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Veltkamp M.,Center for Interstitial Lung Diseases | Van Moorsel C.H.M.,Center for Interstitial Lung Diseases | Rijkers G.T.,St. Antonius Hospital | Ruven H.J.T.,St. Antonius Hospital | And 2 more authors.
Tissue Antigens | Year: 2012

Sarcoidosis is an inflammatory disease of unknown etiology. Various microorganisms have been proposed as etiologic agent suggesting a role for pattern-recognition receptors such as Toll-like receptors (TLRs) in disease pathogenesis, with a special interest in TLR-2. TLR-10, TLR-1, and TLR-6 act as co-receptors for TLR-2 and the genes encoding these receptors are located in a gene cluster on chromosome 4. The aim of our study was to assess differences in genetic variation in the TLR10-TLR1-TLR6 gene cluster between patients and controls. A total of eight single nucleotide polymorphisms were genotyped in 447 healthy controls and 533 patients, divided in 425 with sarcoidosis and 108 with Löfgren's syndrome. Comparison of the total patient cohort with controls showed that the allele frequencies of rs1109695, rs7658893 (TLR-10), and rs5743604 as well as rs5743594 (TLR-1) differed significantly. Haplotype analysis showed that the most common haplotype found was significantly decreased in patients with chronic sarcoidosis. Furthermore, a less common haplotype was found to be significantly increased in patients with Löfgren's syndrome as well as sarcoidosis patients with self-remitting disease, indicating that it could act as a disease modifying haplotype. In conclusion, our study suggests that absence of the common haplotype in the TLR10-TLR1-TLR6 gene cluster increases the risk of developing chronic disease in patients already affected by sarcoidosis. Based on their role as co-receptors for TLR-2, this study supports the growing evidence that aberrant TLR-2 function is important in sarcoidosis disease pathogenesis. © 2011 John Wiley & Sons A/S.


Kruit A.,St. Antonius Hospital | Ruven H.J.T.,St. Antonius Hospital | Grutters J.C.,Center for Interstitial Lung Diseases | Van Den Bosch J.M.M.,Center for Interstitial Lung Diseases
Sarcoidosis Vasculitis and Diffuse Lung Diseases | Year: 2010

Background: The angiotensin II type 1 receptor (AT2R1) is the receptor for angiotensin II, a potent vasoconstrictor produced by ACE from angiotensin I. A recent study by Biller and colleagues revealed a gender-specific association between the AT2R1 1166 A/C gene polymorphism and disease susceptibility as well as a co-dependent association between AT2R1 1166 A/C and the angiotensin-converting enzyme (ACE) insertion/deletion polymorphism on ACE levels in a group of German sarcoidosis patients. Objective: The aim of our study was to compare our results from Dutch Caucasian sarcoidosis patients with the results of Biller et al. Design: Serum and DNA from 99 patients with sarcoidosis and from 327 healthy controls were included. The AT2R1 1166 A/C and ACE I/D polymorphisms and serum ACE levels were analyzed in all subjects. Results: No significant differences were found between the genotype distributions between the sarcoidosis patients and controls. The genotype distributions for either polymorphism between genders and between patients with progressive/chronic disease and those with acute/remission type disease were not different. The ACE D allele contributed significantly to higher ACE levels. This was true for both sarcoidosis patients and controls. There was no association between the AT2R1 1166 A/C genotype and ACE levels, nor did AT2R1 modify the ACE D/I effects on ACE levels. No significant differences were observed in co-incidence of ACE and AT2R1 genotypes between patients and controls. Conclusion: Our study could not confirm the findings by Biller and colleagues other than the influence of the ACE I/D polymorphism on serum ACE levels in both sarcoidosis patients and controls. © Mattioli 1885.


Kruit A.,St. Antonius Hospital | Gerritsen W.B.M.,St. Antonius Hospital | Pot N.,St. Antonius Hospital | Grutters J.C.,Center for Interstitial Lung Diseases | And 2 more authors.
Sarcoidosis Vasculitis and Diffuse Lung Diseases | Year: 2010

Background: KL-6 is a mucin that is increased in interstitial lung diseases (ILD), and in some malignancies. CA 15-3, a tumor marker for breast cancer, refers to the same mucin but utilizes antibodies against different epitopes. Objective: The aim of our study was to evaluate CA 15-3 as a viable alternative to KL-6 as a marker for ILDs with and without fibrosis. Design: Serum from 242 patients with ILDs and from 327 healthy controls were included and KL-6 and CA 15-3 were measured in all subjects. Regression analyses and ROC curves were used to compare the performances of both markers. Results: KL-6 and CA 15-3 levels were both significantly higher in the ILD patients compared to the controls (p < 0.0001). A weak yet significant correlation was found between serum KL-6 and CA 15-3 levels in the controls (R=0.39, p<0.0001), but showed a much higher correlation in the patient group (R=0.85, p<0.0001). CA 15-3 correlated best with KL-6 in patients with fibrotic ILDs (R=0.83, p<0.0001). KL-6 performed better as a marker compared to CA 15-3 in most ILDs. Both markers performed best in identifying idiopathic pulmonary fibrosis (IPF) and were equally able to differentiate between ILDs with and without fibrosis: (sensitivity and specificity %): 100/97, 95/92, and 90/72, respectively. Conclusion: CA 15-3 and KL-6 are equally sensitive and specific in terms of differentiating between ILDs with and without fibrosis. The wide availability, ease of use, and cost effectiveness, make CA 15-3 a viable alternative for KL-6 as a possible marker for pulmonary fibrosis. © Mattioli 1885.


Heron M.,Center for Interstitial Lung Diseases | Van Moorsel C.H.M.,Center for Interstitial Lung Diseases | Grutters J.C.,Center for Interstitial Lung Diseases | Huizinga T.W.J.,Leiden University | And 4 more authors.
Tissue Antigens | Year: 2011

Sarcoidosis is a granulomatous systemic disorder most often affecting the lung. Pulmonary fibrosis develops in approximately 10%-15% of patients with sarcoidosis. The human gene GREM1 encodes gremlin, a member of the bone morphogenetic protein antagonist family. Bone morphogenetic proteins are essential for the maintenance of tissue homeostasis and regeneration after injury. We examined associations between genetic variation in GREM1 and pulmonary disease outcome in patients with pulmonary sarcoidosis. Four common tag single nucleotide polymorphisms spanning GREM1 were genotyped in 483 controls and in 237 sarcoidosis patients with radiographic data at pulmonary disease outcome, defined by chest X-ray after a minimum of 4 years follow-up. Highly significant differences were found between GREM1 genotype frequencies in sarcoidosis patients without chest X-ray abnormalities (stage 0) (n = 116) versus patients who had fibrosis on chest X-ray (stage IV) (n = 59) at pulmonary disease outcome. The most significant association was with GREM1 rs1919364. The recessive model resulted in an increased risk of fibrosis development for homozygous carriers of the C allele at GREM1 rs1919364 versus carriers of the G allele [P = 9.3 × 10-7, χ2 = 24.1, odds ratio (OR) = 6.37 (2.89-14.1)]. This study is the first to suggest that genetic variation of GREM1 predisposes to pulmonary fibrosis in sarcoidosis patients. Carriers of the GREM1 CC genotype at position rs1919364 were at 6.4 times greater risk for developing fibrosis. © 2010 John Wiley & Sons A/S.


Heron M.,Center for Interstitial Lung Diseases | Claessen A.M.E.,St. Antonius Hospital | Grutters J.C.,Center for Interstitial Lung Diseases | Grutters J.C.,University Utrecht | And 2 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.

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