Expression and prognostic potential of TMEM204: a pan-cancer analysis

TMEM204 (Transmembrane Protein 204) is a member of the TMEM family that regulates cell function and angiogenesis. Previous studies showed that TMEM204 is related to pancreatic cancer, but its roles in other cancers remain unknown. To reveal this relationship, we conducted a pan-cancer analysis by several online databases. The expression of TMEM204 was analyzed by Oncomine and Tumor Immune Estimation Resource2.0 (TIMER2.0). The prognostic potential of TMEM204 was evaluated by the GEPIA2, UALCAN, and Oncolnc. The methylation level of gene expression was analyzed by UALCAN, and the relationship between cancer and immune invasion was displayed by TIMER2.0. The Protein-Protein Interactions Network and functional analysis of TMEM204 and its related genes were conducted by STRING and Webgestalt. We found that TMEM204 expression was up-regulated and correlated with prognosis in multiple cancers. In liver hepatocellular carcinoma (LIHC), high TMEM204 expression was associated with a good prognosis, and with high infiltrating levels of CD8⁺ T and CD4⁺ T cells, macrophages, neutrophils, and myeloid dendritic cells. In addition, the methylation level in LIHC was higher than in normal tissues. p53 signaling pathway and Fanconi anemia pathway were implicated by KEGG pathway analysis. These results indicate that TMEM204 is associated with the prognosis, methylation, and immune invasion of cancers, especially LIHC. TMEM204 may act as a prognostic marker of LIHC and its role in other cancers should be studied.     

Cellular immune responses in amniotic fluid of women with preterm clinical chorioamnionitis

Objective

Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Some preterm births are associated with clinical chorioamnionitis; yet, this condition has been poorly investigated. Herein, we characterized the amniotic fluid cellular immune responses in women with preterm clinical chorioamnionitis.

Methods and subjects

Amniotic fluid samples were obtained from women with preterm clinical chorioamnionitis and a positive or negative microbiological culture (n?=?17). The cellular composition of amniotic fluid was evaluated using fluorescence microscopy, scanning and transmission electron microscopy, and flow cytometry. Women without preterm clinical chorioamnionitis were also examined (n?=?10).

Results

Amniotic fluid from women with preterm clinical chorioamnionitis and a positive culture had: (1) abundant neutrophils associated with viable and non-viable bacteria, (2) neutrophils performing phagocytosis, (3) neutrophils forming NETs, (4) increased numbers of neutrophils, monocytes/macrophages, and CD4+?T cells, and (5) high expression of IL-1β by neutrophils and monocytes/macrophages. Amniotic fluid from women with preterm clinical chorioamnionitis and proven infection tended to have fewer monocytes/macrophages and CD4+?T cells compared to those without chorioamnionitis.

Conclusion

We provide the first morphologic and phenotypic characterization of the cellular immune responses in the amniotic cavity of women with preterm clinical chorioamnionitis, a condition associated with adverse neonatal outcomes.

     

Tumor-infiltrating B cell is associated with the control of progression of gastric cancer

This study aimed to further explore the clinicopathological correlation of B cell infiltration in gastric cancer (GC) and its impact on prognostic. By immunohistochemical method, CD20+ B cells, CD3+ T cells, CD66b+ tumor-associated neutrophils, CD163+ tumor-associated macrophages, and CD57+ natural killer cells were analyzed in consecutive sections of 584 GC tissues and 69 normal adjacent tissues. Kaplan–Meier and Cox regression analyses determined the relationship between clinical relevance or prognosis and B cell infiltration. The correlation between total B cell infiltration and various T cell subtype infiltration in GC tissues from 407 patients in the TCGA data was also analyzed. Kaplan–Meier and Cox regression analyses determined the effects of total B cell infiltration and various B cell subtype infiltration on the prognosis of patients with GC. The infiltration level of CD20+ B cells was positively correlated with that of T cells (risk ratio [RR] = 0.0930), especially CD4+ T cells and CD8+ T cells (P < 0.05). A high level of CD20+ B cell infiltration was significantly associated with low lymph node involvement and low TNM stage (P < 0.05). High levels of CD20+ B cell infiltration were significantly associated with improvements in overall survival and disease-free survival. Univariate Cox regression and multivariate Cox regression analysis showed that CD20+ B cell infiltration was an independent protective factor of prognosis. Higher levels of class-switched memory B cell and plasma cell also reflected better overall survival, and class-switched memory B cell and plasma cell were independent protective factors for prognosis. The findings indicate that B cell infiltration in GC, especially switched memory B cells and plasma cells, has a significant effect on tumor progression and prognosis.

     

Localization in situ of the co-stimulatory molecules B7.1, B7.2, CD40 and their ligands in normal human lymphoid tissue

Functional interactions between B and T lymphocytes are known to depend on the expression of co-stimulatory molecules B7.1/CD80, B7.2/CD86 and their counter-receptors CD28 and CTLA4, as well as CD40 and its ligand CD40L. To study the role of these molecules in situ, an immunohistochemical analysis was carried out on normal human lymphoid tissue. In the germinal centers (GC), B7.1 and B7.2 were differentially expressed. In the dark zone, centroblasts were predominantly B7.1⁺, while centrocytes in the light zone were B7-2⁺, resulting in reversed gradients of both markers in GC. Follicle mantle cells were negative for B7.1 and B7.2. Macrophages and interdigitating dendritic cells (IDC) in T cell zones both expressed B7.1 and B7.2. Moreover, clusters of B7.2⁺ T cells were demonstrated in interfollicular areas. Intrafollicular CD4⁺ T cells in GC, predominantly in the apical light zone, expressed CD28 and CTLA4, as did the majority of interfollicular T cells. CTLA4 showed a striking excentric cytoplasmic staining, which was also seen on T cells activated in vitro. CD40 was expressed on all B cells and more strongly on macrophages and IDC. Moreover, small clusters of T cells in a rim outside the GC showed CD40 expression. CD40L was expressed both on intrafollicular CD4⁺ T cells as well as on T cells in T cell zones. The differential distribution of co-stimulatory molecules in different compartments of normal human lymphoid tissue in situ indicates that these interactions play a distinctive role in different stages of B cell differentiation and in the immune response.     

Activated M1 macrophages suppress c-kit expression via TNF-α-mediated upregulation of miR-222 in Neonatal Necrotizing Enterocolitis

Background

Activation of intestinal macrophages is implicated in the pathogenesis of neonatal necrotizing enterocolitis (NEC), yet its precise mechanisms remain unclear.

Objective

The purpose of this study is to investigate the role of macrophages and TNF-α via an inflammatory MicroRNA in NEC.

Materials and methods

Immunofluorescence (IF) staining of CD68, iNOS, and Arg-1 was employed to identify phenotypes of macrophage in the intestines of NEC infants and NEC mice. Expression of TNF-α, c-kit, and miR-222 was evaluated by qRT-PCR, Western blot, and immunochemical staining from the tissue samples.

Results

Large number of M1 macrophage infiltration was found in the NEC intestines. Expression of CD68, iNOS, and TNF-α were significantly increased, while c-kit was decreased distinctly in the NEC group. In the early phase of NEC mouse model, inhibition of M1 macrophages reduced the incidence of NEC and intestinal inflammation. We found that TNF-α upregulated the expression of miRNA-222 and inhibited the expression of c-kit. Conversely, such decrease of c-kit expression could be reversed by miR-222 antagonists. Furtherly, dual-luciferase assay confirmed that c-kit can be inhibited by miR-222 directly.

Conclusion

Macrophages activation in NEC intestine results in an increased inflammatory response and TNF-α production, accompanied with miR-222 upregulation and c-kit suppression. Modulations of M1 macrophages, TNF-α or miR-222 may be potential therapeutic targets for NEC treatment.

     

Alterations of lymphocyte subpopulations and TGF-β in children with transient or persistent cow’s milk allergy

The aim of the study was to evaluate changes in surface receptor expression of B and T lymphocytes and concentration of TGF-β in children who either developed tolerance to cow’s milk protein (CMP) or manifested persistent cow’s milk allergy (CMA). The study involved 30 patients with CMA who underwent an open food challenge after 12 months of milk-free diet. After the milk challenge, decreased concentration of CD19⁺CD23+ was observed in children who acquired tolerance to CMP, in comparison with the test before cow’s milk (CM) challenge (42.2% vs. 29.1%, p?=?.006). The same group demonstrated lower concentration of TGF-β than patients with persistent allergy (median 37.9 pg/ml vs. 52.8 pg/ml, p?=?.003, respectively). Moreover, before CM challenge, higher percentage of CD3+CD8+CD28+CD152+ cells (median 2.88% vs. 1.2%, p?=?.03) and CD3+CD4⁺CD25⁺CD62L⁺ (median 42.3% vs. 13.4%, p?=?.032) was noted in children who acquired tolerance to CMP, in comparison with subjects who remained allergic to CMP.     

Trypanosoma cruzi-infected macrophages are defective in major histocompatibility complex class II antigen presentation

Trypanosoma cruzi, the intracellular protozoan parasite that causes Chagas' disease, interferes with the host immune response to establish a persistent infection. In this report, we demonstrate that macrophages infected with T. cruzi are unable to effectively present antigens to CD4 T cells. The interference is due to defective antigen-presenting cell (APC) function, as antigen-independent stimulation of the T cell in the presence of infected macrophages is not affected. The defect is distal to antigen processing and is not due to decreased major histocompatibility complex (MHC) class II expression, decreased viability, defective peptide loading in the infected macrophages, nor absence of CD28 co-stimulation. There was a role for gp39:CD40 co-stimulation during antigen presentation to the T cells we studied, but the expression of CD40 on T. cruzi-infected macrophages was not decreased. Antigen-specific adhesion between macrophages and T cells was reduced by infection. Equivalent levels of the adhesion molecules lymphocyte function-associated antigen-1, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 or very late antigen-4 are found on infected and uninfected APC, suggesting that reduced expression of these adhesion molecules was not responsible for the defect in antigen-specific adhesion. The defective T cell:macrophage adhesion may be due to the reduced expression of other adhesion molecules or other changes in the cell induced by infection. Interfering with MHC class II antigen presentation in infected macrophages may help T. cruzi to blunt the immune response by the host.     

Integrated Analysis of Expression and Prognostic Values of Acyl-CoA Dehydrogenase short-chain in Colorectal Cancer

Background: Acyl-CoA dehydrogenase short-chain (ACADS) is a crucial enzyme in the fatty acid metabolism pathway located in mitochondria. However, the expression level and prognostic value of ACADS in colorectal cancer (CRC) remain unclear.Methods: The mRNA and protein expression data of ACADS was obtained from The Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Oncomine. Prognostic values of ACADS were calculated using Kaplan-Meier survival analysis. Correlations between ACADS and immune infiltration were estimated using TIMER, CIBERSORT, EPIC, quanTIseq, and xCell. The UALCAN and MEXPRESS databases were utilized for Methylation analysis. The co-expression analysis based on mRNA expression and interaction network of ACADS were performed via several online tools. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis on ACADS co-expressed genes were performed using the Metascape.Results: The expression analysis demonstrated that ACADS was down-regulated in CRC tissues compared with paired normal tissue. Expression of ACADS was found to be significantly associated with clinical cancer stages and the consensus molecular subgroups (CMS) constituent ratio in CRC patients. Besides, lower ACADS expression was found to predict poor prognosis and be significantly associated with common immune checkpoint genes and MMR genes in CRC. ACADS expression levels were positively related to B cells, CD4⁺ T cells, CD8⁺ T cells, M1 macrophages, neutrophils, and Tregs, while negatively correlated with M0 macrophages, M2 macrophages. The methylation level of ACADS in normal tissues was significantly higher than that in tumor tissues, and several methylation sites were identified. The enrichment analysis suggested the co-expressed genes mainly enriched in cell mitochondrial metabolism.Conclusions: The present study provided multilevel evidences for expression of ACADS in CRC and the function of ACADS in prognostic prediction, immune infiltration, and methylation. ACADS might have the potential as the novel biomarker and therapeutic target in CRC patients.     

Nanomedicine-mediated prevention of inflammatory monocytes infiltration ameliorate ovalbumin-induced allergic rhinitis in mouse model

Abstract

Th2 immune cells infiltration into nasal mucosa is one of the characters of allergic rhinitis (AR). We aimed to explore whether inhibition of Th2 immune cells infiltration would attenuate AR progression. AR mouse model was established by i.p. injection of ovalbumin (OVA). The infiltrated immune cells into nasal lavage fluid were detected by flow cytometry. Cytokine concentration in serum was determined by ELISA. AR mice symptoms were indicated by the number of sneezing and nasal rubbing events. In AR mice, CCL2 expression levels and CD45⁺CD11b⁺Ly6C^hi inflammatory monocytes cells significantly increased as compared with control mice. CCL2 siRNA encapsulated nanoparticles (NP_siCCL2) prevent CCL2 expression and inflammatory monocytes infiltration in AR mice. NP_siCCL2 treatment dramatically decreased the number of sneezing and nasal rubbing events in AR mice. Moreover, NP_siCCL2 treatment attenuated serum OVA-specific IgE, OVA-specific IgG1 and histamine levels. Mechanically, NP_siCCL2 treatment attenuates AR symptoms via inhibiting Th2 cytokine (IL-4, IL-5 and IL-13) production. Nanomedicine-mediated prevention of inflammatory monocytes infiltration ameliorates ovalbumin-induced allergic rhinitis in mouse model.     

Regulation of Toll-like receptor-mediated inflammatory response by microRNA-152-3p-mediated demethylation of MyD88 in systemic lupus erythematosus

Objective

microRNAs (miRNAs) play critical roles in embryogenesis, cell differentiation and the pathogenesis of several human diseases, including systemic lupus erythematosus (SLE). Toll-like receptors (TLRs) are also known to exert crucial functions in the immune response activation occurring in the pathogenesis of autoimmune diseases like SLE. Herein, the current study aimed to explore the potential role of miR-152-3p in TLR-mediated inflammatory response in SLE.

Methods

We determined the miR-152-3p expression profiles in CD4⁺ T cells and peripheral blood mononuclear cells (PBMCs) harvested from patients with SLE and healthy controls, and analyzed the correlation between miR-152-3p expression and clinicopathological parameters. CD70 and CD40L expression patterns in CD4⁺ T cells were assessed by RT-qPCR and flow cytometry. ChIP was adopted to determine the enrichment of DNA methyltransferase 1 (DNMT1) in the promoter region of myeloid differentiation factor 88 (MyD88).

Results

The obtained findings revealed that miR-152-3p was highly-expressed in CD4⁺ T cells and PBMCs of patients with SLE, and this high expression was associated with facial erythema, joint pain, double-stranded DNA, and IgG antibody. DNMT1 could be enriched in the MyD88 promoter, and miR-152-3p inhibited the methylation of MyD88 by targeting DNMT1. We also found that silencing miR-152-3p inhibited MyD88 expression not only to repress the autoreactivity of CD4⁺ T cells and but also to restrain their cellular inflammation, which were also validated in vivo.

Conclusion

Our study suggests that miR-152-3p promotes TLR-mediated inflammatory response in CD4⁺ T cells by regulating the DNMT1/MyD88 signaling pathway, which highlights novel anti-inflammatory target for SLE treatment.

     

Prognostic significance of PU.1 in follicular lymphoma

Very few prognostic factors are known in follicular lymphoma (FL), a common malignancy of germinal centre (GC) B-cells. The Follicular Lymphoma International Prognostic Index (FLIPI) thus far appears to be the most important predictor of clinical outcome. This study explores the predictive power of the degree of GC differentiation for outcome in FL. Samples from 73 patients with FL were evaluated by immunohistochemistry for expression of GC markers. Strong PU.1, CD20, and CD75 expression were significantly associated with longer progression-free survival (PFS) and overall survival (OS). Results for PFS were independent of the International Prognostic Index or the Italian Lymphoma Intergroup prognostic index for CD75 and PU.1, but only PU.1 expression was independent of FLIPI for PFS and OS. Oct-2 was weakly expressed overall, but more strongly in higher grades of FL; it had a trend for negative linear association with PU.1 and strong positive linear association with CD27, which possibly reflects its role in terminal B-cell differentiation. We show that the level of GC differentiation, as determined by the levels of PU.1, CD75, CD20, Bcl-6, and CD10 expression, has an association with outcome in patients with FL. While this is determined qualitatively in most studies of diffuse large B-cell lymphoma, in FL there is a quantitative positive association between a high level of expression of GC antigens and longer OS and PFS even when data are stratified by the FLIPI score.     

Hypoxanthine Guanine Phosphoribosyltransferase expression is negatively correlated with immune activity through its regulation of purine synthesis

IntroductionThe purpose of this study was to examine the effects of elevated Hypoxanthine Guanine Phosphoribosyltransferase (HPRT) on the immune response in the tumor microenvironment.MethodologyHPRT expression was evaluated in cancer patients and correlated with cytokine expression, survival, and immune cell infiltration. An HPRT knockdown cell line was created to evaluate HPRT impact on purine expression and subsequent purine treatment was administered to immune cells to determine their influence on cell activation.ResultsHPRT expression was negatively correlated with the general expression of both pro-inflammatory and anti-inflammatory cytokines. Additionally, HPRT expression was also negatively correlated with the infiltration of immune cell subsets: B-cells, CD4 + T cells, macrophages, neutrophils, and dendritic cells (p < 0.001) and CD8 + T-cells (p < 0.01). When HPRT was knocked down in a Raji cell line, the levels of adenosine were reduced significantly compared to the wild type. When examining the level of Ca2+ influx of Raji compared to the HPRT Raji knockdown cell, there was a significant decrease in calcium influx in the knockdown cells when compared to the wild type cells. This demonstrates that HPRT had a significant impact on overall cell activation and the ability of the cells to properly influx calcium needed for their activation.ConclusionsWe conclude that purine levels significantly reduce immune cell activation in cancer and the upregulation of HPRT in malignant tissue is a contributing factors to the immunosuppressive microenvironment.     

Impact of chemokine receptor CXCR3 on tumor-infiltrating lymphocyte recruitment associated with favorable prognosis in advanced gastric cancer

Chemokine receptor CXCR3 has been proved to play an important role in tumorigenesis and tumor progression in many malignancies, but its precise efficacy on gastric cancer (GC) has not been evaluated yet. The present study was aimed to explore the correlation of chemokine receptor CXCR3 with tumor-infiltrating lymphocytes (TILs) and prognosis in advanced gastric cancer (GC). Expression of CXCR3 and CD4+, CD8+ TILs was conducted in 192 advanced GC specimens and 48 corresponding paracancerous tissues by immunohistochemical (IHC) analysis. CXCR3 expression in GC tissues was significantly higher than that in paracancerous tissues (P<0.001) and CD8+, CD4+ TILs infiltration increased with high CXCR3 expression (P=0.032 and P<0.001, respectively). Our study showed significantly lower CXCR3 expression in patients with greater tumor invasion depth and lymph node metastasis compared with patients with lesser tumor invasion depth and without lymph node metastasis (P=0.002 and P=0.001, respectively). Univariate analysis indicated that patients with high CXCR3 expression and high CD8+ TILs infiltration had longer overall survival (OS) (log-rank test, P<0.001 and P=0.002, respectively). Univariate and multivariate analyses indicated that CXCR3 expression was an independent prognostic factor for OS (P=0.002). The present study suggested that CXCR3 expression was upregulated in advanced GC and was associated with increased CD4+, CD8+ TILs infiltration and improved OS. Therefore, CXCR3 overexpression is implicated as a favorable prognostic biomarker in human advanced GC.     

T-cell specific upregulation of Sema4A as risk factor for autoimmunity in systemic lupus erythematosus and rheumatoid arthritis

Abstract

The aim of the present study was to evaluate the impact of SEMA4A genetic variants on expression of sema4A protein and its relation to autoimmunity development in Systemic Lupus Erythematosus and Rheumatoid Arthritis patients. A total of 541 SLE patients, 390 RA patients and 607 healthy individuals were genotyped. We also assessed SEMA4A mRNA expression from whole blood cells and the in vitro protein production from resting and activated T lymphocytes as well as mature dendritic cells from healthy individuals stratified according to their genotypes for SLE/RA associated SEMA4A variants. Our results showed that T/T genotype for rs3738581 SNP is associated with both RA and SLE development (p?=?.000053, OR = 2.35; p?=?.0019, OR = 2.07, respectively; statistical power = 100%) and also to an increased in vitro sema4A production in active T lymphocytes. Our findings are indicative of a T cell-specific upregulation of sema4A in the presence of T/T genotype, being a risk factor for SLE and RA.     

Alteration of liver immunity by increasing inflammatory response during co-administration of methamphetamine and atazanavir

Abstract

Objective: Use of methamphetamine (METH) is prevalent among HIV-infected individuals. Previous research has shown that both METH and HIV protease inhibitors exert influences on mitochondrial respiratory metabolism and hepatic nervous system. This study aims to study the joint effect of METH and HIV protease inhibitors on hepatic immune function.

Materials and methods: Based on the differentially expressed genes obtained from RNA-seq of the liver from mouse model, the expression levels of CD48 and Macrophage Receptor with Collagenous Structure (MARCO) were examined using qRT-PCR and flow cytometry, and the expression and secretion of cytokines IL-1β, IL-6, IL-8, IL-10, IFN-γ, IFN-β, and TNF-α were determined using qRT-PCR and ELISA in THP-1-derived macrophages.

Results: Our results indicated that compared with the control group, CD48 molecules were significantly down-regulated by METH–atazanavir co-treatment, and the expression level of CD48 decreased as METH concentration increases. MARCO molecules were increased, especially at larger doses of METH and atazanavir treatment. In addition, in the presence of METH–atazanavir, the expression and secretion of a series of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-8 increased while the expression and secretion of anti-inflammatory cytokine IL-10 decreased.

Conclusion: These results demonstrated that METH and atazanavir had a combined impact on the liver immunity, suggesting that the co-treatment could enhance inflammatory response and suppress NK cell activation via CD48.     

The CD151-midkine pathway regulates the immune microenvironment in inflammatory breast cancer

The immune microenvironment in inflammatory breast cancer (IBC) is poorly characterised, and molecular and cellular pathways that control accumulation of various immune cells in IBC tissues remain largely unknown. Here, we discovered a novel pathway linking the expression of the tetraspanin protein CD151 in tumour cells with increased accumulation of macrophages in cancerous tissues. It is notable that elevated expression of CD151 and a higher number of tumour-infiltrating macrophages correlated with better patient responses to chemotherapy. Accordingly, CD151-expressing IBC xenografts were characterised by the increased infiltration of macrophages. In vitro migration experiments demonstrated that CD151 stimulates the chemoattractive potential of IBC cells for monocytes via mechanisms involving midkine (a heparin-binding growth factor), integrin α6β1, and production of extracellular vesicles (EVs). Profiling of chemokines secreted by IBC cells demonstrated that CD151 increases production of midkine. Purified midkine specifically stimulated migration of monocytes, but not other immune cells. Further experiments demonstrated that the chemoattractive potential of IBC-derived EVs is blocked by anti-midkine antibodies. These results demonstrate for the first time that changes in the expression of a tetraspanin protein by tumour cells can affect the formation of the immune microenvironment by modulating recruitment of effector cells to cancerous tissues. Therefore, a CD151-midkine pathway can be considered as a novel target for controlled changes of the immune landscape in IBC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Intranasal immunization with plasmid DNA encoding spike protein of SARS-coronavirus/polyethylenimine nanoparticles elicits antigen-specific humoral and cellular immune responses

Background

The expression of metallothionein (MT) is involved in acquiring resistance to immune-mediated apoptosis; it is also a negative regulator of the immune response. Nasal polyps are typified by a resistance to immune-mediated apoptosis as well as by excessive immune cell infiltration. RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) is a membrane protein capable of inducing the apoptosis of CTLs and NK cells. The aim of the present study has been to explore the expression of metallothionein with respect to immune cell presence and immune cell activity. In our study, we identified immune cells using CD4 and CD68 antigen expression and evaluated their activity using CD25 antigen expression. We then analyzed metallothionein, RCAS1, CD25, CD4, and CD68 in a sampling of 50 nasal polyps using the immunohistochemistry method. We were able to divide the nasal polyps into three main groups according to their predominant immune cell infiltration: eosinophilic nasal polyps (21 cases), lymphocytic nasal polyps (17 cases), and neutrophilic nasal polyps (12 cases).

Results

In the present study, statistically significant differences between the MT expression in the epithelium and that in the stroma of the nasal polyps along with the accompanying alterations in activation markers on immune cells were found and the number of macrophages in both the eosinophilic and the lymphocytic nasal polyps was assessed. RCAS1-expressing macrophages were found only in the eosinophilic nasal polyps.

Conclusion

MT expression seems to favor the survival of nasal polyp epithelial cells in the adjacent area of increasingly cytotoxic immune activity. RCAS1-expressing macrophages seem to participate in creating the immune suppressive microenvironment and so help to sustain local inflammation.     

Distribution of tumor-infiltrating dendritic cells in human non-small cell lung carcinoma in relation to apoptosis

Host defense mechanisms play important roles in suppressing the development and growth of tumors. It is known that S‐100 protein‐positive immature dendritic cells (S100DC), as antigen presenting cells (APC), and macrophages have roles in the immune responses to tumor growth. Mediators such as nitric oxide are also important in the surveillance against cancer. We examined the distribution of S100DC and CD68‐positive macrophages (CD68MØ) immunohistochemically to compare the condition of apoptotic tumor cells in 69 patients with human non‐small cell lung carcinoma. The expression of inducible nitric oxide synthases (iNOS) in tumors was also studied. Unlike macrophages, S100DC were distributed predominantly in cancer nests. In the areas with infiltration of ‘many’ S100DC (i.e. more than 10 DC/HPF), we found two distinct patterns of tumor infiltration: scattered and aggregated infiltration of DC in tumor nests. In areas of scattered S100DC distribution, only a few apoptotic tumor cells could be detected. However, in the areas of DC aggregations, apoptotic tumor cells were significantly more abundant (P = 0.0491). In contrast to S100DC, the distribution and density of CD68MØ were associated with iNOS expression of tumor cells (P < 0.0001), but not with distribution of apoptotic tumor cells. These findings reveal differences in the in vivo condition between S100DC and CD68MØ in tumors, and suggest there is a relationship between tumor‐infiltrating S100DC aggregation and apoptosis in in vivo non‐small cell lung cancers.     

Switched phenotypes of macrophages during the different stages of Schistosoma japonicum infection influenced the subsequent trends of immune responses

BackgroundMacrophages play crucial roles in immune responses during the course of schistosomal infections.MethodsWe currently investigated influence of immunocompetent changes in macrophages via microarray-based analysis, mRNA expression analysis, detection of serum cytokines, and subsequent evaluation of the immune phenotypes following the differentiation of infection-induced lymphocytes in a unique T1/T2 double-transgenic mouse model.ResultsThe gradual upregulation of genes encoding YM1, YM2, and interleukin (IL)-4/IL-13 receptors in infected mice indicated the role of type 2 alternatively activated macrophages (M2, AAMφs) in immune responses after Schistosoma japonicum egg production. FACS analysis showed that surface markers MHC class II (IA/IE) and CD8α⁺ of the macrophages also exhibited a dramatic change at the various time points before and after egg-production. The transgenic mouse experiments further demonstrated that the shifting of macrophage phenotypes influenced the percentage of helper T (Th)-2 cells, which was observed to be higher than that of Th1 cells, which increased only at 3 and 5 weeks post-infection. The differentiation of effector B cells showed a similar but more significant trend toward type-2 immunity.ConclusionThese results suggest that the infection of mice with S. japonicum resulted in a final Th2- and Be2-skewed immune response. This may be due to phenotypic changes in the macrophages. The influence of alternatively activated macrophages was also activated by S. japonicum egg production. This study elucidated the existence of variations in immune mechanisms at the schistosome infection stages.