The Role of Innate and Adaptive Immune System in the Pathogenesis of Schizophrenia.

Schizophrenia is one of the most severely debilitating mental disorders that affects 1.1% of the world's population. The exact cause of the disease is not known, but genetics, environmental factors (such as infectious agents, season and region of birth, exposure to viruses, low birth weight, advanced paternal age, and tobacco), and immune system dysfunction can all contribute to the development of schizophrenia. Recently, the role of the immune system in schizophrenia has received much attention. Both acquired and innate immune systems are involved in the pathogenesis of schizophrenia and facilitate the disease's progression. Almost all cells of the immune system including microglia, B cells, and T cells play an important role in the blood-brain barrier damage, inflammation, and in the progression of this disease. In schizophrenia, the integrity of the blood-brain barrier is reduced and then the immune cells are recruited into the endothelium following an increase in the expression of cell adhesion molecules. The entry of immune cells and cytokines leads to inflammation and antibody production in the brain. Accordingly, the results of this study strengthen the hypothesis that the innate and acquired immune systems are involved in the pathogenesis of schizophrenia.

The Role of Immune Regulatory Molecules in COVID-19.

As the fifth pandemic in the 21st century, coronavirus 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the most prominent global concern in the last 2 years. Variable manifestations characterize SARS-CoV-2 infection. Despite the design and production of effective vaccines and their considerable effect on reducing the COVID-19 prevalence and mortality rate, no definitive cure for the disease has yet been found. Mutations may also affect the effectiveness of vaccines. The host immune response to the pathogen has a critical role in the course of the disease. Positive and negative signals often balance the immune system. Immune regulatory molecules, also known as immune checkpoint receptors, balance the immune responses. These molecules mainly have inhibitory functions and prevent hyperactivation of immune cells or trigger adverse signaling pathways. For a decade, the immune checkpoint blockade, as a therapeutic target for cancer immunotherapy, has been utilized. Some of the inhibitory receptors are recognized as exhaustion markers on T cells. The signaling pathway of these markers restricts the function of T cells against viral infection. Dysregulation of T cells was observed in SARS-CoV-2 infection and can modify proliferation, differentiation, cytokine production, and type of response. The pivotal role of immune inhibitory receptors in the function of acquired, cell-mediated, immune defense T cells makes them a fascinating subject to study. This review article summarized recent findings on immune regulatory molecules and their role in SARS-CoV-2 infection, hoping to find a way to design novel treatments.

PI3K/Akt/mTOR pathway: a potential target for anti-SARS-CoV-2 therapy.

Coronavirus disease 2019 (COVID-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A single-stranded RNA virus from a ß-Coronaviridae family causes acute clinical manifestations. Its high death rate and severe clinical symptoms have turned it into the most significant challenge worldwide. Up until now, several effective COVID-19 vaccines have been designed and marketed, but our data on specialized therapeutic drugs for the treatment of COVID-19 is still limited. In order to synthesis virus particles, SARS-CoV-2 uses host metabolic pathways such as phosphoinositide3-kinase (PI3K)/protein kinase B (PKB, also known as AKT)/mammalian target of rapamycin (mTOR). mTOR is involved in multiple biological processes. Over-activation of the mTOR pathway improves viral replication, which makes it a possible target in COVID-19 therapy. Clinical data shows the hyperactivation of the mTOR pathway in lung tissues during respiratory viral infections. However, the exact impact of mTOR pathway inhibitors on the COVID-19 severity and death rate is yet to be thoroughly investigated. There are several mTOR pathway inhibitors. Rapamycin is the most famous inhibitor of mTORC1 among all. Studies on other respiratory viruses suggest that the therapeutic inhibitors of the mTOR pathway, especially rapamycin, can be a potential approach to anti-SARS-CoV-2 therapy. Using therapeutic methods that inhibit harmful immune responses can open a new chapter in treating severe COVID-19 disease. We highlighted the potential contribution of PI3K/Akt/mTOR inhibitors in the treatment of COVID-19.

Correlation between aryl hydrocarbon receptor and IL-17+ and Foxp3+ T-cell infiltration in bladder cancer.

Bladder cancer (BC) is one of the most prevalent cancers around the world and, if not treated well, has high morbidity and mortality. Many studies have indicated that there may be various roles for the aryl hydrocarbon receptor (AHR) in the immune system. The aim of this study was to determine the frequency of Foxp3+ regulatory T (Treg) and T helper 17 cells (Th17) in BC tissue in comparison with controls and determine the relationship between AHR, Foxp3+ Treg and Th17 cells in BC. A total of 40 patients with BC were enrolled in this study. The control group was selected from non-tumoural parts of bladder tissues from the patients who have undergone cystoscopy. The percentage of regulatory T cells (Foxp3+ /CD4+ ) and Th17 (IL-17+ /CD4+ ), as well as AHR+ cells in BC tissues and controls, were determined by immunohistochemistry. The results of this study showed that the number of Foxp3+ Treg and Th17 is significantly higher in bladder tumour tissues in comparison with non-tumoural tissues. Also, the percentage of AHR+ lymphocytes and AHR+ cells was increased significantly in bladder tumour tissues rather than non-tumoural tissues. This study also found a relation between AHR and Foxp3+ /CD4+ T lymphocytes ratio cells in BC. The percentage of Foxp3+ Tregs and AHR+ cells were significantly correlated with the grade and stage of BC. An increase in the percentage of Foxp3+ Treg and Th17 cells may play an important role in tumour immunity; and determining the relationship between AHR and differentiation of Th17/Foxp3+ Treg in BC can lead to a potential cancer therapeutic possibility.

The association of VEGF rs833061 and rs2010963 polymorphisms with susceptibility to colorectal cancer in an Iranian population.

Vascular endothelial growth factor (VEGF) is one of the most important regulators of angiogenesis. Several single nucleotide polymorphisms (SNPs) are associated with the VEGF overexpression and tumor progression in several cancers. This study aimed to determine the association of VEGF rs833061 and rs2010963 polymorphism and their haplotypes with susceptibility to colorectal cancer (CRC) in the Iranian population. A total of 284 colorectal cancer patients (37.3% women, 62.7% men) were enrolled in this study. Healthy controls without evidence of cancer history or family cancer predispositions were frequency-matched to the cases by sex and age (± 5 years). Genotyping was performed by the Sequenom mass ARRAY method and the genotype distribution and risk estimate were analyzed by SPSS software. The correlation between the genotypes and clinicopathological parameters (Dukes stage, phenotype, location, differentiation, and tumor size) among colorectal cancer patients were investigated. We found a significant relationship, between rs833061T/C genotype and their TG haplotype with the age of diagnosis < 60; (p = 0.012, p = 0.014) and rs2010963G/C genotype with female gender and TG haplotype with third and fourth tumor stage and tumor location (p = 0.04and p = 0.047). This study showed that rs833061T/C genotype and TG haplotype increase the susceptibility to colon cancer in the Iranian population. This susceptibility has a significant relationship with the age of diagnosis and different stages of the tumor.

Serum levels of IL-32 in patients with coronary artery disease and its relationship with the serum levels of IL-6 and TNF-α.

The coronary artery disease (CAD) is a chronic inflammatory disease caused by atherosclerosis, in which arteries become clogged due to plaque formation, fat accumulation, and various sorts of immune cells. IL-32 is a proinflammatory cytokine, which enhances inflammation through inducing the secretion of different inflammatory cytokines. The main objective of the current study was to assess the serum levels of IL-32 in subjects with obstructive CAD and its relationship with the serum levels of IL-6 and TNF-α. This study was performed on 42 subjects with obstructive CAD and 42 subjects with non-obstructive CAD. The serum levels of TNF-α, IL-6, and IL-32 were measured using the enzyme-linked immunosorbent assay (ELISA). The serum levels of TNF-α, IL-6, and IL-32 were 3.2, 3.48, and 2.7 times higher in obstructive CAD compared to non-obstructive CAD, respectively. Moreover, the serum levels of TNF-α and IL-32 in obstructive CAD with cardiac arterial stenosis in one major vessel were significantly higher than the levels in obstructive CAD with cardiac arterial stenosis in more than one major vessel. ROC curve analysis revealed that the serum levels of TNF-α, IL-6, and IL-32 were good predictors of obstructive CAD. Moreover, multiple logistic regression analyses suggested that the serum levels of TNF-α, IL-6, IL-32, LDL, and ox-LDL were independently related to the presence of obstructive CAD, while serum levels of HDL were not. TNF-α, IL-32, and IL-6 showed an increase in obstructive CAD, and the serum levels of these cytokines showed a satisfactory ability for predicting obstructive CAD.

The relation between the ghrelin receptor and FOXP3 in bladder cancer.

Immune responses play an important role in the fate of bladder cancer tumors. Treg cells are immunosuppressive and down-regulate the proliferation of effector T cells, which favor tumor survival. Ghrelin is a hormone that stimulates release of growth hormone and anti-inflammatory response to cancer cells. Ghrelin also is a gastrointestinal hormone that regulates immune responses via the growth hormone secretagogue receptor (GHS-R1a). The relation among ghrelin, its receptor, and Treg cells that surround bladder tumors is not clear. We found that Foxp3+ T and GHS-R1a cells are increased significantly in bladder tumor tissues. Therefore, we suggest that ghrelin may increase the number of Treg cells in the tumor and suppress activity of the immune system against bladder cancer.