结节病易误诊,据王洪武等~([1])收集国内18篇关于此病误诊的文献,误诊率高达63.2%,当然有误诊就会有误治,如孙永昌等~([2])报道26例结节病在影像学检查诊断的第一印象中拟诊结核5例,其中就有2例完成规范的抗结核治疗,为此应引起临床对本病诊治的重视。

Sarcoidosis

Telomeres, the protective ends of linear chromosomes, shorten throughout an individual's lifetime. Telomere shortening is proposed to be a primary molecular cause of aging. Short telomeres block the proliferative capacity of stem cells, affecting their potential to regenerate tissues, and trigger the development of age-associated diseases. Mutations in telomere maintenance genes are associated with pathologies referred to as telomere syndromes, including Hoyeraal-Hreidarsson syndrome, dyskeratosis congenita, pulmonary fibrosis, aplastic anemia, and liver fibrosis. Telomere shortening induces chromosomal instability that, in the absence of functional tumor suppressor genes, can contribute to tumorigenesis. In addition, mutations in telomere length maintenance genes and in shelterin components, the protein complex that protects telomeres, have been found to be associated with different types of cancer. These observations have encouraged the development of therapeutic strategies to treat and prevent telomere-associated diseases, namely aging-related diseases, including cancer. Here we review the molecular mechanisms underlying telomere-driven diseases and highlight recent advances in the preclinical development of telomere-targeted therapies using mouse models.

/pdf/telomere-driven-diseases-and-telomere-targeting-therapies-3jqi9kxhqs.pdf

Telomere-driven diseases and telomere-targeting therapies

Alveolar epithelial type II cells (AT2) are a heterogeneous population that have critical secretory and regenerative roles in the alveolus to maintain lung homeostasis. However, impairment to their normal functional capacity and development of a pro-fibrotic phenotype has been demonstrated to contribute to the development of idiopathic pulmonary fibrosis (IPF). A number of factors contribute to AT2 death and dysfunction. As a mucosal surface, AT2 cells are exposed to environmental stresses that can have lasting effects that contribute to fibrogenesis. Genetical risks have also been identified that can cause AT2 impairment and the development of lung fibrosis. Furthermore, aging is a final factor that adds to the pathogenic changes in AT2 cells. Here, we will discuss the homeostatic role of AT2 cells and the studies that have recently defined the heterogeneity of this population of cells. Furthermore, we will review the mechanisms of AT2 death and dysfunction in the context of lung fibrosis.

https://www.mdpi.com/1422-0067/21/7/2269/pdf

Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

Telomere maintenance dysfunction has been implicated in the pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). However, the mechanism of how telomere length is related to fibrosis in the lungs is unknown. Surgical lung biopsies of IPF patients typically show a heterogeneous pattern of non-fibrotic and fibrotic areas. Therefore, telomere length (TL) in both lung areas of patients with IPF and familial interstitial pneumonia was compared, specifically in alveolar type 2 (AT2) cells. Fluorescent in situ hybridization was used to determine TL in non-fibrotic and fibrotic areas of 35 subjects. Monochrome multiplex quantitative polymerase chain reaction (MMqPCR) was used for 51 whole lung biopsies and blood TL measurements. For sporadic IPF subjects, AT2 cell TL in non-fibrotic areas was 56% longer than in fibrotic areas. No such difference was observed in the surrounding lung cells. In subjects carrying a telomerase reverse transcriptase (TERT) mutation, AT2 cell TL was significantly shorter than in sporadic subjects. However, no difference in surrounding cell TL was observed between these subject groups. Finally, using biopsy MMqPCR TL measurements, it was determined that IPF subjects with shortest lung TL had a significantly worse survival than patients with long TL. This study shows that shortening of telomeres critically affects AT2 cells in fibrotic areas, implying TL as a cause of fibrogenesis. Furthermore, short lung telomere length is associated with decreased survival.

/pdf/short-telomere-length-in-ipf-lung-associates-with-fibrotic-3wa4t5lqxl.pdf

Short telomere length in IPF lung associates with fibrotic lesions and predicts survival.

Purpose of reviewGenomic mutations in telomere-related genes have been recognized as a cause of familial forms of idiopathic pulmonary fibrosis (IPF). However, it has become increasingly clear that telomere syndromes and telomere shortening are associated with various types of pulmonary disease. Add

Pulmonary phenotypes associated with genetic variation in telomere-related genes.

Pulmonary fibrosis is a frequent manifestation of telomere syndromes. Telomere gene mutations are found in up to 25% and 3% of patients with familial disease and sporadic disease, respectively. The telomere gene TINF2 encodes an eponymous protein that is part of the shelterin complex, a complex involved in telomere protection and maintenance. A TINF2 gene mutation was recently reported in a family with pulmonary fibrosis. We identified a heterozygous Ser245Tyr mutation in the TINF2 gene of previously healthy female patient that presented with progressive cough due to pulmonary fibrosis as well as panhypogammaglobulinemia at age 52. Retrospective multidisciplinary evaluation classified her as a case of possible idiopathic pulmonary fibrosis. Telomere length-measurement indicated normal telomere length in the peripheral blood compartment. This is the first report of a TINF2 mutation in a patient with sporadic pulmonary fibrosis, which represents another association between TINF2 mutations and this disease. Furthermore, this case underlines the importance of telomere dysfunction and not telomere length alone in telomere syndromes and draws attention to hypogammaglobulinemia as a manifestation of telomere syndromes.

/pdf/tinf2-gene-mutation-in-a-patient-with-pulmonary-fibrosis-4zq32cph2l.pdf

TINF2 Gene Mutation in a Patient with Pulmonary Fibrosis

Macrophage migration inhibitory factor (MIF) -173 polymorphism is associated with clinical erythema nodosum in Löfgren's syndrome.

Genetic susceptibility for sarcoidosis and Lofgren's syndrome (LS) has been associated with prognosis. Human leukocyte antigen (HLA)-DRB1*03 is over-represented in LS, and is associated with a good prognosis, whereas HLA-DRB1*15-positive patients have a more chronic course of sarcoidosis. These HLA-DRB1 types can be easily tagged by single nucleotide polymorphisms (SNPs). Our aim was to evaluate the association between these tag SNPs and bronchoalveolar lavage (BAL) characteristics. In 29 patients, both complete HLA-DRB1* locus genotyping and SNP tagging was performed in parallel. HLA-DRB1 type was inferred from the presence of *03 tag rs2040410 allele A and referred to as *03. HLA-DRB1*15 was inferred from the presence of tag SNP rs3135388 allele A and referred to as *15. For BAL analysis, 122 patients with LS and 165 patients with non-LS sarcoidosis were included. BAL lymphocyte subsets were analyzed by flow cytometry. The presence of tag SNPs completely corresponded with HLA-DRB1*03/*15 genotypes in all 29 patients in whom both HLA-DRB1* genotyping and SNP tagging was performed. In all patients together, *03+ /*15- patients showed a higher CD4+ /CD8+ ratio than *03- /*15+ (P = 0·004) and *03- /*15- (P = 0·001). LS patients with *03+ /*15- had a lower BAL lymphocyte count compared to *03- /*15+  patients (P = 0·011). Non-LS sarcoidosis patients with *03+ /*15- patients showed a decreased CD103+ CD4+ /CD4+ ratio compared to *03- /*15+  patients (P = 0·045) and *03- /*15- patients (P = 0·018). We found that HLA-DRB1*03 and HLA-DRB1*15 can be approximated by genotyping of tag SNPs and corresponds with the degree of lymphocytosis and cell phenotypes in BAL in both LS and non-LS sarcoidosis patients.

J J van der Vis

Papers

TINF2 Gene Mutation in a Patient with Pulmonary Fibrosis

Macrophage migration inhibitory factor (MIF) -173 polymorphism is associated with clinical erythema nodosum in Löfgren's syndrome.

Bronchoalveolar lavage characteristics correlate with HLA tag SNPs in patients with Löfgren's syndrome and other sarcoidosis.