Expression of toll-like receptor 2 and 4 is increased in the respiratory epithelial cells of chronic idiopathic interstitial pneumonia patients

SummaryBackgroundIdiopathic interstitial pneumonia (IIP) is characterized by chronic interstitial inflammation and fibrosis. Although mounting evidence has suggested that toll-like receptor (TLR) 2 and TLR4 are involved in the pathogenesis of non-infectious lung injury in vitro and in mouse models, their roles in human IIP remain unknown.MethodsTo address this issue, we investigated the expression patterns of TLR2 and TLR4 by immunohistochemistry in resected lung tissues from patients with usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP).ResultsType II pneumocytes, bronchial epithelial cells (BECs), and alveolar macrophages accounted for the majority of TLR2- and TLR4-expressing cells in both UIP and NSIP. The numbers of TLR2 and TLR4-positive respiratory epithelial (RE) cells, including type II pneumocytes and BECs, were significantly greater in UIP and NSIP than in the control. In particular, the numbers of TLR2-positive RE cells were much greater in UIP than in NSIP. The intensities of TLR2 and TLR4 expression in type II pneumocytes were also significantly stronger in UIP and NSIP than in the control. A comparison of the TLR expression patterns between the fibroblastic and fibrotic areas in UIP indicated that the numbers TLR2 and TLR4-positive RE cells were similar in fibroblastic areas, whereas the TLR2-positive RE cells outnumbered the TLR4-positive RE cells in the fibrotic areas.ConclusionsThis study demonstrates that RE cells over-express TLR2 and TLR4 in the lungs of IIP patients. These findings suggest that high expression of TLRs may contribute to the pathogenesis of human IIP

NKT cells promote antibody-induced joint inflammation by suppressing transforming growth factor β1 production

Although NKT cells has been known to exert protective roles in the development of autoimmune diseases, the functional roles of NKT cells in the downstream events of antibody-induced joint inflammation remain unknown. Thus, we explored the functional roles of NKT cells in antibody-induced arthritis using the K/BxN serum transfer model. NKT cell–deficient mice were resistant to the development of arthritis, and wild-type mice administrated with α-galactosyl ceramide, a potent NKT cell activator, aggravated arthritis. In CD1d−/− mice, transforming growth factor (TGF)-β1 was found to be elevated in joint tissues, and the blockade of TGF-β1 using neutralizing monoclonal antibodies restored arthritis. The administration of recombinant TGF-β1 into C57BL/6 mice reduced joint inflammation. Moreover, the adoptive transfer of NKT cells into CD1d−/− mice restored arthritis and reduced TGF-β1 production. In vitro assay demonstrated that interleukin (IL)-4 and interferon (IFN)-γ were involved in suppressing TGF-β1 production in joint cells. The adoptive transfer of NKT cells from IL-4−/− or IFN-γ−/− mice did not reverse arthritis and TGF-β1 production in CD1d−/− mice. In conclusion, NKT cells producing IL-4 and IFN-γ play a role in immune complex–induced joint inflammation by regulating TGF-β1

Differential Expression of Glut1 in Pulmonary Neuroendocrine Tumors: Correlation with Histological Grade

Background : Increased glucose uptake, a process that is mediated by glucose transporter (Glut1) proteins, is an important metabolic feature in a variety of cancer cells. The overexpression of Glut1 in human cancers is known to be related to a variety of histopathological parameters, including histological grade, proliferation rate, and lymphatic invasion. The principal objective of this study was to evaluate Glut1 expression in the spectrum of pulmonary neuroendocrine (NE) tumors including typical carcinoid tumor (TC), atypical carcinoid tumor (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCC), and to characterize the relationship between Glut1 expression and the histologic grade of NE tumors. Methods : 19 TC, 7 AC, 13 LCNEC, and 6 SCC patients were included in this study. The percentages of Glut1-positive tumor cells in these patients were determined. For statistical analysis, Glut1 expression was subdivided into a Glut1-low expression group (0-30%) and a Glut1-high expression group (31-90%). Results : In our subgroup analyses, the histological grade of pulmonary neuroendocrine (NE) tumors was significantly correlated with Glut1 expression; TC (n=19, 3.6 +/- 4.2%), AC (n=7, 20.0 +/- 4.9%), LCNEC (n=13, 60.0 +/- 21.1%), and SCC (n= 6, 74.2 +/- 16.9%). Glut1-high expression was significantly associated with high-grade NE tumors such as LCNEC and SCC (n=19, 62.6 +/- 21.0%) (p=0.000). Conclusions: The results of this study appear to indicate that Glut1 overexpression is a consistent feature of high-grade NE lung tumors.This work was supported by grant no 02-2008-029 from the SNUBH Research Fund and partly supported by the Korean Science & Engineering Foundation (KOSEF) through the Tumor Immunity Medical Research Center at Seoul National University College of Medicine.Song YS, 2008, LUNG CANCER, V61, P54, DOI 10.1016/j.lungcan.2007.11.012Nguyen XC, 2007, EUR J RADIOL, V62, P214, DOI 10.1016/j.ejrad.2006.12.008Khandani AH, 2007, NUCL MED COMMUN, V28, P173Chung JH, 2004, J NUCL MED, V45, P999TRAVIS WD, 2004, WHO INT HISTOLOGICALKalir T, 2002, CANCER, V94, P1078, DOI 10.1002/cncr.10280Wong CYO, 2001, EUR J NUCL MED, V28, P1702Wang BY, 2000, CANCER, V88, P2774Brown RS, 1999, J NUCL MED, V40, P556Ito T, 1998, MODERN PATHOL, V11, P437Travis WD, 1998, HUM PATHOL, V29, P272Baer SC, 1997, J AM ACAD DERMATOL, V37, P575Younes M, 1997, CANCER, V80, P1046Voldstedlund M, 1997, APMIS, V105, P537Haber RS, 1997, THYROID, V7, P363Younes M, 1997, CANCER EPIDEM BIOMAR, V6, P303Younes M, 1996, CLIN CANCER RES, V2, P1151Younes M, 1996, CANCER RES, V56, P1164Younes M, 1995, ANTICANCER RES, V15, P2895NAGASE Y, 1995, J UROLOGY, V153, P798MELLANEN P, 1994, INT J CANCER, V56, P622BROWN RS, 1993, CANCER, V72, P2979TAKATA K, 1992, CELL TISSUE RES, V267, P407PESSIN JE, 1992, ANNU REV PHYSIOL, V54, P911PARDRIDGE WM, 1990, J BIOL CHEM, V265, P18035ISSELBAC.KJ, 1972, NEW ENGL J MED, V286, P929

Colorectal Lymphoid Polyposis in a Child

Lymphoid polyposis is a lymphoid hyperplasia of the gastrointestinal tract that usually presents as multiple small polyps in the colon during childhood. This should be differentiated from other neoplastic or familial polyposis of the intestine. We report a case of benign lymphoid polyposis of the colon in a 17-month-old boy who presented with perianal fistula and mucosal ulceration. Colon study and rectal examinations showed multiple polyps in the sigmoid colon and rectum. Segmental resection of the sigmoid colon and rectum showed over 100 smallt 3 - 7 mrn) sessile or pedunculated polyps that were diffusely scattered through out the removed segment. The polyps consisted of mature lymphoid tissue with numerous germinal centers, that was located mostly in the lamina propria and submucosa

Evaluation for Damaged Degree of Vegetation by Forest Fire Using LiDAR and Digital Aerial Photograph

The amount of vegetation physically damaged by forest fire can be evaluated using lidar (Light Detection And Ranging) data because the loss of canopy height and width by forest fire can be relevant to the number of points transmitted to the ground through the canopy of the damaged forest. On the other hand, the biological damage of vegetation caused by forest fire can be obtained from the Normalized Difference Vegetation Index (NDVI), which determines the vegetation vitality. In this study, the degree of physical damage from the lidar data was classified into serious physical damage (SPD) and light physical damage (LPD). The degree of biological damage using NDVI was likewise classified into serious biological damage (SBD) and light biological damage (LBD). Finally, the damaged area was graded into four categories: (a) SPD and SBD, (b) LPD and SBD, (c) SPD and LBD, and (d) LPD and LBD. The accuracy assessment for the area classified into four grades showed an overall accuracy of 0.74, and a kappa value of 0.61 which provides improvement over previous works

Notch controls the number of intraepithelial TCRαβ+CD8αα+ T cells

Intestinal intraepithelial lymphocytes (IELs) expressing CD8αα on αβ T cells (TCRαβ+CD8αα+ IELs) have suppressive capabilities in enterocolitis, but the mechanism that maintains homeostasis and cell number is not fully understood. Here, we demonstrated that the number of TCRαβ+CD8αα+ IELs was severely reduced in mice lacking recombination signal binding protein for immunoglobulin kappa J region (Rbpj) or Notch1 and Notch2 in T cells. Rbpj-deficient TCRαβ+CD8αα+ IELs expressed low levels of Atp8a2, which encodes a protein with flippase activity that regulates phospholipid asymmetry of plasma membrane such as flipping phosphatidylserine in the inner leaflet of plasma membrane. Rbpj-deficient TCRαβ+CD8αα+ IELs cannot maintain phosphatidylserine in the inner leaflet of the plasma membrane. Furthermore, depletion of intestinal macrophages restored TCRαβ+CD8αα+ IELs in Rbpj-deficient mice, suggesting that exposure of phosphatidylserine on the plasma membrane in Rbpj-deficient TCRαβ+CD8αα+ IELs acts as an “eat-me” signal. Together, these results revealed that Notch–Atp8a2 is a fundamental regulator for IELs and highlighted that membrane phospholipid asymmetry controlled by Notch-mediated flippase expression is a critical determinant in setting or balancing the number of TCRαβ+CD8αα+ IELs

成熟T細胞の生存はHOIPを介するシグナルに依存する

T cell development in the thymus is controlled by a multistep process. The NF-κB pathway regulates T cell development as well as T cell activation at multiple differentiation stages. The linear ubiquitin chain assembly complex (LUBAC) is composed of Sharpin, HOIL-1L and HOIP, and it is crucial for regulating the NF-κB and cell death pathways. However, little is known about the roles of LUBAC in T-cell development and activation. Here, we show that in T-HOIPΔlinear mice lacking the ubiquitin ligase activity of LUBAC, thymic CD4+ or CD8+ T cell numbers were markedly reduced with severe defects in NKT cell development. HOIPΔlinear CD4+ T cells failed to phosphorylate IκBα and JNK through T cell receptor-mediated stimulation. Mature CD4+ and CD8+ T cells in T-HOIPΔlinear mice underwent apoptosis more rapidly than control T cells, and it was accompanied by lower CD127 expression on CD4+CD24low and CD8+CD24low T cells in the thymus. The enforced expression of CD127 in T-HOIPΔlinear thymocytes rescued the development of mature CD8+ T cells. Collectively, our results showed that LUBAC ligase activity is key for the survival of mature T cells, and suggest multiple roles of the NF-κB and cell death pathways in activating or maintaining T cell-mediated adaptive immune responses

Clinical factors affecting progression-free survival with crizotinib in ALK-positive non-small cell lung cancer

Background/Aims: Although crizotinib is standard chemotherapy for advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), clinical factors affecting progression-free survival (PFS) have not been reported. The purpose of this study was to identify clinical factors affecting PFS of crizotinib and develop a prognostic model for advanced ALK-positive NSCLC. Methods: Clinicopathologic features of patients enrolled in PROFILE 1001, 1005, 1007, and 1014 (training cohort) were reviewed. We conducted multivariate Cox analysis for PFS and overall survival (OS) in the training cohort (n = 159) and generated a proportional hazards model based on significant clinicopathologic factors, and then validated the model in an independent validation cohort (n = 40). Results: In the training cohort, the objective response rate was 81.5%. Median PFS and OS from the start of crizotinib were 12.4 and 31.3 months, respectively. Multivariate Cox analysis showed poor performance status, number of metastatic organs (>= 3), and no response to crizotinib independently associated shorter PFS. Based on a score derived from these three factors, median PFS and OS of patients with one or two factors were significantly shorter compared to those without these factors (median PFS, 22.4 months vs. 10.5 months vs. 6.5 months; median OS, not reached vs. 29.1 months vs. 11.8 months, respectively; p < 0.001 for each group). This model also had validated in an independent validation cohort. Conclusions: Performance status, number of metastatic organs, and response to crizotinib affected PFS of crizotinib in ALK-positive NSCLC. Based on these factors, we developed a simple and useful prediction model for PFS.