Increased proportions of circulating PD-1+ CD4+ memory T cells and PD-1+ regulatory T cells associate with good response to prednisone in pulmonary sarcoidosis.

BACKGROUND: The treatment response to corticosteroids in patients with sarcoidosis is highly variable. CD4+ T cells are central in sarcoid pathogenesis and their phenotype in peripheral blood (PB) associates with disease course. We hypothesized that the phenotype of circulating T cells in patients with sarcoidosis may correlate with the response to prednisone treatment. Therefore, we aimed to correlate frequencies and phenotypes of circulating T cells at baseline with the pulmonary function response at 3 and 12 months during prednisone treatment in patients with pulmonary sarcoidosis. METHODS: We used multi-color flow cytometry to quantify activation marker expression on PB T cell populations in 22 treatment-naïve patients and 21 healthy controls (HCs). Pulmonary function tests at baseline, 3 and 12 months were used to measure treatment effect. RESULTS: Patients with sarcoidosis showed an absolute forced vital capacity (FVC) increase of 14.2% predicted (± 10.6, p < 0.0001) between baseline and 3 months. Good response to prednisone (defined as absolute FVC increase of ≥ 10% predicted) was observed in 12 patients. CD4+ memory T cells and regulatory T cells from patients with sarcoidosis displayed an aberrant phenotype at baseline, compared to HCs. Good responders at 3 months had significantly increased baseline proportions of PD-1+CD4+ memory T cells and PD-1+ regulatory T cells, compared to poor responders and HCs. Moreover, decreased fractions of CD25+ cells and increased fractions of PD-1+ cells within the CD4+ memory T cell population correlated with ≥ 10% FVC increase at 12 months. During treatment, the aberrantly activated phenotype of memory and regulatory T cells reversed. CONCLUSIONS: Increased proportions of circulating PD-1+CD4+ memory T cells and PD-1+ regulatory T cells and decreased proportions of CD25+CD4+ memory T cells associate with good FVC response to prednisone in pulmonary sarcoidosis, representing promising new blood biomarkers for prednisone efficacy. TRIAL REGISTRATION: NL44805.078.13.

Transbronchial cryobiopsy followed by as-needed surgical lung biopsy versus immediate surgical lung biopsy for diagnosing interstitial lung disease (the COLD study): a randomised controlled trial.

BACKGROUND: An adequate diagnosis for interstitial lung disease (ILD) is important for clinical decision making and prognosis. In most patients with ILD, an accurate diagnosis can be made by clinical and radiological data assessment, but in a considerable proportion of patients, a lung biopsy is required. Surgical lung biopsy (SLB) is the most common method to obtain tissue, but it is associated with high morbidity and even mortality. More recently, transbronchial cryobiopsy has been introduced, with fewer adverse events but a lower diagnostic yield than SLB. The aim of this study is to compare two diagnostic strategies: a step-up strategy (transbronchial cryobiopsy, followed by SLB if the cryobiopsy is insufficiently informative) versus immediate SLB. METHODS: The COLD study was a multicentre, randomised controlled trial in six hospitals across the Netherlands. We included patients with ILD with an indication for lung biopsy as assessed by a multidisciplinary team discussion. Patients were randomly assigned in a 1:1 ratio to the step-up or immediate SLB strategy, with follow-up for 12 weeks from the initial procedure. Patients, clinicians, and pathologists were not masked to the study treatment. The primary endpoint was unexpected chest tube drainage, defined as requiring any chest tube after transbronchial cryobiopsy, or prolonged (>24 h) chest tube drainage after SLB. Secondary endpoints were diagnostic yield, in-hospital stay, pain, and serious adverse events. A modified intention-to-treat analysis was performed. This trial is registered with the Dutch Trial Register, NL7634, and is now closed. FINDINGS: Between April 8, 2019, and Oct 24, 2021, 122 patients with ILD were assessed for study participation; and 55 patients were randomly assigned to the step-up strategy (n=28) or immediate SLB (n=27); three patients from the immediate SLB group were excluded. Unexpected chest tube drainage occurred in three of 28 patients (11%; 95% CI 4-27%) in the step-up group, and the number of patients for whom the chest tube could not be removed within 24 h was 11 of 24 patients (46%; 95% CI 2-65%) in the SLB group, with an absolute risk reduction of 35% (11-56%; p=0·0058). In the step-up strategy, the multidisciplinary team diagnostic yield after transbronchial cryobiopsy alone was 82% (64-92%), which increased to 89% (73-96%) when subsequent SLB was performed after inconclusive transbronchial cryobiopsy. In the immediate surgery strategy, the multidisciplinary team diagnostic yield was 88% (69-97%). Total in-hospital stay was 1 day (IQR 1-1) in the step-up group versus 5 days (IQR 4-6) in the SLB group. One (4%) serious adverse event occurred in step-up strategy versus 12 (50%) in the immediate SLB strategy. INTERPRETATION: In ILD diagnosis, if lung tissue assessment is required, a diagnostic strategy starting with transbronchial cryobiopsy, followed by SLB when transbronchial cryobiopsy is inconclusive, appears to result in a significant reduction of patient burden and in-hospital stay with a similar diagnostic yield versus immediate SLB. FUNDING: Netherlands Organisation for Health Research and Development (ZonMW) and Amsterdam University Medical Centers.

Circulating T cells in sarcoidosis have an aberrantly activated phenotype that correlates with disease outcome.

RATIONALE: Disease course in sarcoidosis is highly variable. Bronchoalveolar lavage fluid and mediastinal lymph nodes show accumulation of activated T cells with a T-helper (Th)17.1 signature, which correlates with non-resolving sarcoidosis. We hypothesize that the peripheral blood (PB) T cell phenotype may correlate with outcome. OBJECTIVES: To compare frequencies, phenotypes and function of circulating T cell populations in sarcoidosis patients with healthy controls (HCs) and correlate these parameters with outcome. METHODS: We used multi-color flow cytometry to quantify activation marker expression on PB T cell subsets in treatment-naïve patients and HCs. The disease course was determined after 2-year follow-up. Cytokine production was measured after T cell stimulation in vitro. MEASUREMENTS AND MAIN RESULTS: We observed significant differences between patients and HCs in several T cell populations, including CD8+ and CD4+ T cells, Th1/Th17 subsets, CD4+ T memory stem cells, regulatory T cells (Tregs) and γδ T cells. Decreased frequencies of CD4+ T cells and increased frequencies of Tregs and CD8+ γδ T cells correlated with worse outcome. Naïve CD4+ T cells displayed an activated phenotype with increased CD25 expression in patients with active chronic disease at 2-year follow-up. A distinctive Treg phenotype with increased expression of CD25, CTLA4, CD69, PD-1 and CD95 correlated with chronic sarcoidosis. Upon stimulation, both naïve and memory T cells displayed a different cytokine profile in sarcoidosis compared to HCs. CONCLUSIONS: Circulating T cell subpopulations of sarcoidosis patients display phenotypic abnormalities that correlate with disease outcome, supporting a critical role of aberrant T cell activation in sarcoidosis pathogenesis.

Antibodies against angiotensin II receptor type 1 and endothelin A receptor are increased in COVID-19 patients.

Background: Increased titers of autoantibodies targeting the G-protein-coupled receptors angiotensin II type 1 receptor (AT1R) and endotelin-1 type A receptor (ETAR) are associated with severe coronavirus disease 2019 (COVID-19) infection. The aim of this study was to determine whether 1) these antibodies are specifically related to COVID-19 disease pathogenesis or increased during any severe respiratory illness, 2) if they are formed during illness, and 3) if they correlate with inflammatory markers or long-term symptoms. Methods: Antibodies against AT1R, ETAR, and antinuclear antibodies (ANAs) were measured in n=40 prospectively enrolled COVID-19 patients and n=207 COVID-19 patients included in a biobank. Clinical and laboratory findings were prospectively and retrospectively assessed in both cohorts, and results were combined for analysis. The presence of auto-antibodies against AT1R or ETAR in peripheral blood was compared between hospitalized patients with COVID-19 and controls (n=39). Additionally, AT1R and ETAR titers were compared between patients with an unfavorable disease course, defined as intensive care admission and/or death during hospital admission (n=121), to those with a favorable disease course (n=126). A subset of intubated patients with severe COVID-19 were compared to intubated patients with acute respiratory distress syndrome (ARDS) due to any other cause. Results: Significantly increased AT1R and ETAR antibody titers were found in COVID-19 patients compared to controls, while titers were equal between favorable and unfavorable COVID-19 disease course groups. On ICU, intubated patients with COVID-19 had significantly increased AT1R and ETAR titers compared to patients with ARDS due to any other cause. The titers did not correlate with baseline inflammatory markers during admission or with diffusion capacity, cognitive impairment, or fatigue measured at 3 months follow-up. Conclusions: In patients hospitalized for COVID-19, antibodies against AT1R and ETAR are increased compared to controls and patients with ARDS due to other causes than COVID-19. The baseline antibody titers do not correlate with inflammatory markers or long-term symptoms in this study.

Safety and tolerability of pirfenidone in asbestosis: a prospective multicenter study.

BACKGROUND: Pirfenidone slows down disease progression in idiopathic pulmonary fibrosis (IPF). Recent studies suggest a treatment effect in progressive pulmonary fibrosis other than IPF. However, the safety and effectiveness of pirfenidone in asbestosis patients remain unclear. In this study, we aimed to investigate the safety, tolerability and efficacy of pirfenidone in asbestosis patients with a progressive phenotype. METHODS: This was a multicenter prospective study in asbestosis patients with progressive lung function decline. After a 12-week observational period, patients were treated with pirfenidone 801 mg three times a day. Symptoms and adverse events were evaluated weekly and patients completed online patient-reported outcomes measures. At baseline, start of therapy, 12 and 24 weeks, in hospital measurement of lung function and a 6 min walking test were performed. Additionally, patients performed daily home spirometry measurements. RESULTS: In total, 10 patients were included of whom 6 patients (66.7%) experienced any adverse events during the study period. Most frequently reported adverse events were fatigue, rash, anorexia and cough, which mostly occurred intermittently and were reported as not very bothersome. No significant changes in hospital pulmonary function (forced vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLCO), 6 min walking test or patient-reported outcomes measures before and after start of pirfenidone were found. Home spirometry demonstrated a FVC decline in 12 weeks before start of pirfenidone, while FVC did not decline during the 24 week treatment phase, but this difference was not statistically significant. CONCLUSIONS: Treatment with pirfenidone in asbestosis has an acceptable safety and tolerability profile and home spirometry data suggest this antifibrotic treatment might attenuate FVC decline in progressive asbestosis. Trial registration MEC-2018-1392; EudraCT number: 2018-001781-41.

The influence of green tea extract on nintedanib's bioavailability in patients with pulmonary fibrosis.

Nintedanib is an oral small-molecule kinase inhibitor and first-line treatment for idiopathic pulmonary fibrosis. Nintedanib is a substrate of the drug efflux transporter ABCB1. Green tea flavonoids --especially epigallocatechin gallate (EGCG)-- are potent ABCB1 modulators. We investigated if concomitant administration of green tea extract (GTE) could result in a clinically relevant herb-drug interaction. Patients were randomized between A-B and B-A, with A being nintedanib alone and B nintedanib with GTE. Both periods lasted 7 days, in which nintedanib was administered twice daily directly after a meal. In period B, patients additionally received capsules with GTE (500 mg BID, >60% EGCG). Pharmacokinetic sampling for 12 h was performed at day 7 of each period. Primary endpoint was change in geometric mean for the area under the curve (AUC0-12 h). A linear mixed model was used to analyse AUCs and maximal concentration (Cmax). In 26 included patients, the nintedanib AUC0-12 h was 21% lower (95% CI -29% to -12%; P < 0.001) in period B (with GTE) compared to period A. Cmax did not differ significantly between periods; - 14% (95% CI -29% to +4%; P = 0.12). The detrimental effect was predominant in patients with the ABCB1 3435 C>T wild type variant. No differences in toxicities were observed. Exposure to nintedanib decreased with 21% when administered 60 min after GTC for only 7 days. This is a statistically significant interaction which could potentially impair treatment efficacy. Before patients and physicians should definitely be warned to avoid this combination, prospective clinical validation of an exposure-response relationship is necessary.

Altered fibrin network structure and fibrinolysis in intensive care unit patients with COVID-19, not entirely explaining the increased risk of thrombosis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 infection is associated with an increased incidence of thrombosis. OBJECTIVES: By studying the fibrin network structure of coronavirus disease 2019 (COVID-19) patients, we aimed to unravel pathophysiological mechanisms that contribute to this increased risk of thrombosis. This may contribute to optimal prevention and treatment of COVID-19 related thrombosis. PATIENTS/METHODS: In this case-control study, we collected plasma samples from intensive care unit (ICU) patients with COVID-19, with and without confirmed thrombosis, between April and December 2020. Additionally, we collected plasma from COVID-19 patients admitted to general wards without thrombosis, from ICU patients with pneumococcal infection, and from healthy controls. Fibrin fiber diameters and fibrin network density were quantified in plasma clots imaged with stimulated emission depletion microscopy and confocal microscopy. Finally, we determined the sensitivity to fibrinolysis. RESULTS: COVID-19 ICU patients (n = 37) and ICU patients with pneumococcal disease (n = 7) showed significantly higher fibrin densities and longer plasma clot lysis times than healthy controls (n = 7). No differences were observed between COVID-19 ICU patients with and without thrombosis, or ICU patients with pneumococcal infection. At a second time point, after diagnosis of thrombosis or at a similar time point in patients without thrombosis, we observed thicker fibers and longer lysis times in COVID-19 ICU patients with thrombosis (n = 19) than in COVID-19 ICU patients without thrombosis (n = 18). CONCLUSIONS: Our results suggest that severe COVID-19 is associated with a changed fibrin network structure and decreased susceptibility to fibrinolysis. Because these changes were not exclusive to COVID-19 patients, they may not explain the increased thrombosis risk.

Clinical features and immune-related protein patterns of anti-MDA5 positive clinically amyopathic dermatomyositis Dutch patients.

OBJECTIVES: The presence of melanoma differentiation-associated protein 5 (MDA5) antibodies in patients with DM is associated with the development of a rapidly progressive interstitial lung disease (RPILD), unresponsive to conventional treatment. We characterize patients and provide more insight into potential biomarkers to identify patients with RPILD. METHODS: Patients diagnosed with anti-MDA5 positive DM between December 2015 and November 2017 were included in this study. Clinical data were retrospectively retrieved from medical records. A total of 180 immune-related markers were measured in sera of 16 patients and 15 healthy controls using proximity extension assay-based technology. RESULTS: Twenty patients were included, with a median time from symptoms till diagnosis of 4 months. All patients had clinically amyopathic DM. Interstitial lung disease (ILD) was present at diagnosis in 94% of the patients, 45% presented with RPILD. The mortality rate was 35% within 4 months after diagnosis and respiratory failure was the main cause of death in these patients. Furthermore, unsupervised analysis revealed that patients with RPILD show clearly different inflammatory serum profiles than healthy controls. In addition, in comparison to healthy controls, the IFN, IL1, IL10 and IL18 signalling pathways are different regulated in anti-MDA5 positive patients. CONCLUSION: In this Dutch anti-MDA5 positive clinically amyopathic DM (CADM) cohort, one-third of the patients died due to RPILD soon after diagnosis, which underlines the severity of this disease. In addition, we have found several possible pathways that are differentially regulated in RPILD vs no RPILD DM and healthy controls. These markers await further validation before clinical use.

COVID outcome prediction in the emergency department (COPE): using retrospective Dutch hospital data to develop simple and valid models for predicting mortality and need for intensive care unit admission in patients who present at the emergency department with suspected COVID-19.

OBJECTIVES: Develop simple and valid models for predicting mortality and need for intensive care unit (ICU) admission in patients who present at the emergency department (ED) with suspected COVID-19. DESIGN: Retrospective. SETTING: Secondary care in four large Dutch hospitals. PARTICIPANTS: Patients who presented at the ED and were admitted to hospital with suspected COVID-19. We used 5831 first-wave patients who presented between March and August 2020 for model development and 3252 second-wave patients who presented between September and December 2020 for model validation. OUTCOME MEASURES: We developed separate logistic regression models for in-hospital death and for need for ICU admission, both within 28 days after hospital admission. Based on prior literature, we considered quickly and objectively obtainable patient characteristics, vital parameters and blood test values as predictors. We assessed model performance by the area under the receiver operating characteristic curve (AUC) and by calibration plots. RESULTS: Of 5831 first-wave patients, 629 (10.8%) died within 28 days after admission. ICU admission was fully recorded for 2633 first-wave patients in 2 hospitals, with 214 (8.1%) ICU admissions within 28 days. A simple model-COVID outcome prediction in the emergency department (COPE)-with age, respiratory rate, C reactive protein, lactate dehydrogenase, albumin and urea captured most of the ability to predict death. COPE was well calibrated and showed good discrimination for mortality in second-wave patients (AUC in four hospitals: 0.82 (95% CI 0.78 to 0.86); 0.82 (95% CI 0.74 to 0.90); 0.79 (95% CI 0.70 to 0.88); 0.83 (95% CI 0.79 to 0.86)). COPE was also able to identify patients at high risk of needing ICU admission in second-wave patients (AUC in two hospitals: 0.84 (95% CI 0.78 to 0.90); 0.81 (95% CI 0.66 to 0.95)). CONCLUSIONS: COPE is a simple tool that is well able to predict mortality and need for ICU admission in patients who present to the ED with suspected COVID-19 and may help patients and doctors in decision making.

The Value of the Surprise Question to Predict One-Year Mortality in Idiopathic Pulmonary Fibrosis: A Prospective Cohort Study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fatal disease with a heterogeneous disease course. Timely initiation of palliative care is often lacking. The surprise question "Would you be surprised if this patient died within the next year?" is increasingly used as a clinical prognostic tool in chronic diseases but has never been evaluated in IPF. OBJECTIVE: We aimed to evaluate the predictive value of the surprise question for 1-year mortality in IPF. METHODS: In this prospective cohort study, clinicians answered the surprise question for each included patient. Clinical parameters and mortality data were collected. The sensitivity, specificity, accuracy, negative, and positive predictive value of the surprise question with regard to 1-year mortality were calculated. Multivariable logistic regression analysis was performed to evaluate which factors were associated with mortality. In addition, discriminative performance of the surprise question was assessed using the C-statistic. RESULTS: In total, 140 patients were included. One-year all-cause mortality was 20% (n = 28). Clinicians identified patients with a survival of <1 year with a sensitivity of 68%, a specificity of 82%, an accuracy of 79%, a positive predictive value of 49%, and a negative predictive value of 91%. The surprise question significantly predicted 1-year mortality in a multivariable model (OR 3.69; 95% CI 1.24-11.02; p = 0.019). The C-statistic of the surprise question to predict mortality was 0.75 (95% CI 0.66-0.85). CONCLUSIONS: The answer on the surprise question can accurately predict 1-year mortality in IPF. Hence, this simple tool may enable timely focus on palliative care for patients with IPF.

Case report: a fatal combination of hemophagocytic lymphohistiocytosis with extensive pulmonary microvascular damage in COVID-19 pneumonia.

The clinical features of COVID-19 have a considerable range from a mild illness to severe disease. Underlying pathophysiological mechanisms of the rapidly progressive, and often fatal, pulmonary disease frequently observed in COVID-19 need to be elucidated, in order to develop new treatment strategies for different disease endotypes. Fatal cases can display features of a cytokine storm, which may be related to hemophagocytic lymphohistiocytosis. Also, a spectrum of vascular changes, including microvascular damage, is known to accompany severe COVID-19. In this paper, we describe the co-occurrence of hemophagocytic lymphohistiocytosis and extensive pulmonary microvascular damage with thrombosis and its sequelae in a patient with fatal COVID-19. We believe these response patterns may be linked by common mechanisms involving hypercytokinemia and require further investigation as a fatal constellation in COVID-19, to generate appropriate treatment in patients who display these combined features.

The tough process of unmasking the slow-growing mycobacterium: case report of Mycobacterium microti infection.

Mycobacterium microti belongs to the Mycobacterium tuberculosis complex (MTBC). It can cause pulmonary and extrapulmonary tuberculosis in humans. Compared to M. tuberculosis , which is the most prevalent subspecies of the MTBC, M. microti infection has a different etiology. Moreover, establishing the diagnosis with conventional bacteriology can be difficult. We will illustrate this with a case of an extrapulmonary tuberculosis of the hip caused by M .microti in an immunocompetent patient in The Netherlands.

Looking into the future of sarcoidosis: what is next for treatment?

PURPOSE OF REVIEW: Sarcoidosis is a complex granulomatous disease of unknown cause. Corticosteroids and immune suppressants are often given long term in chronic disease, which may result in substantial toxicity. Validated strategies for selecting patients at risk for disease progression, who might benefit from early and targeted treatment, are lacking. Consequently, the unmet need for new treatment options in sarcoidosis is high. In this review, we critically discuss potential therapeutic targets and ongoing clinical trials in sarcoidosis. RECENT FINDINGS: Despite the heterogeneous clinical manifestations and the lack of a reliable animal model, our knowledge and understanding of the pathogenesis of sarcoidosis has improved in recent years, which has resulted in the identification of several potential therapeutic strategies. They include the inhibition of cytokines involved in maturation of macrophages, activation of dendritic cells, and maturation and activation of pathogenic T-lymphocytes. The inflammasome and the autophagy are additional areas for future research. Antifibrotic therapy might also be a reasonable choice in selected patients, although the best treatment strategy in progressive fibrotic sarcoidosis remains undetermined. SUMMARY: In this article, we review novel approaches to sarcoidosis treatment and potential therapeutic targets.

Sensitivity and specificity of serum soluble interleukin-2 receptor for diagnosing sarcoidosis in a population of patients suspected of sarcoidosis.

BACKGROUND: The soluble interleukin 2 receptor (sIL-2R) has been proposed as a marker of disease activity in patients with sarcoidosis. However, no studies have evaluated whether serum sIL-2R measurement is of use in establishing the diagnosis of sarcoidosis in patients who are suspected of sarcoidosis among other diseases. METHODS: A cohort study was conducted, consisting of new patients who visited the immunology outpatient clinic and whose serum sIL-2R levels were available before a definitive diagnosis was established between February 2011 and February 2016. All patients underwent standard diagnostic testing for sarcoidosis (e.g. laboratory tests, radiographic and/or nuclear imaging and/or affected site biopsy). This resulted either in the diagnosis of sarcoidosis or the exclusion of sarcoidosis with the diagnosis of another disease. Results of sIL-2R and angiotensin-converting enzyme (ACE) levels, radiographic and nuclear imaging and histology results were collected and definitive diagnoses were recorded. Sensitivity, specificity, the concordance statistic from the receiver operating characteristic curve and Youden's Index were calculated to assess the performance of sIL-2R in the diagnosis of sarcoidosis and were compared to ACE, currently one of the most used diagnostic biomarkers in the diagnosis of sarcoidosis. RESULTS: In total 983 patients were screened for inclusion, of which 189 patients met the inclusion criteria. A total of 101 patients were diagnosed with sarcoidosis after diagnostic workup, of whom 79 were biopsy-proven. In 88 patients a diagnosis other than sarcoidosis was made. The sensitivity and specificity of serum soluble interleukin 2 receptor levels to detect sarcoidosis were 88% and 85%. The sensitivity and specificity of ACE were 62% and 76%. Receiver operating characteristic curve analysis revealed that sIL-2R receptor is superior to ACE (p<0.0001). CONCLUSION: Serum sIL-2R is a sensitive biomarker and superior to ACE in establishing the diagnosis of sarcoidosis and can be used to rule out sarcoidosis in patients suspected of sarcoidosis.

Enhanced Bruton's tyrosine kinase in B-cells and autoreactive IgA in patients with idiopathic pulmonary fibrosis.

RATIONALE: Idiopathic Pulmonary Fibrosis (IPF) is thought to be triggered by repeated alveolar epithelial cell injury. Current evidence suggests that aberrant immune activation may contribute. However, the role of B-cell activation remains unclear. We determined the phenotype and activation status of B-cell subsets and evaluated the contribution of activated B-cells to the development of lung fibrosis both in humans and in mice. METHODS: B-cells in blood, mediastinal lymph node, and lung single-cell suspensions of IPF patients and healthy controls (HC) were characterized using 14-color flow cytometry. Mice were exposed to bleomycin to provoke pulmonary fibrosis. RESULTS: More IgA+ memory B-cells and plasmablasts were found in blood (n = 27) and lungs (n = 11) of IPF patients compared to HC (n = 21) and control lungs (n = 9). IPF patients had higher levels of autoreactive IgA in plasma, which correlated with an enhanced decline of forced vital capacity (p = 0.002, r = - 0.50). Bruton's tyrosine kinase expression was higher in circulating IPF B-cells compared to HC, indicating enhanced B-cell activation. Bleomycin-exposed mice had increased pulmonary IgA+ germinal center and plasma cell proportions compared to control mice. The degree of lung fibrosis correlated with pulmonary germinal center B-cell proportions (p = 0.010, r = 0.88). CONCLUSION: Our study demonstrates that IPF patients have more circulating activated B-cells and autoreactive IgA, which correlate with disease progression. These B-cell alterations were also observed in the widely used mouse model of experimental pulmonary fibrosis. Autoreactive IgA could be useful as a biomarker for disease progression in IPF.

Th17-lineage cells in pulmonary sarcoidosis and Löfgren's syndrome: Friend or foe?

Sarcoidosis, a multisystem granulomatous disorder, has historically been classified as Th1-driven disease. However, increasing data demonstrate a key role of Th17-cell plasticity in granuloma formation and maintenance. In Löfgren's syndrome (LS), an acute and distinct phenotype of sarcoidosis with a favorable outcome, differences in Th17-lineage cell subsets, cytokine expression and T-cell suppressive mechanisms may account for differences in clinical presentation as well as prognosis compared to non-LS sarcoidosis. In contrast with LS, up to 20% of non-LS sarcoidosis patients may progress to irreversible pulmonary fibrosis. In non-LS sarcoidosis patients, IFN-γ-producing Th17.1-cells appear to be more pathogenic and possibly linked to disease progression, while a broader range of cytokines is found in bronchoalveolar lavage fluid (BALF) in LS patients. Differences in Cytotoxic T-lymphocyte antigen 4 (CTLA-4) expression on Th17-cells and regulatory T-cells (Treg) could contribute to Th17-cell pathogenicity and consequently to either disease resolution or ongoing inflammation in sarcoidosis. Furthermore, several genes and SNPs are associated with disease susceptibility and outcome in sarcoidosis, the majority of which are involved in antigen presentation, T-cell activation or regulation of T-cell survival. Novel insights into the role of Th17-cells in the pathogenesis of both LS and non-LS sarcoidosis will unravel pathogenic and benign Th17-lineage cell function and drivers of Th17-cell plasticity. This will also help identify new treatment strategies for LS and non-LS sarcoidosis patients by altering Th17-cell activation, suppress conversion into more pathogenic subtypes, or influence cytokine signaling towards a beneficial signature of Th17-lineage cells. In this review, we summarize new insights into Th17-cell plasticity in the complex pathogenesis of sarcoidosis and connect these cells to the different disease phenotypes, discuss the role of genetic susceptibility and autoimmunity and focus on possible treatment strategies.