Comparison of the efficacy of combined budesonide and fexofenadine versus combined fluticasone propionate and fexofenadine on the expression of class-4 semaphorins and their receptors in the peripheral blood cells of patients with allergic rhinitis.

Background: Allergic rhinitis (AR) is a common immunoglobulin (Ig) E-mediated disease. This study aimed to evaluate the gene expression levels of class 4 semaphorins and their receptors in AR patients before and after treatment with budesonide and fexofenadine (B/F) compared to fluticasone propionate and fexofenadine (FP/F). Methods: In this study, 29 AR patients (age 34.4 ± 1.2 years, 18 men and 11 women) were treated with B/F, and 24 AR patients (age 32.8 ± 1.9 years, 15 men and 9 women) were treated with FP/F for one month. Before and after treatment, peripheral blood samples were taken from patients. The expression levels of SEMA4A, SEMA4C, SEMA4D, Plexin-B2, and Plexin-D1 genes were measured using the qPCR method. In addition, the serum levels of IgE were measured using an enzyme-linked immunosorbent assay (ELISA). Results: The expression levels of SEMA4A (P = 0.011), 4C (P = 0.017), Plexin-B2 (P = 0.0005), and Plexin-D1 (P = 0.008) remarkably increased in AR patients treated with B/F. Our results show a significant reduction in the gene expression levels of SEMA4A (P = 0.002), 4C (P = 0.014), 4D (P = 0.003), Plexin-B2 (P = 0.033), and Plexin-D1 (P = 0.035) after treatment with FP/F. The serum levels of IgE increased in FP/F treated group (P = 0.017) and conversely decreased in the treated group with B/F (P = 0.019). Moreover, the percentages of eosinophils were reduced in both FP/F and B/F groups (P = 0.015 and P = 0.0001, respectively). Conclusion: In conclusion, concomitant use of fexofenadine and fluticasone propionate reduced SEMA4A, 4C, 4D, Plexin-B2, and Plexin-D1, while the SEMA4A, 4C, Plexin-B2, and Plexin-D1 gene expression levels were increased in the patient group treated with B/F.

Association of Single Nucleotide Polymorphisms (SNPs) of Chemoattractant Receptor23 (ChemR23) Gene with Susceptibility to Allergic Rhinitis.

The chemoattractant Receptor23 (ChemR23) plays an essential role in triggering and resolving acute inflammation. This study aimed to evaluate the association between four potentially functional SNPs of the chemR23 gene (rs4373981 G > C, rs73201532 C > T, rs35121177 G > A, and rs4964676 G > A) with susceptibility to Allergic rhinitis (AR). 130 patients with allergic rhinitis and 130 healthy individuals were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Our findings showed that genotypes and alleles frequencies were not significantly different between patient and control groups (p > 0.05). Furthermore, haplotype analysis (rs4373981, rs73201532, and rs4964676, respectively) revealed a protective effect of CTG, GTA, and GTG haplotypes against AR (p = 0.009, p = 0.0001, p = 0.001, respectively), and CCG, GCA, and GCG haplotypes of ChemR23 polymorphisms were associated with increased risk of AR (p = 0.03, p = 0.02, p = 0.0002, respectively). These findings suggested a possible role for ChemR23 in the pathogenesis of AR.

Association of IFIH1 and DDX58 genes polymorphism with susceptibility to COVID-19.

Pattern recognition receptors of the innate immune system, such as RIG-I and MDA5, are responsible for recognizing viruses and inducing interferon production. Genetic polymorphisms in the coding regions of RLR may be associated with the severity of COVID-19. Considering the contribution of the RLR signaling in immune-mediated reactions, this study investigated the association between three SNP in the coding region of IFIH1 and DDX58 genes with the susceptibility to COVID-19 in the Kermanshah population, Iran. 177 patients with severe and 182 with mild COVID-19 were admitted for this study. Genomic DNA was extracted from peripheral blood leukocytes of patients to determine the genotypes of two SNPs, rs1990760(C>T) and rs3747517(T>C) IFIH1 gene and rs10813831(G>A) DDX58 gene using PCR-RFLP method. Our results showed that the frequency of the AA genotype of rs10813831(G>A) was associated with susceptibility to COVID-19 compared to the GG genotype (p = 0.017, OR = 2.593, 95% CI 1.173-5.736). We also observed a statistically significant difference in the recessive model for SNPs rs10813831 variant (AA versus GG + GA, p = 0.003, OR = 2.901, 95% CI 1.405-6.103). Furthermore, No significant association was found between rs1990760 (C>T) and rs3747517(T>C) of IFIH1 gene polymorphisms with COVID-19. Our findings suggest that DDX58 rs10813831(A>G) polymorphism may be associated with COVID-19 severity in the Kermanshah population, Iran.

Dysregulation of Long Noncoding RNA NEAT1/miR-199a-5/BiP Axis in Patients with Diabetic Neuropathy.

OBJECTIVE: Diabetic neuropathy (DN) is a type of nerve damage and the most common complication of diabetes. Regarding the association between endoplasmic reticulum (ER) stress with the pathogenesis of neuropathy, this study aims to examine binding immunoglobulin protein (BiP) gene expression and long noncoding RNA nuclear enriched abundant transcript 1 (NEAT1), miR-199a-5 as its regulator in the peripheral blood of DN patients compared to diabetic patients without neuropathy. METHODS: Peripheral blood samples were obtained from DN (n = 20) patients and diabetic patients without neuropathy (non-DN) (n = 20). After RNA extraction from peripheral blood mononuclear cells, reverse transcription-quantitative polymerase chain reaction was performed to evaluate RNA expression. RESULTS: The results showed that the expression level of NEAT1 and BiP genes in the DN group increased significantly compared to the non-DN group. Also, the expression level of miR-199a-5p in the DN group was significantly downregulated. CONCLUSION: As a result, the axis of NEAT1, miR-199a-5p, and BiP may have a role in the DN pathogenesis.

Association of Rs7217186 Polymorphism of Arachidonic Acid 15-Lipoxygenase (ALOX15) Gene with Susceptibility to Allergic Rhinitis.

Background: Allergic rhinitis (AR) is an inflammatory disorder of the nasal mucosa, caused by exposure to environmental allergens. It is known that 15-lipoxygenase (15-LOX) is involved in the biosynthetic pathways of anti-inflammatory lipid mediators, including resolvins and protectins. Methods: In this study, which was performed on 130 AR patients and 130 healthy controls, we aimed to investigate the association of susceptibility to AR with two selected single-nucleotide polymorphisms (SNPs), that is, rs2619112:A>G and rs7217186:C>T, in the intron regions of arachidonic acid 15-LOX (ALOX15) gene, using SNPinfo and Regulome DB tools. Results: The results showed that the CT genotype of rs7217186: C>T was significantly associated with the increased risk of AR compared to the CC genotype (P= 0.037, OR=1.943, CI: 1.038-0.638). However, there was no strong evidence of the association of rs2619112: A>G with susceptibility to AR (P> 0.05). Conclusions: The present results indicated that rs7217186 polymorphism of ALOX15 gene might be a potential biomarker for susceptibility to AR.

Evaluation of the relationship between IL-6 gene single nucleotide polymorphisms and the severity of COVID-19 in an Iranian population.

BACKGROUND: Emerged coronavirus disease 2019 (COVID-19) is a pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). Disease severity is associated with elevated levels of proinflammatory cytokines, such as interleukin-6 (IL-6). Genetic polymorphisms in the regulatory regions of cytokine genes may be associated with differential cytokine production in COVID-19 patients. This study aimed to investigate the association between three potentially functional single-nucleotide polymorphisms (SNPs) in the promoter region of IL-6 and the severity of susceptibility to COVID-19 in an Iranian population. METHODS: In total, 346 individuals (175 patients with severe COVID-19 and 171 patients with mild COVID-19) were recruited for this cohort study. Genomic DNA was extracted from peripheral blood leukocytes of patients to determine the genotypes of three selected SNPs (rs1800795 (-174 G > C), rs1800796 (-572 G > C), and rs1800797 (-597 G > A)) in the promoter region of the IL-6 gene using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: There were no significant differences in the genotype or allele distribution of selected SNPs (rs1800795 (-174 G > C), rs1800796 (-572 G > C), and rs1800797 (-597 G > A)) in the promoter region of the IL-6 gene in patients with severe COVID-19 and patients with mild COVID-19. DISCUSSION: Our study indicated that these SNPs are not associated with COVID-19 severity in the Kurdish population from Kermanshah, Iran.

The axis of long non-coding RNA MALAT1/miR-1-3p/CXCR4 is dysregulated in patients with diabetic neuropathy.

Background: Diabetic neuropathy (DN) is a prevalent complication of diabetes mellitus characterized by pain and inflammation. Long non-coding RNAs (lncRNAs) have been associated with DN. This study aimed to investigate transcript levels of Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), microRNA (miR)-1-3p, and C-X-C motif chemokine receptor 4 (CXCR4) in the DN patients and type 2 diabetes mellitus (T2DM) cases without neuropathy. Methods: Here, 20 cases with DN and 20 T2DM subjects without neuropathy (as the control group) were included. Total RNA was extracted from peripheral blood mononuclear cells (PBMCs) of all participants. The expression levels of targets were evaluated by Real-time-PCR. Results: Results showed that MALAT1 (Fold change = 2.47, P = 0.03) and CXCR4 (Fold change = 1.65, P = 0.023) were significantly upregulated, while miR-1-3p was downregulated (Fold change = 0.9, P = 0.028) in whole blood samples from DN patients compared to the control group. A significant correlation was found between transcript levels of MALAT1 and CXCR4 (rho = 0.84; P < 0.0001). Conclusions: This study suggests a possible involvement of the MALAT1/miR-1-3p/CXCR4 axis in the pathogenesis of DN.

Association between IL-33 Gene Polymorphism (Rs7044343) and Risk of Allergic Rhinitis.

BACKGROUND: Allergic rhinitis (AR) is a T helper type 2 (Th2)-mediated upper airways disease in which genetics factors including cytokine genes play a prominent role. Interleukin-33 (IL-33) is a major cytokine for naive T cells polarization into Th2 phenotype as well as enhances the secretion of Th2 cytokines. The aim of the present study was to investigate the relationship between IL-33 single nucleotide polymorphisms (SNPs) and IL-33 serum level with Allergic rhinitis. METHODS: Blood samples were collected from 130 AR patients and 130 healthy individuals. SNPs (rs7044343 C > T, rs1929992 A > G, rs12551256 A > G) of IL-33 gene were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum level of IL-33 was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Statistical analysis showed that the TT genotype (OR = 1.996, CI: 1.168-3.412, P = .01), as well as the T allele (OR = 0.675, CI: 0.476-0.957, P = .02) of rs7044343 C > T were significantly associated with reduced risk of AR. In addition, individuals carrying the TT genotype were associated with lower levels of IL-33 compared to subjects with CC and CT genotypes; however, these differences were not statistically significant. No association was found between rs1929992 and rs12551256 variants and risk of AR, but the GG genotype from rs1929992 A > G was associated with increased serum levels of IL-33 in control group (p = .01). Furthermore, serum IL-33 levels were not significantly different between AR patients and healthy controls (p > .05). CONCLUSION: Our results suggest that the TT genotype of rs7044343 C > T may act as a protective agent against allergic rhinitis.

The effect of treatment with fexofenadine and fluticasone propionate on the gene expression levels of Th9 transcription factors in patients with allergic rhinitis.

T helper-9 (Th9) is a new T cell subset involved in allergic rhinitis (AR) pathogenesis. Fexofenadine and fluticasone propionate are the first effective line of AR treatment. This study aimed to evaluate the effect of fexofenadine and fluticasone propionate on the gene expression levels of Interferon regulatory factor 4 (IRF4), B cell-activating transcription factor-like (BATF), and SPI1 gene-encoded protein (PU.1), essential transcription factors for Th9 cell differentiation, in AR patients. Twenty-six AR patients (aged 32.8 ± 9.1 years, 13 men and 13 women) were treated with fexofenadine and fluticasone propionate for one month. Expression levels of PU.1, IRF4, and BATF genes were measured using Real-Time PCR. Our results showed that after one month of treatment, the expression level of IRF4 and BATF genes decreased significantly (P < 0.001, P < 0.01, respectively), while PU.1 gene expression was not remarkably different. Overall, our results showed that after one month of treatment with fexofenadine and fluticasone propionate, the expression levels of IRF4 and BATF genes in AR patients decreased, which may be due to this treatment regimen. However, the exact mechanism of action of fexofenadine and fluticasone propionate needs further study.

Retinoic Acid Correlates with Reduced Serum IL-10 And TGF-ß in Allergic Rhinitis.

BACKGROUND: Retinoic acid (RA) plays a key role in naïve T cell differentiation into FOXP3+ Treg cell in the respiratory airways. The present study aims to investigate RA and Treg-related cytokine serum levels, salivary IgA levels, FOXP3 and IL-4 gene expression, and the relationships between RA serum levels and Treg-related cytokines in allergic rhinitis (AR) patients and healthy controls. METHODS: Salivary IgA and serum IgE, RA, IL-10, and TGF-ß concentrations were measured by ELISA in 37 AR patients and 30 age- and sex-matched healthy controls. RESULTS: IL-10 and TGF-ß concentrations were significantly less in AR patients than in healthy controls (p< 0.01 and P< 0.0001, respectively). Salivary IgA was significantly greater in patients than in controls (p< 0.05). RA was not significantly different between patients and controls (p> 0.05); however, a significant positive correlation was found between serum RA and both IL-10 and TGF-ß in AR patients. CONCLUSION: Our data suggest that RA may influence AR risk via affecting the TGF-ß and IL-10 production.

Association of interleukin-12B rs6887695 with susceptibility to allergic rhinitis.

Interleukin-12 (IL-12) is a heterodimeric cytokine encoded by two separate genes, IL12A and IL12B, which may play a regulatory role in allergen-induced inflammation through CD4+ T-cell subsets polarization. The aim of this study was to investigate the association of single-nucleotide polymorphisms (SNPs) in the IL12B gene with susceptibility to allergic rhinitis (AR). We performed a case-control study including 130 AR patients and 130 healthy controls to evaluate the possible association between IL12B gene SNPs (rs3212227, rs6887695) and the risk of AR using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Our results showed no significant association between IL12B rs3212227 A > C polymorphism with AR. In contrast, the GC genotype of rs6887695 G > C was associated with susceptibility to AR in comparison with the GG genotype (p = 0.049, OR = 1.684, 95% CI: 1.002-2.83). We also observed a statistically significant difference in the additive model (GC versus GG + CC, p = 0.03, OR = 1.705, 95% CI: 1.040-2.794) for SNPs rs6887695. Furthermore, haplotypes analysis demonstrated that C-C haplotype was associated with an increased risk of AR (p = 0.01, OR = 1.845, 95% CI: 1.114-3.057). Our findings suggest that IL12B rs6887695 polymorphism may be a potential biomarker for susceptibility to AR in an Iranian population.

Determination of the transcriptional level of long non-coding RNA NEAT-1, downstream target microRNAs, and genes targeted by microRNAs in diabetic neuropathy patients.

BACKGROUND: Diabetic neuropathy (DN) is one of the microvascular complications of diabetes that leads to peripheral sensorimotor and autonomic nervous system damages. In this study, we first examined the expression of lncRNA NEAT-1 and its downstream microRNAs, miR-183-5p, miR-433-3p, and then examined mRNA expression of ITGA4, ITGB1, SESN1, and SESN3 as the downstream targets of miR-183-5p, miR-433-3p. METHODS: The blood sample was obtained from a total of 40 patients with type 2 diabetes (20 DN patients and 20 non-DN diabetic cases) and ten healthy individuals. After RNA extraction from peripheral blood samples and cDNA synthesis, expression measurements were performed by the RT-qPCR technique. RESULTS: Our results showed that the expression level of lncRNA NEAT-1 was significantly higher, and the expression level of miR-183-5p was significantly lower in DN patients compared to the healthy control group. Besides, the expression level of miR-433-3p was significantly lower, and the mRNA expression of ITGA4, SESN1, and SESN3 was significantly higher in DN patients compared to the diabetes group. The ROC curve analysis showed that the miR-183-5p with high levels of accuracy could discriminate DN patients from healthy control (AUC = 0.836) and NEAT-1, SESN1, SESN3, ITGA4 have a high ability to distinguish DN from non-DN patients (AUC = 0.701, 0.772, 0.815 and 0.780, respectively). CONCLUSION: It seems that the NEAT-1 probably targets miR-183-5p and miR-433-3p, as a result of which the expression of ITGA4, SESN1, and SESN3 is affected. Dysregulated expression of NEAT-1 and related miRNAs and genes might be involved in the pathogenesis of DN.

Imbalanced serum levels of resolvin E1 (RvE1) and leukotriene B4 (LTB4) in patients with allergic rhinitis.

Timely and successful resolution of acute inflammation plays a crucial role in preventing the development of chronic airway inflammation in allergic rhinitis (AR). This study intends to assess the serum levels of pro-inflammatory leukotriene B4 (LTB4), anti-inflammatory mediators, including resolvin E1 (RvE1), RvD1, IL-10, and TGF-ß, besides mRNA expression level of G-protein coupled receptor 120 (GPR120) and peroxisome proliferator-activated receptor-γ (PPAR-γ) receptors in peripheral blood leukocytes of AR patients. Thirty-seven AR patients and thirty age- and gender-matched healthy subjects were enrolled in this study. The serum levels of LTB4, RvE1, RvD1, IL-10, and TGF-ß were measured using enzyme-linked immunosorbent assay (ELISA) technique, and the mRNA expression level of GPR120 and PPAR-γ was assessed by the real-time PCR method. The serum levels of RvE1 and LTB4 were significantly higher in patients with AR than in healthy subjects (P < 0.01 and P < 0.0001, respectively). However, a significantly lower ratio of RvE1 and RvD1 to LTB4 was found in patients with AR relative to healthy subjects (P < 0.05 and P < 0.0001, respectively). Likewise, the serum levels of both IL-10 and TGF-ß cytokines were significantly reduced in patients with AR compared to healthy subjects (P < 0.01 and P < 0.0001, respectively). Furthermore, the mRNA expression of PPAR-γ was significantly lower in patients with AR than in healthy subjects (P < 0.05). Our findings indicate that imbalanced pro-resolving lipid mediator RvE1 and pro-inflammatory LTB4 might contribute to the defective airway inflammation-resolution and subsequent progression toward chronic inflammation in AR patients.

Semaphorin 4A, 4C, and 4D: Function comparison in the autoimmunity, allergy, and cancer.

Semaphorins are a group of proteins that are divided into eight subclasses and identified by a conserved Sema domain on their carboxyl terminus. Sema4A, 4C, and 4D are the members of the fourth class of semaphorin family, which are known as membrane semaphorins; however, these molecules can be altered to soluble semaphorins by proteolytic cleavage. Semaphorins have various roles in the immune, nervous, and metabolic systems. In the immune system, these molecules contribute to the formation of cellular, humoral, and innate immune responses, such as inflammation, leukocyte migration, immunological synapse formation, and germinal center events. Given the diverse roles of semaphorins in the immune system, in this review, we have tried to give a comprehensive look at the role of these molecules in autoimmunity, allergy, and cancer. Sema4D and 4A seem to play a critical role in the pathogenesis of some autoimmune diseases, such as multiple sclerosis. In contrast, it has been shown that Sema4A and 4C have beneficial effects on allergies, and their absence can exacerbate the severity of the disease. In the case of cancer, an increase in all three of these molecules has been reported. Sema4D and 4C can contribute to tumor progression in human patients or experimental models, while the role of Sema4A has not yet been fully understood. In conclusion, semaphorins seem to be a favorable therapeutic target for autoimmune diseases and allergies. However, in cancer, studies have not yet been able to identify the exact role of semaphorins, and further studies are needed.

Regulatory T cells for amyotrophic lateral sclerosis/motor neuron disease: A clinical and preclinical systematic review.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by neuronal degeneration and inflammation in the nerves. The role of the immune system has been concentrated by researchers in the etiopathogenesis of the disease. Given the inhibitory roles of regulatory T cells (Tregs), it is expected that increasing or activating their populations in patients with ALS can have significant therapeutic effects. Here we searched databases, including CENTRAL, MEDLINE, CINAHL Plus, clinicaltrials.gov, and ICTRP for randomized clinical trials (RCTs) and non-RCTs until March 2019. For preclinical studies, we searched PubMed, Scopus, and Google Scholar up to June 2019. We also included preclinical studies, due to the lack of clinical information available, which used Tregs (or directly targeting them) for treating mice models of ALS. We identified 29 records (CENTRAL 7, MEDLINE 4, CINAHL Plus 8, and clinicaltrials.gov 10) and removed 10 duplicated publications. After screening, we identified one RCT which had been published as an abstract, three non-RCTs, and four ongoing studies. We also identified 551 records (PubMed 446, Google Scholar 68, and Scopus 37) for preclinical studies and performed a meta-analysis. Finally, we found three papers that matched our inclusion criteria for preclinical studies. Results indicated the effectiveness of the application of Tregs in the treatment of ALS. Our meta-analysis on preclinical studies revealed that Tregs significantly prolonged survival in mice models of ALS. Overall, our analysis testified that exertion of Tregs in the treatment of ALS is a promising approach, that notwithstanding, requires further evaluations.

The role of myeloid-derived suppressor cells in the pathogenesis of rheumatoid arthritis; anti- or pro-inflammatory cells?

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of the immature myeloid cells that are derived from the myeloid progenitors with immunosuppressive functions. MDSCs are accumulated in the inflammatory sites during some autoimmune disorders, such as rheumatoid arthritis (RA) and can be an important factor in the pathogenesis of these diseases. Some research has shown the anti-inflammatory role of MDSCs during the RA progression and supports the hypothesis that MDSCs can be a potential treatment option for autoimmunity with their immunosuppressive activity. In contrast, some papers have reported the opposite effects of MDSCs, and support the hypothesis that MDSCs have a pro-inflammatory role in autoimmune disease. MDSCs functions in RA have not been fully understood, and some controversies, as well as many unanswered questions, remain. Although the two well-known subgroups of MDSCs, M-MDSC, and PMN-MDSC, seem to have different suppressive functions and regulate the immune system responses in a different manner; some studies have shown these cells are converted to each other and even to other cells under different pathological conditions. This review summarises some of the latest papers with respect to the MDSCs functions and discusses the relationship between MDSCs and inflammation in the context of rheumatoid arthritis.