Do chemokine/chemokine receptor axes play paramount parts in trafficking and oriented locomotion of monocytes/macrophages toward the lungs of COVID-19 infected patients? A systematic review.

The COVID-19 (coronavirus disease 2019) is a well-defined viral infection, resulting from SARS-CoV-2 (severe acute respiratory syndrome- coronavirus-2). The innate immune system serves as the first line of defense to limit viral spreading and subsequently stimulate adaptive immune responses by the prominent aids of its cellular and molecular arms. Monocytes are defined as the most prominent innate immune cells (IICs) that are reactive against invading pathogens. These cells support host protection against the virus that is mediated by several non-specific mechanisms such as phagocytosis, producing antiviral enzymes, and recruitment of immune cells toward and into the infected tissues. They have the ability to egress from blood and migrate to the SARS-CoV-2 infected regions by the aid of some defense-related functions like chemotaxis, which is mediated by chemical compounds, e.g., chemokines. Chemokines, in addition to their related ligands are categorized within the most important and deserved agents involved in oriented trafficking of monocytes/macrophages towards and within the lung parenchyma in both steady state and pathological circumstances, including COVID-19-raised infection. However, the overexpression of chemokines could have deleterious effects on various organs through the induction of cytokine storm and may be the most important leading mechanisms in the pathogenesis of COVID-19. Authors have aimed the current review article to describe present knowledge about the interplay between monocytes/macrophages and SARS-CoV-2 with a focus on the ability of IICs to migrate and home into the lung of COVID-19 patients through various chemokine-chemokine receptor axes to promote our understanding regarding this disease.

A better understanding of the role of the CTLA-CD80/86 axis in the treatment of autoimmune diseases.

Autoimmune diseases are diseases in which the regulatory mechanisms of the immune response are disturbed. As a result, the body loses self-tolerance. Since one of the main regulatory mechanisms of the immune response is the CTLA4-CD80/86 axis, this hypothesis suggests that autoimmune diseases potentially share a similar molecular basis of pathogenesis. Hence, investigating the CTLA4-CD80/86 axis may be helpful in finding an appropriate treatment strategy. Therefore, this study aims to investigate the molecular basis of the CTLA4-CD80/86 axis in the regulation of the immune response, and then its role in developing some autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. As well, the main therapeutic strategies affecting the CTLA4-CD80/86 axis have been summarized to highlight the importance of this axis in management of autoimmune diseases.

Teucrium polium Extract Alleviates Pathological Features of Asthma via lL-12 and IFN-γ Modulation in Murine OVA-induced Allergic Asthma.

Asthma is a chronic disorder characterized by airway overreaction and remodeling, eosinophilia, and neutrophilic inflammation, accompanied by thickening of the airways and breathlessness. Teucrium polium (TP) is a plant with anti-inflammatory properties and is considered for the treatment of allergic disorders. In this study, we examined the effects of TP extract on ovalbumin (OVA)-induced asthma. Thirty female mice (5-6 weeks old) were divided into 5 groups of 6 each, including a control group and 4 groups treated with OVA, OVA + TP extract (50 mg/kg), OVA + TP extract (150 mg/kg), OVA + TP extract (300 mg/kg). Twenty-four hours after the last treatment, lung, serum, and spleen samples were collected and used for the evaluation of leukocyte infiltration, serum cytokine Interferon-gamma (IFN-γ) levels, and the expression of the Interleukin-12A (IL12A) gene, respectively. Hematoxylin-eosin staining was used to evaluate pathological changes in the lung tissue sections. Treatment with TP extract reduced inflammatory cells such as eosinophils and neutrophils in the airways. Furthermore, it increased serum levels of IFN-γ and IL-12A at a dose of 50, 150, and 300 mg/kg compared to the OVA group. This study showed that the administration of TP extract could improve pathological features, such as airway inflammation, and reduce systemic inflammation.

Royal Jelly Nanoparticle Alleviates Experimental Model of Breast Cancer Through Suppressing Regulatory T Cells and Upregulating TH1 Cells.

BACKGROUND: Royal jelly, a natural product from bees' hypopharyngeal glands, is commonly used in biomedicine due to its antioxidant and anti-tumor activities. The aim of this study was to compare royal jelly in free form and loaded in layered double hydroxide (LDH) nanoparticle for the treatment of breast cancer with a focus on Th1 and T regulatory parameters in an animal model. METHODS: Nanoparticles were produced using the coprecipitation method and characterized using DLS, FTIR, and SEM techniques. Forty female BALB/c mice were inoculated with 7.5 x 105 4T1 cells and treated with royal jelly in free and nanoparticle form. Clinical signs and tumor volume were assessed weekly. The effect of royal jelly products on the serum level of IFN-γ and TGF-ß was measured by ELISA. In addition, the mRNA expression of these cytokines and Th1 and regulatory T cells' transcription factors (T-bet and FoxP3) was assessed by real-time PCR in the splenocytes of tumor-bearing mice. RESULTS: The physicochemical analysis of nanoparticles confirmed the synthesis of LDH nanoparticles and loading of royal jelly into the LDH structures (RJ-LDH). Animal studies showed that royal jelly and RJ-LDH significantly reduced the size of tumor in BALB/c mice. Additionally, treatment with RJ-LDH significantly inhibited TGF-ß and increased IFN-γ production. The data also revealed that RJ-LDH inhibited the differentiation of regulatory T cells, while promoting Th1 cell differentiation via regulating their master transcription factors. CONCLUSIONS: These results indicated that royal jelly and RJ-LDH could inhibit breast cancer progression by in-hibiting regulatory T cells and expansion of Th1 cell. Furthermore, the current study demonstrated the therapeutic efficacy of royal jelly is enhanced by LDH nanoparticles; hence, RJ-LDH is significantly more efficient than Free-RJ in the treatment of breast cancer.

Enhancing the efficacy of Hypericum perforatum in the treatment of an experimental model of multiple sclerosis using gold nanoparticles: an in vivo study.

Objective: Hypericum perforatum is a herbal medicine used in traditional medicine for the treatment of depression due to its antidepressant and anti-inflammatory activities. Therefore, we evaluated the therapeutic efficacy of H. perforatum extract (HPE) in combination with gold nanoparticles (HPE-GNP) against experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Materials and Methods: EAE was induced in C57BL/6 mice with subcutaneous injection of MOG35-55 emulsified in complete Freund's adjuvant, and intraperitoneal pertussis toxin. Mice were treated with drugs in free (HPE) and nano-form (HPE-GNP) preparations. Splenocytes were isolated from all mice and the level of inflammatory and anti-inflammatory cytokines were evaluated by ELISA. The expression of T cells' transcription factors was also assessed using Real-Time PCR. Results: Clinical score was reduced after HPE-GNP treatment. This change was associated with a decrease in the incidence and infiltration of inflammatory cells into the central nervous system. Additionally, treatment with HPE-GNP decreased the level of pro-inflammatory cytokines (IFN-γ, IL-17A and IL-6) and increased anti-inflammatory cytokines (TGF-ß, IL-10 and IL-4). The real-time analysis revealed a decrease in the level of T-bet and ROR-γt but an increase in FoxP3 and GATA3 expression. Conclusion: The current study demonstrated that HPE-GNP could potentially reduce clinical and pathological complications of EAE, but laboratory data showed that HPE-GNP was significantly more effective than HPE in the treatment of EAE.

Interleukin 17A: A Potential Target for Its Plausible Roles in the Pathogenesis of Idiopathic Epistaxis.

INTRODUCTION: It has been reported that inflammation may be a potential risk factor for the progression of epistaxis. Due to the major roles played by Th17 in the induction of inflammation, the present study aimed to assess the serum levels of Interleukin 17A (IL-17A) and IL-23, as the most important cytokines in the Th17 pathway, as well as IFN-, IL-4, and IL-10 serum levels, as regulatory cytokines for Th17 cells in patients with idiopathic epistaxis. MATERIALS AND METHODS: The serum levels of IL-4, IL-10, IL-17A, IL-23, and IFN- were evaluated in 90 patients with idiopathic epistaxis and 90 healthy controls using enzyme-linked immunosorbent assay (ELISA) technique. RESULTS: The obtained results pointed out that the serum levels of IL-17A and IL-10, but not IL-4 and IL-23, were significantly up-regulated, and IFN- serum levels were significantly down-regulated in patients with idiopathic epistaxis. Furthermore, female patients with epistaxis had higher IL-10 serum levels. CONCLUSIONS: As evidenced by the results of the present study, IL-17A is the main cytokine which participates in the pathogenesis of idiopathic epistaxis; moreover, in association with IL-10, it can be regarded as the suppressor of IFN- in patients.

Involvement of various chemokine/chemokine receptor axes in trafficking and oriented locomotion of mesenchymal stem cells in multiple sclerosis patients.

Multiple sclerosis (MS) is a specific type of chronic immune-mediated disease in which the immune responses are almost run against the central nervous system (CNS). Despite intensive research, a known treatment for MS disease yet to be introduced. Thus, the development of novel and safe medications needs to be considered for the disease management. Application of mesenchymal stem cells (MSCs) as an emerging approach was recruited forthe treatment of MS. MSCs have several sources and they can be derived from the umbilical cord, adipose tissue, and bone marrow. Chemokines are low molecular weight proteins that their functional activities are achieved by binding to the cell surface G protein-coupled receptors (GPCRs). Chemokine and chemokine receptors are of the most important and effective molecules in MSC trafficking within the different tissues in hemostatic and non-hemostatic circumstances. Chemokine/chemokine receptor axes play a pivotal role in the recruitment and oriented trafficking of immune cells both towards and within the CNS and it appears that chemokine/chemokine receptor signaling may be the most important leading mechanisms in the pathogenesis of MS. In this article, we hypothesized that the chemokine/chemokine receptor axes network have crucial and efficacious impacts on behavior of the MSCs, nonetheless, the exact responsibility of these axes on the targeted tropism of MSCs to the CNS of MS patients yet remained to be fully elucidated. Therefore, we reviewed the ability of MSCs to migrate and home into the CNS of MS patients via expression of various chemokine receptors in response to chemokines expressed by cells of CNS tissue, to provide a great source of knowledge.

Severe Acute Respiratory Syndrome Coronavirus 2: The Role of the Main Components of the Innate Immune System.

At the end of December 2019, the COVID-19 pandemic began in Wuhan of China. COVID-19 affects different people with a wide spectrum of clinical manifestations, ranging from asymptomatic with recovery without hospitalization up to a severe acute respiratory syndrome (SARS). The innate and adaptive immunity appears responsible for the defense against the virus and recovery from the disease. The innate immune system, as the first line of defense, is essential for the detection of virus and subsequent activation of acquired immunity. The innate immune response is carried out by sentinel cells such as monocytes/macrophages and dendritic cells and by receptors known as pattern recognition receptors (PRR). These receptors can recognize various components of the virus, which lead to intracellular signaling and subsequently the synthesis of various cytokines. These cytokines then recruit other immune cells, activate adaptive immune responses, and inhibit viral spreading. The most common receptors include Toll-like receptors, C-type lectin receptors, and RIG-I like receptors. This review describes the current knowledge about the interplay between innate immune responses and SARS-CoV-2 with a focus on the innate immune cells and the role of their receptors in viral RNA recognition, as well as their mechanisms for recognizing SARS-CoV-2.

A Review of Immunomodulatory Effects of Fluoroquinolones.

Past researches indicate that some types of antibiotics, apart from their antimicrobial effects, have some other important effects which indirectly are exerted by modulating and regulating the immune system's mediators. Among the compounds with antimicrobial effects, fluoroquinolones (FQs) are known as synthetic antibiotics, which exhibit the property of decomposing of DNA and prevent bacterial growth by inactivating the enzymes involved in DNA twisting, including topoisomerase II (DNA gyrase) and IV. Interestingly, immune responses are indirectly modulated by FQs through suppressing pro-inflammatory cytokines, such as interleukin 1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-α), and super-inducing IL-2, which tend to increase both the growth and activity of T and B lymphocytes. In addition, they affect the development of immune responses by influencing of expression of other cytokines and mediators. This study aims to review past research on the immunomodulatory effects of FQs on the expression of cytokines, especially IL-2 and to discuss controversial investigations.

Exposure of metals and PAH through local foods and risk of cancer in a historically contaminated glassworks area.

BACKGROUND: Production of crystal glass and colored art glassware have been going on in the south-eastern part of Sweden since the 1700s, at over 100 glassworks and smaller glass blowing facilities, resulting in environmental contamination with mainly arsenic (As), cadmium (Cd), lead (Pb) and polycyclic hydrocarbons (PAH). High levels of metals have been found in soil, and moderately elevated levels in vegetables, mushrooms and berries collected around the glassworks sites compared with reference areas. Food in general, is the major exposure source to metals, such as Cd and Pb, and PAHs. Exposure to these toxic metals and PAH has been associated with a variety of adverse health effects in humans including cancer. OBJECTIVE: The aim of the present study was to evaluate the occurrence of cancer in a cohort from the contaminated glasswork area in relation to long-term dietary intake of locally produced foods, while taking into account residential, occupational and life styles factors. METHODS: The study population was extracted from a population cohort of 34,266 individuals who, at some time between the years 1979-2004, lived within a 2 km radius of a glassworks or glass landfill. Register information on cancer incidence and questionnaire information on consumption of local foods (reflecting 30 years general eating habits), life-time residence in the area, life style factors and occupational exposure was collected. Furthermore, blood (n = 660) and urine (n = 400) samples were collected in a subsample of the population to explore associations between local food consumption frequencies, biomarker concentrations in blood (Cd, Pb, As) and urine (PAH metabolite 1-OHPy) as well as environmental and lifestyle factors. The concurrent exposure to persistent organic pollutants (POPs) from food was also considered. A case-control study was performed for evaluation of associations between intakes of local food and risk of cancer. RESULTS: Despite high environmental levels of Cd, Pb and As at glasswork sites and landfills, current metal exposure in the population living in the surrounding areas was similar or only moderately higher in our study population compared to the general population. Reported high consumption of certain local foods was associated with higher Cd and Pb, but not As, concentrations in blood, and 1-OHPy in urine. An increased risk of cancer was associated with smoking, family history of cancer, obesity, and residence in glasswork area before age 5 years. Also, a long-term high consumption of local foods (reflecting 30 years general eating habits), i.e. fish and meat (game, chicken, lamb), was associated with increased risk of various cancer forms. CONCLUSIONS: The associations between consumption of local food and different types of cancer may reflect a higher contaminant exposure in the past, and thus, if consumption of local food contributes to the risk of acquiring cancer, that contribution is probably lower today than before. Furthermore, it cannot be ruled out that other contaminants in the food contribute to the increased cancer risks observed.

Acylated and deacylated quillaja saponin-21 adjuvants have opposite roles when utilized for immunization of C57BL/6 mice model with MOG35-55 peptide.

BACKGROUND: The majority of patients with multiple sclerosis (MS) suffer from central neuropathic pain (CNP). Using experimental autoimmune encephalomyelitis (EAE) model, only a few experiments were performed to assess pain behaviors in MS. To address this issue, complete Freund's adjuvant (CFA) was replaced with an acylated triterpene glycoside saponin adjuvant named quillaja saponin-21 (QS-21) to develop CNP in the EAE mouse model. The deacylated form of QS-21, named QT-0101, has been suggested to have an immunomodulatory effect. Thus, QT-0101 was used as a vaccine adjuvant to modulate the immune system against myelin oligodendrocyte glycoprotein (MOG35-55) antigen. METHODS: In this study, C57BL/6 mice, except for mice in the negative control (PBS) and MOG groups, were divided into three groups and immunized by MOG35-55 emulsified with CFA, QS-21, or QT-0101 adjuvants, respectively. Thermal hyperalgesia, as a CNP clinical manifestation, through the Hot Plate test and the clinical signs, was assessed for 60 days after immunization. On days 21 and 60, mice were sacrificed and the frequency of TCD4+, TCD8+, IL-17+, IL-4+, and CD25+/FoxP3+ cells population in the total splenocytes population was assessed by flow cytometry. Infiltration of Leukocytes into the brain and demyelination of white matter were also evaluated by histopathologic studies. RESULTS: Our results revealed that unlike the MOG+QT-0101 group, the MOG+QS-21 and MOG+CFA groups represented clinical symptoms that mimic the mild relapsing-remitting and monophasic models, respectively. Thermal hyperalgesia, as a CNP clinical manifestation, developed in the bilateral hind paws in the MOG+CFA and MOG+QS-21 mice groups during the onset of neurologic deficits, but it is maintained until completion of the study only in MOG+QS-21 mice group. The frequency of TCD4+, TCD8+ and IL-17+ cells population in the MOG+QS-21 and MOG+CFA mice groups, as well as IL-4+ and CD25+/Foxp3+ cells population in the MOG+QT-0101 mice group, significantly increased in comparison with the PBS mice group. Infiltration of inflammatory cells increased significantly in the MOG+QS-21 and MOG+CFA mice groups compared with the PBS mice group. Demyelination of white matter was identified significantly only in the MOG+CFA mice group compared with the PBS mice group. CONCLUSION: These results showed that QS-21 is a suitable adjuvant for the establishment of a mild relapsing-remitting EAE model for CNP development and open a new avenue to future pre-clinical and clinical research studies related to CNP treatment. Nevertheless, QT-0101 seems to have the potential to act as a vaccine adjuvant with immunomodulatory property against auto-antigens.

Analysis of Th22, Th17 and CD4+cells co-producing IL-17/IL-22 at different stages of human colon cancer.

T-helper (Th) 22 cells are involved in the immunopathogenesis of inflammatory diseases, but their specific role in the immunopathogenesis of cancer is unknown. In this study, we examined the profile of circulating and intratumoral Th17, Th22 and CD4+ cells co-producing IL-17/IL-22 in colon cancer (CC) patients in relation to tumor staging. Thirty newly diagnosed colon cancer (CC) patients participated in this study. The percentage of Th1 (CD4+IFN-γ+IL-17-IL-22-), Th17 (CD4+IFN-γ-IL-17+IL-22-), Th22 (CD4+IFN-γ-IL-17-IL-22+) and CD4+ cells co-producing IL-17/IL-22 (CD4+IFN-γ-IL-17+IL-22+) in the peripheral blood, tumor and paratumor tissues was assessed by multicolor flow cytometry. The percentage of circulating Th17 and Th22 cells was significantly increased in CC patients compared to that in healthy controls (HCs). In addition, the percentage of infiltrating Th1, Th17, Th22 and CD4+ cells co-producing IL-17/IL-22 was significantly increased in the tumor tissues compared to that in the parartumor tissues. Furthermore, we also found that the percentage of circulating and intratumoral Th17, Th22 and CD4+ cells co-producing IL-17/IL-22 was higher in advanced stages than in early stages. Our findings revealed that Th17, Th22 and CD4+ cells co-producing IL-17/IL-22 were accumulated in colon cancer tissues and may be involved in the tumor development and progression. A better comprehension of the immunopathogenesis of Th17, Th22 and CD4+ cells co-producing IL-17/IL-22 in colon cancer patients would help in the development of novel therapies.

Vitamin D and toll like receptors.

It has been demonstrated that vitamin D (VD) significantly modulates immune responses. Toll like receptors (TLRs) are the main innate immunity receptors which are expressed on the cell membrane and intracellular vesicles and recognize several pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) to induce immune responses. Based on the important roles played by TLRs in physiologic and pathologic functions of immune responses and due to the immunomodulatory functions of VD, it has been hypothesized that VD may present its immunomodulatory functions via modulation of TLRs. This review article collates recent studies regarding the interactions between VD and TLRs and discussed the controversial investigations.

Protective effect against brain tissues oxidative damage as a possible mechanism for beneficial effects of L-arginine on lipopolysaccharide induced memory impairment in rats.

L-Arginine (LA) and nitric oxide (NO) have been suggested to have some effects on learning, memory, brain tissues oxidative damage, and neuroinflammation. In this study, protective effect against brain tissues oxidative damage as a possible mechanism for beneficial effects of LA on lipopolysaccharide (LPS) induced memory impairment was investigated. The rats were grouped into and treated by (1) control (saline), (2) LPS (1 mg/kg, IP), (3) LA (200 mg/kg) - LPS (4) LA. In passive avoidance (PA) test, LPS administration shortened the latency to enter the dark compartment in LPS group compared to control (p < .001) which was accompanied with a high level of malondialdehyde (MDA) and NO metabolite concentrations in the hippocampal tissues (p < .001and p < .05, respectively). Pretreatment with LA prolonged the latency in LA-LPS group compared with LPS group (p < .01-.001) and re-stored MDA and NO metabolites in the hippocampal tissues (p < .05). LPS also reduced superoxide dismutase (SOD) and catalase (CAT) activities and thiol content in the hippocampal tissues in LPS group compared to control (p < .05 and p < .001, respectively) which improved by LA when it was administered before LPS in LA-LPS group (p < .05 and p < .001). Finally, the serum TNFα level of LPS group was higher than the control (p < .01) while, in LA-LPS group it was lower than LPS group (p < .01). It seems that the beneficial effects of LA on memory impairment of LPS-treated rats may be due to its protective effects against brain tissues oxidative damage.

Association of S100 calcium-binding protein A12, receptor for advanced glycation endproducts, and nuclear factor-κB expression with inflammation in pulp tissues from tooth caries.

AIM: S100 calcium-binding protein A1 (S100A12) is a pro-inflammatory molecule which is secreted during inflammation and induces chemotaxis and the production of pro-inflammatory cytokines via interaction with receptor for advanced glycation endproducts (RAGE) and subsequent, activation of nuclear factor-κB (NF-κB). The present study was designed to determine the expression levels of S100A12, RAGE, and NF-κB in the inflamed pulp of carried teeth. METHODS: In the present study, mRNA from 50 inflamed pulp and 50 healthy pulp were used for expression studies using real-time polymerase chain reaction. The expression levels of S100A12, RAGE, and NF-κB were compared between inflamed and healthy tissues. RESULTS: The results revealed that the expression of S100A12, but not of RAGE or NF-κB, was significantly decreased in inflamed pulp when compared to healthy pulp. mRNA levels of RAGE were also increased in the inflamed pulp taken from men when compared with women. CONCLUSION: The results suggest that S100A12 does not participate in the induction of inflammation in dental pulp. However, RAGE can participate in the inflammation in the pulp of males.

Bifidobacterium animalis in combination with human origin of Lactobacillus plantarum ameliorate neuroinflammation in experimental model of multiple sclerosis by altering CD4+ T cell subset balance.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS). Recent reports have shown that probiotics can induce immunomodulatory activity with promising effects in inflammatory diseases. This study was designed to reveal the molecular and cellular mechanisms underlying the effect of Lactobacillus plantarum A7, which comprises human commensal bacteria, and Bifidobacterium animalis, a potential probiotic strain, on alleviation of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. METHODS: To evaluate the therapeutic effects of probiotic strains, female C57BL/6 mice (8-10 wks old) received Lactobacillus plantarum A7, Bifidobacterium animalis PTCC 1631or a mixture of both strains through oral administration daily for 22days beginning simultaneous with induction of EAE. The clinical parameters were recorded daily. On Day 22, each mouse was bled, and their spinal cord was removed for histology analysis. The effects of the treatments on regulatory T (Treg) cells level were evaluated using flow cytometry, and T-cell proliferation was assessed using a BrdU incorporation assay. The supernatants of spleen and lymph nodes cultured and mononuclear cells were collected for quantification of different panel of pro and anti-inflammatory cytokines by ELISA. The analysis of gene expression was performed at RNA level for transcription factors by real-time PCR. RESULTS: The results showed that treatment with a mixture of the two strains caused a more significant delay in the time of disease onset and clinical score compared to when the strains were used alone. The pathological features of the disease, such as mononuclear infiltration into the CNS, were also inhibited more significantly by the combinational approach. The results also revealed that treatment with combination of both strains enhanced the population of CD4+CD25+Foxp3+-expressing T-cells in the lymph nodes and the spleen. TREATMENT: with our probiotic strains markedly inhibited disease associated cytokines while increased anti-inflammatory cytokines. Additionally, L. plantarumA7 and B. animalis ameliorated EAE condition by favoring Th2 and Treg differentiation via up-regulation of Foxp3 and GATA3 in the brain and spleen as well as inhibited the differentiation of Th1 and Th17 cells. CONCLUSIONS: The current research provided evidence that probiotic therapy with L. plantarum and B. animalis can effectively attenuate EAE progression as well as reinforce the polarization of regulatory T-cells.

The Effect of Zataria multiflora on Th1/Th2 and Th17/T Regulatory in a Mouse Model of Allergic Asthma.

Asthma is a chronic inflammatory disease with no definite treatment and more research is needed to overcome this condition. The aim of this study was to investigate the effect of the extract of Zataria multiflora (Z. multiflora) as a medicinal plant on cytokine genes expression in an experimental mouse model of asthma. Adult mice were randomly divided into the following groups: control (C), untreated asthma (A), asthmatic groups treated with dexamethasone (D) and Z. multiflora extract (200, 400, and 800 µg/mL; Z1, Z2, and Z3, respectively), (for groups C, A, and D n = 5 and for groups Z1, Z2, and Z3 n = 6). For induction of the mouse model of asthma, animals were sensitized with intraperitoneal injection and inhalation of ovalbumin (OVA). The number of T helper (Th) subtype cells (using flow cytometry) and the levels of IFN-γ, FOXP3, IL-4, TGF-ß, IL-17 gene expression (by real time PCR) were assessed in mice splenocytes. The observed changes in spleen cells of group A compared to group C were increased number of Th2 and Th17 cells, enhancement of gene expression of IL-4, IL-17, and TGF-ß (p < 0.001 for all cases), reduction of Th1 cells and Th1/Th2 ratio (p < 0.001 for both cases) and decrease in gene expression of IFN-γ, FOXP3 and IFN-γ/IL-4 ratio (p < 0.01 for IFN-γ and p < 0.001 for other cases). The observed changes in spleen cells of treated compared to untreated A group were enhancement of Treg cells and Th1/Th2 ratio (p < 0.001 for both cases), increase in IFN-γ (p < 0.05) and FOXP3 (p < 0.001) gene expression and IFN-γ/IL-4 ratio (p < 0.01) as well as reduction of Th2 and Th17 cells (p < 0.01 to p < 0.001), decrease gene expression of IL-4, IL-17, and TGF-ß (p < 0.05 to p < 0.001). The findings showed that the extract of Z. multiflora decreased pro-inflammatory cytokines in asthma (IL-4 and IL-17 and TGF-ß) but increased anti-inflammatory cytokines (IFN-γ) gene expression and the number of Treg (FOXP3) in splenocytes of asthmatic mice which may indicate the specific therapeutic effect of the plant extract in allergy, autoimmunity, and infectious diseases via potentiating Th1 and suppressing Th2 and Th17 cells.

Innate immunity related pathogen recognition receptors and chronic hepatitis B infection.

Innate immunity consists of several kinds of pathogen recognition receptors (PRRs), which participate in the recognition of pathogens and consequently activation of innate immune system against pathogens. Recently, several investigations reported that PRRs may also play key roles in the induction/stimulation of immune system related complications in microbial infections. Hepatitis B virus (HBV), as the main cause of viral hepatitis in human, can induce several clinical forms of hepatitis B and also might be associated with hepatic complications such as cirrhosis and hepatocellular carcinoma (HCC). Based on the important roles of PRRs in the eradication of microbial infections including viral infections and their related complications, it appears that the molecules may be a main part of immune responses against viral infections including HBV and participate in the HBV related complications. Thus, this review article has brought together information regarding the roles of PRRs in immunity against HBV and its complications.

Evaluation of NLRC4, NLRP1, and NLRP3, as Components of Inflammasomes, in Chronic Hepatitis B Virus-Infected Patients.

Nucleotide-binding domain leucine repeats (NLRs) are required for the recognition of various molecules that are expressed within microbes and are able to actuate appropriate immune responses via activation of cytokines. The current study evaluates the expression levels of NLRP1 and NLRC4, which are components of inflammasomes, in chronic hepatitis B (CHB) virus-infected patients. This study recruited two series of CHB patients (each contained 60 patients) and 60 healthy controls. Real-time polymerase chain reaction (PCR) was employed to evaluate mRNA expression levels of NLRP1, NLRP3, and NLRC4 as well as hepatitis B virus (HBV)-DNA copy number. Serum levels of liver markers were also used to evaluate the patients. Hepatitis B envelope antigen (HBeAg) and hepatitis B surface antigen (HBsAg) were also examined in all patients to evaluate infection. The data showed that expression levels of NLRC4 and NLRP1 were not significantly different in circulating monocytes of CHB patients when compared with those of healthy controls. Furthermore, the data indicate that mRNA levels of NLRP1, NLRP3, and NLRC4 were also not altered in CHB patients regardless of HBV-DNA copy numbers/mL and HBeAg status. The data revealed that mRNA expression levels of NLRP1 and NLRC4 were not altered in CHB patients, suggesting that these genes are not responsible for the impaired immune responses against HBV observed in these patients.

Medium-dose estrogen ameliorates experimental autoimmune encephalomyelitis in ovariectomized mice.

Estrogen is a neuro-protective hormone in various central nervous system (CNS) disorders. The present study evaluated the role of estrogen during experimental autoimmune encephalomyelitis (EAE) at doses selected to mimic any suppressive potential from the hormone during pregnancy. Here, mice were ovariectomized and then 2 weeks later treated with MOG antigen to induce EAE. Concurrently, mice then received (subcutaneously) an implanted pellet to deliver varying estrogen amounts over a 21-day period. Clinical scores and other parameters were monitored daily for the 21 days. At the end of the period, brain/spinal cord histology was performed to measure lymphocyte infiltration; T-cell profiles were determined through ELISA, flow cytometry, and real-time PCR. Transcription factor expression levels in the CNS were assessed using real-time PCR; T-cell differentiation was evaluated via flow cytometry. The results demonstrated that estrogen inhibited development of EAE. Histological studies revealed limited leukocyte infiltration into the CNS. High and medium dose of estrogen increased TH2 and Treg cell production of interleukin (IL)-4, IL-10, and transforming growth factor (TGF)-ß, but concurrently resulted in a significant reduction in production of interferon (IFN)-γ, IL-17, and IL-6. Flow cytometry revealed there were also significant decreases in the percentages of TH1 and TH17 cells, as well as significant increase in percentages of Treg and TH2 cells in the spleen and lymph nodes. Real-time PCR results indicated that high- and medium-dose estrogen treatments reduced T-bet and ROR-γt factor expression, but enhanced Foxp3 and GATA3 expression. Collectively, these results demonstrated that a medium dose of estrogen - similar to a pregnancy level of estrogen - could potentially reduce the incidence and severity of autoimmune EAE and possibly other autoimmune pathologies.