Nieuwegein, Netherlands
Nieuwegein, Netherlands

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Barlo N.P.,Center for Interstitial Lung Diseases | Van Moorsel C.H.M.,Center for Interstitial Lung Diseases | Van Moorsel C.H.M.,University Utrecht | Korthagen N.M.,Center for Interstitial Lung Diseases | And 6 more authors.
Clinical and Experimental Immunology | Year: 2011

Idiopathic pulmonary fibrosis (IPF) is a rapidly progressive interstitial lung disease of unknown aetiology. Interleukin (IL)-1β plays an important role in inflammation and has been associated with fibrotic remodelling. We investigated the balance between IL-1β and IL-1 receptor antagonist (IL-1Ra) in bronchoalveolar lavage fluid (BALF) and serum as well as the influence of genetic variability in the IL1B and IL1RN gene on disease susceptibility and cytokine levels. In 77 IPF patients and 349 healthy controls, single nucleotide polymorphisms (SNPs) in the IL1RN and IL1B genes were determined. Serum and BALF IL-1Ra and IL-1β levels were measured using a multiplex suspension bead array system and were correlated with genotypes. Both in serum and BALF a significantly decreased IL-1Ra/IL-1β ratio was found in IPF patients compared to healthy controls. In the IL1RN gene, one SNP was associated with both the susceptibility to IPF and reduced IL-1Ra/IL-1β ratios in BALF. Our results show that genetic variability in the IL1RN gene may play a role in the pathogenesis of IPF and that this role may be more important than thought until recently. The imbalance between IL-1Ra and IL-1β might contribute to a proinflammatory and pro-fibrotic environment in their lungs. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.

Ruven H.J.T.,Center for Interstitial Lung Diseases | Grutters J.C.,Longziekten
Nederlands Tijdschrift voor Klinische Chemie en Laboratoriumgeneeskunde | Year: 2012

Interstitial lung diseases (ILDs) are a group of more than hundred heterogeneous disease entities sharing the pulmonary interstitium as primary focus of origin or manifestation of pathogenesis. Sarcoidosis (M. Besnier-Boeck), the most common ILD, is stereotyped for the presence of lung-localized, noncaseating granulomas of unknown origin (1). Stereotyped indeed, since sarcoidosis as a disease displays such a clear heterogeneity in partly overlapping characteristics or phenotypes that 'sarcoidoses' is a factually better description than sarcoidosis. For instance, Löfgren's syndrome, a spontaneously-resolving disease within a few months to two years and leaving no physical limitations has a clearly distinct disease course than chronic sarcoidosis leading to fibrosis of the lung and finally to the necessity of a lung transplantation. In the 'sarcoidoses', granulomas are also localized extrapulmonary making disease management even more challenging. Triggered by the clearly recognizable granuloma, consisting of a gathering of macrophages and T-cells, numerous speculations about the trigger or triggers causing sarcoidoses could not be substantiated. An environmental e.g. extracorporal trigger, obviously a chemical substance being most probably part of a micro-organism, in combination with the personal genetic layout and immune status, results in a patient's unique course of sarcoidosis (2). In many cases ILDs exhibit a unique disease course through the unique composition of an individual's genome and the involvement of not only the innate immune system, but also the dynamic processes of fibrogenesis and tissue remodelling in not only the environmentally exposed lungs but also in other organs. Idiopathic pulmonary fibrosis (IPF), a devastating disease in the group of ILDs, is characterized by an unknown cause of onset of pulmonary fibrosis progressing towards inevitable lung transplantation. The severe manifestations of sarcoidoses and IPF, which are overlapping with both familial pulmonary fibrosis and sarcoidoses, require improvement of treatment possibilities (3, 4).

Heron M.,Center for Interstitial Lung Diseases | Heron M.,St Antonius Hospital | Claessen A.M.E.,St Antonius Hospital | Grutters J.C.,Center for Interstitial Lung Diseases | And 3 more authors.
Clinical and Experimental Immunology | Year: 2010

Summary Lymphocytes play a crucial role in lung inflammation. Different interstitial lung diseases may show distinct lymphocyte activation profiles. The aim of this study was to examine the expression of a variety of activation markers on T lymphocyte subsets from blood and bronchoalveolar lavage fluid (BALF) of patients with different granulomatous interstitial lung diseases and healthy controls. Bronchoalveolar lavage cells and blood cells from 23 sarcoidosis patients, seven patients with hypersensitivity pneumonitis and 24 healthy controls were analysed. Lymphocyte activation status was determined by flow cytometry. Lymphocytes were stained with antibodies against CD3, CD4, CD8, CD25, CD28, CD69, very late antigen-1 (VLA)-1, VLA-4 and human leucocyte antigen D-related (HLA-DR). In general, CD28, CD69 and VLA-1 expression on BALF CD4+ lymphocytes and HLA-DR expression on BALF CD8+ lymphocytes was different in patients with hypersensitivity pneumonitis and sarcoidosis patients with parenchymal involvement. This BALF lymphocyte phenotype correlated with carbon monoxide diffusing lung capacity (Dlco) values across interstitial lung diseases (ILD) (r2 = 0·48, P = 0·0002). In sarcoidosis patients, CD8+CD28null blood lymphocytes correlated with lower Dlco values (r = -0·66, P = 0·004), chronic BALF lymphocyte activation phenotype (r2 = 0·65, P < 0·0001), radiographic staging (stage I versus stage II and higher, P = 0·006) and with the need for corticosteroid treatment (P = 0·001). Higher expression of CD69, VLA-1 and HLA-DR and lower expression of CD28 on BALF lymphocytes suggests prolonged stimulation and chronic lymphocyte activation in patients with ILD. In sarcoidosis, blood CD8+CD28null cells might be a new biomarker for disease severity but needs further investigation. © 2009 British Society for Immunology.

Heron M.,Center for Interstitial Lung Diseases | Heron M.,St Antonius Hospital | Grutters J.C.,Center for Interstitial Lung Diseases | Grutters J.C.,University Utrecht | And 9 more authors.
Clinical and Experimental Immunology | Year: 2012

Bronchoalveolar lavage (BAL) is widely accepted as a key diagnostic procedure in interstitial lung diseases (ILD). We performed a study to obtain reference intervals of differential cell patterns in BAL fluid with special attention to the origin of lavage fluid, e.g. bronchial/alveolar, to atopy and smoking status and to age of the healthy people. We performed bronchoalveolar lavage in 55 healthy subjects with known atopy status (age: 18-64 years, non-smokers/smokers: 34/21) and determined differential cell counts and lymphocyte subsets in BAL fluid and blood. Moreover, in a subgroup of non-smoking healthy individuals we measured the expression of the regulatory T cell marker forkhead box protein 3 (FoxP3) on blood and BAL fluid lymphocytes in addition to a comprehensive set of activation markers. Differential cell counts from the alveolar lavage fraction differed significantly from calculated pooled fractions (n=11). In contrast, marginal differences were found between atopic and non-atopic subjects. Interestingly, the BAL fluid CD4 +/CD8 + ratio correlated strongly with age (r 2=0·50, P<0·0001). We consider the bronchial and alveolar fraction to be lavage fluid from fundamentally different compartments and recommend analysis of the alveolar fraction in diagnostic work-up of ILD. In addition, our data suggest that age corrected BAL fluid CD4 +/CD8 + ratios should be used in the clinical evaluation of patients with interstitial lung diseases. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.

Veltkamp M.,Center for Interstitial Lung Diseases | Van Moorsel C.H.M.,Center for Interstitial Lung Diseases | Van Moorsel C.H.M.,St Antonius Hospital | Rijkers G.T.,St Antonius Hospital | And 5 more authors.
Clinical and Experimental Immunology | Year: 2010

Summary Sarcoidosis is a systemic disorder characterized by the formation of non-caseating granulomas in variable organs. Toll-like receptor (TLR)-9 is important in the innate immune response against both Mycobacterium tuberculosis and Propionibacterium acnes, candidate causative agents in sarcoidosis. The aim of our study was to investigate possible genetic and functional differences in TLR-9 between patients and controls. TLR-9 single nucleotide polymorphisms were genotyped in 533 patients and divided into a study cohort and validation cohort and 185 healthy controls. Furthermore, part of the promotor as well as the entire coding region of the TLR-9 gene were sequenced in 20 patients in order to detect new mutations. No genetic differences were found between patients and controls. In order to test TLR-9 function, peripheral blood mononuclear cells (PBMCs) of 12 healthy controls and 12 sarcoidosis patients were stimulated with a TLR-9 agonist and the induction of interleukin (IL)-6, interferon (IFN)-γ and IL-23 was measured. Sarcoidosis patients produce significantly less IFN-γ upon stimulation with different stimuli. Regarding IL-23 production, a significant difference between patients and controls was found only after stimulation with the TLR-9 agonist. In conclusion, we did not find genetic differences in the TLR-9 gene between sarcoidosis patients and controls. Sarcoidosis patients produce less IFN-γ regardless of the stimulating agent, probably reflecting the anergic state often seen in their peripheral blood T lymphocytes. The differences in TLR-9-induced IL-23 production could indicate that functional defects in the TLR-9 pathway of sarcoidosis patients play a role in disease susceptibility or evolution. © 2010 British Society for Immunology.

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