Porcine Brain Enzyme Hydrolysate Enhances Immune Function and Antioxidant Defense via Modulation of Gut Microbiota in a Cyclophosphamide-Induced Immunodeficiency Model.

This study examined how consuming porcine brain enzyme hydrolysate (PBEH) affects the immune function and composition of the gut microbiota in an immunodeficient animal model. Male Wistar rats aged 6 weeks were fed casein (control), 100 mg/kg body weight (BW), red ginseng extract (positive-control), and 6, 13, and 26 mg PBEH per kg BW (PBEH-L, PBEH-M, and PBEH-H, respectively) daily for 4 weeks. At 30 min after consuming assigned compounds, they were orally administered cyclophosphamide (CTX; 5 mg/kg BW), an immunosuppressive agent, to suppress the immune system by inhibiting the proliferation of lymphocytes. The normal-control rats were fed casein and water instead of CTX. Natural killer cell activity and splenocyte proliferation induced by 1 µg/mL lipopolysaccharide were lower in the control group than the normal-control group, and they significantly increased with PBEH consumption, particularly at high doses. The PBEH consumption increased dose-dependently in the Th1/Th2 ratio compared to the control. The lipid peroxide contents were lower in the PBEH group than in the control group. Moreover, PBEH m and PBEH-H consumption mitigated white pulp cell damage, reduced red pulp congestion, and increased spleen mast cells in the histological analysis. Intestinal microbiota composition demonstrated differences between the groups at the genus levels, with Akkermansia being more abundant in the control group than the normal-control group and the PBEH-H group showing a decrease. However, Bifidobacterium decreased in the control group but increased in the PBEH-H group. The ß-diversity revealed distinct microbial communities of PBEH and positive-control groups compared to the control group (p < 0.05). The metagenome predictions revealed that PBEH-H influenced amino acid metabolism, antioxidant defense, insulin sensitivity, and longevity pathways. In conclusion, PBEH-H intake boosted immune responses and reduced lipid peroxides by modulating gut microbiota composition. These findings suggest that PBEH-H has the potential as a dietary supplement for improving immune function and gut health in individuals with immunodeficiency.

Ferroptosis Inhibitor Regulates the Disease Progression of Systematic Lupus Erythematosus Mice Model Through Th1/Th2 Ratio.

BACKGROUND: Systematic lupus erythematosus (SLE) is an autoimmunemediated disease. So far, there is no relevant report on ferroptosis in SLE research, and the role of T helper 1 (Th1) and T helper 2 (Th2) cells in SLE is still unclear. METHODS: This study employed SLE mice models with and without ferroptosis inhibitors (Liproxstatin­1) and normal control mice. Treated mice were analyzed with hematoxylin and eosin (H&E) staining, immunohistochemical detection of glutathione peroxidase 4 (GPX4), malondialdehyde (MDA) detection, ELISA(enzyme-linked immunosorbent assay) detection of Th1 and Th2 cytokines and flow cytometry detection of Th1 and Th2 ratio. RESULTS: The results showed that compared with the normal group, the SLE group exhibited significantly higher expression of anti-double-stranded deoxyribonucleic acid (anti-dsDNA), MDA and Th1 cytokines, significantly lower expression of GPX4 and Th2 cytokines and increased Th1/Th2 ratio. Similarly, compared with the SLE group, the SLE + liproxstatin-1 group showed significantly low expression of anti-dsDNA, MDA and Th1 cytokines, significantly high expression of GPX4 and Th2 cytokines and reduced Th1/Th2 ratio. CONCLUSION: These results demonstrate that ferroptosis may be involved in promoting SLE development. Therefore, inhibiting ferroptosis may be a potential treatment for SLE. Similarly, the Th1/Th2 ratio may have a role in promoting SLE development.

Serum brain-derived neurotrophic factor in coronary heart disease: Correlation with the T helper (Th)1/Th2 ratio, Th17/regulatory T (Treg) ratio, and major adverse cardiovascular events.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) exerts protective roles against dyslipidemia, atherosclerosis, and inflammation in cardiovascular diseases; meanwhile, it retards CD4+ T cell differentiation into T helper (Th)1 and Th17 cells. Hence, this study aimed to investigate the linkage of serum BDNF with Th1/Th2 ratio, Th17/regulatory T (Treg) ratio, and major adverse cardiovascular events (MACE) risk in the coronary heart disease (CHD) patients. METHODS: This prospective study detected serum BDNF in 210 CHD patients, 50 disease controls (DCs), and 50 healthy controls (HCs) using an enzyme-linked immunosorbent assay. For CHD patients only, the proportion of Th1, Th2, Th17, and Treg cells in blood CD4+ T cells was calculated by flow cytometry. RESULTS: The BDNF varied among CHD patients, DC, and HC (p < 0.001). Specifically, BDNF was declined in CHD patients compared with DCs (p < 0.001) and HCs (p < 0.001). In CHD patients, BDNF was negatively related to Th1 cells (p = 0.031), Th1/Th2 ratio (p = 0.026), Th17 cells (p = 0.001), and Th17/Treg ratio (p = 0.002). Concerning the prognosis, BDNF was reduced in patients with MACE occurrence compared to patients without MACE occurrence (p = 0.006). Furthermore, BDNF showed a trend (lacked statistical significance) to relate to longer MACE-free survival (p = 0.059). Besides, BDNF was related to the absence of obesity (p = 0.019), decreased total cholesterol (p = 0.043), low-density lipoprotein cholesterol (p = 0.019), C-reactive protein (p = 0.012), and Gensini score (p = 0.005). CONCLUSION: Serum BDNF negatively correlates with Th1/Th2 ratio, Th17/Treg ratio, and estimates lower MACE risk in CHD patients.

MicroRNA-451a and Th1/Th2 ratio inform inflammation, septic organ injury, and mortality risk in sepsis patients.

Aims: MicroRNA-451a (miR-451a) regulates Th1/Th2 cell differentiation, inflammation, and septic organ injury in several experiments. Therefore, the present study aimed to explore the inter-correlation of miR-451a with the Th1/Th2 ratio, and their association with inflammation, septic organ injury, and mortality risk in patients with sepsis. Methods: Consecutively, 117 patients with sepsis and 50 healthy controls (HCs) were enrolled. Peripheral blood mononuclear cell samples were collected to detect miR-451a expression and the Th1/Th2 ratio in all subjects. Results: MiR-451a (p < 0.001), Th1 cells (p = 0.014), and the Th1/Th2 ratio (p < 0.001) increased, while Th2 cells (p < 0.001) declined in patients with sepsis compared with HCs. It was of note that miR-451a was positively correlated with Th1 cells (p = 0.002) and the Th1/Th2 ratio (p = 0.001), while it was negatively related to Th2 cells (p = 0.005) in patients with sepsis. Meanwhile, miR-451a and the Th1/Th2 ratio correlated with most of the following indexes: TNF-α, IL-1ß, IL-6, C-reactive protein, sequential organ failure assessment (SOFA) score, or Acute Physiology and Chronic Health Evaluation II (APACHE II) score (most p < 0.05). Moreover, miR-451a (p < 0.001) and the Th1/Th2 ratio (p = 0.001) increased in deaths compared to survivors of sepsis; further ROC curve showed both miR-451a and the Th1/Th2 ratio possessed a certain value to predict mortality of patients with sepsis. Additionally, the Th1/Th2 ratio [odds ratio (OR): 2.052, p = 0.005] was independently related to 28-day mortality risk from multivariate logistic regression. Conclusion: MiR-451a correlates with the Th1/Th2 ratio, and they both relate to inflammation, septic organ injury, and mortality risk in patients with sepsis.

Circulating Th2 cell reduction and Th1/Th2 imbalance are correlated with primary Sjogren's syndrome-associated interstitial lung disease.

OBJECTIVE: Primary Sjogren's syndrome (pSS) is a heterogeneous chronic autoimmune disorder characterized by lymphocyte infiltration of the exocrine glands and the involvement and dysfunction of multiple organs and tissues. Interstitial lung disease (ILD) is the most common type of respiratory system damage. This study ascertained the factors related to ILD in patients with pSS (pSS-ILD), such as altered levels of circulating lymphocyte subtypes. METHODS: Eighty healthy controls and 142 patients diagnosed with pSS were included. The pSS patients were classified into groups with pSS-ILD or pSS without ILD (pSS-non-ILD). Baseline clinical and laboratory data were collected for all subjects, including the levels of lymphocytes measured by modified flow cytometry. RESULTS: The pSS-ILD patients were older, had higher ESSDAI scores, had higher positivity rates for anti-SSB and anti-Ro52 antibodies, and had more frequent symptoms of respiratory system involvement than pSS-non-ILD patients. pSS-ILD patients had the lowest Th2 cell counts among the three groups. Although the absolute numbers of Treg and NK cells were lower in pSS patients with and without ILD than in the healthy controls, there was no significant difference between the two pSS groups. The Th1/Th2 ratio was significantly higher in patients with ILD than in patients without ILD. Further analysis showed that older age (OR=1.084), lower Th2 count (OR=0.947), higher Th1/Th2 ratio (OR=1.021), and positivity for anti-SSB (OR=3.620) and anti-Ro52 (OR=5.184) antibodies were associated with the occurrence of ILD in patients with pSS. CONCLUSION: Decreased circulating Th2 cells and an elevated Th1/Th2 ratio may be the immunological mechanism underlying the development of ILD in pSS patients.

Ageratina adenophora Inhibits Spleen Immune Function in Rats via the Loss of the FRC Network and Th1-Th2 Cell Ratio Elevation.

The objective of this study was to determine the impact of Ageratina adenophora (A. adenophora) on splenic immune function in a rat model. Rats were fed with 10 g/100 g normal feed and an experimental feed, which was composed of 3:7 A. adenophora powder and normal feed for 60 days. On days 14, 28, and 60, subsets of rats (n = 8 rats/group/time point) were selected for blood and spleen tissue sample collection. The results showed that the proportion of CD3+ T cells in the spleen was decreased at day 60 (vs. control). Also, mRNA and protein expression of chemokines CCL21 and CCL19 and functional protein gp38 in spleen decreased significantly versus the control at day 60. In addition, ER-TR7 antigen protein expression was also decreased at day 60. Levels of T-helper (Th)1 cells significantly increased, whereas those of Th2 cells decreased significantly versus the control at day 60 in spleen. The finding revealed that A. adenophora could affect splenic immune function in rats by altering the fibroblast reticulocyte (FRC) network, as well as by causing an imbalance in Th1/Th2 cell ratios. This research provides new insights into potential mechanisms of spleen immunotoxicity due to exposures to A. Adenophora.

Immunological Characteristics in Type 2 Diabetes Mellitus Among COVID-19 Patients.

Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04365634. Context: Diabetes mellitus was associated with increased severity and mortality of disease in COVID-19 pneumonia. So far the effect of type 2 diabetes (T2DM) or hyperglycemia on the immune system among COVID-19 disease has remained unclear. Objective: We aim to explore the clinical and immunological features of type 2 diabetes mellitus (T2DM) among COVID-19 patients. Design and Methods: In this retrospective study, the clinical and immunological characteristics of 306 hospitalized confirmed COVID-19 patients (including 129 diabetic and 177 non-diabetic patients) were analyzed. The serum concentrations of laboratory parameters including cytokines and numbers of immune cells were measured and compared between diabetic and non-diabetic groups. Results: Compared with non-diabetic group, diabetic cases more frequently had lymphopenia and hyperglycemia, with higher levels of urea nitrogen, myoglobin, D-dimer and ferritin. Diabetic cases indicated the obviously elevated mortality and the higher levels of cytokines IL-2R, IL-6, IL-8, IL-10, and TNF-α, as well as the distinctly reduced Th1/Th2 cytokines ratios compared with non-diabetic cases. The longitudinal assays showed that compared to that at week 1, the levels of IL-6 and IL-8 were significantly elevated at week 2 after admission in non-survivors of diabetic cases, whereas there were greatly reductions from week 1 to week 2 in survivors of diabetic cases. Compared with survival diabetic patients, non-survival diabetic cases displayed distinct higher serum concentrations of IL-2R, IL-6, IL-8, IL-10, TNF-α, and lower Th1/Th2 cytokines ratios at week 2. Samples from a subset of participants were evaluated by flow cytometry for the immune cells. The counts of peripheral total T lymphocytes, CD4+ T cells, CD8+ T cells and NK cells were markedly lower in diabetic cases than in non-diabetic cases. The non-survivors showed the markedly declined counts of CD8+ T cells and NK cells than survivors. Conclusion: The elevated cytokines, imbalance of Th1/Th2 cytokines ratios and reduced of peripheral numbers of CD8+ T cells and NK cells might contribute to the pathogenic mechanisms of high mortality of COVID-19 patients with T2DM.

Role of Exercise Intensity on Th1/Th2 Immune Modulations During the COVID-19 Pandemic.

The COVID-19 pandemic has led to several pioneering scientific discoveries resulting in no effective solutions with the exception of vaccination. Moderate exercise is a significant non-pharmacological strategy, to reduce the infection-related burden of COVID-19, especially in patients who are obese, elderly, and with additional comorbidities. The imbalance of T helper type 1 (Th1) or T helper type 2 (Th2) cells has been well documented among populations who have suffered as a result of the COVID-19 pandemic, and who are at maximum risk of infection and mortality. Moderate and low intensity exercise can benefit persons at risk from the disease and survivors by favorable modulation in Th1/Th2 ratios. Moreover, in COVID-19 patients, mild to moderate intensity aerobic exercise also increases immune system function but high intensity aerobic exercise may have adverse effects on immune responses. In addition, sustained hypoxia in COVID-19 patients has been reported to cause organ failure and cell death. Hypoxic conditions have also been highlighted to be triggered in COVID-19-susceptible individuals and COVID-19 survivors. This suggests that hypoxia inducible factor (HIF 1α) might be an important focus for researchers investigating effective strategies to minimize the effects of the pandemic. Intermittent hypoxic preconditioning (IHP) is a method of exposing subjects to short bouts of moderate hypoxia interspersed with brief periods of normal oxygen concentrations (recovery). This methodology inhibits the production of pro-inflammatory factors, activates HIF-1α to activate target genes, and subsequently leads to a higher production of red blood cells and hemoglobin. This increases angiogenesis and increases oxygen transport capacity. These factors can help alleviate virus induced cardiopulmonary hemodynamic disorders and endothelial dysfunction. Therefore, during the COVID-19 pandemic we propose that populations should engage in low to moderate exercise individually designed, prescribed and specific, that utilizes IHP including pranayama (yoga), swimming and high-altitude hiking exercise. This would be beneficial in affecting HIF-1α to combat the disease and its severity. Therefore, the promotion of certain exercises should be considered by all sections of the population. However, exercise recommendations and prescription for COVID-19 patients should be structured to match individual levels of capability and adaptability.

Immuno-modulatory effects of methanolic extract of Ferula szowitsiana on isolated human Th1/Th2/Treg cytokines levels, and their genes expression and nitric oxide production.

BACKGROUND: Anti-inflammatory and anti-oxidants activities of Ferula szowitsiana L. (F. szowitsiana) were shown in ancient texts and assayed by modern studies. However, immunomodulatory properties of the plant are poorly understood. METHODS: The effects of F. szowitsiana extract (10, 40 and 160 µg/ml), dexamethasone and vehicle were investigated on nitric oxide (NO) level, cell proliferation, and cytokines (IL-4, IL10 and IFN-γ) expression at gene and protein levels in non-stimulated and phytohaemagglutinin-stimulated human lymphocytes (n = 15 in each group). RESULTS: Cell proliferation, cytokines secretion, NO production and levels of genes expression were significantly inhibited but IFN-γ/IL-4 and IL-10/IL-4 ratios (T helper 1/Th2 and Treg/Th2 balances respectively) were increased by dexamethasone and all three concentrations of the extract compared to control group in stimulated lymphocytes (P < 0.001 for all cases). The effect of three concentrations of the extract in all experiments was significantly lower than dexamethasone (P < 0.001 for all cases). CONCLUSION: The extract of F. szowitsiana concentration-dependently decreased NO level but increased Th1/Th2 and Treg/Th2 ratios toward Th1 and Treg. These results suggest the therapeutic potential of the plant's extract in inflammatory diseases with dominant Th2 polarization such as asthma or cancers.

All-trans-retinoic acid shifts Th1 towards Th2 cell differentiation by targeting NFAT1 signalling to ameliorate immune-mediated aplastic anaemia.

Severe acquired aplastic anaemia (AA) is a serious disease characterised by autoreactive T cells attacking haematopoietic stem cells, leading to marrow hypoplasia and pancytopenia. Immunosuppressive therapy combined with antithymocyte globulin and ciclosporin can rescue most patients with AA. However, the relapse after ciclosporin withdrawal and the severe side effects of long-term ciclosporin administration remain unresolved. As such, new strategies should be developed to supplement current therapeutics and treat AA. In this study, the possibility of all-trans-retinoic acid (ATRA) as an alternative AA treatment was tested by using an immune-mediated mouse model of AA. Results revealed that ATRA inhibited T-cell proliferation, activation and effector function. It also restrained the Fas/Fasl pathway, shifted Th1 towards Th2 cell development, rebalanced T-cell subsets at a relatively high level and corrected the Th1/Th2 ratio by targeting NFAT1 signalling. In addition, ATRA inhibited Th17 cell differentiation and promoted regulatory T-cell development. Therefore, ATRA was an effective agent to improve AA treatment outcomes.

CCL2 conditionally determines CCL22-dependent Th2-accumulation during TGF-ß-induced breast cancer progression.

We investigated expressions of -CC chemokine ligand 2 (CCL2) and CCL5 in tumor samples from 147 breast cancer (BCa) patients and correlated with transforming growth factor-ß (TGF-ß) expression. We observed an inverse correlation of TGF-ß expression with CCL2, CCL5 expression in early stages of BCa. On contrary, in late stages, CCL2, not CCL5, expression was found to be directly proportional with TGF-ß expression. TGF-ß stimulated MDA-MB-231 cells to express CCL2, however, downregulated both CCL2 and CCL5 in MCF-7. Interestingly, a significant swing of Th1-Th2 ratio towards Th2 is seen within the primary tumors expressing moderate/high-CCL2-low/negative-CCL5. We observed that CCL2-CCR2 interaction induces monocytes/macrophages to secrete Th2-attracting chemokine CCL22 in vitro. Therefore, CCL2 secreted from the tumor microenvironment may attract and interact with monocytes/macrophages, and favor Th2 accumulation by inducing CCL22 secretion. Study in 4T1-BALB/c BCa mouse model demonstrated significant (p<0.05) decrease in CCL2, CCL5 and CCL22 levels and reduction in lung metastatic nodule numbers upon administering TGF-ß inhibitor. These findings collectively indicate that TGF-ß regulates CCL2 and CCL5 expression in a stage-dependent manner during BCa progression, which in turn, determines Th1-Th2 balance within the tumor microenvironment.

Age-Related Changes in Immunological Factors and Their Relevance in Allergic Disease Development During Childhood.

PURPOSE: Allergic diseases are triggered by Th2-mediated immune reactions to allergens and orchestrated by various immunological factors, including immune cells and cytokines. Although many reports have suggested that childhood is the critical period in the onset of allergic diseases and aging leads to alter the susceptibility of an individual to allergic diseases, age-related changes in various immunological factors in healthy individuals as well as their difference between healthy and allergic children have not yet been established. METHODS: We investigated the ratio of Th1/Th2 cells and the levels of 22 allergy-related cytokines across all age groups in individuals who were classified as clinically non-atopic and healthy. We also examined their differences between healthy and allergic children to evaluate immunological changes induced by the development of allergic diseases during childhood. RESULTS: The Th1/Th2 ratio rose gradually during the growth period including childhood, reaching peak values in the twenties-thirties age group. Th1/Th2 ratios were significantly lower in allergic children than in healthy controls, whereas 14 of 22 cytokines were significantly higher in allergic children than in healthy controls. On the other hand, there were no differences in Th1/Th2 ratios and cytokines between healthy and allergic adolescents. CONCLUSIONS: In this study, age-related changes in Th1/Th2 ratios were found in normal controls across all age groups, and decreases in Th1/Th2 ratio were observed with increasing of 14 cytokines in allergic children. The results of this study may be helpful as reference values for both monitoring immunological changes according to aging in healthy individuals and distinguishing between normal and allergic subjects in terms of immune cells and soluble factors.

Age-Related Changes in Immunological Factors and Their Relevance in Allergic Disease Development During Childhood

PURPOSE: Allergic diseases are triggered by Th2-mediated immune reactions to allergens and orchestrated by various immunological factors, including immune cells and cytokines. Although many reports have suggested that childhood is the critical period in the onset of allergic diseases and aging leads to alter the susceptibility of an individual to allergic diseases, age-related changes in various immunological factors in healthy individuals as well as their difference between healthy and allergic children have not yet been established. METHODS: We investigated the ratio of Th1/Th2 cells and the levels of 22 allergy-related cytokines across all age groups in individuals who were classified as clinically non-atopic and healthy. We also examined their differences between healthy and allergic children to evaluate immunological changes induced by the development of allergic diseases during childhood. RESULTS: The Th1/Th2 ratio rose gradually during the growth period including childhood, reaching peak values in the twenties-thirties age group. Th1/Th2 ratios were significantly lower in allergic children than in healthy controls, whereas 14 of 22 cytokines were significantly higher in allergic children than in healthy controls. On the other hand, there were no differences in Th1/Th2 ratios and cytokines between healthy and allergic adolescents. CONCLUSIONS: In this study, age-related changes in Th1/Th2 ratios were found in normal controls across all age groups, and decreases in Th1/Th2 ratio were observed with increasing of 14 cytokines in allergic children. The results of this study may be helpful as reference values for both monitoring immunological changes according to aging in healthy individuals and distinguishing between normal and allergic subjects in terms of immune cells and soluble factors.

A prospective evaluation of the role of Vascular Endothelial Growth Factor (VEGF) and the immune system in stage III/IV melanoma.

BACKGROUND: The immune system and vascular endothelial growth factor (VEGF) may be influential in melanoma behavior. We performed a prospective, exploratory analysis in 10 stage III and 22 stage IV melanoma patients to observe factors influencing outcomes. PATIENTS AND METHODS: Patients accrued during 2010 and 2011 were treated according to standard protocols for disease stage. We analyzed selected biomarkers for predictive patterns of clinical response. Survival outcomes were calculated using Kaplan-Meier curves. RESULTS: Baseline LDH was negatively correlated with length of survival and positively correlated to baseline VEGF in stage IV melanoma patients. We found a positive correlation between peripheral blood Treg concentrations and baseline VEGF in stage IV patients. No stage III patients died during the study period; median survival for stage IV patients was 48 months using a Kaplan-Meier survival curve, which illustrates the enrichment for exceptional stage IV survivors. Six stage IV patients remain disease free, including 4 of the 10 patients who received IL-2 +/- metastatectomy. CONCLUSIONS: Recent advances in immunotherapy have demonstrated durable therapeutic responses which may favorably impact survival. Examining T-cell characteristics of metastatic melanoma patients may gain further insight into underlying immunomodulation mechanisms to guide improved therapies.

Relationship between NADPH and Th1/Th2 ratio in patients with non-Hodgkin lymphoma who have been exposed to pesticides.

The effect of pesticides on nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), including its level and relationship with the T helper 1 (Th1)/Th2 ratio, in patients suffering from non-Hodgkin lymphoma (NHL) was investigated. One hundred newly diagnosed patients with aggressive NHL (53 men, 47 women) and 40 healthy age-, sex-, and body mass index-matched controls (23 men, 17 women), exposed or not to pesticides, were recruited for a cross-sectional study conducted at the Clinical Hematology Departments of Tlemcen and Sidi Bel-Abbès University Medical Centers in the northwest of Algeria. NADPH levels were significantly increased in patients compared with controls; and in exposed patients compared with those not exposed, and controls (one-way analysis of variance; P=0.000). Albumin, glutathione peroxidase, superoxide dismutase, catalase activity, and oxygen radical absorbance capacity levels were significantly decreased in patients compared with in the control group. Oxygen radical absorbance capacity levels were significantly decreased in exposed patients compared with in unexposed patients; however, malondialdehyde levels were significantly increased in exposed patients when compared with controls and unexposed patients. Protein carbonyl and xanthine oxidase levels were significantly increased in exposed patients compared with controls; meanwhile, there were no significant differences between the two patient groups or between unexposed patients and controls. The Th1/Th2 ratio was significantly decreased in patients when compared with controls; the neutrophil-to-lymphocyte ratio was significantly increased (for both comparisons, P<0.001). In addition, NADPH was strongly associated with NHL (Mantel-Haenszel common odds ratio estimate =5.55; 95% confidence interval, 2.22-13.88; P=0.000). Moreover, NADPH levels were significantly negatively related to the Th1/Th2 ratio, either in exposed patients or in unexposed patients (respectively, r=-0.498 [P=0.004] and r=-0.327 [P=0.006]). In conclusion, pesticide exposure was strongly associated with NADPH alteration in NHL. The relationship between NADPH and Th1/Th2 ratio should focus on new therapeutic strategies for the disease.

Increased circulating Th1/Th2 ratios but not other lymphocyte subsets during controlled ovarian stimulation are linked to subsequent implantation failure after transfer of in vitro fertilized embryos.

PROBLEM: To investigate alterations of circulating lymphocyte subsets in women undergoing controlled ovarian stimulation (COS) and survey their relations with pregnancy outcome. METHOD OF STUDY: Fifty-one women were included in this study, of which 24 women were successfully pregnant in the index IVF cycle (the successful pregnancy group, sPG) and 27 women failed to get pregnant (the non-pregnancy group, nPG). Peripheral blood was collected at three time points during COS: on the day before the first GnRHa administration (GnRHa day), on the day before the first Gn administration (Gn day), and on the day before HCG administration (HCG day). The intracellular Th1(IFN-γ and TNF-α)/Th2(IL-10) ratios in circulating Th cells after in vitro phorbol-12-myristate-13-acetate stimulation, the NK cytotoxicity, and the percentage of T, B and NK cell subsets were assessed by flow cytometer. A third group consisting of patients with recurrent implantation failure (RIF group, n = 18) was also enrolled, and the intracellular Th1/Th2 ratios were assessed at HCG day. RESULTS: Intergroup comparison: The ratios of IFN-γ/IL-10 and TNF-α/IL-10 at HCG day were significantly higher (P < 0.05) in nPG than those in sPG, while no change at GnRHa day or Gn day. Higher (P < 0.05) ratios of IFN-γ/IL-10 and TNF-α/IL-10 at HCG day were also observed in RIF group compared to those in sPG. No significant change (P > 0.05) was found in other assessed lymphocyte subsets or in the concentrations of progesterone, estradiol, luteinizing hormone, or follicle-stimulating hormone between the sPG and nPG at the three time points. Intragroup comparison: The ratios of IFN-γ/IL-10 and TNF-α/IL-10 at HCG day were significantly (P < 0.05) lower than those at GnRHa day in sPG, but not in nPG. No significant (P > 0.05) difference was found in other assessed parameters or at other time points. CONCLUSIONS: The ratios of Th1/Th2 were fluctuated during COS, and they might affect the pregnancy outcome of IVF. The circulating NK cytotoxicity and percentage of lymphocyte subsets were relatively stable during the COS.

Role of T helper lymphokines in the immune-inflammatory pathophysiology of schizophrenia: Systematic review and meta-analysis.

BACKGROUND: Schizophrenia is highly complex multifactorial psychiatric disorder with poorly defined etiopathophysiology, which also has manifestations in the immune system. AIMS: The aim of this review is to meta-analyze the available evidence regarding the role of immune activation indicated by the T helper cells in order to evaluate etiopathophysiological links between the immune system and schizophrenia. METHODS: A literature search was performed in multiple electronic databases for relevant research papers published between 1990 and May 2014. Meta-analyses were conducted under both random- (REM) and fixed-effect models (FEM) by calculating weighted mean differences with 95% confidence intervals. Heterogeneity was assessed with the I(2) index. RESULTS: Twenty-one studies were selected after observing inclusion and exclusion criteria. In vitro interferon-gamma (INF-γ) and interleukin (IL)-2 production was significantly lower in the schizophrenic patients compared with non-schizophrenic control individuals under both FEM and REM. Serum levels of IL-2 and serum/in vitro IL-4 were not significantly different in both groups under both FEM and REM. Overall Th1:Th2 ratio (INF-γ:IL-4 and IL-2:IL-4) in the serum samples was significantly deflected towards Th2 under both models in the serum samples (- 0.33 [- 0.59 to - 0.06]; P < 0.03, FEM and - 2.44 [- 4.27 to - 0.60]; P < 0.009, REM) but in vitro production Th1:Th2 ratio (INF-γ:IL-4 and IL-2:IL-4) was deflected towards Th1 under both the models (1.11 [0.45-1.78]; P < 0.002, FEM and 6.68 [0.72-12.64]; P < 0.03, REM). CONCLUSIONS: Whereas the Th1:Th2 ratio in the serum samples deflected towards T2, in vitro Th1:Th2 ratio favored Th1 when the individual study data were meta-analyzed.

Vitamin D3 influence the Th1/Th2 ratio in C57BL/6 induced model of experimental autoimmune encephalomyelitis.

OBJECTIVES: Multiple Sclerosis (MS) is known as a progressive inflammatory CNS disease. Cytokines belong to Th1 or Th2 family and inflammatory cells, play significant role in pathophysiology of MS. Thus, any treatment supposed to influence the relation between Th1 to Th2 cytokines expression. Although vitamin D has been prescribed as a therapeutic supplement of MS for a long time, it is not clear how much it may affect the Th1/Th2 ratio. To answer this question the present research was designed. MATERIALS AND METHODS: Thirty C57BL/6 adult female mice were used. The animals were randomly divided into trial and control groups. Experimental Autoimmune Encephalomyelitis (EAE) modeling for MS and clinical scoring as cited by others was used. Based on scoring and step of the disease vitamin D3 prescription (5 mg/kg) started and continued for three weeks. RESULTS: By using ELISA and RT-PCR the brain level of TNF-α, IL-10, IL-4 and IL-12 determined. Significant decrease of clinical symptoms in trial group which received vitamin D was seen comparing to control animals (P<0.05). The level of TNF-α but not IL-10 significantly decreased following vitamin D3 administration. By comparing the level of Th1 and Th2 Interleukins and counting the ratio of them we found that in treated animals the ratio was significantly less than non-treated (P=0.01). CONCLUSION: According to the results, vitamin D3 may be able to suppress the inflammatory ways that lead to progression of MS. Whether this ability is clinically valuable in human subjects is not clear and needs more clinical research.