitial lung diseases.

Metabolic changes are coupled with alteration in protein glycosylation. In this review, we will focus on macrophages that are pivotal in the pathogenesis of pulmonary fibrosis and sarcoidosis and thanks to their adaptable metabolism are an attractive therapeutic target. Examples presented in this review demonstrate that protein glycosylation regulates metabolism-driven immune responses in macrophages, with implications for fibrotic processes and granuloma formation. Targeting proteins that regulate glycosylation, such as fucosyltransferases, neuraminidase 1 and chitinase 1 could effectively block immunometabolic changes driving inflammation and fibrosis, providing novel avenues for therapeutic interventions.

Transthyretin-derived amyloid (ATTR) and sarcoidosis: Does ATTR deposition cause a granulomatous inflammatory response in older adults with sarcoidosis?

This study aimed to assess the frequency and association between transthyretin-derived (ATTR) amyloidosis and sarcoidosis in a large autopsy cohort including many cases of sudden cardiac death (SCD). We identified 73 sporadic ATTR amyloidosis cases and 11 sarcoidosis cases, among which we found two cases with concomitant ATTR amyloidosis and sarcoidosis (2.4% of all cases; 2.7% within the sporadic ATTR group). The first case involved a 92-year-old man who experienced SCD. In this patient's heart, we observed ATTR deposition and noncaseating epithelioid granulomas consistent with sarcoidosis. Focally, ATTR deposits and granulomas co-localized, with histiocyte phagocytosis of transthyretin-immunoreactive fragments. However, in most lesions, they were distributed independently. The second case was that of an 86-year-old woman who also experienced SCD. In this patient, we detected ATTR deposition in the heart and lung, while noncaseating epithelioid granulomas were only observed in the lung, liver, kidney, and thyroid. Furthermore, no co-localization of the two lesions was observed. Based on these findings, we concluded that the coexistence of ATTR amyloidosis and sarcoidosis was likely coincidental. Nevertheless, despite the rarity of the combination of these two diseases, it should be recognized as a potential cause of SCD, especially among elderly people.

Aberrant Lipid Metabolism in Macrophages Is Associated with Granuloma Formation in Sarcoidosis.

Rationale: Chronic sarcoidosis is a complex granulomatous disease with limited treatment options that can progress over time. Understanding the molecular pathways contributing to disease would aid in new therapeutic development. Objectives: To understand whether macrophages from patients with nonresolving chronic sarcoidosis are predisposed to macrophage aggregation and granuloma formation and whether modulation of the underlying molecular pathways influence sarcoidosis granuloma formation. Methods: Macrophages were cultivated in vitro from isolated peripheral blood CD14+ monocytes and evaluated for spontaneous aggregation. Transcriptomics analyses and phenotypic and drug inhibitory experiments were performed on these monocyte-derived macrophages. Human skin biopsies from patients with sarcoidosis and a myeloid Tsc2-specific sarcoidosis mouse model were analyzed for validatory experiments. Measurements and Main Results: Monocyte-derived macrophages from patients with chronic sarcoidosis spontaneously formed extensive granulomas in vitro compared with healthy control participants. Transcriptomic analyses separated healthy and sarcoidosis macrophages and identified an enrichment in lipid metabolic processes. In vitro patient granulomas, sarcoidosis mouse model granulomas, and those directly analyzed from lesional patient skin expressed an aberrant lipid metabolism profile and contained increased neutral lipids. Conversely, a combination of statins and cholesterol-reducing agents reduced granuloma formation both in vitro and in vivo in a sarcoidosis mouse model. Conclusions: Together, our findings show that altered lipid metabolism in sarcoidosis macrophages is associated with its predisposition to granuloma formation and suggest cholesterol-reducing therapies as a treatment option in patients.

Prospective Analysis of Immunosuppressive Therapy in Cardiac Sarcoidosis With Fluorodeoxyglucose Myocardial Accumulation: The PRESTIGE Study.

BACKGROUND: Fluorodeoxyglucose positron emission tomography (18F-FDG-PET) can noninvasively assess active inflammatory myocardium in patients with cardiac sarcoidosis (CS). Prednisolone (PSL) is the initial drug of choice for active CS; however, its efficacy has not been prospectively evaluated. Moreover, there are no alternative systematic treatment strategies. OBJECTIVES: The goal of this study was to evaluate the efficacy of methotrexate (MTX) in patients refractory to PSL assessed by using cardiac metabolic activity (CMA) in 18F-FDG-PET. METHODS: A total of 59 patients with active CS were prospectively enrolled. CMA (standardized uptake value × accumulation area) was used as an indicator of active inflammation, and a 6-month regimen of PSL therapy was introduced, followed by a second FDG scan. Poor responders to PSL therapy (CMA reduction rate <70%) and patients with recurrent CS (CMA reduction rate ≥70% after initial PSL therapy but CMA recurred after an additional 6 months of therapy) were randomly assigned to the MTX or repeat PSL (re-PSL) therapy groups for another 6 months. RESULTS: Fifty-six patients completed the initial 6-month PSL therapy regimen. Median CMA reduced from 203.3 to 1.0 (P < 0.001), and 47 patients were allocated to the response group, 9 to the poor response group, and 2 to the recurrent group. Accordingly, 11 patients were randomly assigned to the MTX (n = 5) or re-PSL (n = 6) groups. After 6 months, neither group showed a significant reduction in CMA values. MTX was comparable to re-PSL in reducing CMA. CONCLUSIONS: The 6-month regimen of PSL was a potent therapeutic tool for active CS. When MTX was added to low-dose PSL in patients refractory to the initial PSL therapy, there was no significant difference compared with re-PSL. Further studies are needed to evaluate the therapeutic potential of MTX for active CS, including how MTX works when it is administered in higher doses or for longer periods.

Vitreous Humor Proteomic Profile in Patients With Vitreoretinal Lymphoma.

Purpose: Vitreoretinal lymphoma is a high-grade malignant non-Hodgkin lymphoma with poor prognosis. The objective of this study was to elucidate the proteome profile of the vitreous in patients with vitreoretinal lymphoma (VRL), aiming to advance understanding of the pathophysiology of VRL. Methods: Comprehensive proteomic analyses of vitreous humor using liquid chromatography with tandem mass spectrometry were performed for 10 patients with VRL, 10 control patients with idiopathic epiretinal membrane or macular hole, and 10 patients with ocular sarcoidosis. Differentially expressed proteins (DEPs) were identified by comparing VRL with controls and sarcoidosis, and functional pathway analysis was performed. Finally, vitreous concentrations of representative DEPs that were significantly upregulated in proteomics study were measured by ELISA using a separate cohort. Results: In total, 1594 proteins were identified in the vitreous humor of VRL, control, and sarcoidosis samples. Also, 282 DEPs were detected in VRL, 249 upregulated and 33 downregulated, compared with controls. Enrichment pathway analysis showed alterations in proteasome-related pathways. Compared to controls and sarcoidosis, 14 DEPs in VRL showed significant upregulation. In the validation study, ELISA confirmed significantly higher vitreous concentrations of PSAT1, YWHAG, and 20S/26S proteasome complex in VRL compared with controls and sarcoidosis. Among the upregulated DEPs, vitreous PITHD1 and NCSTN concentrations correlated positively with vitreous IL-10 concentrations. Conclusions: This study highlights aberrations in protein expression pattern in the vitreous of patients with VRL. The DEPs identified in this study may play pivotal roles in VRL pathogenesis, providing insights to enhance understanding of VRL pathophysiology and contribute to the development of VRL biomarkers.

Th17.1 cell driven sarcoidosis-like inflammation after anti-BCMA CAR T cells in multiple myeloma.

Pseudo-progression and flare-up phenomena constitute a novel diagnostic challenge in the follow-up of patients treated with immune-oncology drugs. We present a case study on pulmonary flare-up after Idecabtagen Vicleucel (Ide-cel), a BCMA targeting CAR T-cell therapy, and used single-cell RNA-seq (scRNA-seq) to identify a Th17.1 driven autoimmune mechanism as the biological underpinning of this phenomenon. By integrating datasets of various lung pathological conditions, we revealed transcriptomic similarities between post CAR T pulmonary lesions and sarcoidosis. Furthermore, we explored a noninvasive PET based diagnostic approach and showed that tracers binding to CXCR4 complement FDG PET imaging in this setting, allowing discrimination between immune-mediated changes and true relapse after CAR T-cell treatment. In conclusion, our study highlights a Th17.1 driven autoimmune phenomenon after CAR T, which may be misinterpreted as disease relapse, and that imaging with multiple PET tracers and scRNA-seq could help in this diagnostic dilemma.

FDG uptake patterns in isolated and systemic cardiac sarcoidosis.

AIMS: We aimed to investigate the pre-treatment characteristics and treatment responses of isolated and systemic cardiac sarcoidosis (ICS and SCS) from FDG-PET/CT studies and to compare the prognoses of the two groups. METHODS: FDG-PET/CT images taken before and after treatment of 31 ICS and 91 SCS patients were analyzed retrospectively. Treatment response and recurrence were determined from the course of FDG-PET/CT. Treatment response and the incidence of both recurrence and major adverse cardiac events (MACE) were assessed in 16 ICS and 35 SCS patients who had been treated for more than 2 years. RESULTS: A focal uptake pattern was more often observed than a focal-on-diffuse uptake pattern in both the ICS (74.2%) and SCS (63.7%) groups. Right ventricular involvement was significantly more frequent in SCS than ICS (44.0% vs. 9.6%, p < .001). SUVmax, cardiac metabolic volume (CMV), and cardiac metabolic activity (CMA) were significantly higher in SCS than ICS (SUVmax, 9.1 ± 4.1 vs. 4.8 ± 2.1; CMV, 118.0 ± 111.3 ml vs. 68.3 ± 94.7 ml; CMA, 541.6 ± 578.7 MBq vs. 265.1 ± 396.0 MBq, p < .001). Treatment responses in the two groups were similar, and complete resolution of cardiac uptake after immunosuppressive treatment was obtained in 62.5% of ICS patients and 77.1% of SCS patients (not significantly different). Likewise, no significant difference was found in the incidence of recurrence (40.0% for ICS, 44.4% for SCS) or MACE (25.0% for ICS, 22.8% for SCS). CONCLUSION: SCS patients had more active and extensive CS lesions than ICS patients before treatment, but the two groups showed similar treatment responses and prognoses.

FOXP3+ regulatory T cells are associated with the severity and prognosis of sarcoidosis.

Rationale: Sarcoidosis is an inflammatory granulomatous disease of unknown etiology with predominant lung involvement. Organ involvement and disease severity, as well as the nature of immune alterations, vary among patients leading to a range of clinical phenotypes and outcomes. Our objective was to evaluate the association of disease course and immune responses in pulmonary sarcoidosis. Methods: In this prospective cohort study of 30 subjects, most of whom were followed for one year, we evaluated 14 inflammatory markers in plasma, 13 Treg/T cell flow cytometry markers and 8 parameters of FOXP3+ Treg biology, including suppressive function, epigenetic features and stability. Results: We identified a set of 13 immunological parameters that differ in sarcoidosis subjects in comparison with healthy donors. Five of those were inversely correlated with suppressive function of Tregs in sarcoidosis, and six (TNFα, TNFR I and II, sCD25, Ki-67 and number of Tregs) were particularly upregulated or increased in subjects with thoracic lymphadenopathy. Treg suppressive function was significantly lower in patients with thoracic lymphadenopathy, and in patients with higher burdens of pulmonary and systemic symptoms. A combination of five inflammatory markers, Ki-67 expression, Treg function, and lung diffusion capacity evaluated at study entry predicted need for therapy at one year follow-up in 90% of cases. Conclusion: Tregs may suppress ongoing inflammation at local and systemic levels, and TNFα, TNFR I and II, sCD25 and Ki-67 emerge as attractive biomarkers for in vivo sarcoid inflammatory activity.

Could different aqueous humor and plasma cytokine profiles help differentiate between ocular sarcoidosis and ocular tuberculosis?

OBJECTIVE AND DESIGN: A cross-sectional single-center study was conducted to assess cytokine levels in aqueous humor (AH) and plasma of three different uveitis entities: definite ocular sarcoidosis (OS), definite OS associated with QuantiFERON®-TB Gold test positivity (Q + OS) and presumed tubercular uveitis (TBU). SUBJECTS: Thirty-two patients (15 OS, 5 Q + OS, 12 TBU) were included. METHODS: Quantification of selected cytokines was performed on blood and AH samples collected before starting any treatment. Statistical analysis was conducted using the Kruskal-Wallis test, the Mann-Whitney or Fisher test and the Principal Component Analysis (PCA). RESULTS: IL-6, IL-8 and IP-10 levels were higher in AH samples than in peripheral blood. In AH samples, BLC, IL-8 and IP-10 were significantly higher in definite OS than in presumptive TBU. There were no statistically significant differences in terms of cytokine levels between Q + OS and presumptive TBU. PCA showed a similar cytokine pattern in the latter two groups (IFNγ, IL-15, IL-2, IP-10, MIG), while the prevalent expression of BLC, IL-10 and MIP-3 α was seen in definite OS. CONCLUSIONS: The different AH and plasma cytokine profiles observed in OS compared to Q + OS and TBU may help to differentiate OS from TBU in overlapping clinical phenotypes of granulomatous uveitis (Q + OS).

Identification of key regulators in Sarcoidosis through multidimensional systems biological approach.

Sarcoidosis is a multi-organ disorder where immunology, genetic and environmental factors play a key role in causing Sarcoidosis, but its molecular mechanism remains unclear. Identification of its genetics profiling that regulates the Sarcoidosis network will be one of the main challenges to understand its aetiology. We have identified differentially expressed genes (DEGs) by analyzing the gene expression profiling of Sarcoidosis and compared it with healthy control. Gene set enrichment analysis showed that these DEGs were mainly enriched in the inflammatory response, immune system, and pathways in cancer. Sarcoidosis protein interaction network was constructed by a total of 877 DEGs (up-down) and calculated its network topological properties, which follow hierarchical scale-free fractal nature up to six levels of the organization. We identified a large number of leading hubs that contain six key regulators (KRs) including ICOS, CTLA4, FLT3LG, CD33, GPR29 and ITGA4 are deeply rooted in the network from top to bottom, considering a backbone of the network. We identified the transcriptional factors (TFs) which are closely interacted with KRs. These genes and their TFs regulating the Sarcoidosis network are expected to be the main target for the therapeutic approaches and potential biomarkers. However, experimental validations of KRs needed to confirm their efficacy.

PD1, CTLA4 and TIGIT Expression on T and NK Cells in Granulomatous Diseases: Sarcoidosis and ANCA-Associated Vasculitis.

Sarcoidosis is a granulomatous diseases affecting the lungs. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a histologically granulomatous B-mediated disorder characterized by activated T cells. The expression of immune checkpoint (IC) molecules (PD1, CTLA4, TIGIT) on T- and NK-cells negatively regulate the T-cell immune function. The present study aimed to explore the peripheral distribution of IC molecules to better elucidate their peripheral tolerance failure, which might reflect the development of diseases. Patients referred to Respiratory Diseases and Rheumatology Unit of Siena University Hospital were prospectively and consecutively enrolled. Healthy subjects were also enrolled as a control group. Multicolor flow cytometric analysis was performed to detect IC molecules in the peripheral blood of patients. Twenty-three patients were consecutively and prospectively enrolled in the study: 11 patients had an AAV diagnosis and 12 had sarcoidosis. CD4+PD1+ cells were higher in sarcoidosis and GPA than in HC (p = 0.0250 and p = 0.0253, respectively). CD56+CTLA4+ were higher in sarcoidosis than GPA, MPA and HC (p = 0.0085, p = 0.0042 and p = 0.0004, respectively). CTLA4+NK cells clustered for 100% of sarcoidosis patients according to decision tree analysis, while PD1+CD4 and CD8 cells for clustered for 100% of GPA patients. Our analyses showed substantial differences between sarcoidosis and AAV, further confirming the immunological peculiarity of this disease. Despite these advances, the pathogenesis remains incompletely understood, indicating an urgent need for further research to reveal the distinct immunological events in this process, with the hope to open up new therapeutic avenues and, if possible, to develop preventive measures.

Characterization of natural killer and T cells in bronchoalveolar lavage and peripheral blood of sarcoidosis patients.

The characterization of frequency and phenotypes of natural killer (NK) cells and T cells in BAL and peripheral blood of patients with sarcoidosis was evaluated, to discriminate the differential status of these cells in these two compartments. The analysis revealed that CD56brightCD16neg resulted higher in BAL than PB of sarcoidosis and healthy subjects, while CD56dimCD16+ showed a different proportion between BAL and PB of both Sarcoidosis patients and HC. Moreover, in comparison with autologous PB, BAL was characterized by a higher expression of activated NK cell markers NKp44, CD69 and CD25. Significantly increased levels of PD-1+ NK cells in the BAL of patients were detected. Regarding the maturation of CD4 and CD8, an increase of Effector Memory T cells (TEM) was reported in BAL compared to PB. A better characterization of NK and T cells may lead to an improvement of the pathogenetic mechanisms in sarcoidosis.

The Role of Diverse Immune Cells in Sarcoidosis.

Sarcoidosis is a systemic inflammatory disorder of unknown etiology characterized by tissue infiltration with macrophages and lymphocytes and associated non-caseating granuloma formation. The disease primarily affects the lungs. Patients suffering from sarcoidosis show a wide range of clinical symptoms, natural history and disease outcomes. Originally described as a Th1-driven disease, sarcoidosis involves a complex interplay among diverse immune cells. This review highlights recent advances in the pathogenesis of sarcoidosis, with emphasis on the role of different immune cells. Accumulative evidence suggests Th17 cells, IFN-γ-producing Th17 cells or Th17.1 cells, and regulatory T (Treg) cells play a critical role. However, their specific actions, whether protective or pathogenic, remain to be clarified. Macrophages are also involved in granuloma formation, and M2 polarization may be predictive of fibrosis. Previously neglected cells including B cells, dendritic cells (DCs), natural killer (NK) cells and natural killer T (NKT) cells were studied more recently for their contribution to sarcoid granuloma formation. Despite these advances, the pathogenesis remains incompletely understood, indicating an urgent need for further research to reveal the distinct immunological events in this process, with hope to open up new therapeutic avenues and if possible, to develop preventive measures.

The Role of Oxidative Stress in Sarcoidosis.

Sarcoidosis is a rare, systemic inflammatory disease whose diagnosis and management can pose a challenge for clinicians and specialists. Scientific knowledge on the molecular pathways that drive its development is still lacking, with no standardized therapies available and insufficient strategies to predict patient outcome. In recent years, oxidative stress has been highlighted as an important factor in the pathogenesis of sarcoidosis, involving several enzymes and molecules in the mechanism of the disease. This review presents current data on the role of oxidative stress in sarcoidosis and its interaction with inflammation, as well as the application of antioxidative therapy in the disease.

Structural localization of pathogenic mutations in the central nucleotide-binding domain (NBD) of nucleotide-binding oligomerization domain-2 (NOD2) protein and their inference in inflammatory disorders.

The human NBD domain which is centrally located in the NOD2 protein displays an essential role in oligomerization and initiates the immune response via CARD-RIPK2 interaction. The mutations associated with the NBD domain have been largely implicated in inflammatory disorders such as Blau syndrome and sarcoidosis. This study aims to determine the structural and phenotypic effect of a lethal mutation that occurs in the NBD domain which has an axiomatic impact on protein dysfunction. Initially, the most deleterious missense mutations were screened through various in silico analysis. Out of 33 variants, I-Mutant 3.0, SIFT, PolyPhen 2, Align GVGD, PHD SNP and SNP&GO have statistically identified 5 variants (R42W, D90E, E91K, G189D & W198L) as less stable, deleterious and damaging. Our predicted models have paved the way to understand the various structural properties such as physiochemical, secondary structural arrangements and stabilizing residues in folding associated with the native and mutant NBD domain especially of the functionally important regions. From the aforementioned results, R42W and G189D were found to be the more predominant among the mutants. Precisely, through molecular simulation, we have strongly justified the significant conformational disruption of R42W and G189D through the stabilization factors, folding and essential dynamics. Conclusively, these regions (α341-44, α13185-191 and ß6133-143ß7) seem to adopt such structures that are not conducive to wild-type-like functionality. Our prediction and validation of lethal mutations based on structural stability may be useful for conducting experimental studies in detail to uncover the protein deregulation leading to inflammatory disorders.

Hypoxia Promotes a Mixed Inflammatory-Fibrotic Macrophages Phenotype in Active Sarcoidosis.

Background: Macrophages 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. Methods: We 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. Results: We 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. Conclusions: Hypoxia 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.

Myocardial Accumulations of Reg3A, Reg3γ and Oncostatin M Are Associated with the Formation of Granulomata in Patients with Cardiac Sarcoidosis.

Cardiac sarcoidosis (CS) is a poorly understood disease and is characterized by the focal accumulation of immune cells, thus leading to the formation of granulomata (GL). To identify the developmental principles of fatal GL, fluorescence microscopy and Western blot analysis of CS and control patients is presented here. CS is visualized macroscopically by positron emission tomography (PET)/ computed tomography (CT). A battery of antibodies is used to determine structural, cell cycle and inflammatory markers. GL consist of CD68+, CD163+ and CD206+ macrophages surrounded by T-cells within fibrotic areas. Cell cycle markers such as phospho-histone H3, phospho-Aurora and Ki67 were moderately present; however, the phosphorylated ERM (ezrin, radixin and moesin) and Erk1/2 proteins, strong expression of the myosin motor protein and the macrophage transcription factor PU.1 indicate highly active GL. Mild apoptosis is consistent with PI3 kinase and Akt activation. Massive amounts of the IL-1R antagonist reflect a mild activation of stress and inflammatory pathways in GL. High levels of oncostatin M and the Reg3A and Reg3γ chemokines are in accordance with macrophage accumulation in areas of remodeling cardiomyocytes. We conclude that the formation of GL occurs mainly through chemoattraction and less by proliferation of macrophages. Furthermore, activation of the oncostatin/Reg3 axis might help at first to wall-off substances but might initiate the chronic development of heart failure.

Elevated IL-15 concentrations in the sarcoidosis lung are independent of granuloma burden and disease phenotypes.

Sarcoidosis is a systemic granulomatous disease predominantly affecting the lungs. The mechanisms promoting disease pathogenesis and progression are unknown, although interleukin-15 (IL-15) has been associated with the immune-mediated inflammation of sarcoidosis. Because the identification of a mechanistically based, clinically relevant biomarker for sarcoidosis remains elusive, we hypothesized this role for IL-15. Pulmonary sarcoidosis granuloma formation was modeled using trehalose 6,6'-dimicolate (TDM), which was administered into wild-type and three lineages of mice: those overexpressing IL-15, deficient in IL-15, and deficient in IL-15 receptor α. The number of granulomas per lung was counted and normalized to the wild type. IL-15 concentrations were measured in the bronchoalveolar lavage (BAL) from healthy controls and subjects with sarcoidosis in our cohort, where associations between IL-15 levels and clinical manifestations were sought. Findings were validated in another independent sarcoidosis cohort. TDM administration resulted in similar granuloma numbers across all lineages of mice. IL-15 concentrations were elevated in the BAL of both human cohorts, irrespective of disease phenotypes. In exploratory analysis, an association with obesity was observed, and various other soluble mediators were identified in the BAL of both cohorts. Although IL-15 is enriched in the sarcoidosis lung, it was independent of disease pathogenesis or clinical manifestations in our mouse model and human cohorts of sarcoidosis. An association with obesity perhaps reflects the ongoing inflammatory processes of these comorbid conditions. Our findings showed that IL-15 is redundant for disease pathogenesis and clinical progression of sarcoidosis.

The Short- and Long-Term Impact of Pulmonary Rehabilitation in Subjects with Sarcoidosis: A Prospective Study and Review of the Literature.

BACKGROUND: Sarcoidosis is a heterogeneous multisystemic disorder of unknown etiology. Dyspnea and fatigue are two of the most common and debilitating symptoms experienced by subjects with sarcoidosis. There is limited evidence regarding the short- and long-term impact of pulmonary rehabilitation (PR) on exercise capacity and fatigue in these individuals. OBJECTIVE: To evaluate the benefit of PR in subjects with pulmonary sarcoidosis at different severity stages and to review the current literature about PR in sarcoidosis. METHODS: PR included a 12-week training program of a twice-weekly 90-min workouts. Fifty-two subjects with stable pulmonary sarcoidosis were recruited. Maximal exercise capacity, defined as VO2max, was measured using the cardiopulmonary exercise test (CPET). Pulmonary function tests, 6-min walking distance (6MWD), St. George's Respiratory Questionnaire (SGRQ), and the modified Medical Research Council (mMRC) and Hospital Anxiety and Depression Scale (HADS) questionnaires were given before and after PR and following 6 months (follow-up). RESULTS: The PR program significantly increased the VO2max (1.8 ± 2.3 mL/kg/min, p = 0.002), following 12 weeks. mMRC and SGRQ scores were also improved (-0.3 ± 0.8, p = 0.03, and -3.87 ± 10.4, p = 0.03, respectively). The impact of PR on VO2max was more pronounced in subjects with pulmonary parenchymal involvement. The increase in VO2max correlated with initial disease severity (indicated by FEV1/FVC, p = 0.01). Subjects with FEV1/FVC <70% showed greater improvement in 6MWD. 6MWD also improved in those with a transfer coefficient of the lung for CO (KCO) above 80% predicted (p < 0.05). At 6-month follow-up, the VO2max, 6MWD, and SGRQ scores remained stable, thus suggesting lasting effects of PR. CONCLUSION: PR is a promising complementary therapeutic intervention for subjects with sarcoidosis. Further study is needed to validate these findings.