Biomedical subjects

Karoline I Gaede

Publications and source records attributed to Karoline I Gaede.

6 recordsLinked to original sources

PubMed2005

Function associated transforming growth factor-beta gene polymorphism in chronic beryllium disease.

Chronic beryllium disease (CBD) is a rare occupational, granulomatous lung disease clinically resembling sarcoidosis. The immune response to beryllium is thought to depend on genetic susceptibility. Although a glutamic acid in position 69 of the human leukocyte antigen-DP beta chain (HLA-DPB1-Glu69) is associated with the development of CBD, it cannot fully explain susceptibility. It is likely that additionally other genes are involved in regulating the immune and inflammatory response in the pathogenesis of this disease. Functional gene polymorphisms (PMs) of the tumor necrosis factor (TNF)A and transforming growth factor (TGF) beta(1) genes are suspected to modify the course of granulomatous disorders. We analyzed the TGF-beta(1) (codon 25) PM in 59 patients with CBD and 164 matched healthy controls, from two groups of European/Israeli and United States origin. Additionally, patients were genotyped for HLA class II gene variants and the TNFA (-308) PM. The most significant results were found for the TGF-beta(1) (codon 25) PM with a shift towards the low producing non-GG genotypes in the subgroup of European and Israeli patients with CBD (62.50% vs. 13.82% in healthy controls; P<0.001). This phenomenon was not observed in the group from the United States. Moreover, TGF-beta(1) (codon 25) PM genotype frequencies from United States CBD patients differed significantly from those of European and Israeli patients. In contrast, increased frequencies for the high producing TNFA2 allele were found only in the patients from the United States (28.20% vs. 8.96% in healthy controls; P<0.005) but not in the group of Europe and Israel. In conclusion, the increase in TGF-beta(1) (codon 25) PM genotype frequency associated with a low TGF-beta release suggests that immunoregulatory cytokines such as TGF-beta are involved in the pathogenesis of CBD. Moreover, based on the interaction of gene PMs associated with the control of the immune response, such as TNF-alpha and TGF-beta(1), with a specific immune response gene such as HLA-DPB1-Glu69 or other HLA-class II PMs driving the immune response to Be, the present data suggest that a combination of different genetic backgrounds determine susceptibility for the same immunopathological reaction and disease.

Adult↗

PubMed2005

Sarcoidosis is associated with a truncating splice site mutation in BTNL2.

Sarcoidosis is a polygenic immune disorder with predominant manifestation in the lung. Genome-wide linkage analysis previously indicated that the extended major histocompatibility locus on chromosome 6p was linked to susceptibility to sarcoidosis. Here, we carried out a systematic three-stage SNP scan of 16.4 Mb on chromosome 6p21 in as many as 947 independent cases of familial and sporadic sarcoidosis and found that a 15-kb segment of the gene butyrophilin-like 2 (BTNL2) was associated with the disease. The primary disease-associated variant (rs2076530; P(TDT) = 3 x 10(-6), P(case-control) = 1.1 x 10(-8); replication P(TDT) = 0.0018, P(case-control) = 1.8 x 10(-6)) represents a risk factor that is independent of variation in HLA-DRB1. BTNL2 is a member of the immunoglobulin superfamily and has been implicated as a costimulatory molecule involved in T-cell activation on the basis of its homology to B7-1. The G --> A transition constituting rs2076530 leads to the use of a cryptic splice site located 4 bp upstream of the affected wild-type donor site. Transcripts of the risk-associated allele have a premature stop in the spliced mRNA. The resulting protein lacks the C-terminal IgC domain and transmembrane helix, thereby disrupting the membrane localization of the protein, as shown in experiments using green fluorescent protein and V5 fusion proteins.

Bronchoalveolar Lavage↗

PubMed2004

Differential gene expression pattern in alveolar macrophages of patients with sarcoidosis and tuberculosis.

Sarcoidosis is a multisystem granulomatous disorder of unknown origin characterized by the presence of epithelioid granulomata in the affected organs. Histological and clinical similarities between sarcoidosis and tuberculosis caused by M. tuberculosis suggest a shared underlying pathophysiology. However, specific markers are needed. This study examined the differential gene expression pattern in alveolar macrophages of patients with granulomatous disorders. The differential mRNA regulation pattern of alveolar macrophages in the bronchoalveolar lavage of healthy controls was compared to that of patients with sarcoidosis and tuberculosis by means of differential display reverse transcription PCR. Comparative analysis of 2,498 PCR products in controls, sarcoidosis, and tuberculosis revealed a differential regulation of expressed sequence tags in only 6.5%. 1.8% showed a shared expression pattern between sarcoidosis and tuberculosis in contrast to the control. It can be assumed that these alterations are associated with common granulomatous features. In contrast, 3.0% of the amplified sequence tags showed specific up- or downregulation in sarcoidosis and 1.6% in tuberculosis. These data indicate a significant proportion of common granuloma-associated features, independent of the origin of the granulomatous disorder.

Adult↗

PubMed2003

Different gender-associated genotype risks of Wegener's granulomatosis and microscopic polyangiitis.

Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) are systemic small vessel vasculitides associated with ANCA (AAV). Predominant Th1 and Th2 cytokine patterns have been reported for WG and MPA, respectively. Consequently, genotypes suppressing Th1 responses or augmenting Th2 responses may be more frequent in MPA than in WG. Transforming growth beta1 (TGF-beta1) and interleukin-10 (IL-10) genes may modify the course of vasculitis. Therefore, we investigated associations between genotype frequencies of functional polymorphisms of these cytokine genes and clinical manifestations in AAV. One hundred sixty-one AAV patients and 153 healthy blood donors were genotyped for the biallelic polymorphism in codon 25 of the TGF-beta1 gene and the biallelic polymorphism at position -1082 of the IL-10 gene. No difference was found for TGF-beta1 codon 25 polymorphism between control and patient groups. In contrast, a significant shift toward the homozygous AA genotype of the IL-10 (-1082) polymorphism was found in WG (25%, p<0.005) and MPA patients (39%; p<0.00001) compared to controls (10.5%). Furthermore, in MPA the AA homozygous genotype was significantly more frequent in females (62.5%) compared to males (20%, p<0.05). A contribution of the TGF-beta1 codon 25 polymorphism to the susceptibility-defining genetic backgrounds of AAV appears unlikely. In contrast, our findings suggest a role of the enhanced IL-10 (-1082) PM in WG and MPA with a significant gender difference in MPA.

Alleles↗

PubMedDate not supplied

Analysis of differentially regulated mRNAs in monocytic cells induced by in vitro stimulation with Kveim-Siltzbach test reagent.

Sarcoidosis is a granulomatous disorder of unknown origin. The sarcoid spleen-derived Kveim-Siltzbach test reagent (KSTR) elicits a sarcoid-specific, granulomatous response and was used to diagnose sarcoidosis. The active component and the pathomechanism by which KSTR induces granuloma are still unknown. This study investigated the KSTR-associated gene expression pattern in cells of patients with sarcoidosis or chronic beryllium disease (CBD). The monocytic-like cell line U937, alveolar macrophages of sarcoidosis patients, and peripheral blood monocytes of patients with CBD were stimulated with KSTR and other granuloma-associated stimuli. The KSTR-associated gene expression pattern was analyzed by means of differential display reverse transcription-polymerase chain reaction in combination with a multiple comparison of expressed sequence tags induced in response to KSTR and other granuloma-associated stimuli. Depending on the origin of cells tested, 3.7% to 14.6% of the analyzed sequence tags showed differential regulation induced by granuloma-associated stimuli. Alterations restricted to KSTR stimulation could be observed in 1.2% for the cell line U937, in 2.8% for blood monocytes of patients with CBD, and 1.3% for alveolar macrophages of sarcoidosis patients. These data are comparable to those achieved for the other granuloma-associated stimuli tested in this study. Therefore, it can be assumed that KSTR induces pathomechanisms for granuloma formation in sarcoidosis as beryllium in CBD.

Adult↗

PubMedDate not supplied

Systemic immune cell activation in a subgroup of patients with idiopathic pulmonary fibrosis.

BACKGROUND: The prognosis of idiopathic pulmonary fibrosis (IPF/UIP) is poor and its immunopathogenesis is insufficiently understood. OBJECTIVES: The aim of our study was to elucidate the compartmentalization of cell activation and the influence of corticosteroid therapy upon this activation in IPF/UIP. We determined the concentrations of proinflammatory cytokines released by bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMNC) in treated and untreated patients with IPF/UIP. We chose tumor necrosis factor-alpha (TNFalpha) since it is a cytokine predominantly secreted by cells of the monocyte/macrophage lineage and interleukin-2 (IL-2) exclusively by T lymphocytes. METHODS: The release of TNFalpha and IL-2 by BAL cells and PBMNC was measured in cell culture supernatants of 72 treated and untreated IPF/UIP patients. Additionally, in the blood compartment serological parameters reflecting the monocyte/macrophage and lymphocyte activation, such as neopterin and soluble IL-2 receptor (sIL-2R), were determined. RESULTS: The TNFalpha release by BAL cells was significantly elevated in both groups compared to controls but did not differ between treated and untreated patients with IPF/UIP. In 7 of 19 untreated patients with IPF, PBMNC were activated and released increased amounts of TNFalpha. In only 1 of 17 treated patients with IPF, TNFalpha release by PBMNC could be found. The serum level of neopterin, a marker of cell activation of the monocyte/macrophage lineage did not differ between treated and untreated patients. The BAL lymphocyte and PBMNC IL-2 release was significantly elevated in IPF/UIP patients without therapy compared to controls (p < 0.05). In contrast, no IL-2 release of BAL cells or PBMNC was observed in treated IPF/UIP patients. Lymphocyte activation was furthermore identified in untreated IPF patients by elevated soluble IL-2 receptor serum concentrations (p < 0.0001). CONCLUSIONS: Cells of the monocyte/macrophage lineage and T lymphocytes are activated in BAL cells and PBMNC of patients with IPF/UIP. During treatment, the systemic and local activation of T cells is suppressed. BAL macrophages, however, maintain their activated status, which might be the cause for the frequent chronic progression of the disease.

Bronchoalveolar Lavage Fluid↗