Laurent Nicod

Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis

Metabolites from intestinal microbiota are key determinants of host-microbe mutualism and, consequently, the health or disease of the intestinal tract. However, whether such host-microbe crosstalk influences inflammation in peripheral tissues, such as the lung, is poorly understood. We found that dietary fermentable fiber content changed the composition of the gut and lung microbiota, in particular by altering the ratio of Firmicutes to Bacteroidetes. The gut microbiota metabolized the fiber, consequently increasing the concentration of circulating short-chain fatty acids (SCFAs). Mice fed a high-fiber diet had increased circulating levels of SCFAs and were protected against allergic inflammation in the lung, whereas a low-fiber diet decreased levels of SCFAs and increased allergic airway disease. Treatment of mice with the SCFA propionate led to alterations in bone marrow hematopoiesis that were characterized by enhanced generation of macrophage and dendritic cell (DC) precursors and subsequent seeding of the lungs by DCs with high phagocytic capacity but an impaired ability to promote T helper type 2 (TH2) cell effector function. The effects of propionate on allergic inflammation were dependent on G protein–coupled receptor 41 (GPR41, also called free fatty acid receptor 3 or FFAR3), but not GPR43 (also called free fatty acid receptor 2 or FFAR2). Our results show that dietary fermentable fiber and SCFAs can shape the immunological environment in the lung and influence the severity of allergic inflammation.

Dominant TNF-α + Mycobacterium tuberculosis –specific CD4 + T cell responses discriminate between latent infection and active disease

Rapid diagnosis of active Mycobacterium tuberculosis (Mtb) infection remains a clinical and laboratory challenge. We have analyzed the cytokine profile (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2)) of Mtb-specific T cells by polychromatic flow cytometry. We studied Mtb-specific CD4+ T cell responses in subjects with latent Mtb infection and active tuberculosis disease. The results showed substantial increase in the proportion of single-positive TNF-α Mtb-specific CD4+ T cells in subjects with active disease, and this parameter was the strongest predictor of diagnosis of active disease versus latent infection. We validated the use of this parameter in a cohort of 101 subjects with tuberculosis diagnosis unknown to the investigator. The sensitivity and specificity of the flow cytometry–based assay were 67% and 92%, respectively, the positive predictive value was 80% and the negative predictive value was 92.4%. Therefore, the proportion of single-positive TNF-α Mtb-specific CD4+ T cells is a new tool for the rapid diagnosis of active tuberculosis disease.

European union standards for tuberculosis care.

The European Centre for Disease Prevention and Control (ECDC) and the European Respiratory Society (ERS) jointly developed European Union Standards for Tuberculosis Care (ESTC) aimed at providing European Union (EU)-tailored standards for the diagnosis, treatment and prevention of tuberculosis (TB). The International Standards for TB Care (ISTC) were developed in the global context and are not always adapted to the EU setting and practices. The majority of EU countries have the resources and capacity to implement higher standards to further secure quality TB diagnosis, treatment and prevention. On this basis, the ESTC were developed as standards specifically tailored to the EU setting. A panel of 30 international experts, led by a writing group and the ERS and ECDC, identified and developed the 21 ESTC in the areas of diagnosis, treatment, HIV and comorbid conditions, and public health and prevention. The ISTCs formed the basis for the 21 standards, upon which additional EU adaptations and supplements were developed. These patient-centred standards are targeted to clinicians and public health workers, providing an easy-to-use resource, guiding through all required activities to ensure optimal diagnosis, treatment and prevention of TB. These will support EU health programmes to identify and develop optimal procedures for TB care, control and elimination.

Follow-up of the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA 2) 1991–2003: methods and characterization of participants

Summary.Objectives: The Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) was designed to investigate the health effects from long-term exposure to air pollution.Methods: The health assessment at recruitment (1991) and at the first reassessment (2001–3) consisted of an interview about respiratory health, occupational and other exposures, spirometry, a methacholine bronchial challenge test, end-expiratory carbon monoxide (CO) measurement and measurement for atopy. A bio bank for DNA and blood markers was established. Heart rate variability was measured using a 24-hour ECG (Holter) in a random sample of participants aged 50xa0years and older. Concentrations of nitrogen dioxide (NO2), sulphur dioxide (SO2), ozone (O3) and particulates in ambient air have been monitored in all study areas since 1991. Residential histories collected over the 11xa0year follow-up period coupled with GIS modelling will provide individual long-term air pollutant exposure estimates.Results: Of 9651 participants examined in 1991, 8715 could be traced for the cohort study and 283 died. Basic information about health status was obtained for 8047 individuals (86% of alive persons), 6528 individuals (70%) agreed to the health examination and 5973 subjects (62%) completed the entire protocol. Non-participants in the reassessment were on average younger than participants and more likely to have been smokers and to have reported respiratory symptoms in the first assessment. Average weight had increased by 5.5xa0kg in 11xa0years and 28% of smokers in 1991 had quit by the time of the reassessment.Zusammenfassung.Die Schweizer SAPALDIA-Kohortenstudie (SAPALDIA 2) 1991–2003: Methoden und TeilnehmendencharakteristikaFragestellung: Die Schweizer Kohortenstudie Luftverschmutzung und Atemwegserkrankungen bei Erwachsenen (SAPALDIA) untersucht die gesundheitlichen Auswirkungen der Langzeitbelastung durch Luftschadstoffe in der Bevölkerung.Methoden: 1991 und 2002 wurden ein Interview zur respiratorischen Gesundheit und deren Risikofaktoren, eine Spirometrie, ein bronchialer Reagibilitätstest mit Methacholin, eine endexpiratorische Kohlenmonoxidmessung und Tests zur allergischen Sensibilisierung durchgeführt. Für SAPALDIA 2 wurde eine Biobank mit Blut-, Serum-, Plasma- und DNA-Proben eingerichtet. Eine Stichprobe der über 50-jährigen Teilnehmenden erhielt ein 24-Stunden EKG (Holter). Luftschadstoffkonzentrationen von Stickstoffdioxid (NO2), Schwefeldioxid (SO2), Ozon (O3) und Schwebstaub (PM10) wurden in allen acht Studiengebieten seit 1991 gemessen. Die seit SAPALDIA 1 erfassten Adressgeschichten und auf GIS-Technologie beruhenden Schadstoffverteilungsdaten für NO2 und PM10 werden die Schätzung der individuellen Langzeitbelastung jedes SAPALDIA-Teilnehmenden ermöglichen.Ergebnisse: Von der ursprünglichen Kohorte von 9 651 Teilnehmern in 1991 waren 283 verstorben und Adressen konnten von 8715 aufgefunden werden. Basisinformationen zum Gesundheitszustand von 8047 Personen (86% aller lebenden Personen) wurden erfasst, 6528 (70%) nahmen an der Untersuchung teil und für 5973 (62%) liegen vollständige SAPALDIA2-Untersuchungen vor. Nichtteilnehmende waren im Durchschnitt jünger, weniger gut ausgebildet, eher Raucher und hatten eher respiratorische Symptome. Die untersuchten Personen haben in den letzten 11 Jahren durchschnittlich 5,5xa0kg Körpergewicht zugelegt, 28% der RaucherInnen haben aufgehört zu rauchen.Résumé.Etude de cohorte SAPALDIA (Etude Suisse sur la pollution atmosphérique et les maladies respiratoires chez l’adulte): méthodes et caractéristiques des participantsObjectifs: L’étude SAPALDIA a pour objectif de mesurer les effets sur la santé d’une exposition à long terme aux polluants atmosphériques dans la population adulte.Méthodes: Les participants ont été interrogés en 1991 et en 2002 sur leur état de santé respiratoire et ses facteurs de risque. Ils ont passé les examens suivants: spirométrie, test de la réactivité bronchique et de l’atopie, mesure du CO en fin d’expiration. Une banque biologique a été créée. Un ECG (Holter) a été pratiqué auprès d’un échantillon de participants âgés de plus de 50 ans. Les concentrations des polluants atmosphériques (dioxyde d’azote (NO2), dioxyde de soufre (SO2), ozone, particules fines (PM10)) ont été mesurées dans huit régions de Suisse depuis 1991. L’exposition individuelle sur 11 ans sera déterminée à partir des adresses, de la distribution de NO2 et PM10 et les modèles GIS.Résultats: Sur les 9 651 participants examinés en 1991, 283 sont décédés, 87 15 ont été localisés, 8047 ont donné des informations sur leur état de santé (86% des personnes en vie), 6 528 participants (70 %) ont accepté d’effectuer l’examen de santé et 5 973 (62 %) ont réalisé entièrement le protocole. Les non participants étaient en moyenne plus jeunes, moins éduqués, plus fréquemment fumeurs et souffraient plus fréquemment de symptômes respiratoires. Les personnes examinées ont pris en moyenne 5,5xa0kg de poids en 11 ans. 28% des fumeurs ont cessé de fumer.

Mycobacterium tuberculosis‐specific CD8+ T cells are functionally and phenotypically different between latent infection and active disease

Protective immunity to Mycobacterium tuberculosis (Mtb) remains poorly understood and the role of Mtb‐specific CD8+ T cells is controversial. Here we performed a broad phenotypic and functional characterization of Mtb‐specific CD8+ T cells in 326 subjects with latent Mtb infection (LTBI) or active TB disease (TB). Mtb‐specific CD8+ T cells were detected in most (60%) TB patients and few (15%) LTBI subjects but were of similar magnitude. Mtb‐specific CD8+ T cells in LTBI subjects were mostly TEMRA cells (CD45RA+CCR7−), coexpressing 2B4 and CD160, and in TB patients were mostly TEM cells (CD45RA−CCR7−), expressing 2B4 but lacking PD‐1 and CD160. The cytokine profile was not significantly different in both groups. Furthermore, Mtb‐specific CD8+ T cells expressed low levels of perforin and granulysin but contained granzymes A and B. However, in vitro‐expanded Mtb‐specific CD8+ T cells expressed perforin and granulysin. Finally, Mtb‐specific CD8+ T‐cell responses were less frequently detected in extrapulmonary TB compared with pulmonary TB patients. Mtb‐specific CD8+ T‐cell proliferation was also greater in patients with extrapulmonary compared with pulmonary TB. Thus, the activity of Mtb infection and clinical presentation are associated with distinct profiles of Mtb‐specific CD8+ T‐cell responses. These results provide new insights in the interaction between Mtb and the host immune response.

Biomedical nanoparticles modulate specific CD4+ T cell stimulation by inhibition of antigen processing in dendritic cells

Abstract Understanding how nanoparticles may affect immune responses is an essential prerequisite to developing novel clinical applications. To investigate nanoparticle-dependent outcomes on immune responses, dendritic cells (DCs) were treated with model biomedical poly(vinylalcohol)-coated super-paramagnetic iron oxide nanoparticles (PVA-SPIONs). PVA-SPIONs uptake by human monocyte-derived DCs (MDDCs) was analyzed by flow cytometry (FACS) and advanced imaging techniques. Viability, activation, function, and stimulatory capacity of MDDCs were assessed by FACS and an in vitro CD4+ T cell assay. PVA-SPION uptake was dose-dependent, decreased by lipopolysaccharide (LPS)-induced MDDC maturation at higher particle concentrations, and was inhibited by cytochalasin D pre-treatment. PVA-SPIONs did not alter surface marker expression (CD80, CD83, CD86, myeloid/plasmacytoid DC markers) or antigen-uptake, but decreased the capacity of MDDCs to process antigen, stimulate CD4+ T cells, and induce cytokines. The decreased antigen processing and CD4+ T cell stimulation capability of MDDCs following PVA-SPION treatment suggests that MDDCs may revert to a more functionally immature state following particle exposure.

Lack of Mycobacterium tuberculosis–specific interleukin-17A–producing CD4+ T cells in active disease

Protective immunity to Mycobacterium tuberculosis (Mtb) is commonly ascribed to a Th1 profile; however, the involvement of Th17 cells remains to be clarified. Here, we characterized Mtb‐specific CD4+ T cells in blood and bronchoalveolar lavages (BALs) from untreated subjects with either active tuberculosis disease (TB) or latent Mtb infection (LTBI), considered as prototypic models of uncontrolled or controlled infection, respectively. The production of IL‐17A, IFN‐γ, TNF‐α, and IL‐2 by Mtb‐specific CD4+ T cells was assessed both directly ex vivo and following in vitro antigen‐specific T‐cell expansion. Unlike for extracellular bacteria, Mtb‐specific CD4+ T‐cell responses lacked immediate ex vivo IL‐17A effector function in both LTBI and TB individuals. Furthermore, Mtb‐specific Th17 cells were absent in BALs, while extracellular bacteria‐specific Th17 cells were identified in gut biopsies of healthy individuals. Interestingly, only Mtb‐specific CD4+ T cells from 50% of LTBI but not from TB subjects acquired the ability to produce IL‐17A following Mtb‐specific T‐cell expansion. Finally, IL‐17A acquisition by Mtb‐specific CD4+ T cells correlated with the coexpression of CXCR3 and CCR6, currently associated to Th1 or Th17 profiles, respectively. Our data demonstrate that Mtb‐specific Th17 cells are selectively undetectable in peripheral blood and BALs from TB patients.

Diagnosis and management of chronic obstructive pulmonary disease: the swiss guidelines. Official guidelines of the Swiss Respiratory Society

The new Swiss Chronic Obstructive Pulmonary Disease (COPD) Guidelines are based on a previous version, which was published 10 years ago. The Swiss Respiratory Society felt the need to update the previous document due to new knowledge and novel therapeutic developments about this prevalent and important disease. The recommendations and statements are based on the available literature, on other national guidelines and, in particular, on the GOLD (Global Initiative for Chronic Obstructive Lung Disease) report. Our aim is to advise pulmonary physicians, general practitioners and other health care workers on the early detection and diagnosis, prevention, best symptomatic control, and avoidance of COPD as well as its complications and deterioration.

The Airway Microbiome and Disease

Although traditionally thought to be sterile, accumulating evidence now supports the concept that our airways harbor a microbiome. Thus far, studies have focused upon characterizing the bacterial constituents of the airway microbiome in both healthy and diseased lungs, but what perhaps provides the greatest impetus for the exploration of the airway microbiome is that different bacterial phyla appear to dominate diseased as compared with healthy lungs. As yet, there is very limited evidence supporting a functional role for the airway microbiome, but continued research in this direction is likely to provide such evidence, particularly considering the progress that has been made in understanding host-microbe mutualism in the intestinal tract. In this review, we highlight the major advances that have been made discovering and describing the airway microbiome, discuss the experimental evidence that supports a functional role for the microbiome in health and disease, and propose how this emerging field is going to impact clinical practice.

Combined Use of Mycobacterium tuberculosis–Specific CD4 and CD8 T-Cell Responses Is a Powerful Diagnostic Tool of Active Tuberculosis

Immune-based assays are promising tools to help to formulate diagnosis of active tuberculosis. A multiparameter flow cytometry assay assessing T-cell responses specific to Mycobacterium tuberculosis and the combination of both CD4 and CD8 T-cell responses accurately discriminated between active tuberculosis and latent infection.