Clinical characteristics of idiopathic interstitial pneumonias with anti-Ro52/tripartite motif-containing 21 antibodies.
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ABSTRACT:
SUBMITTER: Tahara M
PROVIDER: S-EPMC9249750 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Antibodies provide effective antiviral immunity despite the fact that viruses escape into cells when they infect. Here we show that antibodies remain attached to viruses after cell infection and mediate an intracellular immune response that disables virions in the cytosol. We have discovered that cells possess a cytosolic IgG receptor, tripartite motif-containing 21 (TRIM21), which binds to antibodies with a higher affinity than any other IgG receptor in the human body. TRIM21 rapidly recruits to incoming antibody-bound virus and targets it to the proteasome via its E3 ubiquitin ligase activity. Proteasomal targeting leads to rapid degradation of virions in the cytosol before translation of virally encoded genes. Infection experiments demonstrate that at physiological antibody concentrations TRIM21 neutralizes viral infection. These results reveal an intracellular arm of adaptive immunity in which the protection mediated by antibodies does not end at the cell membrane but continues inside the cell to provide a last line of defense against infection.
| S-EPMC2993423 | biostudies-literature
Project description:BackgroundPleuroparenchymal fibroelastosis (PPFE) is characterised by predominant upper lobe pleural and subpleural lung parenchymal fibrosis. Radiological PPFE-like lesion has been associated with various types of interstitial lung diseases. However, the prevalence and clinical significance of radiological PPFE-like lesion in patients with idiopathic interstitial pneumonias (IIPs) are not fully understood. We aimed to determine the prevalence and clinical impact on survival of radiological PPFE-like lesion in patients with IIPs.MethodsA post-hoc analysis was conducted using data from the Japanese nationwide cloud-based database of patients with IIPs. All the patients in the database were diagnosed as having IIPs by multidisciplinary discussion. Patients diagnosed with idiopathic PPFE were excluded. Clinical data and chest computed tomography (CT) image of 419 patients with IIPs were analysed. The presence of radiological PPFE-like lesion was independently evaluated by two chest radiologists blind to the clinical data.ResultsOf the 419 patients with IIPs, radiological PPFE-like lesions were detected in 101 (24.1%) patients, mainly in idiopathic pulmonary fibrosis (IPF) and unclassifiable IIPs, but less in idiopathic nonspecific interstitial pneumonia. Prognostic analyses revealed that radiological PPFE-like lesion was significantly associated with poor outcome in patients with IIPs, which was independent of age, IPF diagnosis and %FVC. In survival analyses, the patients with radiological PPFE-like lesions had poor survival compared with those without (log-rank, p < 0.0001). Subgroup analyses demonstrated that radiological PPFE-like lesion was significantly associated with poor survival both in patients with IPF and those with unclassifiable IIPs.ConclusionRadiological PPFE-like lesion is a condition that could exist in IIPs, mainly in IPF and unclassifiable IIPs. Importantly, the radiological PPFE-like lesion is a non-invasive marker to predict poor outcome in patients with IIPs, which should be carefully considered in clinical practice.
| S-EPMC8582158 | biostudies-literature
Project description:Rationale: The fibrosing idiopathic interstitial pneumonias (IIPs) are classified based on clinical, radiographic, and pathologic criteria. The separation into phenotypic subgroups is useful in predicting outcome and therapeutic strategy; however a large degree of ambiguity remains. Gene expression profiling may contribute to traditional criteria in IIPs by characterizing the dynamic biology that more accurately distinguishes subtypes of these diseases or their prognoses. Methods: We collected transcriptional and miRNA profiles on lung tissue from 167 subjects with IIP and 50 non-diseased controls. Differential expression of individual transcripts and miRNAs was identified using an ANCOVA model incorporating the clinical diagnosis of each subject as well as age, gender, and smoking status. Validation was performed in an independent cohort of 131 IIPs and 39 non-diseased controls. Results: Our results demonstrate a substantial degree of overlap in mRNA and miRNA signatures of clinical subtypes of IIP. However, we identify two subtypes of IPF/UIP based on a strong molecular signature associated with expression of cilium genes. We demonstrate that elevated expression of cilium genes is associated with more extensive microscopic honeycombing, more fibroblastic foci, higher expression of the airway mucin gene MUC5B, and better survival in an independent cohort of IPF/UIP patients. Moreover, we identify miRNAs involved in the regulation of cilium-associated gene expression that contribute to novel molecular subphenotypes of IPF. Conclusions: While subtypes of IIP are related biologically with similar transcriptional profiles, expression of cilium genes appear to identify two unique clinical presentations of IPF/UIP.
2013-06-21 | GSE32538 | GEO
Project description:Rationale: The fibrosing idiopathic interstitial pneumonias (IIPs) are classified based on clinical, radiographic, and pathologic criteria. The separation into phenotypic subgroups is useful in predicting outcome and therapeutic strategy; however a large degree of ambiguity remains. Gene expression profiling may contribute to traditional criteria in IIPs by characterizing the dynamic biology that more accurately distinguishes subtypes of these diseases or their prognoses. Methods: We collected transcriptional and miRNA profiles on lung tissue from 167 subjects with IIP and 50 non-diseased controls. Differential expression of individual transcripts and miRNAs was identified using an ANCOVA model incorporating the clinical diagnosis of each subject as well as age, gender, and smoking status. Validation was performed in an independent cohort of 131 IIPs and 39 non-diseased controls. Results: Our results demonstrate a substantial degree of overlap in mRNA and miRNA signatures of clinical subtypes of IIP. However, we identify two subtypes of IPF/UIP based on a strong molecular signature associated with expression of cilium genes. We demonstrate that elevated expression of cilium genes is associated with more extensive microscopic honeycombing, more fibroblastic foci, higher expression of the airway mucin gene MUC5B, and better survival in an independent cohort of IPF/UIP patients. Moreover, we identify miRNAs involved in the regulation of cilium-associated gene expression that contribute to novel molecular subphenotypes of IPF. Conclusions: While subtypes of IIP are related biologically with similar transcriptional profiles, expression of cilium genes appear to identify two unique clinical presentations of IPF/UIP.
2013-06-21 | GSE32537 | GEO
Project description:Pulmonary hypertension (PH) is a common finding in patients with chronic fibrosing idiopathic interstitial pneumonias (IIP). Little is known about the response to pulmonary vasodilator therapy in this patient population. COMPERA is an international registry that prospectively captures data from patients with various forms of PH receiving pulmonary vasodilator therapies.We retrieved data from COMPERA to compare patient characteristics, treatment patterns, response to therapy and survival in newly diagnosed patients with idiopathic pulmonary arterial hypertension (IPAH) and PH associated with IIP (PH-IIP).Compared to patients with IPAH (n = 798), patients with PH-IIP (n = 151) were older and predominantly males. Patients with PH-IIP were treated predominantly with phosphodiesterase-5 inhibitors (88% at entry, 87% after 1 year). From baseline to the first follow-up visit, the median improvement in 6MWD was 30 m in patients with IPAH and 24.5 m in patients with PH-IIP (p = 0.457 for the difference between both groups). Improvements in NYHA functional class were observed in 22.4% and 29.5% of these patients, respectively (p = 0.179 for the difference between both groups). Survival rates were significantly worse in PH-IIP than in IPAH (3-year survival 34.0 versus 68.6%; p<0.001). Total lung capacity, NYHA class IV, and mixed-venous oxygen saturation were independent predictors of survival in patients with PH-IIP.Patients with PH-IIP have a dismal prognosis. Our results suggest that pulmonary vasodilator therapy may be associated with short-term functional improvement in some of these patients but it is unclear whether this treatment affects survival.clinicaltrials.gov NCT01347216.
| S-EPMC4667900 | biostudies-literature
Project description:BackgroundThe types of cells most significantly linked to individual subtypes of idiopathic interstitial pneumonias (IIPs) remain unclear. Few studies have examined CD163+ macrophages in IIPs.ObjectiveWe retrospectively aimed to immunohistochemically characterize the CD163+ macrophages in IIPs.MethodsParaffin-embedded lung tissue samples were obtained from 47 patients with IIPs, including idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia (NSIP), and cryptogenic organizing pneumonia (COP), and 12 normal controls were immunohistochemically analyzed, using primary antibodies against CD68 and CD163 as indicators of pan and M2 macrophages, respectively.ResultsCD68+ macrophage density was significantly increased in the 3 subtypes of IIPs relative to that in the control group, although no difference was detected within the different IIPs. CD163+ macrophage density was significantly increased in NSIP and COP samples relative to that in IPF samples. The density ratio of CD163+ macrophages to CD68+ macrophages was significantly decreased in IPF/UIP samples relative to that in the others, while the densities in NSIP and COP were significantly higher than those in control cases.ConclusionCD163+ macrophages show distinct profiles among IIPs, and the standardized numerical density is decreased in IPF cases that have poor prognoses.
| S-EPMC5817286 | biostudies-literature
Project description:Rationale: The fibrosing idiopathic interstitial pneumonias (IIPs) are classified based on clinical, radiographic, and pathologic criteria. The separation into phenotypic subgroups is useful in predicting outcome and therapeutic strategy; however a large degree of ambiguity remains. Gene expression profiling may contribute to traditional criteria in IIPs by characterizing the dynamic biology that more accurately distinguishes subtypes of these diseases or their prognoses. Methods: We collected transcriptional and miRNA profiles on lung tissue from 167 subjects with IIP and 50 non-diseased controls. Differential expression of individual transcripts and miRNAs was identified using an ANCOVA model incorporating the clinical diagnosis of each subject as well as age, gender, and smoking status. Validation was performed in an independent cohort of 131 IIPs and 39 non-diseased controls. Results: Our results demonstrate a substantial degree of overlap in mRNA and miRNA signatures of clinical subtypes of IIP. However, we identify two subtypes of IPF/UIP based on a strong molecular signature associated with expression of cilium genes. We demonstrate that elevated expression of cilium genes is associated with more extensive microscopic honeycombing, more fibroblastic foci, higher expression of the airway mucin gene MUC5B, and better survival in an independent cohort of IPF/UIP patients. Moreover, we identify miRNAs involved in the regulation of cilium-associated gene expression that contribute to novel molecular subphenotypes of IPF. Conclusions: While subtypes of IIP are related biologically with similar transcriptional profiles, expression of cilium genes appear to identify two unique clinical presentations of IPF/UIP. 167 subjects with IIP and 50 non-diseased controls with no replicates
2013-06-21 | E-GEOD-32538 | biostudies-arrayexpress
Project description:Rationale: The fibrosing idiopathic interstitial pneumonias (IIPs) are classified based on clinical, radiographic, and pathologic criteria. The separation into phenotypic subgroups is useful in predicting outcome and therapeutic strategy; however a large degree of ambiguity remains. Gene expression profiling may contribute to traditional criteria in IIPs by characterizing the dynamic biology that more accurately distinguishes subtypes of these diseases or their prognoses. Methods: We collected transcriptional and miRNA profiles on lung tissue from 167 subjects with IIP and 50 non-diseased controls. Differential expression of individual transcripts and miRNAs was identified using an ANCOVA model incorporating the clinical diagnosis of each subject as well as age, gender, and smoking status. Validation was performed in an independent cohort of 131 IIPs and 39 non-diseased controls. Results: Our results demonstrate a substantial degree of overlap in mRNA and miRNA signatures of clinical subtypes of IIP. However, we identify two subtypes of IPF/UIP based on a strong molecular signature associated with expression of cilium genes. We demonstrate that elevated expression of cilium genes is associated with more extensive microscopic honeycombing, more fibroblastic foci, higher expression of the airway mucin gene MUC5B, and better survival in an independent cohort of IPF/UIP patients. Moreover, we identify miRNAs involved in the regulation of cilium-associated gene expression that contribute to novel molecular subphenotypes of IPF. Conclusions: While subtypes of IIP are related biologically with similar transcriptional profiles, expression of cilium genes appear to identify two unique clinical presentations of IPF/UIP. 167 subjects with IIP and 50 non-diseased controls with no replicates
2013-06-21 | E-GEOD-32537 | biostudies-arrayexpress
Project description:BACKGROUND:Idiopathic interstitial pneumonias (IIPs) are a group of heterogeneous, somewhat unpredictable diseases characterized by progressive scarring of the interstitium. Since lung function is a key determinant of survival, we reasoned that the transcriptional profile in IIP lung tissue would be associated with measures of lung function, and could enhance prognostic approaches to IIPs. RESULTS:Using gene expression profiling of 167 lung tissue specimens with IIP diagnosis and 50 control lungs, we identified genes whose expression is associated with changes in lung function (% predicted FVC and % predicted DLCO) modeled as categorical (severe vs mild disease) or continuous variables while adjusting for smoking status and IIP subtype; false discovery rate (FDR) approach was used to correct for multiple comparisons. This analysis identified 58 transcripts that are associated with mild vs severe disease (categorical analysis), including those with established role in fibrosis (ADAMTS4, ADAMTS9, AGER, HIF-1α, SERPINA3, SERPINE2, and SELE) as well as novel IIP candidate genes such as rhotekin 2 (RTKN2) and peptidase inhibitor 15 (PI15). Protein-protein interactome analysis of 553 genes whose expression is significantly associated with lung function when modeled as continuous variables demonstrates that more severe presentation of IIPs is characterized by an increase in cell cycle progression and apoptosis, increased hypoxia, and dampened innate immune response. Our findings were validated in an independent cohort of 131 IIPs and 40 controls at the mRNA level and for one gene (RTKN2) at the protein level by immunohistochemistry in a subset of samples. CONCLUSIONS:We identified commonalities and differences in gene expression among different subtypes of IIPs. Disease progression, as characterized by lower measures of FVC and DLCO, results in marked changes in expression of novel and established genes and pathways involved in IIPs. These genes and pathways represent strong candidates for biomarker studies and potential therapeutic targets for IIP severity.
| S-EPMC4621862 | biostudies-literature
Project description:Chronic fibrosing idiopathic interstitial pneumonia (IIP) can be divided into two main types: idiopathic pulmonary fibrosis (IPF), a steroid-resistant and progressive disease with a median survival of 2-3 years, and idiopathic non-specific interstitial pneumonia (INSIP), a steroid-sensitive and non-progressive autoimmune disease. Although the clinical courses of these two diseases differ, they may be difficult to distinguish at diagnosis. We performed a comprehensive analysis of serum autoantibodies from patients definitively diagnosed with IPF, INSIP, autoimmune pulmonary alveolar proteinosis, and sarcoidosis. We identified disease-specific autoantibodies and enriched KEGG pathways unique to each disease, and demonstrated that IPF and INSIP are serologically distinct. Furthermore, we discovered a new INSIP-specific autoantibody, anti-myxovirus resistance-1 (MX1) autoantibody. Patients positive for anti-MX1 autoantibody constituted 17.5% of all cases of chronic fibrosing IIPs. Notably, patients rarely simultaneously carried the anti-MX1 autoantibody and the anti-aminoacyl-transfer RNA synthetase autoantibody, which is common in chronic fibrosing IIPs. Because MX1 is one of the most important interferon-inducible anti-viral genes, we have not only identified a new diagnostic autoantibody of INSIP but also obtained new insight into the pathology of INSIP, which may be associated with viral infection and autoimmunity.
| S-EPMC5322336 | biostudies-literature