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The skin is permanently exposed to physical, chemical, and biological aggression by the environment. In addition, acute and chronic inflammatory events taking place in the skin are accompanied by abnormal release of pro-oxidative mediators. In this paper, we will briefly overview the homeostatic systems active in the skin to maintain the redox balance and also to counteract abnormal oxidative stress. We will concentrate on the evidence that a local and/or systemic redox dysregulation accompanies the chronic inflammatory disorder events associated to psoriasis, contact dermatitis, and atopic dermatitis. We will also discuss the fact that several well-established treatments for the therapy of chronic inflammatory skin disorders are based on the application of strong physical or chemical oxidants onto the skin, indicating that, in selected conditions, a further increase of the oxidative imbalance may lead to a beneficial outcome. [ABSTRACT FROM AUTHOR]

Regulatory T cells play an important role in the progression of atherosclerosis. GARP is a newly biological membrane molecule existed on activated Tregs, which is related to the release of TGF-β. The antiatherosclerosis effects of statins partly depend on their multiple immune modulatory potencies. In this paper, we present that atorvastatin could upregulate the expression of GARP and TGF-β in CD4+ T cells and increase the numbers of CD4+LAP+ and CD4+Foxp3+ regulatory T cells in ApoE−/− mice. Also, we indicate that atorvastatin promotes the aggregation of GARP+ and Foxp3+ cells and secretory of the TGF-β1 in atherosclerotic plaques. Furthermore, we prove that atorvastatin could delay the procession of atherosclerosis and improve the stability of atherosclerotic plaques. Interestingly, we report that inhibition of GARP distinctly inhibits the anti-inflammatory effects of atorvastatin. We conclude that atorvastatin improves the inflammatory response in atherosclerosis partly by upregulating the expression of GARP on regulatory T cells. [ABSTRACT FROM AUTHOR]

Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and affects ca. 10 million people worldwide. About 30% of Chagas disease patients develop chronic Chagas disease cardiomyopathy (CCC), a particularly lethal inflammatory cardiomyopathy that occurs decades after the initial infection, while most patients remain asymptomatic. Mortality rate is higher than that of noninflammatory cardiomyopathy. CCC heart lesions present a Th1 T-cell-rich myocarditis, with cardiomyocyte hypertrophy and prominent fibrosis. Data suggest that the myocarditis plays a major pathogenetic role in disease progression. Major unmet goals include the thorough understanding of disease pathogenesis and therapeutic targets and identification of prognostic genetic factors. Chagas disease thus remains a neglected disease, with no vaccines or antiparasitic drugs proven efficient in chronically infected adults, when most patients are diagnosed. Both familial aggregation of CCC cases and the fact that only 30%of infected patients develop CCC suggest there might be a genetic component to disease susceptibility.Moreover, previous case-control studies have identified some genes associated to human susceptibility to CCC. In this paper,wewill reviewthe immunopathogenesis and genetics of Chagas disease, highlighting studies that shed light on the differential progression of Chagas disease patients to CCC. [ABSTRACT FROM AUTHOR]

To date, Kawasaki disease (KD) has only been able to be diagnosed and evaluated using clinical characteristics. Additionally, the therapeutic effect and cardiovascular complications could not be verified until its occurrence. The present retrospective study analyzed the dynamic alterations of inflammatory cytokines, platelet (PLT) count, and subgroups of lymphocytes, such as cluster of differentiation (CD) 8+ T cells and CD19+ B cells, under different conditions in 64 children with KD. The percentage distribution of lymphocyte subgroups and the altered neutrophil lymphocyte ratio demonstrated that the inflammatory response was dominated by the B cell-mediated humoral immune response before intravenous immunoglobulin (IVIG) treatment, but mainly by T cells via cellular cytotoxic effects after IVIG treatment. Among the different types of inflammatory cytokines, the results of the present study revealed that the altered levels of interleukin-2 receptor (IL-2R) and interleukin-10 (IL-10) were closely associated with the percentage of CD8+ T cells and CD19+ B cells. Additionally, the two cytokines exhibited more sensitive fluctuations based on the status of the children with KD in various circumstances compared with other indexes, such as the percentages of CD8+ T cells and CD19+ B cells or the PLT count. These results suggested that children with KD who are ≥4 years old may benefit from IVIG but will not benefit from decreased platelet activation or suffer less cardiovascular complications. Additionally, starting clopidogrel usage earlier as an antiplatelet strategy should be considered based on the observed continuous rise in the PLT count in children with KD receiving IVIG. In conclusion, dynamically monitoring the levels of IL-2R and IL-10 has the potential to provide indications of the intensity and development of the inflammatory response in children with KD and may contribute to the early prediction and adjustment of pathological and pharmacological effects of therapy. [ABSTRACT FROM AUTHOR]

Statins are pharmacological inhibitors of the activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), an enzyme responsible for the synthesis of cholesterol. Some recent experimental studies have shown that besides their effects on the primary and secondary prevention of cardiovascular diseases, statins may also have beneficial anti-inflammatory effects through diverse mechanisms. On the other hand, the induction and activity of regulatory T cells (Treg) are key processes in the prevention of pathology during chronic inflammatory and autoimmune diseases. Hence, strategies oriented towards the therapeutic expansion of Tregs are gaining special attention among biomedical researchers. The potential effects of statins on the biology of Treg are of particular importance because of their eventual application as in vivo inducers of Treg in the treatment of multiple conditions. In this paper we review the experimental evidence pointing out to a potential effect of statins on the role of regulatory T cells in different conditions and discuss its potential clinical significance. [ABSTRACT FROM AUTHOR]

Exosomes are membrane-bound extracellular vesicles that are produced in the endosomal compartment of most eukaryotic cells. Containing proteins, RNA, and DNA, exosomes mediate intercellular communication between different cell types by transferring their contents and thus are involved in numerous physiological and pathological processes. T cells are an indispensable part of adaptive immunity, and the functions of T cell-derived exosomes have been widely studied. In the more than three decades since the discovery of exosomes, several studies have revealed that T cell-derived exosomes play a novel role in cell-to-cell signaling, especially in inflammatory responses, autoimmunity, and infectious diseases. In this review, we will summarize the function of T cell-derived exosomes and their therapeutic potential. [ABSTRACT FROM AUTHOR]

A TP II analogue, [l-Nal[sup 3] ] TP II, was synthesized by a conventional solution method, followed by deprotection with 1M TFMSA-thioanisole (molar ratio 1:1) in TFA in the presence of Me[sub 2] Se and m-cresol as scavengers. The synthetic [l-Nal[sup 3] ] TP II, TP II and [Phe (4 F)[sup 3] ] TP II were tested for comparative effect on the impaired T-lymphocyte transformation by PHA in uremic patients suffering from recurrent infectious diseases. The synthetic analogue was found to have stronger restorative activity than those of our synthetic TP II and [Phe (4 F)[sup 3] ] TP II. [ABSTRACT FROM AUTHOR]

Psoriasis is a common immune-mediated, chronic inflammatory genetic-related disease that affects patients' quality of life. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of progenitor and immature myeloid cells which are expanded in psoriatic skin lesions and peripheral blood. However, the role of MDSCs in the pathogenesis of psoriasis remains unclear. Here, we confirmed that the accumulation of human MDSCs is remarkably increased in skin lesions of psoriasis patients by flow cytometry. Depleting MDSCs by Gemcitabine significantly suppresses IMQ-induced psoriatic inflammation and epidermal thickening as well as Th17 and Treg cell accumulation. Moreover, through the RNA-Seq technique, we validated some differentially expressed genes on CD4+ T-cells of IMQ-induced-MDSC-depleted mice such as IL-21 and Timd2, which are involved in Th17-cell differentiation or T-cell activation. Interestingly, neutralizing IL-21R by antibody reduces IMQ-induced epidermal thickening through downregulating the infiltration of MDSCs and Th17 cells. Our data suggest that targeting myeloid-derived suppressor cells is a novel strategy for antipsoriasis therapy. IL-21 may be a potential therapeutic target in psoriasis. [ABSTRACT FROM AUTHOR]

Background. Sarcoidosis and hypersensitivity pneumonitis (HP) are immunologically mediated processes caused by hypersensitivity reaction accompanied by similar features including lymphocytic alveolitis and granuloma formation. Recent studies describe the role of TREM receptors in T cell activation, differentiation, and granuloma formation. Alveolar macrophages activation via TREM receptors may be the key factor mediating subsequent immune response. The aim of the study was to analyse TREM-1 and TREM-2 expression to identify further molecular mechanisms participating in the immunopathogenesis of sarcoidosis and HP. Methods. Flow cytometry was performed to analyse TREM-1 and TREM-2 expression on CD14+ cells in bronchoalveolar lavage fluid from patients having sarcoidosis or HP and a control group. Results. The study proved increased TREM-1 expression on alveolar macrophages in pulmonary sarcoidosis and diminished TREM-1 expression in HP-Sarcoidosis: median: 76.7; HP: median: 29.9; control: median: 53.3, (sarcoidosis versus HP: p < 0.001 ; sarcoidosis versus control: p < 0.05). TREM-2 expression was increased in both, sarcoidosis and HP-sarcoidosis: median: 34.79; HP: median: 36.00; control: median: 12.98, (sarcoidosis versus control: p < 0.05 ; HP versus control: p < 0.05). Correlation analysis showed negative correlation between TREM-1 and total number of CD8+ cytotoxic T cells. In sarcoidosis TREM-1 expression decreased with changes of HRCT image, decrease in CD4/CD8 ratio and decrease in DLCO. Conclusions. Differences in TREM receptor expression in sarcoidosis (increase in TREM-1 and TREM-2) and HP (increase in TREM-2) and correlation analysis suggests that activation via TREM may participate in typical immunological characteristics of sarcoidosis and HP. [ABSTRACT FROM AUTHOR]

The transcription factor Bach2 which is predominantly expressed in B and T lymphocytes represses the expression of genes by forming heterodimers with small Maf and Batf proteins and binding to the corresponding sequence on the DNA. In this way, Bach2 serves as a highly conserved repressor which controls the terminal differentiation and maturation of both B and T lymphocytes. It is required for class switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes in activated B cells, and its function in B cell differentiation has been well-described. Furthermore, emerging data show that Bach2 regulates transcriptional activity in T cells at super enhancers or regions of high transcriptional activity, thus stabilizing immunoregulatory capacity and maintaining T cell homeostasis. Bach2 is also critical for the formation and function of CD4+ T cell lineages (Th1, Th2, Th9, Th17, T follicular helper (Tfh), and regulatory T (Treg) cells). Genetic variations within Bach2 locus are associated with numerous immune-mediated diseases including multiple sclerosis (MS), rheumatoid arthritis (RA), chronic pancreatitis (CP), type 2 chronic airway inflammation, inflammatory bowel disease (IBD), and type 1 diabetes. Here, we reveal a critical role of Bach2 in regulating T cell biology and the correlation with these immune-mediated diseases. [ABSTRACT FROM AUTHOR]

Background. Interleukin-37 (IL-37) acts as an inhibitor of innate and adaptive immunity. However, the exact role of IL-37 in the patients with acute coronary syndrome (ACS) remains to be elucidated. Methods. Patients were classified into 4 groups: normal coronary artery (NCA), stable angina (SA), unstable angina (UA), and acute myocardial infarction (AMI). The circulating Treg, Th1, and Th17 frequencies were measured. The effect of IL-37 on stimulated peripheral blood mononuclear cells (PBMCs) and the influence of IL-37 on DCs were explored. In addition, the role of IL-37-treated tDCs on Treg cell expansion and the stability of these tDCs were also tested. Results. Our results showed that the circulating Treg frequencies were decreased, while Th1 and Th17 frequencies were increased in ACS patients, and that IL-37 expanded Tregs but suppressed Th1 and Th17 cells in activated PBMCs derived from ACS patients. Of note, IL-37-treated human DCs obtained a tolerogenic phenotype, and such tDCs promoted expansion of Tregs and decreased the Th1 and Th17 populations when cocultured with CD4+ T cells. Interestingly, IL-37-treated DCs from patients with ACS are phenotypically and functionally comparable to IL-37-treated DCs from NCA patients, and tolerogenic properties of IL-37-treated DCs were highly stable. Conclusion. In conclusion, our results reveal a beneficial role of IL-37 in the patients with ACS and suggest that autologous IL-37-treated tDCs may be a novel therapeutic strategy for the patients with ACS. [ABSTRACT FROM AUTHOR]

Colitis-associated colorectal cancer (CRC) development has been shown to be related to chronically enhanced inflammation. Macrophage migration inhibitory factor (MIF) is an inflammatory mediator that favors inflammatory cytokine production and has chemotactic properties for the recruitment of macrophages (Møs) and T cells. Here, we investigated the role of MIF in the inflammatory response and recruitment of immune cells in a murine model of chemical carcinogenesis to establish the impact of MIF on CRC genesis and malignancy. We used BALB/c MIF-knockout (MIF-/-) and wild-type (WT) mice to develop CRC by administering intraperitoneal (i.p.) azoxymethane and dextran sodium sulfate in drinking water. Greater tumor burdens were observed in MIF-/- mice than in WT mice. Tumors from MIF-/- mice were histologically identified to be more aggressive than tumors from WT mice. The localization of MIF suggests that it is also involved in cell differentiation. The relative gene expression of il-17, measured by real-time PCR, was higher in MIF-/- CRC mice, compared to the WT CRC and healthy MIF-/- mice. Importantly, compared to the WT intestinal epithelium, lower percentages of tumor-associated Møs were found in the MIF-/- intestinal epithelium. These results suggest that MIF plays a role in controlling the initial development of CRC by attracting Møs to the tumor, which is a condition that favors the initial antitumor responses. [ABSTRACT FROM AUTHOR]

To investigate the effect of ILC2s on Th2-type adaptive immunity during the acute exacerbation of chronic obstructive pulmonary disease (AECOPD), the study enrolled healthy people, stable COPD patients, and AECOPD patients. Flow cytometry was used to detect Th1, Th2, and ILC2 in the peripheral blood and CD80 and MHC II levels on ILC2. The mRNA levels of GATA3, RORα, and CRTH2 of ILC2s were detected by RT-PCR. In addition, ILC2s from the peripheral blood of AECOPD patients were cocultured with CD4+ T cells from the peripheral blood of healthy controls. Cytokine levels in serum of the three groups and the in vitro coculture supernatants were measured by ELISA. Compared with the stable COPD group or the healthy control group, Th2 in the peripheral blood of AECOPD group increased dramatically, inducing an increase of Th2/Th1 ratio in AECOPD patients. Meanwhile, the level of IL-4 in the serum of this group was also increased. However, we also detected ILC2s in the peripheral blood of the AECOPD group and found that it was also increased, alone with the increased GATA3, RORα, and CRTH2 mRNA levels. We also found that the CD80 and MHC II on ILC2 were significantly upregulated and the proportion of MHC II+ ILC2 cells was significantly positively correlated with the proportion of Th2 cells in AECOPD patients. To further demonstrate the effect of ILC2 on Th2 cells, we cocultured ILC2 with CD4+ T cells in vitro, which also showed a significant increase of Th2 ratio as well as Th2-associated cytokines IL-4, IL-5, and IL-13. However, we found that this effect of ILC2s on Th2 cells could be inhibited by the addition of anti-MHC II. The Th2/Th1 balance shifts to Th2 in AECOPD. ILC2s may function as APC by the upregulation of MHC II and regulate adaptive immunity shift to Th2-type response in AECOPD. [ABSTRACT FROM AUTHOR]

This study is to investigate the role of regulatory B (Breg) cells in cervical cancer. In total, 70 cases of cervical cancer, 52 cases of cervical intraepithelial neoplasia (CIN), and 40 normal controls were enrolled. The percentage of Breg cells was detected by flow cytometry. Serum levels of IL-10 were measured by ELISA. The correlation between Breg cells and the clinical characterizations of cervical cancer was analyzed. The inhibition effect of Breg cells on CD8+ T cells was tested by blocking IL-10 in vitro. The percentage of CD19+CD5+CD1d+ Breg cells and the level of IL-10 of patients with cervical cancer or CIN were significantly higher than those in the control group (P<0.05). And the postoperative levels of Breg cells and IL-10 were significantly lower than the preoperative levels (P<0.05). Breg cells and the IL-10 level were positively correlated in cervical cancer patients (r=0.516). In addition, the Breg cell percentage was closely related to the FIGO stages, lymph node metastasis, tumor differentiation, HPV infection, and the tumor metastasis of cervical cancer (P<0.05). The Breg cell percentage was negatively correlated with CD8+ T cells of cervical cancer patients (r=‐0.669). The level of IL-10 in the culture supernatant of Bregs treated with CpG was significantly higher than that of non-Bregs (P<0.05). After coculture with Bregs, the quantity of CD8+ T cells to secrete perforin and Granzyme B was significantly decreased, and this effect was reversed after blocking IL-10 by a specific antibody. Breg cells are elevated in cervical cancer and associated with disease progression and metastasis. Moreover, they can inhibit the cytotoxicity of CD8+ T cells. [ABSTRACT FROM AUTHOR]

BCG, the only registered vaccine against Mycobacterial Tuberculosis (TB) infection, has been questioned for its protective efficacy for decades. Although lots of efforts were made to improve the BCG antigenicity, few studies were devoted to understand the role of host factors in the variability of the BCG protection. Using the IL-10KO mice and pulmonary tuberculosis infection model, we have addressed the role of IL-10 in the BCG vaccination efficacy. The data showed that IL-10-deficient dendritic cells (DCs) could promote the immune responses through upregulation of the surface costimulatory molecule expression and play an orchestra role through activating CD4+T cell. IL-10-deficient mice had higher IFN γ, TNF α, and IL-6 production after BCG vaccination, which was consistent with the higher proportion of IFN γ+CD3+, IFN γ+CD4+, and IFN γ+CD8+ T cells in the spleen. Particularly, the BCG-vaccinated IL-10KO mice showed less inflammation after TB challenge compared to WT mice, which was supported by the promoted Th1 and Tc, as well as the downregulated Treg responses in IL-10 deficiency. In a conclusion, we demonstrated the negative relationship between Th1/Tc responses with IL-10 production. IL-10 deficiency restored the type 1 immune response through DC activation, which provided better protection against TB infection. Hence, our study offers the first experimental evidence that, contrary to the modulation of BCG, host immunity plays a critical role in the BCG protective efficacy against TB. [ABSTRACT FROM AUTHOR]

Apoptosis of CD4+ T cells plays a central role in the progression of sepsis because it is associated with subsequent immunosuppression and the lack of specific treatment. Thus, developing therapeutic strategies to attenuate the apoptosis of CD4+ T cells in sepsis is critical. Several studies have demonstrated that Mdivi-1, which is a selective inhibitor of the dynamin-related protein 1 (Drp1), attenuates apoptosis of myocardial cells and neurons during various pathologic states. The present study revealed the impact of Mdivi-1 on the apoptosis of CD4+ T cells in sepsis and the potential underlying mechanisms. We used lipopolysaccharide (LPS) stimulation and cecal ligation and puncture (CLP) surgery as sepsis models in vitro and in vivo, respectively. Our results showed that Mdivi-1 attenuated the apoptosis of CD4+ T cells both in vitro and in vivo. The potential mechanism underlying the protective effect of Mdivi-1 involved Mdivi-1 reestablishing mitochondrial fusion-fission balance in sepsis, as reflected by the expression of the mitofusin 2 (MFN2) and optic atrophy 1 (OPA1) , Drp1 translocation, and mitochondrial morphology, as observed by electron microscopy. Moreover, Mdivi-1 treatment reduced reactive oxygen species (ROS) production and prevented the induction of endoplasmic reticulum stress (ERS) and associated apoptosis. After using tunicamycin to activate ER stress, the protective effect of Mdivi-1 on CD4+ T cells was reversed. Our results suggested that Mdivi-1 ameliorated apoptosis in CD4+ T cells by reestablishing mitochondrial fusion-fission balance and preventing the induction of endoplasmic reticulum stress in experimental sepsis. [ABSTRACT FROM AUTHOR]

Objective. Ischemia-reperfusion injury (IRI) produces systemic inflammation with the potential for causing organ failure in tissues peripheral to the initial site of injury. We speculate that treatment strategies that dampen inflammation may be therapeutically beneficial to either the initial site of injury or peripheral organs. To test this, we evaluated the impact of FTY720-induced sequestration of circulating mature lymphocytes on renal IRI and secondary organ injury. Methods. A microvascular clamp was surgically placed around the left renal pedicle of anesthetized male Sprague-Dawley rats with either vehicle or FTY720 treatment (0.3 mg/kg) intravenously injected after 15 min of ischemia. Blood flow was restored after 60 min. Cohorts of anesthetized rats were euthanized at 6, 24, or 72 hrs with tissue samples collected for analysis. Results. FTY720 treatment resulted in profound T lymphocyte reduction in peripheral blood. Histopathologic examination, clinical chemistries, and gene transcript expression measurements revealed that FTY720 treatment reduced hepatocellular degeneration, reduced serum markers of liver injury (ALT/AST), and reduced the expression of gene targets associated with IRI. Conclusion. These findings support an anti-inflammatory effect of FTY720 in the liver where the expression of genes associated with apoptosis, chemotaxis, and the AP-1 transcription factor was reduced. Findings presented here provide the basis for future studies evaluating FTY720 as a potential therapeutic agent to treat complications resulting from renal IRI. [ABSTRACT FROM AUTHOR]

Neutrophils are the most abundant leukocytes in peripheral blood and respond rapidly to danger, infiltrating tissues within minutes of infectious or sterile injury. Neutrophils were long thought of as simple killers, but now we recognise them as responsive cells able to adapt to inflammation and orchestrate subsequent events with some sophistication. Here, we discuss how these rapid responders release mediators which influence later adaptive T cell immunity through influences on DC priming and directly on the T cells themselves. We consider how the release of granule contents by neutrophils—through NETosis or degranulation—is one way in which the innate immune system directs the phenotype of the adaptive immune response. [ABSTRACT FROM AUTHOR]

Background. Although glucagon-like peptide 1- (GLP-1-) based therapy of hyperglycemia in burn injury has shown great potential in clinical trials, its safety is seldom evaluated. We hypothesize that exendin-4, a GLP-1 analogue, might affect the immune response via the activation of the sympathetic nervous system in burn injury. Methods. Male Balb/c mice were subjected to sham or thermal injury of 15% total body surface area. Exendin-4 on T cell function in vitro was examined in cultured splenocytes in the presence of β-adrenoceptor antagonist propranolol (1 nmol/L) or GLP-1R antagonist exendin (9-39) (1 μmol/L), whereas its in vivo effect was determined by i.p. injection of exendin-4 (2.4 nmol/kg) in mice. To further elucidate the sympathetic mechanism, propranolol (30 mg/kg) or vehicle was applied 30 min prior to injury. Results. Although the exacerbated burn-induced mortality by exendin-4 was worsened by propranolol pretreatment, the inhibition of T cell proliferation by exendin-4 in vitro could be restored by propranolol instead of exendin (9-39). However, a Th2 switch by exendin-4 in vitro could only be reversed by exendin (9-39). Likewise, the inhibition of splenic T cell function and NFAT activity by exendin-4 in vivo was restored by propranolol. By contrast, the increased splenic NF-κB translocation by exendin-4 in vivo was potentiated by propranolol in sham mice but suppressed in burn mice. Accordingly, propranolol abrogated the heightened inflammatory response in the lung and the accelerated organ injuries by exendin-4 in burn mice. On the contrary, a Th2 switch and higher serum levels of inflammatory mediators by exendin-4 were potentiated by propranolol in burn mice. Lastly, exendin-4 raised serum stress hormones which could be remarkably augmented by propranolol. Conclusions. Exendin-4 suppresses T cell function and promotes organ inflammation through the activation of the sympathetic nervous system, while elicits Th2 switch via GLP-1R in burn injury. [ABSTRACT FROM AUTHOR]

The development of an acidic tissue environment is a hallmark of a variety of inflammatory processes and solid tumors. However, little attention has been paid so far to analyze the influence exerted by extracellular pH on the immune response. Tissue acidosis (pH 6.0 to 7.0) is usually associated with the course of infectious processes in peripheral tissues. Moreover, it represents a prominent feature of solid tumors. In fact, values of pH ranging from 5.7 to 7.0 are usually found in a number of solid tumors such as breast cancer, brain tumors, sarcomas, malignant melanoma, squamous cell carcinomas, and adenocarcinomas. Both the innate and adaptive arms of the immune response appear to be finely regulated by extracellular acidosis in the range of pH values found at inflammatory sites and tumors. Low pH has been shown to delay neutrophil apoptosis, promoting their differentiation into a proangiogenic profile. Acting on monocytes and macrophages, it induces the activation of the inflammasome and the production of IL-1β, while the exposure of conventional dendritic cells to low pH promotes the acquisition of a mature phenotype. Overall, these observations suggest that high concentrations of protons could be recognized by innate immune cells as a danger-associated molecular pattern (DAMP). On the other hand, by acting on T lymphocytes, low pH has been shown to suppress the cytotoxic response mediated by CD8+ T cells as well as the production of IFN-γ by TH1 cells. Interestingly, modulation of tumor microenvironment acidity has been shown to be able not only to reverse anergy in human and mouse tumor-infiltrating T lymphocytes but also to improve the antitumor immune response induced by checkpoint inhibitors. Here, we provide an integrated view of the influence exerted by low pH on immune cells and discuss its implications in the immune response against infectious agents and tumor cells. [ABSTRACT FROM AUTHOR]

Background. The mediators produced by CD4+ T lymphocytes are involved in the pathogenesis of aneurysmal lesions in abdominal aortic aneurysm (AAA) patients. The aim of this study was to identify and characterize the CD4+ T cell subsets involved in human AAA. Methods. The CD4+ T cell subsets in 30 human aneurysmal lesions were determined using flow cytometry (FC) and immunohistochemistry (IHC). The peripheral blood mononuclear cells (PBMCs) from patients with AAA were also analyzed by FC and compared with control subjects. Results. Human aneurysmal lesions contained IFN-γ, IL-12p35, IL-4, IL-23p19, IL-17R, and IL-22 positive cells. PBMCs from AAA patients had higher expression levels of IFN-γ, TNF-α, IL-4, and IL-22 when compared to controls. Conclusions. Our results show the presence of TH1, TH2, TH17, and TH22 subsets in aneurysmal lesions of AAA patients and suggest that these cells may be mainly activated in situ, where they can induce tissue degradation and contribute to the pathogenesis of AAA. [ABSTRACT FROM AUTHOR]

We aim to investigate the effects of Tim-3 and programmed cell death-1 (PD-1) on the monocytes and T lymphocytes in septic patients. Expression of Tim-3 and PD-1 on the CD3, CD4, and CD8 lymphocytes and monocytes was determined using flow cytometry. CBA technique was utilized to determine the expression of cytokines in the lymphocyte supernatant in addition to the IL-10 and TNF-α positivity in monocytes in the presence of Tim-3 and/or PD-1 receptor blockade. Compared with the normal control, significant elevation was observed in the expression of PD-1 on CD3 (P=0.004), CD4, and CD8 monocytes. Blockade of the Tim-3 signaling pathway contributed to the significant elevation of IL-10 and TNF-α in the supernatant of T lymphocytes in the septic patients, while the PD-1 signaling pathway blockade only triggered the obvious elevation of TNF-α in the T lymphocytes. Blockade of Tim-3 and PD-1 induced the positivity of IL-10- and TNF-α-expressing cells in the peripheral monocytes. Significant changes were noticed in the Tim-3 and PD-1 in the T lymphocytes and monocytes. Blockade of Tim-3 and PD-1 contributed to the function of lymphocytes and monocytes. In the septic process, Tim-3 and PD-1 played crucial roles in the immune response of T lymphocytes and monocytes. [ABSTRACT FROM AUTHOR]

Our previous studies showed that γδ T cells provided immune protection against Chlamydial muridarum (Cm), an obligate intracellular strain of chlamydia trachomatis, lung infection by producing abundant IL-17. In this study, we investigated the proliferation and activation of lung γδ T cell subsets, specifically the IL-17 and IFNγ production by them following Cm lung infection. Our results found that five γδ T cell subsets, Vγ1+ T, Vγ2+ T, Vγ4+ T, Vγ5+ T, and Vγ6+ T, expressed in lungs of naïve mice, while Cm lung infection mainly induced the proliferation and activation of Vγ4+ T cells at day 3 p.i., following Vγ1+ T cells at day 7 p.i. Cytokine detection showed that Cm lung infection induced IFNγ secretion firstly by Vγ4+ T cells at very early stage (day 3) and changed to Vγ1+ T cells at midstage (day 7). Furthermore, Vγ4+ T cell is the main γδ T cell subset that secretes IL-17 at the very early stage of Cm lung infection and Vγ1+ T cell did not secrete IL-17 during the infection. These findings provide in vivo evidence that Vγ4+T cells are the major IL-17 and IFNγ-producing γδ T cell subsets at the early period of Cm lung infection. [ABSTRACT FROM AUTHOR]

Systemic immune activation has emerged as an essential component of the immunopathogenesis of HIV. It not only leads to faster disease progression, but also to accelerated decline of overall immune competence. HIV-associated immune activation is characterized by an increase in proinflammatory mediators, dysfunctional T regulatory cells, and a pattern of T-cell-senescent phenotypes similar to those seen in the elderly. These changes predispose HIV-infected persons to comorbid conditions that have been linked to immunosenescence and inflamm-ageing, such as atherosclerosis and cardiovascular disease, neurodegeneration, and cancer. In the antiretroviral treatment era, development of such non-AIDS-defining, age-related comorbidities is a major cause of morbidity and mortality. Treatment strategies aimed at curtailing persistent immune activation and inflammation may help prevent the development of these conditions. At present, the most effective strategy appears to be early antiretroviral treatment initiation. No other treatment interventions have been found effective in large-scale clinical trials, and no adjunctive treatment is currently recommended in international HIV treatment guidelines. This article reviews the role of systemic immune activation in the immunopathogenesis of HIV infection, its causes and the clinical implications linked to immunosenescence in adults, and the therapeutic interventions that have been investigated. [ABSTRACT FROM AUTHOR]

T regulatory (Treg) cells have a key role in the pathogenesis of chronic inflammatory and autoimmune diseases. A CD4+CD69+ T cell subset has been described that behaves as Treg lymphocytes, exerting an important immune suppressive effect. In this study, we analyzed the levels and function of CD4+CD69+ Treg cells in patients with systemic lupus erythematosus (SLE). Blood samples were obtained from 22 patients with SLE and 25 healthy subjects. Levels of CD4+CD69+ Treg cells were analyzed by multiparametric flow cytometry, and their function was measured by an assay of suppression of lymphocyte activation and through the inhibition of cytokine synthesis. We found an increased percent of CD4+CD25varCD69+TGF-β+IL-10+Foxp3− lymphocytes in patients with SLE compared to controls. In addition, a significant diminution in the suppressive effect of these cells on the activation of autologous T lymphocytes was observed in most patients with SLE. Accordingly, CD69+ Treg cells from SLE patients showed a defective capability to inhibit the release of IL-2, IL-6, IL-10, and IL-17A by autologous lymphocytes. Our findings suggest that while CD4+CD69+ Treg lymphocyte levels are increased in SLE patients, these cells are apparently unable to contribute to the downmodulation of the autoimmune response and the tissue damage seen in this condition. [ABSTRACT FROM AUTHOR]

The immune system has long been thought to be involved in the pathophysiology of complex regional pain syndrome (CRPS). However, not much is known about the role of the immune system and specifically T-cells in the onset and maintenance of this disease. In this study, we aimed to evaluate T-cell activity in CRPS by comparing blood soluble interleukin-2 receptor (sIL-2R) levels between CRPS patients and healthy controls. CRPS patients had statistically significant elevated levels of sIL-2R as compared to healthy controls (median sIL-2R levels: 4151 pg/ml (Q3 − Q1 = 5731 pg/ml − 3546 pg/ml) versus 1907 pg/ml (Q3 − Q1: 2206 pg/ml − 1374 pg/ml), p<0.001, resp.). Furthermore, sIL-2R level seems to be a good discriminator between CRPS patients and healthy controls with a high sensitivity (90%) and specificity (89.5%). Our finding indicates increased T-cell activity in patients with CRPS. This finding is of considerable relevance as it could point towards a T-cell-mediated inflammatory process in this disease. This could pave the way for new anti-inflammatory therapies in the treatment of CRPS. Furthermore, sIL-2R could be a promising new marker for determining inflammatory disease activity in CRPS. [ABSTRACT FROM AUTHOR]

Adefovir dipivoxil treatment has significantly improved the outcome of chronic hepatitis B virus (HBV) infection. However, it remains largely unknown how immune system responds to the treatment. Chronic HBV patients were treated with adefovir dipivoxil and examined for serum HBV DNA loads, cytokines, and T helper (Th1) and 2 (Th2) cytokine producing T cells during 104 weeks of the treatment. Th1/Th2 cytokines producing T cells were significantly lower in chronic HBV patients as compared to normal individuals. Adefovir dipivoxil treatment led to the increase of Th1/Th2 cytokines producing T cells and serum cytokine levels in association with the decline of HVB DNA load. In contrast, Th1/Th2 cytokines producing T cells remained lower in one patient detected with adefovir dipivoxil resistant HBV A181T/V mutation. This study has established inverse correlation of the increase of Th1/Th2 immunity and the decline of HBV DNA load in chronic HBV patients during adefovir dipivoxil treatment. [ABSTRACT FROM AUTHOR]

Sepsis-induced diaphragmatic inflammation has been associated with respiratory failure, but the role of chemokines in this process has not been evaluated. Here we sought to study the local expression and molecular regulation of the chemokines, regulated upon activation normal T cell expressed and secreted (RANTES) and macrophage inflammatory protein (MIP)-1α, in the murine diaphragm during sepsis. Constitutive expression levels of RANTES and MIP-1α, as well as their receptors, CCR1 and CCR5, were significantly higher in diaphragm than limb muscle. Sepsis was induced by acute lipopolysaccharide (LPS) delivery or subacutely by intratracheal administration of live Pseudomonas aeruginosa bacteria. Both sepsis models triggered a marked upregulation of RANTES and MIP-1α in the diaphragm. In vitro, stimulation of diaphragmatic muscle cells with LPS also led to RANTES upregulation. Inhibition of the NF-kB pathway using pharmacologic or dominant negative genetic approaches blocked the LPS-induced RANTES upregulation, while free radical scavengers had no effect. We conclude that sepsis leads to greatly increased expression of RANTES, MIP-1α and their cognate receptors in the diaphragm. Manipulation of the NF-kB pathway and other regulators of chemokine expression in the diaphragm could represent a novel method for mitigating the skeletal muscle inflammatory response associated with sepsis-induced diaphragmatic dysfunction. [ABSTRACT FROM AUTHOR]

TOM1L (target of Myb-1 Like) was identified as a binding partner for the full length and catalytically-active Lck in a yeast 2-hybrid screening assay. Here we show that in Jurkat T cells stimulated by CD3/CD28 coligation where the expression of TOM1L is reduced by lenti virus mediated-siRNA results in a dramatically lower IL-2 production. The production of IL-2 in siRNA treated cells stimulated with PMA/ionomycin was not affected indicating an involvement of TOM1L in a pathway proximal of TCR and CD28. The coexpression of Fyn with TOM1L increased the level of the phosphorylated form of Fyn indicating that TOM1L has the ability to activate Fyn. The ability of TOM1L to activate Fyn was further shown in a kinase assay using angiotensin II as a substrate. By confocal microscopy, we show that the expression of TOM1L in non-treated HeLa and SK-N-SH cells colocalizes with the mitochondrial membrane but not with lysosomal compartments or the trans-Golgi network. Furthermore, we show that the over-expression of TOM1L in Jurkat cells causes an increase of the STAT3 expression. Based on our results, we here propose that TOM1L is involved in a novel signaling pathway that is important for the IL-2 production in T cells. [ABSTRACT FROM AUTHOR]

BACKGROUND: Endometriosis, uncontrolled proliferation of ectopic and eutopic endometriotic tissues, is common in women at reproductive age, and may affect fertility. The role of macrophages in the pathogenesis is well proved, but engagement of T cells in the pathogenesis of endometriosis is a matter of controversy Aims: T-cell involvement in the pathogenesis of endometriosis was the objective of our study performed on women aged 243/46 years with diagnosed endometriosis. All the patients that were studied underwent diagnostic laparoscopy. Methods: We evaluated the distribution of T-lymphocyte subpopulations in peripheral blood (PB), peritoneal fluid (PF) and in endometriotic tissues (ET), as well as cytokines [interleukin (IL)-2, IL-4, IL-10, IL-12, interferon (IFN)-γ] production by peripheral blood lymphocytes. IFN-γ, tumor necrosis factor (TNF)-α, IL-4 and IL-6 were investigated for their intracellular presence. The experiments were carried out before and after 6 months treatment with the GnRH-Analogous Goserelin (Zeneca Pharmaceuticals). The number of performed investigations is presented. Statistical analysis was performed using Statistica/ Win 5.0 software and Student's t-test, the paired Student t-test and Fisher's exact test when appropriate. Results: We have compared the lymphocyte subset re-distribution with regard to the American Fertility Society (AFS) stages and scores, but no differences were observed. The significant increase in CD4:CD8 ratio, the decrease in the number of natural killer (NK) cells in PB and the decrease in CD4:CD8 ratio in PF and ET of women with endometriosis was noted. The diminished IFN-γ secretion by phytohemagglutinim (PHA)-stimulated lymphocytes in vitro derived from women with endometriosis and increased IL-4 production may be responsible for defective immu-nosurveillance against overgrowth of endometriotic tissues. The diminished NK cells number in PB of women with endometriosis argues for such a... [ABSTRACT FROM AUTHOR]

AIMS: Annexin I (ANXA1), a 37 kDa member of the annexin family of Ca[sup 2+]-binding and phospholipidbinding proteins, is particularly abundant in various populations of peripheral blood leukocytes. Since this protein modulates the anti-inflammatory actions of the steroid hormones, the purpose of this study was to investigate the effects of the female sex steroid hormone, 17β-estradiol (E[sub 2]β), on the synthesis and secretion of ANXA1 in the human CCRF-CEM acute lymphoblastic leukemia cell line. Methods: Complementary reverse transcription-polymerase chain reaction and Western blot assays were performed to study the effect of E[sub 2]β on the expression of mRNA and protein ANXA1, respectively. Results and discussion: Treatment of CCRF-CEM cells with E[sub 2]β, for 30 min, stimulated the synthesis of ANXA1 mRNA molecules, and increased the cellular level of ANXA1 protein. Moreover, when the cells were incubated with E[sub 2]β, under the same experimental conditions, a significant increase in the amount of ANXA1 secreted from the cells was also detected. ICI 182,780, a selective inhibitor of the intracellular estrogen receptor, had no effect on the E[sub 2]β-stimulated expression and externalisation of ANXA1. Taken together, these results indicate that E[sub 2]β induces de novo synthesis of ANXA1 and stimulates its secretion in the CCRF-CEM cell line, apparently through a mechanism independent of the intracellular estrogen receptor. [ABSTRACT FROM AUTHOR]

Human Tγδ lymphocytes constitute from 1 to 15% of all peripheral blood lymphocytes. Recent work has demonstrated that this population plays a major role in the pathogenesis of infectious and immune diseases. Increased numbers of γδ T cells have been found in affected skin from systemic sclerosis and chronic cutaneous lupus erythematosus patients. In our study, we have determined the numbers of Tγδ lymphocytes and their subpopulations in peripheral blood from 29 patients with systemic lupus erythematosus (SLE) and in 19 healthy volunteers using flow cytometry and specific monoclonal antibodies. The same cells in uninvolved skin from SLE patients and human controls using immunohistochemical analysis were estimated. T-Cell receptor (TCR) delta chain gene rearrangement was identified with primers for Vδ1, Vδ2 and Vδ3 by the polymerase chain reaction. Statistical analysis showed a significantly decreased number of γδ T cells in SLE patients (26.4 I 16.9/μl) compared with the control group (55.3 I 20.6/μl) (p < 0.001). The number of Vδ2 TCR+ and Vγ9 TCR+ subpopulations was also lower in SLE patients than in healthy persons. No statistical correlation between disease activity and the number of γδ T cells was demonstrated. The percentage of T γδ lymphocytes in clinically normal skin from SLE patients was twice (22.0 Ī 9.4%) that found in the skin from healthy persons (11.1 Ī 5.5%) (p < 0.002). Higher percentages of the Vδ2 TCR+ and Vγ9 TCR+ subpopulation of lymphocytes were found in the skin from SLE patients. We have also found positive correlation between the percentage of Tγδ lymphocytes in skin and the activity of SLE (r = 0.594, p < 0.001), and between subpopulation Vδ3 TCR+ and disease activity (r = 0.659, p < 0.001). In conclusion, the results of our studies demonstrate that, in patients with SLE, accumulation of Tγδ lymphocytes can be seen in clinically normal skin, and the percentage of these cells correlates with the activity of the disease. [ABSTRACT FROM AUTHOR]

PHE12 of deacetyl-thymosin beta4 is one of the structural essentials for restorative effect on the impaired blastogenic response of uraemic T-lymphocytes. In order to evaluate the functional roles of this phenyl group in the restorative effect on impaired T-lymphocytes, two analogues, [1- Nal12]deacetyl-thymosin beta and [Cha12]deacetyl4 thymosin beta4, were synthesized by a solid-phase method and evaluated for restorative effect on the impaired blastogenic response of uraemic T-lymphocytes. The results indicated that [1-Nal12]deacetyl-thymosin beta4 which had a bulky naphthyl ring showed a stronger restorative effect than that of deacetyl-thymosin beta4, but it was slightly weaker than that of [Phe(4F)12]deacetyl-thymosin beta4. However, [Cha12]deacetyl-thymosin beta4 showed no restorative effect on the impaired blastogenic response of uraemic T-lymphocytes. [ABSTRACT FROM AUTHOR]