Hasil untuk "Immunologic diseases. Allergy"

Jingxin Zhou, Jingxin Zhou, Jinrong Yao et al.

BackgroundEmerging evidence links gut microbiota to tumorigenesis via immune modulation, though subtype-specific microbial signatures in B-cell lymphomas remain unclear. This study explores microbiota-immune interactions across lymphoma subtypes to inform microbiota-targeted therapies.MethodsTwenty-seven treatment-naive B-cell lymphoma patients (8 DLBCL, 5 SLL, 5 FL, 7 MZL, 2 WM) and 20 HCs were enrolled. Fecal 16S rDNA sequencing, flow cytometry for immune cell subsets, and ELISA for cytokines/immunoglobulins were performed. Microbiota differences and correlations with immune parameters were analyzed.ResultsB-cell lymphoma patients showed lower fecal microbiota richness/evenness (P<0.05), with increased Actinobacteriota, Bacilli, Enterobacteriaceae and decreased Bacteroidetes. Small B-cell lymphoma and DLBCL exhibited distinct flora: Selenomonadaceae/Actinobacteriota dominated in DLBCL, while Enterobacteriaceae prevailed in small B-cell subtypes. Correlations showed Enterobacteriaceae positively linked to Th cells/PCT/TNF and negatively to IL-10 in small B-cell lymphoma; Actinobacteriota correlated with B/T cells/Treg/IFN-β and inversely with IL-2/IL-4/CD8+T cells.ConclusionsThis study identifies distinct patterns of gut microbiota dysbiosis across B-cell lymphoma subtypes and explores their correlations with host immune parameters.

Haixin Liu, Haolun Tian, Pengcheng Hao et al.

PoRVA and PEDV coinfections are extremely common in clinical practice. Although coinfections of PoRVA and PEDV are known to result in increased mortality, the underlying mechanism remains unknown. Here, we found that PoRVA infection promoted PEDV infection in vivo and in vitro and that PoRVA G9P[23] (RVA-HNNY strain) enhanced PEDV replication more significantly than did PoRVA G5P[7] (RVA-SXXA strain). Metabolomic analysis revealed that RVA-HNNY more efficiently induced an increase in the intracellular glutamine content in porcine small intestinal epithelial cells than did RVA-SXXA, which more markedly promoted ATP production to facilitate PEDV replication, whereas glutamine deprivation abrogated the effect of PoRVA infection on promoting PEDV replication. Further studies showed that PoRVA infection promoted glutamine uptake by upregulating the expression of the glutamine transporter protein SLC1A5. In SLC1A5 knockout cells, PoRVA infection neither elevated intracellular glutamine nor promoted PEDV replication. During PoRVA infection, the activity and protein expression levels of glutamine catabolism-related enzymes (GLS1 and GLUD1) were also significantly increased promoting ATP production through glutamine anaplerosis into the TCA cycle. Consistent with that, siRNAs or inhibitors of GLS1 and GLUD1 significantly inhibited the promotion of PEDV replication by PoRVA. Notably, RVA-HNNY infection more markedly promoted SLC1A5, GLS1 and GLUD1 expression to more significantly increase the uptake and catabolism of glutamine than RVA-SXXA infection. Collectively, our findings illuminate a novel mechanism by which PoRVA infection promotes PEDV infection and reveal that the modulation of glutamine uptake is key for the different efficiencies of PoRVA G9P[23] and PoRVA G5P[7] in promoting PEDV replication.

Mackenzie E. Turner, Mackenzie E. Turner, Jingru Che et al.

Lysosomes and lysosome related organelles (LROs) are dynamic organelles at the intersection of various pathways involved in maintaining cellular hemostasis and regulating cellular functions. Vesicle trafficking of lysosomes and LROs are critical to maintain their functions. The lysosomal trafficking regulator (LYST) is an elusive protein important for the regulation of membrane dynamics and intracellular trafficking of lysosomes and LROs. Mutations to the LYST gene result in Chédiak-Higashi syndrome, an autosomal recessive immunodeficiency characterized by defective granule exocytosis, cytotoxicity, etc. Despite eight decades passing since its initial discovery, a comprehensive understanding of LYST’s function in cellular biology remains unresolved. Accumulating evidence suggests that dysregulation of LYST function also manifests in other disease states. Here, we review the available literature to consolidate available scientific endeavors in relation to LYST and discuss its relevance for immunomodulatory therapies, regenerative medicine and cancer applications.

Marion Holzapfel, Marion Holzapfel, Marion Holzapfel et al.

Xun Wang, Xun Wang, Jie Wu et al.

The bursa of Fabricius (BF) is the critical humoral immune organ to birds, playing an essential role in B lymphocyte differentiation. However, unlike other poultries, surgical removal of pigeon BF did not limit humoral immune responsiveness. To investigate the expression profiles and the potential role of mRNA and long non-coding RNA (LncRNA) in squab BFs, transcriptome analysis was performed by RNA-Sequencing (RNA-Seq) over three developmental stages (1-day, 13 and 26 days old). We identified 13,072 mRNAs and 19,129 lncRNAs, of which 2,752 mRNAs and 1,515 lncRNAs were differential expressed (DE) in pigeon BFs over three developmental stages. Cluster analysis presented different expression patterns in DE mRNAs and lncRNAs. Functional enrichment analysis revealed that DE lncRNAs and mRNAs with distinct expression patterns might play crucial roles in the immune system process and tissue morphogenesis. In particular, some DE genes and lncRNAs with higher expression levels in 13D or 26D are related to lymphocyte activation and differentiation, adaptive immune response, positive regulation of immune response, leukocyte migration, etc. Protein-protein interaction (PPI) network and Molecular Complex Detection (MCODE) analysis sreened six significant modules containing 37 genes from immune-related DE gene cluster, which is closely linked in B cell activation, lymphocyte differentiation, B cell receptor signaling pathway, etc. Our study characterizes mRNA and lncRNA transcriptomic variability in pigeon BFs over different developmental stages and enhances understanding of the mechanisms underlying physiological functions of pigeon BF.

Enrico Munari, Giulia Querzoli, Matteo Brunelli et al.

Different programmed cell death-ligand 1 (PD-L1) assays and scoring algorithms are being used in the evaluation of PD-L1 expression for the selection of patients for immunotherapy in specific settings of advanced urothelial carcinoma (UC). In this paper, we sought to investigate three approved assays (Ventana SP142 and SP263, and Dako 22C3) in UC with emphasis on implications for patient selection for atezolizumab/pembrolizumab as the first line of treatment. Tumors from 124 patients with invasive UC of the bladder were analyzed using tissue microarrays (TMA). Serial sections were stained with SP263 and SP142 on Ventana Benchmark Ultra and with 22C3 on Dako Autostainer Link 48. Stains were evaluated independently by two observers and scored using the combined positive score (CPS) and tumor infiltrating immune cells (IC) algorithms. Differences in proportions (DP), overall percent agreement (OPA), positive percent agreement (PPA), negative percent agreement (NPA), and Cohen κ were calculated for all comparable cases. Good overall concordance in analytic performance was observed for 22C3 and SP263 with both scoring algorithms; specifically, the highest OPA was observed between 22C3 and SP263 (89.6%) when using CPS. On the other hand, SP142 consistently showed lower positivity rates with high differences in proportions (DP) compared with 22C3 and SP263 with both CPS and IC, and with a low PPA, especially when using the CPS algorithm. In conclusion, 22C3 and SP263 assays show comparable analytical performance while SP142 shows divergent staining results, with important implications for the selection of patients for both pembrolizumab and atezolizumab.

Maxime Nguyen, Maxime Nguyen, Maxime Nguyen et al.

IntroductionDuring peritonitis, lipopolysaccharides (LPS) cross the peritoneum and pass through the liver before reaching the central compartment. The aim of the present study was to investigate the role of lipoproteins and phospholipid transfer protein (PLTP) in the early stages of LPS detoxification.Material and MethodsPeritonitis was induced by intra-peritoneal injection of LPS in mice. We analyzed peritoneal fluid, portal and central blood. Lipoprotein fractions were obtained by ultracentrifugation and fast protein liquid chromatography. LPS concentration and activity were measured by liquid chromatography coupled with mass spectrometry and limulus amoebocyte lysate. Wild-type mice were compared to mice knocked out for PLTP.ResultsIn mice expressing PLTP, LPS was able to bind to HDL in the peritoneal compartment, and this was maintained in plasma from portal and central blood. A hepatic first-pass effect of HDL-bound LPS was observed in wild-type mice. LPS binding to HDL resulted in an early arrival of inactive LPS in the central blood of wild-type mice.ConclusionPLTP promotes LPS peritoneal clearance and neutralization in a model of peritonitis. This mechanism involves the early binding of LPS to lipoproteins inside the peritoneal cavity, which promotes LPS translocation through the peritoneum and its uptake by the liver.

Mario Enrique Rendón-Macías, Irma Susana Zarco-Villavicencio, Miguel Ángel Villasís-Keever

Informar en los estudios sobre el tamaño del efecto de una intervención o del impacto de factor(es) sobre un desenlace, permite tomar mejores decisiones para la aplicación de los resultados a la práctica clínica. En este artículo se presenta la manera de analizar el tamaño del efecto, lo cual puede ser mediante métodos estadísticos directos o indirectos. Dentro de los métodos directos, se encuentra la diferencia de promedios entre grupos y la diferencia de frecuencias absolutas o relativas. Dentro de los métodos indirectos se muestran los índices de la familia de “d” de Cohen (que se basan en valores de desviación estándar), la familia de “r y R2”, medidas de asociación (RM, RR, HR) e impacto (NNT). La decisión del uso de cualquiera de los métodos descritos, depende de los objetivos del estudio, la escala de medición usada para evaluar los resultados y la distribución de los datos. Para facilitar la comprensión, se incluyen ejemplos y se resalta la necesidad de incluir los diferentes estadísticos con su nivel de precisión (ej. intervalos de confianza), junto con los umbrales clínicos de decisión, a fin de mejorar su interpretación.

Mladen Jergović, Heather L. Thompson, Kristin R. Renkema et al.

Rita De Santis

Over the past 3 decades, monoclonal antibodies and their related derivatives, including recently approved antibody-drug conjugates, conquered a central role in cancer therapy because of their contribution to improve survival, time to progression and quality of life of patients compared to chemotherapy protocols. This review summarizes information on approved original and biosimilar products, as well as investigational antibody-based therapeutics, targeting ErbB2. This target has been selected as a paradigmatic example because of its relevant role in sustaining the malignancy of major cancer diseases including, breast, gastric and other chemotherapy-resistant solid tumors. This work analyzes the drivers affecting research and development of next-generation anti-ErbB2 immunotherapeutics, taking into account unmet medical needs and pharmacoeconomic issues related to sustainability. The analysis may help with the design of future research and development strategies.

Beutner C, Forkel S, Gupta S et al.

Caroline Beutner,1 Susann Forkel,1 Sidhi Gupta,1 Thomas Fuchs,1 Michael P Schön,1,2 Johannes Geier,2,3 Timo Buhl1,2 1Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany; 2Lower Saxony Institute of Occupational Dermatology, University Medical Center Göttingen, Göttingen, Germany; 3Information Network of Departments of Dermatology (IVDK), University of Göttingen, Göttingen, GermanyCorrespondence: Caroline BeutnerDepartment of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Georg August University, Robert Koch-Str. 40, Göttingen D-37075, GermanyTel +495513966402Email caroline.beutner@med.uni-goettingen.deIntroduction: The prevalence of airway allergies in Europe has increased from 23% to 31% in recent years. Polysensitization is associated with the development and severity of relevant allergies, particularly allergic asthma.Objective: We investigated age- and sex-dependent monosensitization and polysensitization profiles as well as patterns of sensitization using skin prick test (SPT) reactivity to the most common aeroallergens.Patients and Methods: From 1998 to 2017, SPTs were retrospectively analyzed in 2886 symptomatic patients, referred to the University Medical Center Göttingen, located in central Germany. The major aeroallergen groups early flowering tree pollen, grass pollen, and house dust mites were evaluated in this study. Wheal diameters ≥ 2 mm were considered positive during the entire study period.Results: Polysensitization to the most common aeroallergen groups increased significantly over 20 years. Boys and young men displayed the most remarkable rise in total sensitization rates in our study group over time.Discussion: Our patient-based study demonstrates a continuing increase in polysensitization rates over the last 20 years, with boys and young men being most frequently affected. Our data—without being a population-based study—suggest a scenario with climbing rates of allergic rhinitis and asthma.Keywords: aeroallergens, polysensitization, sensitization pattern, skin prick test

Alberto L. Horenstein, Alberto L. Horenstein, Cristiano Bracci et al.

Tumor microenvironments are rich in extracellular nucleotides that can be metabolized by ectoenzymes to produce adenosine, a nucleoside involved in controlling immune responses. Multiple myeloma, a plasma cell malignancy developed within a bone marrow niche, exploits adenosinergic pathways to customize the immune homeostasis of the tumor. CD38, a multifunctional protein that acts as both receptor and ectoenzyme, is overexpressed at all stages of myeloma. At neutral and acidic pH, CD38 catalyzes the extracellular conversion of NAD+ to regulators of calcium signaling. The initial disassembly of NAD+ is also followed by adenosinergic activity, if CD38 is operating in the presence of CD203a and CD73 nucleotidases. cAMP extruded from tumor cells provides another substrate for metabolizing nucleotidases to signaling adenosine. These pathways flank or bypass the canonical adenosinergic pathway subjected to the conversion of ATP by CD39. All of the adenosinergic networks can be hijacked by the tumor, thus controlling the homeostatic reprogramming of the myeloma in the bone marrow. In this context, adenosine assumes the role of a local hormone: cell metabolism is adjusted via low- or high-affinity purinergic receptors expressed by immune and bone cells as well as by tumor cells. The result is immunosuppression, which contributes to the failure of immune surveillance in cancer. A similar metabolic strategy silences immune effectors during the progression of indolent gammopathies to symptomatic overt multiple myeloma disease. Plasma from myeloma aspirates contains elevated levels of adenosine resulting from interactions between myeloma and other cells lining the niche and adenosine concentrations are known to increase as the disease progresses. This is statistically reflected in the International Staging System for multiple myeloma. Along with the ability to deplete CD38+ malignant plasma cell populations which has led to their widespread therapeutic use, anti-CD38 antibodies are involved in the polarization and release of microvesicles characterized by the expression of multiple adenosine-producing molecules. These adenosinergic pathways provide new immune checkpoints for improving immunotherapy protocols by helping to restore the depressed immune response.

Miao Yang, Haijing Wu, Ming Zhao et al.

Bullous skin diseases are a group of dermatoses characterized by blisters and bullae in the skin and mucous membranes. The etiology and pathogenesis of bullous skin diseases are not completely clear. The most common are pemphigus and bullous pemphigoid (BP). Autoantibodies play critical roles in their pathogenesis. Abnormalities in the adhesion between keratinocytes in patients with pemphigus leads to acantholysis and formation of intra-epidermal blisters. Anti-desmoglein autoantibodies are present both in the circulation and skin lesions of patients with pemphigus. The deficient adhesion of keratinocytes to the basement membrane in BP patients gives rise to subepidermal blisters. Autoantibodies against the components of hemidesmosome can be detected in BP patients. Many novel therapeutics based on knowledge of the pathogenesis have emerged in recent years. Keywords: Tolerance, Autoimmune skin diseases, Bullous pemphigoid, Autoantibody, Immunosuppression

Maria Dobre, Elena Milanesi, Teodora Ecaterina Mănuc et al.

Genetic research has shaped the inflammatory bowel disease (IBD) landscape identifying nearly two hundred risk loci. Nonetheless, the identified variants rendered only a partial success in providing criteria for the differential diagnosis between ulcerative colitis (UC) and Crohn’s disease (CD). Transcript levels from affected intestinal mucosa may serve as tentative biomarkers for improving classification and diagnosis of IBD. The aim of our study was to identify gene expression profiles specific for UC and CD, in endoscopically affected and normal intestinal colonic mucosa from IBD patients. We evaluated a panel of 84 genes related to the IBD-inflammatory pathway on 21 UC and 22 CD paired inflamed and not inflamed mucosa and on age-matched normal mucosa from 21 non-IBD controls. Two genes in UC (CCL11 and MMP10) and two in CD (C4BPB and IL1RN) showed an upregulation trend in both noninflamed and inflamed mucosa compared to controls. Our results suggest that the transcript levels of CCL11, MMP10, C4BPB, and IL1RN are candidate biomarkers that could help in clinical practice for the differential diagnosis between UC and CD and could guide new research on future therapeutic targets.

Wesley H Stepp, James D Stamos, Simran Khurana et al.

We have shown previously that Sp100 (a component of the ND10 nuclear body) represses transcription, replication and establishment of incoming human papillomavirus (HPV) DNA in the early stages of infection. In this follow up study, we show that Sp100 does not substantially regulate viral infection in the maintenance phase, however at late stages of infection Sp100 interacts with amplifying viral genomes to repress viral processes. We find that Sp100 localizes to HPV16 replication foci generated in primary keratinocytes, to HPV31 replication foci that form in differentiated cells, and to HPV16 replication foci in CIN 1 cervical biopsies. To analyze this further, Sp100 was down regulated by siRNA treatment of differentiating HPV31 containing cells and levels of viral transcription and replication were assessed. This revealed that Sp100 represses viral transcription and replication in differentiated cells. Analysis of Sp100 binding to viral chromatin showed that Sp100 bound across the viral genome, and that binding increased at late stages of infection. Therefore, Sp100 represses the HPV life cycle at both early and late stages of infection.

Steve Cornick, France Moreau, Kris Chadee

Critical to the pathogenesis of intestinal amebiasis, Entamoeba histolytica (Eh) induces mucus hypersecretion and degrades the colonic mucus layer at the site of invasion. The parasite component(s) responsible for hypersecretion are poorly defined, as are regulators of mucin secretion within the host. In this study, we have identified the key virulence factor in live Eh that elicits the fast release of mucin by goblets cells as cysteine protease 5 (EhCP5) whereas, modest mucus secretion occurred with secreted soluble EhCP5 and recombinant CP5. Coupling of EhCP5-αvβ3 integrin on goblet cells facilitated outside-in signaling by activating SRC family kinases (SFK) and focal adhesion kinase that resulted in the activation/phosphorlyation of PI3K at the site of Eh contact and production of PIP3. PKCδ was activated at the EhCP5-αvβ3 integrin contact site that specifically regulated mucin secretion though the trafficking vesicle marker myristoylated alanine-rich C-kinase substrate (MARCKS). This study has identified that EhCP5 coupling with goblet cell αvβ3 receptors can initiate a signal cascade involving PI3K, PKCδ and MARCKS to drive mucin secretion from goblet cells critical in disease pathogenesis.

Arthur S Kim, Daniel P Leaman, Michael B Zwick

Human antibody 10E8 targets the conserved membrane proximal external region (MPER) of envelope glycoprotein (Env) subunit gp41 and neutralizes HIV-1 with exceptional potency. Remarkably, HIV-1 containing mutations that reportedly knockout 10E8 binding to linear MPER peptides are partially neutralized by 10E8, producing a local plateau in the dose response curve. Here, we found that virus partially neutralized by 10E8 becomes significantly less neutralization sensitive to various MPER antibodies and to soluble CD4 while becoming significantly more sensitive to antibodies and fusion inhibitors against the heptad repeats of gp41. Thus, 10E8 modulates sensitivity of Env to ligands both pre- and post-receptor engagement without complete neutralization. Partial neutralization by 10E8 was influenced at least in part by perturbing Env glycosylation. With unliganded Env, 10E8 bound with lower apparent affinity and lower subunit occupancy to MPER mutant compared to wild type trimers. However, 10E8 decreased functional stability of wild type Env while it had an opposite, stabilizing effect on MPER mutant Envs. Clade C isolates with natural MPER polymorphisms also showed partial neutralization by 10E8 with altered sensitivity to various gp41-targeted ligands. Our findings suggest a novel mechanism of virus neutralization by demonstrating how antibody binding to the base of a trimeric spike cross talks with adjacent subunits to modulate Env structure and function. The ability of an antibody to stabilize, destabilize, partially neutralize as well as alter neutralization sensitivity of a virion spike pre- and post-receptor engagement may have implications for immunotherapy and vaccine design.

Norimasa Izumi, Hiroyuki Mizuguchi, Hayato Umehara et al.

Background: H1 antihistamines are widely used as therapeutics for allergic diseases. Sedation is a well-known side effect of H1 antihistamines and sometimes it is life-threatening for patients. Thus it is important to evaluate the sedative properties of H1 antihistamines to avoid side effects. For this purpose, histamine H1 receptor (H1R) occupancy and proportional impairment ratios (PIR) are now being used. However, it is not easy to obtain these parameters. Here, we sought to evaluate the sedative properties of H1 antihistamines by means of a large-scale surveillance at health insurance pharmacies. Methods: The survey was conducted at 37 health insurance pharmacies. The therapeutic efficacy and the degree of sleepiness were quantified through a questionnaire using the visual analog scale (VAS) directly from 1742 patients who received H1 antihistamines. Results: The degree of sleepiness caused by the first-generation antihistamines was significantly higher than that of the second-generation antihistamines. The high VAS score in case of efficacy was found in d-chlorpheniramine, olopatadine, and ebastine. Among the mean values of efficacy, all second-generation antihistamines except for loratadine, bepotastine, and mequitazine were significantly higher than that of clemastine. Regarding the degree of sleepiness, clemastine scored the highest VAS score, and significantly lower scores were obtained in all second-generation antihistamines. Conclusions: The sedative properties of the H1 antihistamines obtained from VAS analysis were very similar to those of H1R occupancy from positron emission tomography (PET) studies and PIR from meta-analysis. Our results indicate that large-scale surveillance using VAS might be useful to evaluate the profiles of H1 antihistamines.

María E Alfonso Valdés, Rosa M Lam Díaz, José M Ballester Santovenia et al.

Se desarrolló una investigación para estudiar la estructura y funcionamiento de 4 bancos de sangre provinciales del país, su influencia en la calidad de esta actividad y el grado de satisfacción de los donantes, con el empleo de la guía metodológica para investigación de aspectos socio-culturales relacionados con la donación voluntaria de sangre de la Organización Panamericana de la Salud. El estudio arrojó que, en sentido general, los bancos cuentan con la estructura y equipamiento mínimo indispensable para desarrollar su actividad, pero en la mayoría de los casos, necesitan labores de mantenimiento, remodelación de algunas áreas, así como la adquisición y modernización del equipamiento. El funcionamiento general de estos centros es satisfactorio, pero deben mejorarse algunos aspectos como la calidad de la atención a los donantes, la información que se les brinda, las tareas de promoción de la donación y la retención de donantes<br>A research was developed to study the structure and functioning of 4 provincial blood banks in the country, their influence on the quality of this activity and the satisfaction degree of the donors. To this end, it was used the PHO&#8217;s methodological guide for investigating the sociocultural aspects related to voluntary blood donations. The study showed that, in general, the banks have the structure and indispensable minimum equipment to develop their activity, but in most of the cases they need maintenance, remodelation of some areas, as well as the purchasing and modernization of equipment. The general functioning of these centers is satisfactory, but some aspects as the quality of the attention to donors, the information given, the activities carried out to promote donations and the retention of donors should be improved

David Fredricks, Lalita Ramakrishnan