다중혈관 관상동맥 환자에서 y-문합을 이용하여 양쪽 내흉동맥만을 사용한 우회술의 조기 성적

B and T lymphocytes are the mediators of immunity, but their function is under the control of dendritic cells. Dendritic cells in the periphery capture and process antigens, express lymphocyte co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses. They not only activate lymphocytes, they also tolerize T cells to antigens that are innate to the body (self-antigens), thereby minimizing autoimmune reactions. Once a neglected cell type, dendritic cells can now be readily obtained in sufficient quantities to allow molecular and cell biological analysis. With knowledge comes the realization that these cells are a powerful tool for manipulating the immune system.

Dendritic cells and the control of immunity

Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.

Inflammation and cancer

The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.

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Cancer-related inflammation.

Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions. VEGF has also been implicated in pathological angiogenesis associated with tumors, intraocular neovascular disorders and other conditions. The biological effects of VEGF are mediated by two receptor tyrosine kinases (RTKs), VEGFR-1 and VEGFR-2, which differ considerably in signaling properties. Non-signaling co-receptors also modulate VEGF RTK signaling. Currently, several VEGF inhibitors are undergoing clinical testing in several malignancies. VEGF inhibition is also being tested as a strategy for the prevention of angiogenesis, vascular leakage and visual loss in age-related macular degeneration.

The biology of VEGF and its receptors.

cells Novel markers of normal and neoplastic human plasmacytoid dendritic

Summary Molecules representative of different classes of chemotactic agents, including formyl-Met-LeuPhe (FMLP), CSa, leukotriene B4, platelet-activating factor, and interleukin (IL)-8, caused a rapid reduction in the IL-1 binding capacity by human polymorphonuclear (PMN), a cell type expressing predominantly the IL-1 type II decoy receptor (IL-1 decoy RII). N-t-BocMet-Leu-Phe, an antagonist for the FMLP receptor, inhibited the loss of IL-1 binding capacity induced by FMLP. Monocyte chemotactic protein 1, a chemokine related to IL-8 but inactive on PMN, had no effect on IL-1 binding in this cell type. FMLP was selected for further detailed analysis of chemoattractant-induced loss of IL-1 binding by PMN. The action of FMLP was rapid, reaching 50% of its maximum (80%) at 30 s, the earliest measurable time point, and plateauing between 10 and 30 min. Dose-response analysis revealed that maximal reduction of IL-1 binding was reached at FMLP concentrations that were also optimal for chemotaxis (50% effective dose = 5 x 10 -9 M). The loss of IL-1 binding capacity caused by FMLP was determined by a reduction in receptor number with no change in their affinity. The effect of FMLP on IL-1 receptor (IL-1R) was selective in that the PMN surface structures IL-SR, CD16, CD18, and major histocompatibility complex class I antigens were unaffected under these conditions. Loss of surface IL-1R was not due to an augumented rate of internalization. FMLP caused rapid release of a 45-kD IL-1-binding molecule identified as the IL-1 decoy RII. After FMLP-induced release, PMN reexpressed newly synthesized receptors, reaching basal levels by 4 h. FMLP-induced release of the IL-1 decoy RII did not impair the responsiveness of PMN to IL-1 in terms of promotion of survival and cytokine production. FMLP-induced release of the IL-1 decoy RII was unaffected by protein synthesis inhibitors, was blocked by certain protease inhibitors, and was mimicked by agents (the Ca + + ionophore A23187 and phorbol myristate acetate) that recapitulate elements in the signal transduction pathway of chemoattractant receptors. The time frame and concentration range of chemoattractant-induced rapid release of the IL-1 decoy RII are consistent with the view that IL-1 decoy RII release is an early event in the multistep process of leukocyte recruitment. Rapid chemoattractant-induced IL-1 decoy RII release in the circulation may counteract IL-1 leaking into the systemic circulation from sites of inflammation while preserving the capacity of leukocytes to respond to IL-1 in tissues. This phenomenon may contribute as well to the antiinflammatory effect of systemic administration of chemotactic agents.

Chemoattractants Induce Rapid Release of the Interleukin 1 Type II Decoy Receptor in Human Polymorphonuclear Cells By Francesco Colotta,* Simone Orlando,* Emma Jane Fadlon,*

Patterns of receptors for chemotactic factors regulate the homing of leukocytes to tissues. Here we report that the CCRL2/chemerin/CMKLR1 axis represents a selective pathway for the homing of NK cells to the lung. C-C motif Chemokine Receptor-Like 2 (CCRL2) is a non-signaling seven-transmembrane domain receptor able to control lung tumor growth. CCRL2 constitutive or conditional endothelial cell targeted ablation, or deletion of its ligand chemerin, were found to promote tumor progression in a Kras/p53Flox lung cancer cell model. This phenotype was dependent on the reduced recruitment of CD27-CD11b+ mature NK cells. Other chemotactic receptors identified in lung-infiltrating NK cells by single-cell RNA sequencing (scRNA-seq), such as Cxcr3, Cx3cr1, and S1pr5, were found to be dispensable in the regulation of NK-cell infiltration of the lung and lung tumor growth. scRNA-seq identified CCRL2 as the hallmark of general alveolar lung capillary endothelial cells. CCRL2 expression was epigenetically regulated in lung endothelium and it was upregulated by the demethylating agent 5-aza-2'-deoxycytidine (5-Aza). In vivo administration of low doses of 5-Aza induced CCRL2 upregulation, increased recruitment of NK cells, and reduced lung tumor growth. These results identify CCRL2 as an NK-cell lung homing molecule that has the potential to be exploited to promote NK cell-mediated lung immune surveillance.

CCRL2 expression by specialized lung capillary endothelial cells controls NK-cell homing in lung cancer.

Circulating biomarkers with diagnostic and prognostic value in early Rheumatoid Arthritis (RA) are still an unmet need, especially for the subgroup of seronegative RA [e.g., negative for anti-citrullinated peptides autoantibodies (ACPA) and/or rheumatoid factors (RF)]. In a recent gene-based genome-wide association analysis (GWAS) study, RNASET2 was identified as a potential susceptibility gene [1-3]. Furthermore, the extracellular ribonuclease RNASET2 was demonstrated to be involved in the regulation of several immune processes [4].The aim of this study was to analyse RNASET2 serum levels in a cohort of RA patients upon their disease activity, in comparison with healthy controls (HC).Forty consecutive patients with RA (75% female, 55% seropositive) with a median age (25th-75thpercentile) of 55 years (45-68) and a CRP-DAS28 index of 3.09 (2.50-3.70), and 25 sex and age-matched HC were enrolled in the study. RNASET2 serum levels were assessed through a commercial hELISA test (WuHan Fine Biotech Co., China).Serum levels of RNASET2 were higher in RA patients than in HC [29.42 (17.73 – 69.82) vs 18.15 (12.15 – 28.35) ng/mL; p= 0.001]. Among patients with RA, there were no differences between RNASET2 levels in seropositive or seronegative ones [33.14 (16.79 – 74.89) vs 29.01 (17.83 – 39.85) ng/mL; p=0.308]. Furthermore, there were no differences in RNASET2 serum levels between patients in treatment with corticosteroids or not [42.09 (18.11 – 78.78) vs 23.42 (18.29 – 43.87) ng/mL; p=0.239]. RNASET2 serum levels were significantly different across 3 groups of RA patients identified upon the CRP-DAS28 score (high plus moderate disease activity –group A-; low disease activity –group B-; remission –group C-) (p= 0.024). RNaseT2 levels were higher in both group A and B as compared to group C [56.73 (30.22 – 79.67) - 83.72 (52.68 – 113.89) vs 25.43 (20.15 – 39.85) ng/mL; p= 0.005 & p= 0.007]. No difference was found between group A & B. When combining groups A & B, RNASET2 levels were significantly higher than in group C [67.14 (36.07 – 86.68) vs 25.43 (20.15 – 39.85) ng/mL; p= 0.013]. No significant correlation was found between RNASET2 serum levels and CRP-DAS28 (r= 0.36; p= 0.055).This is the first description of circulating serum levels of RNASET2 as a potential diagnostic biomarker in RA. Higher levels of RNASET2 clustered in RA patients as compared to HC. Low levels of RNASET2 seem to characterize the remission phase of RA. These preliminary results deserve to be expanded in larger cohorts of RA patients, patients with other form of chronic arthritis and other pathological and healthy controls.[1]Zhu et al. PLOSone 2016;[2]Walsh et al. Genome Biology 2016;[3]Muaaz Aslam et al. Disease Markers 2020;[4]Acquati et al. Frontiers Immunol 2019This work was supported by the Italian Ministry for University and Research (Prin 2017NTK4HY).None Declared.

Silvano Sozzani

Papers

cells Novel markers of normal and neoplastic human plasmacytoid dendritic

Chemoattractants Induce Rapid Release of the Interleukin 1 Type II Decoy Receptor in Human Polymorphonuclear Cells By Francesco Colotta,* Simone Orlando,* Emma Jane Fadlon,*

CCRL2 expression by specialized lung capillary endothelial cells controls NK-cell homing in lung cancer.

Ab0059 the potential role of the t2 family of extracellular ribonucleases (rnaset2) as circulating biomarker in rheumatoid arthritis

Pro-angiogenic properties of alternatively activated dendritic cells.