Novel insights in CAR-NK cells beyond CAR-T cell technology; promising advantages.

CAR-T (chimeric antigen receptor T cell) technology, which has recently showed successful results in the treatment of hematological tumors, has been the focus of attention as one of the most potent approaches in tumor immunotherapy. However, side effects and limitations of this application, such as the risk of graft versus host disease (GvHD), make it challenging to be as accessible as other treatments. Natural killer cells (NK) could be transplanted without alloreactivity, making them as an off-the-shelf product. CAR-NK (chimeric antigen receptor NK cell) therapy can circumvent some serious limitations of CAR-T cell therapy. Application of CAR-NK cells have some considerable advantages over CAR-T cells. These include lack of cytokine release syndrome (CRS), neurotoxicity, and GvHD when using allogenic CAR-T cell. These features lessen the risk of tumor antigen loss and disease relapse. Moreover, NK cells which were derived from different sources, can make the CAR therapy more feasible. In this narrative review, we outlined the key features of CAR-NK cells as an alternative to CAR-T cell therapy in cancer immunotherapy and highlighted the main advantages.

Association between complement gene polymorphisms and systemic lupus erythematosus: a systematic review and meta-analysis.

Complement dysfunction results in impaired ability in clearing apoptotic cell debris that may stimulate autoantibody production in systemic lupus erythematosus (SLE). Herein, we provided a comprehensive search to find and meta-analyze any complement gene polymorphisms associated with SLE. The ITGAM, C1q, and MBL gene polymorphisms were included in this meta-analysis to reveal the exact association with SLE risk. Electronic databases, including Scopus, PubMed, and Google Scholar, were searched to find studies investigating the ITGAM, C1q, and MBL gene polymorphisms and SLE risk in different populations. The pooled odds ratio (OR) and its corresponding 95% confidence interval (CI) were used to analyze the association between ITGAM, C1q, and MBL gene polymorphisms and susceptibility to SLE. According to inclusion criteria, a total of 24 studies, comprising 4 studies for C1QA rs292001, 5 studies for C1QA rs172378, 9 studies for ITGAM rs1143679, 8 studies for MBL rs1800450, 3 studies for MBL2 rs1800451, and 3 studies for MBL2 rs5030737, were included in the final meta-analysis. A significant positive association was found between rs1143679 and SLE risk, while rs1800451 significantly associated with decreased SLE susceptibility. In summary, ITGAM gene rs1143679 SNP and MBL gene rs1800451 SNP were positively and negatively associated with SLE risk, respectively.

Toll-Like Receptor-Based Strategies for Cancer Immunotherapy.

Toll-like receptors (TLRs) are expressed and play multiple functional roles in a variety of immune cell types involved in tumor immunity. There are plenty of data on the pharmacological targeting of TLR signaling using agonist molecules that boost the antitumor immune response. A recent body of research has also demonstrated promising strategies for improving the cell-based immunotherapy methods by inducing TLR signaling. These strategies include systemic administration of TLR antagonist along with immune cell transfer and also genetic engineering of the immune cells using TLR signaling components to improve the function of genetically engineered immune cells such as chimeric antigen receptor-modified T cells. Here, we explore the current status of the cancer immunotherapy approaches based on manipulation of TLR signaling to provide a perspective of the underlying rationales and potential clinical applications. Altogether, reviewed publications suggest that TLRs make a potential target for the immunotherapy of cancer.

microRNAs are potentially regulating the survivin gene in PBMCs from systemic sclerosis patients.

Background: Survivin is an important anti-apoptotic protein and is involved in increasing auto-reactivity during the autoimmune diseases like systemic sclerosis (SSc).Aims: In the current study, we investigate the expression level of total survivin (survivin-TS) and its three important variants alongside with evaluation of the expression level of important microRNAs (miRNAs) that are involved in survivin expression regulation.Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 50 healthy controls, 25 diffuse cutaneous SSc (DcSSc), and 25 limited cutaneous SSc (LcSSc) patients. RNA was extracted and single-strand cDNA was synthesized. Quantitative real-time PCR was used to evaluate the expression level of survivin-TS and its variants as well the miRNAs.Results: Overexpression of survivin-2B and downregulation of survivin wild-type (survivin-WT) were found in total-SSc patients; however, expression level of survivin-TS had no significant difference. The expression levels of miR-335-5p, miR-485-5p, miR-16-5p, miR-150-5p, miR-34a-5p, miR-218-5p and miR-708-5p were higher in total-SSc patients. Significantly negative correlations were found between transcript levels of miR-150-5p, miR-16-5p, and miR-485-5p with survivin-TS mRNA expression.Conclusion: Survivin variants had altered expression in total-SSc patients. In addition, miRNAs might potentially and negatively regulate the survivin-TS expression. Altered expression of survivin, regulated by miRNAs, may result in apoptosis resistance and auto-reactivity in lymphocytes from patients and have important roles in SSc pathogenicity.

microRNA involvement in the regulation of survivin in peripheral blood mononuclear cells from rheumatoid arthritis patients.

AIM: Impaired regulation of immune tolerance results in autoimmune diseases, such as rheumatoid arthritis (RA). Survivin is an anti-apoptotic protein and can induce cellular mitosis. In the current study, we assessed the transcript level of total survivin (survivin-TS) and its three major variants and evaluated the expression level of important micro RNAs (miRNAs) involved in survivin expression regulation in RA patients. METHOD: Peripheral blood mononuclear cells (PBMCs) were isolated from 50 healthy controls and 50 RA-active patients. RNA extraction was performed and then single-strand complementary DNA was synthesized. Quantitative real-time polymerase chain reaction was used to assess the expression level of survivin-TS and its variants with effective miRNAs in PBMCs. RESULTS: Overexpression of survivin-2B (fold change = 1.57, P = 0.005), survivn-ΔEx3 (fold change = 1.93, P = 0.009) and downregulation of survivin-WT (fold change = 0.64, P = 0.0002) were found in PBMCs of patients, while messenger RNA (mRNA) expression of survivin-TS had no significant difference between RA patients and controls. Expression levels of miR-335-5p, miR-485-5p, miR-16-5p, miR-150-5p, miR-34a-5p, and miR-203a-3p were significantly increased in PBMCs from patients compared with healthy controls. In a correlation study, dysregulation of these miRNAs were not correlated with mRNA expression level of survivin. CONCLUSION: While survivin-TS was not differently expressed in RA patients, its variants had altered expression. Although miRNAs were aberrantly expressed in PBMCs from RA subjects, they did not regulate survivin-TS. miRNAs might be involved in RA pathogenesis, but not through controlling survivin.

Studying the Association between STAT4 Gene Polymorphism and Susceptibility to Rheumatoid Arthritis Disease: An Updated Meta-Analysis.

BACKGROUND: STAT4 is a transcription factor that plays a role in various cytokine signaling pathways and in T cell subsets differentiation. Several studies have reported STAT4 gene polymorphism in association with various autoimmune diseases. OBJECTIVE: To evaluated the association between STAT4 rs7574865 SNP and RA risk by meta-analysis. METHODS: Two major databases, namely Scopus and PubMed, were searched to find studies investigating the STAT4 polymorphism and RA in different populations up to November 2017. Association between STAT4 polymorphism and RA were analyzed using pooled odds ratio (OR) and their corresponding 95% CI. RESULTS: In this meta-analysis, 21 population studies (16 papers) comprising 15,732 cases and 15641 healthy subjects evaluating the STAT4 gene rs7574865 SNP were included based on inclusion criteria. Herein, we found a significant positive association between minor T allele as well as different genotypes with the risk of RA. CONCLUSIONS: In summary, this study revealed an association between STAT4 gene rs7574865 SNP and risk of RA.

Survivin and autoimmunity; the ins and outs.

Autoimmunity is a status that immune mechanisms react against self-structure. The immune mechanisms, including cellular and molecular elements have been developed to immune body against foreign invades. Multiple factors such as genetic and epigenetic background, hormonal status, microbiome, and other factors can cause launching the autoreactive responses, in which the immune tolerance breaks and immune mechanisms are against self-antigens. Apoptosis is one of the important mechanisms in maintaining the tolerance and eliminating the autoreactive lymphocyte clones. Due to survivin roles in apoptosis and proliferation, numerous researches have been paying attention to survivin expression and function in autoreactive lymphocytes and tissue cells, playing important roles in the pathogenesis of autoimmune diseases. New line of evidence has been supporting the role of survivin dysfunction or aberrant expression in deriving autoreactive lymphocytes or some important immune tissues, which may underpin the autoimmune conditions such as Lichen planus (LP), Rheumatoid arthritis (RA), Systemic lupus erythematosus (SLE), Myasthenia gravis (MG), Multiple sclerosis (MS), Systemic sclerosis (SSc), Psoriasis, and Inflammatory bowel disease (IBD). Hence, the purpose of the current paper was to review the survivin role in the etiology and pathogenesis of abovementioned autoimmune diseases.