Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0206061 (interstitial pneumonia)
 6,105 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The A/Japan/57 influenza hemagglutinin (HA) was expressed in BALB/c mice under the transcriptional control of the surfactant protein C (SP-C) promoter, resulting in expression of HA in type II alveolar epithelial cells, as well as low level variable expression in other tissues, including the thymus in some of the founder lines. Transgenic animals were able to recover from infection with A/Japan/57 influenza, and they were able to mount antibody responses to A/Japan/57 HA in titers similar to wild type. We therefore tested their CD4+ T lymphocyte responses to HA and found them to be similar to wild type responses. However, CD8+ T cells from A/Japan/57-infected transgenic animals were unable to express cytolytic activity against target cells expressing the A/Japan/57 HA. The CD8+ T cell tolerance was also extremely specific, since transgenics immunized with an influenza strain containing a single amino acid substitution in a dominant HA epitope were able to mount full cytolytic responses to that epitope, but not the wild-type epitope. Adoptive transfer of CD8+ T cell clones into transgenic animals resulted extensive interstitial pneumonitis that was antigen-specific and associated with significant morbidity and mortality. We conclude that a lung-specific transgene may lead to specific CD8+ T cell tolerance, with CD4+ T cell and B cell reactivity to the antigen, and that CD4+ T cell reactivity may remain intact to an antigen expressed in the thymus, even when CD8+ T cell tolerance exists. This observation may have profound implications concerning immune-mediated lung diseases, particularly those mediated by CD4+ T cells.
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PMID:A lung-specific neo-antigen elicits specific CD8+ T cell tolerance with preserved CD4+ T cell reactivity. Implications for immune-mediated lung disease. 877 Aug 62

Familial pulmonary fibrosis is a heterogeneous group of interstitial lung diseases of unknown cause that is associated with multiple pathologic subsets. Mutations in the surfactant protein C (SP-C) gene (SFTPC) are associated with familial desquamative and nonspecific interstitial pneumonitis. Genetic studies in familial usual interstitial pneumonitis have been inconclusive. Using a candidate gene approach, we found a heterozygous exon 5 + 128 T-->A transversion of SFTPC in a large familial pulmonary fibrosis kindred, including adults with usual interstitial pneumonitis and children with cellular nonspecific interstitial pneumonitis. The mutation is predicted to substitute a glutamine for a conserved leucine residue and may hinder processing of SP-C precursor protein. SP-C precursor protein displayed aberrant subcellular localization by immunostaining. Electron microscopy of affected lung revealed alveolar type II cell atypia, with numerous abnormal lamellar bodies. Mouse lung epithelial cells transfected with the SFTPC mutation were notable for similar electron microscopy findings and for exaggerated cellular toxicity. We show that an SFTPC mutation segregates with the pulmonary fibrosis phenotype in this kindred and may cause type II cellular injury. The presence of two different pathologic diagnoses in affected relatives sharing this mutation indicates that in this kindred, these diseases may represent pleiotropic manifestations of the same central pathogenesis.
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PMID:Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. 1199 63

Two Japanese brothers were diagnosed in their 20s with familial pulmonary fibrosis, the pathological findings of which were consistent with usual interstitial pneumonia (UIP). However, an atypical characteristic was observed in the lungs of these brothers; 2-mm areas of 'honeycomb' were identified throughout the lungs, which is smaller than the generally observed 5-10 mm honeycombing seen in UIP. Fibroblastic foci were demonstrated in the second eldest brother, but not in the eldest, which indicates that the lungs of the eldest brother was in a more advanced stage of fibrosis. Their youngest brother and parents have no clinical evidence of pulmonary fibrosis. All five family members had low values for the diffusion capacity of the lung for carbon monoxide (DLCO), suggesting the presence of an inheritable disease and the existence of different phenotypes. The genomic DNA of the affected brothers was sequenced for the reported surfactant protein C (SP-C) gene mutations in patients with familial pulmonary fibrosis, but none was documented. It is necessary to clarify the presence of novel gene mutations of SP-C or other genes to explain these particular pathological findings and the low DLCO observed in this family.
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PMID:Adult-onset familial pulmonary fibrosis in Japanese brothers. 1467 94

Nonspecific interstitial pneumonia, a recently described form of idiopathic interstitial pneumonia, is characterized by uniform involvement of the alveolar septae with interstitial inflammation and variable amounts of fibrosis. Histological observations differentiate nonspecific interstitial pneumonia from usual interstitial pneumonia and clinically, patients with a nonspecific interstitial pneumonia pattern show better prognosis than those with usual interstitial pneumonia. We have genetically analyzed a family with a history of usual interstitial pneumonia. Most of the patients presented as adults and their biopsies showed a pattern consistent with usual interstitial pneumonia. However, three family members presented in early childhood and their biopsies revealed a nonspecific interstitial pneumonia pattern. The inheritance pattern of usual interstitial pneumonia is consistent with autosomal dominant inheritance with variable expression. DNA sequence analyses of the surfactant protein C gene in children with nonspecific interstitial pneumonia and adults with usual interstitial pneumonia exhibit a common heterozygous mutation located in exon 5. The mutation causes a Leu188 to Gln188 change in the carboxy-terminal region of prosurfactant protein C, possibly affecting peptide processing. These observations suggest that individuals with this particular mutation in surfactant protein C gene might be at increased risk of interstitial lung disease of variety of types.
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PMID:Nonspecific interstitial pneumonia and usual interstitial pneumonia with mutation in surfactant protein C in familial pulmonary fibrosis. 1513 75

Mutations in the surfactant protein C gene (SFTPC) were recently reported in patients with interstitial lung disease. In a 13-month-old infant with severe respiratory insufficiency, a lung biopsy elicited combined histological patterns of nonspecific interstitial pneumonia and pulmonary alveolar proteinosis. Immunohistochemical and biochemical analyses showed an intra-alveolar accumulation of surfactant protein (SP)-A, precursors of SP-B, mature SP-B, aberrantly processed proSP-C, as well as mono- and dimeric SP-C. Sequencing of genomic DNA detected a de novo heterozygous missense mutation of the SFTPC gene (g.1286T>C) resulting in a substitution of threonine for isoleucine (173T) in the C-terminal propeptide. At the ultrastructural level, abnormal transport vesicles were detected in type-II pneumocytes. Fusion proteins, consisting of enhanced green fluorescent protein and wild-type or mutant proSP-C, were used to evaluate protein trafficking in vitro. In contrast to wild-type proSP-C, mutant proSP-C was routed to early endosomes when transfected into A549 epithelial cells. In contrast to previously reported mutations, the 173T represents a new class of surfactant protein C gene mutations, which is marked by a distinct trafficking, processing, palmitoylation, and secretion of the mutant and wild-type surfactant protein C. This report heralds the emerging diversity of phenotypes associated with the expression of mutant surfactant C proteins.
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PMID:Interstitial lung disease in a baby with a de novo mutation in the SFTPC gene. 1557 58

Human surfactant protein C (hSP-C(1-197)) is synthesized as a 197 amino acid proprotein and cleaved to a mature 3.7 kD form. Although interstitial lung disease in patients with mutations of the hSP-C gene is becoming increasingly recognized, the mechanisms linking molecular events with clinical pathogenesis are not fully defined. We describe a full-term infant with respiratory insufficiency associated with a spontaneous heterozygous mutation resulting in a substitution of lysine for glutamic acid at position 66 (= E66K) of the proximal hSP-C COOH flanking propeptide. Lung histology and biochemical studies of the index patient (hSP-C(E66K)) revealed nonspecific interstitial pneumonia, increased alveolar total phospholipid lacking phosphatidylglycerol, and increased surfactant protein A. Localization of proSP-C from lung sections prepared from this patient using immunofluorescence and immunogold electron microscopy revealed abnormal proSP-C staining in endosomal-like vesicles of type II cells distinct from SP-B. To evaluate the effect of the E66K substitution on intracellular trafficking of proSP-C, fusion proteins consisting of enhanced green fluorescent protein (EGFP) and hSP-C(1-197) (wild type) or mutant hSP-C(E66K) were generated and transfected into A549 cells. EGFP/hSP-C(1-197) was expressed within CD-63-positive, EEA-1-negative vesicles, whereas EGFP/hSP-C(E66K) localized to EEA-1 positive vesicles. The E66K substitution is representative of a new class of SP-C mutation associated with interstitial lung disease that is diverted from the normal biosynthetic pathway. We propose that, similar to other storage disorders, lung injury results from induction of a toxic gain of function induced by the mutant product that is subject to genetic modifiers and environmental influences.
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PMID:Nonspecific interstitial pneumonia, alveolar proteinosis, and abnormal proprotein trafficking resulting from a spontaneous mutation in the surfactant protein C gene. 1555 12

Most of the interstitial lung diseases are rare, chronic, progressive and fatal disorders, especially in familial form. The etiology of the majority of interstitial lung disease is still unknown. Host susceptibility, genetic and environmental factors may influence clinical expression of each disease. With familial interstitial lung diseases, mutations of surfactant protein B and surfactant protein C or other additional genetic mechanisms (e.g. mutation of the gene for ATP-binding cassette transporter A3) could be associated. We found a 21 month-old girl with respiratory symptoms, abnormal radiographic findings and abnormal open lung biopsy findings compatible with nonspecific interstitial pneumonitis that is similar to those of her older sister died from this disease. We performed genetic studies of the patient and her parents, but we could not find any mutation in our case. High-dose intravenous methylprednisolone and oral hydroxychloroquine were administered and she is still alive without progression during 21 months of follow-up.
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PMID:Familial interstitial lung disease in two young Korean sisters. 1636 24

Familial cases of interstitial pneumonia (FIP) have been reported to be linked to mutations of the surfactant protein C (SP-C) gene. Based on this knowledge, we evaluated the characteristics of patients with adult-onset FIP in the Tokyo area using clinical and radiopathological findings, and further evaluated the genetic background of patients with FIP compared with sporadic IP patients using genetic sequencing of the SP-C gene. A total of 22 patients with FIP from 13 families were identified, and the mean age at first diagnosis of these patients was 50 +/- 2.7 years (range: 20-66 years). Based on the specimen histology, UIP and non-specific interstitial pneumonia accounted for 64 and 36%, respectively. Distribution of the interstitial pattern in HRCT imaging resulted in 36% upper lung dominant, 5% whole lung and 59% lower lung dominant. Two missense mutations in exon 4 (N138T) and exon 5 (N186S) were identified in the SP-C gene from 11 cases with FIP. Each exonic mutation consisted of DNA polymorphism. The frequencies of these DNA polymorphisms were evaluated among 11 subjects with FIP, 30 subjects with sporadic IP, and 43 healthy volunteers as controls. Interestingly, the genotype and allele frequencies in exon 5 were statistically different among these groups. In particular, the N186S substitution of exon 5 in the SP-C gene was shown in patients with FIP or sporadic IP, with a statistically higher frequency. While pathophysiological mechanisms remain to be elucidated, the N186S missense variant may have potential susceptibility in the development of IP. The gene or genes that prove to be important in the development of FIP may provide insights into the pathogenesis of other forms of interstitial lung diseases.
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PMID:Clinical features and genetic analysis of surfactant protein C in adult-onset familial interstitial pneumonia. 1642 70

Interstitial pneumonias have recently been associated with mutations in the gene encoding surfactant protein C (SFTPC). In particular, SFTPC mutations have been reported in a number of familial forms of pulmonary fibrosis and in infants with interstitial lung diseases. The present study searched for SFTPC mutations in adult patients with sporadic idiopathic interstitial pneumonia. In total, 35 adult patients with sporadic idiopathic interstitial pneumonia and 50 healthy subjects were investigated for SFTPC mutations by direct DNA sequencing. Of the patients with sporadic idiopathic interstitial pneumonia, 25 suffered from idiopathic pulmonary fibrosis and 10 patients from nonspecific interstitial pneumonia. Only two frequent nonsynonymous variants, T138N and S186N, were detected. Allele frequencies of both variations as well as of other identified noncoding alterations did not differ significantly between the diverse patient groups and control subjects. In conclusion, mutations in the gene encoding surfactant protein C are not common in sporadic cases of idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia, suggesting that the mutated gene does not play an important role in the pathogenesis of these forms of idiopathic interstitial pneumonia.
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PMID:Surfactant protein C mutations in sporadic forms of idiopathic interstitial pneumonias. 1700 85

The availability of high-throughput genotyping and large collaborative clinical networks creating well-characterized patient populations with DNA repositories has facilitated genome-wide scans and candidate gene studies to identify susceptibility alleles for the development of interstitial lung disease. The association of pulmonary fibrosis with rare inherited disorders, and the variable susceptibility of inbred mouse strains to this disease indicate that pulmonary fibrosis is determined by genetic factors. Sarcoidosis represents a complex disease with racial and ethnic differences in disease prevalence, and evidence of familial clustering. Familial aggregation of sarcoidosis from 'A Case-Control Etiologic Study of Sarcoidosis' (ACCESS) reveals a familial odds ratio (OR) of sarcoidosis of 5.8 (95% CI 2.1-15.9) for sibs and 3.8 (95% CI 1.2-11.3) for parents. Several HLA class II alleles have been associated with either increased or decreased risk of sarcoidosis, and results vary depending on study populations of different ethnicity. Genome-wide screening has conclusively identified linkage to chromosome 5q11and the development of sarcoidosis, and HLA genes and BTNL2 are susceptibility genes located in this region. Familial aggregation of idiopathic interstitial pneumonia (IIP) has been established by several groups, and a large US-based study suggests autosomal dominant inheritance with reduced penetrance; furthermore, cigarette smoking was associated with affection status among siblings (OR = 3.6, 95% CI 1.3-9.8, p = 0.01). Families demonstrate more than one type of IIP, suggesting various subtypes of IIP may share a common pathogenesis. Genome-wide linkage scans in familial interstitial pneumonia demonstrate linkage to chromosomes 4, 5 and 11. Candidate gene studies indicate that surfactant protein C and telomerase are susceptibility genes for the development of pulmonary fibrosis. Future challenges include determining how multiple susceptibility alleles interact with each other and environmental factors resulting in disease risk and multiple phenotypes, and determining the mechanism of action and cellular pathways involving susceptibility alleles. Further insight into these areas may lead to new therapeutic interventions.
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PMID:Genetic predisposition to respiratory diseases: infiltrative lung diseases. 1803 11


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