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.

The MALAT1-H19/miR-19b-3p axis can be a fingerprint for diabetic neuropathy.

BACKGROUND: Diabetic neuropathy (DN) is one of the most common microvascular complications of diabetes that is attributed to impaired immune regulation. In this study, we first examined the expression of long non-coding (lncRNAs) MALAT1 and H19, and their downstream microRNAs (miRNAs) miR-19b-3p, miR-125a-5p, and then assayed the mRNA expression of downstream targets of these miRNAs, including SEMA4C, SEMA4D, PLXNB2, ATG14, and ATG16L1. METHODS: Peripheral blood samples were obtained from 20 DN patients, 20 diabetic patients without neuropathy (non-DN), and 10 healthy controls (HC). The expression levels of lncRNAs, miRNAs, and target genes were evaluated in whole blood using Real-time PCR. RESULTS: Upregulation of MALAT1, H19, SEMA4C, PLXNB2, and ATG16L1 and downregulation of miR-19b-3p was seen in the DN group compared to the non-DN and HC groups. Non-DN patients had significantly lower expression levels of miR-125a-5p, SEMA4D, ATG14, and ATG16L1 compared to the HC. MALAT1 and H19 had a positive correlation with each other and had a negative correlation with the expression of miR-19b-3p. Expression levels of SEMA4C, SEMA4D, PLXNB2, and ATG16L1 were positively correlated with each other as well as lncRNAs expression. Receiver operating characteristic (ROC) analysis showed Area under the curve (AUC) = 0.9226 for MALAT1, AUC= 0.9248 for H19, and AUC= 0.7683 for miR-19b-3p. CONCLUSION: The MALAT1-H19/miR-19b-3p axis might be involved in the development of DN and these molecules could be useful biomarkers for DN. Dysregulated expression of SEMA4C, PLXNB2, and ATG16L1, targeted by miR-19b-3p and miR-125a-5p, showed that they probably play a role in the DN development.

Clinical, immunological, and genetic features in 780 patients with autoimmune lymphoproliferative syndrome (ALPS) and ALPS-like diseases: A systematic review.

BACKGROUND: Autoimmune lymphoproliferative syndrome (ALPS) is a group of genetic disorders characterized by early-onset lymphoproliferation, autoimmune cytopenias, and susceptibility to lymphoma. The majority of ALPS patients carry heterozygous germline mutations in the TNFRSF6 gene. In this study, we conducted a systematic review of patients with ALPS and ALPS-like syndrome. METHODS: The literature search was performed in Web of Science, Scopus, and PubMed databases to find eligible studies. Additionally, the reference list of all included papers was hand-searched for additional studies. Demographic, clinical, immunological, and molecular data were extracted and compared between the ALPS and ALPS-like syndrome. RESULTS: Totally, 720 patients with ALPS (532 genetically determined and 189 genetically undetermined ALPS) and 59 cases with ALPS-like phenotype due to mutations in genes other than ALPS genes were assessed. In both ALPS and ALPS-like patients, splenomegaly was the most common clinical presentation followed by autoimmune cytopenias and lymphadenopathy. Among other clinical manifestations, respiratory tract infections were significantly higher in ALPS-like patients than ALPS. The immunological analysis showed a lower serum level of IgA, IgG, and lymphocyte count in ALPS-like patients compared to ALPS. Most (85%) of the ALPS and ALPS-like cases with determined genetic defects carry mutations in the FAS gene. About one-third of patients received immunosuppressive therapy with conventional or targeted immunotherapy agents. A small fraction of patients (3.3%) received hematopoietic stem cell transplantation with successful engraftment, and all except two patients survived after transplantation. CONCLUSION: Our results showed that the FAS gene with 85% frequency is the main etiological cause of genetically diagnosed patients with ALPS phenotype; therefore, the genetic defect of the majority of suspected ALPS patients could be confirmed by mutation analysis of FAS gene.

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.

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.