Potential roles of NLRP3 inflammasome in the pathogenesis of Kawasaki disease.

There is a heterogeneous group of rare illnesses that fall into the vasculitis category and are characterized mostly by blood vessel inflammation. Ischemia and disrupted blood flow will cause harm to the organs whose blood arteries become inflamed. Kawasaki disease (KD) is the most prevalent kind of vasculitis in children aged 5 years or younger. Because KD's cardiovascular problems might persist into adulthood, it is no longer thought of as a self-limiting disease. KD is a systemic vasculitis with unknown initiating factors. Numerous factors, such as genetic predisposition and infectious pathogens, are implicated in the etiology of KD. As endothelial cell damage and inflammation can lead to coronary endothelial dysfunction in KD, some studies hypothesized the crucial role of pyroptosis in the pathogenesis of KD. Additionally, pyroptosis-related proteins like caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), proinflammatory cytokines like IL-1 and IL-18, lactic dehydrogenase, and Gasdermin D (GSDMD) have been found to be overexpressed in KD patients when compared to healthy controls. These occurrences may point to an involvement of inflammasomes and pyroptotic cell death in the etiology of KD and suggest potential treatment targets. Based on these shreds of evidence, in this review, we aim to focus on one of the well-defined inflammasomes, NLRP3, and its role in the pathophysiology of KD.

The potential roles of Th17 cells in the pathogenesis of oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is a T cell-mediated chronic autoimmune disease, whose pathogenesis and etiology are not entirely understood. OLP is characterized by subepithelial lymphocyte infiltration and elevated intra-epithelial lymphocytes. The majority of lamina propria lymphocytes are CD4+ T cells. CD4+ helper T (Th) cells play a crucial role in activating CD8+ cytotoxic T cells (CTLs) through interactions and cytokine production. Th1 and Th2 cells are well-accepted to be associated with OLP pathogenesis. However, OLP treatment is challenging yet, the more information we have about the pathology of OLP, the easier it will be treated. With the discovery of Th17 cells in recent years and the demonstration of their role in autoimmune disease, many researchers started to investigate the role of Th17 in the pathogenesis of OLP. METHODS: To make up this review, studies covering the role of TH17 in different types of lichen planus were selected from major databases. RESULTS: As we review in this article, Th17 cells and their signature cytokines play an important role in OLP pathogenesis. As well, utilizing some anti-IL-17 antibodies showed promising results in improving the disease; however, more studies are still needed to better understand and treat OLP.

Potential roles of hsa_circ_000839 and hsa_circ_0005986 in breast cancer.

BACKGROUND: Breast cancer (BC) is one of the leading causes of death among women around the world. Circular RNAs (circRNAs) are a newly discovered group of non-coding RNAs that their roles are being investigated in BC and other cancer types. In this study, we evaluated the association of hsa_circ_0005986 and hsa_circ_000839 in tumor and adjacent normal tissues of BC patients with their clinicopathological characteristics. MATERIALS AND METHODS: Total RNA was extracted from tumors and adjacent non-tumor tissues by the Trizol isolation reagent, and cDNA was synthesized using First Strand cDNA Synthesis Kit (Thermo Scientific). The expression level of hsa_circ_0005986 and hsa_circ_000839 was quantified using RT-qPCR. Online in silico tools were used for identifying potentially important competing endogenous RNA (ceRNA) networks of these two circRNAs. RESULTS: The expression level of hsa_circ_0005986 and hsa_circ_000839 was lower in the tumor as compared to adjacent tissues. The expression level of hsa_circ_0005986 in the patients who had used hair dye in the last 5 years was significantly lower. Moreover, a statistically significant negative correlation between body mass index (BMI) and hsa_circ_000839 expression was observed. In silico analysis of the ceRNA network of these circRNAs revealed mRNAs and miRNAs with crucial roles in BC. CONCLUSION: Downregulation of hsa_circ_000839 and hsa_circ_0005986 in BC tumors suggests a tumor-suppressive role for these circRNAs in BC, meriting the need for more experimentations to delineate the exact mechanism of their involvement in BC pathogenesis.

Hsa_circ_0000479/Hsa-miR-149-5p/RIG-I, IL-6 Axis: A Potential Novel Pathway to Regulate Immune Response against COVID-19.

Background: COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global pandemic and mortality of people around the world. Some circular RNAs (circRNAs), one of the new types of noncoding RNAs (ncRNAs), act as competing endogenous RNAs (ceRNAs) and compete with mRNAs for shared miRNAs, to regulate gene expression. In the present study, we aimed to evaluate the expression and roles of hsa_circ_0000479/hsa-miR-149-5p/RIG-I, IL-6 in COVID-19 infection. Materials and Methods: After extraction of total RNA from peripheral blood mononuclear cells (PBMC) of 50 patients with symptomatic COVID-19, 50 patients with nonsymptomatic COVID-19, and 50 normal controls, cDNA synthesis was performed. Online in silico tools were applied to evaluate the interaction between the genes in the hsa_circ_0000479/hsa-miR-149-5p/RIG-I, IL-6 axis, and its role in COVID-19-related pathways. Quantification of the expression of these genes and confirmation of their interaction was done using the quantitative real-time PCR (qRT-PCR) technique. Results: The expression levels of hsa_circ_0000479, RIG-I, and IL-6 were increased in COVID-19 patients compared to healthy controls, while hsa-miR-149-5p expression was decreased. Moreover, there was a significant negative correlation between hsa-miR-149-5p and hsa_circ_0000479, RIG-I, IL-6 expressions, and also a positive expression correlation between hsa_circ_0000479 and IL-6, RIG-I. Then, bioinformatics tools revealed the role of hsa_circ_0000479/hsa-miR-149-5p/RIG-I, IL-6 axis in PI3K-AKT and STAT3 signaling pathways. Conclusion: Upregulation of hsa_circ_0000479, RIG-I, and IL-6, and downregulation of hsa-miR-149-5p, along with correlation studies, indicate that hsa_circ_0000479/hsa-miR-149-5p/RIG-I, IL-6 axis could play a role in regulating the immune response against SARS-CoV-2. However, more studies are needed in this area.

The role of magnesium in different inflammatory diseases.

Magnesium deficiency (MgD) can cause inflammation in human body. The known mechanisms of inflammation caused by MgD include activation of phagocytic cells, opening of calcium channels, activation of the N-methyl-D-aspartate (NMDA) receptor, and activation of nuclear factor (NF)-κB. In addition, MgD causes systemic stress response through neuroendocrinological pathways. The inflammation caused by MgD can result in pro-atherogenic changes in the metabolism of lipoproteins, endothelial dysfunction, and high blood pressure. Studies suggest that magnesium may play an important role in the pathophysiology of some inflammatory diseases. Several clinical trials and laboratory studies have been done on the functional role of magnesium. In this study, we review some inflammatory diseases, in which the magnesium has a role in their pathophysiology. Among these diseases, diabetes, asthma, preeclampsia, atherosclerosis, heart damage, and rheumatoid arthritis have been highlighted.

CircRNA-associated ceRNA networks (circCeNETs) in chronic obstructive pulmonary disease (COPD).

Chronic obstructive pulmonary disease (COPD), a chronic airway disorder, which is mostly brought on by cigarette smoke extract (CSE), is a leading cause of death which has a high frequency. In COPD patients, smoking cigarette could also trigger the epithelial-mesenchymal transition (EMT) of airway remodeling. One of the most significant elements of environmental contaminants that is linked to pulmonary damage is fine particulate matter (PM2.5). However, the basic processes of lung injury brought on by environmental contaminants and cigarette smoke are poorly understood, particularly the molecular pathways involved in inflammation. For the clinical management of COPD, investigating the molecular process and identifying workable biomarkers will be important. According to newly available research, circular RNAs (circRNAs) are aberrantly produced and serve as important regulators in the pathological processes of COPD. This class of non-coding RNAs (ncRNAs) functions as microRNA (miRNA) sponges to control the levels of gene expression, changing cellular phenotypes and advancing disease. These findings led us to concentrate our attention in this review on new studies about the regulatory mechanism and potential roles of circRNA-associated ceRNA networks (circCeNETs) in COPD.

Potential roles of inflammasomes in the pathophysiology of Psoriasis: A comprehensive review.

Psoriasis is an inflammatory skin disease whose pathophysiology is attributed to both innate and adaptive immune cells and molecules. Despite the crucial roles of the immune system in psoriasis, it cannot be categorized as an autoimmune disease because of the lack of main signs of autoimmunity, such as specific antibodies, well-defined antigens, and autoimmune genetic risk factors. The presence of some cellular and molecular properties, such as the presence of neutrophils in skin lesions and the activation of the innate immune system, attributes psoriasis to a group of diseases called autoinflammatory disorders. Autoinflammatory diseases refer to a group of inherited disorders whose main manifestations are recurrent fever, a high level of acute-phase reactant, and a tendency for inflammation of the skin, joints, and other organs like the nervous system. In most autoinflammatory disorders, it has been seen that complexes of the high-molecular-weight protein named inflammasomes have significant roles. The inflammasome complex usually is formed and activated in the stimulated immune cell cytoplasm, and its activation consequently leads to inflammatory events such as producing of active caspase-1, mature interleukin-1ß (IL-1ß), and IL-18 and can cause an inflammatory programmed cell death called pyroptosis. Since the identification of inflammasomes, it has been shown that there are close links between them and hereditary and acquired autoinflammatory diseases like psoriasis. In this review, we aim to focus on well-defined inflammasome and their role in the pathophysiology of psoriasis.

Natural killer cells and killer cell immunoglobulin-like receptors in solid organ transplantation: Protectors or opponents?

Among all the cells of innate immunity, natural killer (NK) cells are well-known for the fight against tumors and virally-infected cells. NK cells have been implicated in the pathogenesis of immune-mediated allograft damage, but mounting evidence suggests they can potentially promote allograft tolerance as well. In addition, NK cells express a wide variety of activating and inhibiting receptors, and the signals sent by these molecules, particularly killer cell immunoglobulin-like receptors (KIRs), determine their ultimate function. The role of KIRs and their human leukocyte antigen (HLA) class I ligands have been extensively investigated in hematopoietic stem cell transplantation (HSCT). Previous studies have suggested that, in the setting of solid organ transplantation, having certain KIR genes or KIR/HLA combinations probably affects allograft survival. Therefore, it may be helpful to analyze KIR/HLA combinations in donors and recipients to choose the optimal donor, anticipate harmful effects post-transplantation, and develop NK cell-based immunotherapies to enhance the success of solid organ transplantation. In this review, we will discuss the dual function of NK cells in solid organ transplantation, followed by a brief introduction to KIRs and the association of KIR and HLA genes with kidney, liver, and lung transplant outcomes.

Potential Roles of Long Noncoding RNAs as Therapeutic Targets in Organ Transplantation.

Organ transplantation is the most preferred treatment option for end-stage organ diseases; however, allograft rejection is the major hurdle in successful long-term transplant survival. In spite of developing better HLA matching and more effective immunosuppressive regimen, one-year graft survival has been increased by nearly 90% and the incidence of acute rejection by one-year post-transplantation has been decreased by 12.2% in the last decades, chronic allograft rejection has remained as one of the major obstacles to the long-lasting survival of the transplanted allograft. Therefore, seemingly preventing the allograft rejection and inducing immunological tolerance against transplanted allografts is one of the primary goals in transplantation research to enable long-lasting graft survival. Various mechanisms such as long noncoding RNAs (lncRNAs) have been proposed that induce immune tolerance by modulating the gene expression and regulating innate and adaptive immune responses during transplantation. Besides, because of involvement in regulating epigenetic, transcriptional, and post-translational mechanisms, lncRNAs could affect allograft status. Therefore, these molecules could be considered as the potential targets for prediction, prognosis, diagnosis, and treatment of graft rejection. It is suggested that the noninvasive predictive biomarkers hold promise to overcome the current limitations of conventional tissue biopsy in the diagnosis of rejection. Hence, this review aims to provide a comprehensive overview of lncRNAs and their function to facilitate diagnosis, prognosis, and prediction of the risk of graft rejection, and the suggestive therapeutic choices after transplantation.

Investigating the Role of BAFF and Its Receptors in Renal Transplant Recipients with Chronic Antibody-Mediated Rejection.

BACKGROUND: Kidney transplantation is the best treatment option for end stage renal disease (ESRD), but graft rejection is still a big obstacle that occurs in spite of immunosuppressive therapy. B cells are considered as the major reason for renal graft rejection because of antibody production. Due to their roles in B cell function, we intended to evaluate the B cell activating factor (BAFF) and its receptors including BAFF receptor (BAFF-R), B cell maturation antigen (BCMA), and transmembrane activator and cyclophilin ligand interactor (TACI) in renal transplant patients. METHOD: The study included 40 kidney allograft patients with cAMR, 40 stable kidney allograft patients, and 8 healthy volunteers with normal kidney function. The percentage and absolute number of CD19+ B cells were analyzed by flow cytometry, the serum level of BAFF was analyzed by ELISA, and mRNA expressions of BAFF and BAFF receptors (BAFF-R, BCMA, and TACI) were measured using quantitative real-time PCR. RESULTS: The percentage and the absolute number of B cells decreased significantly in stable and cAMR patients compared to healthy individuals. The serum level and gene expression of BAFF, as well as the mRNA level of BCMA, were increased significantly in both cAMR and stable patients compared to healthy volunteers. There was an overexpression of TACI mRNA in cAMR patients compared to stable patients. CONCLUSIONS: Both soluble protein and mRNA transcript of BAFF increased in transplant recipients. However, BAFF neither at the serum level nor at the mRNA transcript level cannot be a good biomarker for the prediction of cAMR. In addition, expression of TACI, compared to other receptors of BAFF, confers a potential to be used in distinguishing cAMR and stable kidney transplant patients.

Anti-inflammatory activity of a natural herbal-marine drug (MS14 - SANT and SUSP) compared to sodium salicylate or methylprednisolone in a rat model for multiple sclerosis.

A natural compound of marine herbal origin has been used in Persian Traditional Medicine to relieve some symptoms of multiple sclerosis. The present study investigated the anti-inflammatory effects of a patented extracts of the traditional receipt (MS14). In this preliminary experiment, we used seven groups of six rats: the control group received vehicle, the two positive control groups were treated with either sodium salicylate (300 mg/kg) intraperitoneal (i.p.) or methyl prednisolon (MPN 10 mg/kg) i.p., while the test groups were treated with a solution centrifuged MS14 (SANT 100 mg/kg) and suspension of MS14 (SUSP 100, 150, 300 mg/kg) i.p. After thirty minutes, paw volume was measured by plethysmometer and immediately formalin solution was injected subcutaneously into the hind paw and after an hour, inflamed paw volume was measured. In days 2-8, the inflamed paw volume was measured and immediately drugs were injected i.p. The anti-inflammatory effect of MPN was significant only on days 5 and 6. The anti-inflammatory effect of SS was significant only on the 6th day, while the anti-inflammatory effect of SANT MS14 (100 mg/kg) was also significant only on the 6th day. SUSP MS14 (150 mg/kg) significantly reduced edema from second to 6th day. Intra-peritoneal injection of SUSP MS14 with 300 mg/kg was toxic, so excluded from the study. This research indicates that the MS14 possesses an anti-inflammatory effect after intra-peritoneal administration. Comparative anti-inflammatory effects of MS14 with Glucocorticoids in this study, may justify a possible mechanism for its action in multiple sclerosis, if further studies will provid strong statistically confirmatory effects in animals and safety human trials.

Evaluation of Thymic Output and Regulatory T Cells in Kidney Transplant Recipients with Chronic Antibody-Mediated Rejection.

BACKGROUND: Regulatory T cells (Tregs) and recent thymic emigrants (RTEs) have an essential role in the regulation of allogeneic immune responses. However, their mechanisms of action in chronic antibody-mediated rejection (cAMR) are still unclear. In this study, we aimed to compare Treg and RTE levels between stable graft function (SGF) patients and cAMR subjects after kidney transplantation. METHOD: Mononuclear cells (MNs) were separated from peripheral blood, and flow cytometry analysis was performed for detection of CD4+ and CD25high as Treg markers and CD4+, CD31+, and CD45RA+ as RTE immunophenotyping markers. RESULT: The level of peripheral Treg cells was significantly lower in cAMR subjects in comparison to stable graft function patients. Moreover, SGF patients who had received cyclosporine A had a higher level of Treg in comparison to the tacrolimus recipients. Nevertheless, the RTE level between SGF and cAMR patients did not show any significant differences. CONCLUSION: It seems that Treg cells are significantly associated with transplant outcomes in cAMR patients, and prescribed immunosuppressive drugs can influence the frequency of this crucial subset of T cells. Although these drugs are beneficial and inevitable for allograft maintenance, more investigations are needed to elucidate their complete effects on different immune cell subsets which some of them like Tregs are in favor of transplant tolerance. Besides, the thymic output is seemingly not a beneficial biomarker for predicting cAMR; however, more in vivo and in vitro studies are needed for revealing the precise role of Tregs and RTEs in the transplantation context.

B cell modulation strategies in the improvement of transplantation outcomes.

Successful transplantation outcome is the final goal in most end stage and nonfunctional organs; however, despite using different therapeutic strategies, antibody-mediated rejection is still a big obstacle. B cells have a key role in transplant rejection by several functions, such as antibody production, antigen presenting, contribution in T cell activation, forming the germinal center, and tertiary lymphoid organs. Therefore, B cells modulation seems to be very crucial in transplant outcome. A double-edged sword function is considered for B cells during transplantation; On the one hand, antibody production against the transplanted organ induces antibody-mediated rejection. On the other hand, IL10 production by regulatory B (Breg) cells induces graft tolerance. Nowadays, several monoclonal antibodies (mAb) are available for B cell modulation that are routinely used in transplant recipients, among which rituximab (anti-CD20 mAb) act in eliminating B cells. However, there are some other monoclonal antibodies, such as epratuzumab and Inotuzumab ozogamicin (IO), which exert anti-CD22 activity, resulting in disruption of B cell functions and induction of tolerance in autoimmune disease or B cell malignancies; that notwithstanding, these mAbs have not yet been tried in transplantation. In this review, we focus on different methods for modulating the activity of B cells as well as induction of Breg cells, aiming to prevent the allograft rejection.

Intravenous Immunoglobulin Therapy in Myocarditis.

Myocarditis is an inflammatory disease of the myocardium with lymphocyte infiltration and myocyte necrosis leading to a wide range of clinical presentations including heart failure, arrhythmia, and cardiogenic shock. Infectious and noninfectious agents may trigger the disease. The fact that immunosuppressive drugs are useful in several kinds of autoimmune myocarditis is proof of the autoimmune mechanisms involved in the development of myocarditis. Pathogenic mechanisms in myocardial inflammation are including inflammasome activation followed by myocyte destruction, myocarditis, and pericarditis. Intravenous immunoglobulin (IVIG) is a serum product made up of immunoglobulins, widely used in a variety of diseases. This product is effective in several immune-mediated pathologies. As well as the determined usage of IVIG in Kawasaki disease, IVIG may be useful in several kinds of heart failure including fulminant myocarditis, acute inflammatory cardiomyopathy, Giant Cell Myocarditis, and peripartum cardiomyopathy. Generally, IVIG is used in two different doses of low dose (200 to 400 mg/kg) and high dose (2 g/kg) regimen. The exact therapeutic effects of IVIG are not clear, however over the last decades, our knowledge about its mechanism of function has greatly enhanced. IVIG administration should be based on the accepted protocols of its transfusion. In this review article, we try to provide an overview of the different kinds of myocarditis, pathologic mechanisms and their common treatments and evaluation of the administration of IVIG in these diseases. Furthermore, we will review current protocols using IVIG in each disease individually.

IL-27 and autoimmune rheumatologic diseases: The good, the bad, and the ugly.

The footprint of cytokines is evident in almost every biological process, such as development, as well as the pathogenesis of the different diseases, immune responses to pathogens, etc. These small proteins are categorized into different functional classes; for instance, they can play a pro-inflammatory or anti-inflammatory role in different situations, or they can confer a polarization to the immune system. Interleukin (IL)-27 is a member of the IL-12 family. Antigen-presenting cells are the primary source of IL-27 production, which exerts its effects by bindings to the IL-27 receptor expressed on the surface of target cells. Interaction of IL-27 and IL-27 receptor leads to activation of the JAK-STAT and p38 MAPK signaling pathways. Most studies focused on the inflammatory effects of this cytokine, but gradually anti-inflammatory effects were also revealed for this cytokine, which changed the traditional perception of the function of this cytokine. The functionality of IL-27 in the pathogenesis of rheumatic diseases has been attributed to a double-blade sword. Hence, novel therapeutic approaches have been devised targeting IL-12 family that has been accompanied with promising results. In this review, we focused on the inflammatory and anti-inflammatory properties of IL-27 in different autoimmune rheumatologic diseases and its plausible therapeutic potentials.

Transitional immature regulatory B cells and regulatory cytokines can discriminate chronic antibody-mediated rejection from stable graft function.

BACKGROUND: The balance between inflammatory and anti-inflammatory responses of the immune system has been demonstrated to determine the fate of transplanted allografts. Here we analyzed CD19+CD24hiCD38hi immature transitional regulatory B (TRB) cells, as well as the gene and protein levels of interleukin (IL)-10 and transforming growth factor (TGF)-ß in the three separate groups, include of stable transplanted subjects, chronic antibody-mediated rejection (cAMR) patients, and healthy individuals. METHOD: Peripheral blood mononuclear cells (PBMCs) from stable subjects (n = 36), cAMR patients (n = 36) and healthy controls (n = 18) were isolated. Flowcytometry was performed for CD19, CD24, and CD38 surface markers. ELISA and quantitative real-time PCR were performed for IL-10 and TGF-ß cytokines. RESULT: The percentages of immature TRB cells were significantly decrease in cAMR patients (0.98%) versus stable recipients (2.81%) and healthy subjects (4.03%) (P = 0.001 and P < 0.001, respectively). Total lymphocytes, circulating B cells, memory and mature subsets of B cells did not show any significant difference between the groups. TGF-ß mRNA was 3-fold upregulated in the cAMR group compared to stable patients (P < 0.001.), but without significant alteration at the protein level. Also, long-term survival renal transplant recipients had a higher protein but not mRNA levels of IL-10 than short-term survival renal transplant recipients. CONCLUSION: It seems that immature TRB cell subpopulation might be a crucial regulator of immune system response and plays an important role in determining the transplantation outcome. Furthermore, immunosuppressive IL-10 and TGF-ß cytokines might act as a double sword and can exhibit either pathogenic or protective effects against allograft.

Interferon regulatory factors: Where to stand in transplantation.

Interferon regulatory factors (IRFs) are implicated in regulating inflammatory responses to pathogens and alloantigens. Since transplantation is usually accompanied by ischemia reperfusion injury (IRI), acute and chronic rejections, as well as immunodeficiency due to immunosuppressive drugs, IRFs seem to play a considerable role in allograft outcome. For instance, IRF-1 has been shown to be involved in pathogenesis of IRI; however, IRF-2 exhibits an opposite function. Some IRF-3 and 5 SNPs are associated with better or worse graft survival rates. Of note, IRF-4 inhibition has resulted in improved transplant outcomes. Herein we review available studies about IRFs influence on various stages of transplantation.

Increased Serum Levels of IL-17A and IL-23 Are Associated with Decreased Vitamin D3 and Increased Pain in Osteoarthritis.

INTRODUCTION: Osteoarthritis (OA) is the most common type of arthritis and proinflammatory cytokines have been considered as the main etiologic factor in the pathogenesis of the disease. Serum levels of cytokines, that are associated with innate immunity and TH1 cells, have been analyzed in OA patients, however, there is limited research that profiles cytokines associated with Th17 cells and their relation to vitamin D3 and pain. MATERIAL AND METHODS: The sera from 131 patients with OA and 262 healthy controls were evaluated for serum levels of IL-17A, IL-21, IL-23 and vitamin D3 using ELISA. RESULTS: Serum levels of IL-17A, and IL-23 were statistically higher in OA patients than in healthy controls, while IL-21 and vitamin D3 were significantly lower in OA patients when compared to controls. A significant positive correlation was found between the serum levels of IL-17A and IL-23 using WOMAC pain scores and vitamin D3 serum levels. DISCUSSION: The results suggest that IL-17A plays a significant role in OA pathogenesis and the induction of pain. Decreased serum levels of vitamin D3 may reflect a positive role played by the factor in the regulation of immune responses in OA patients.