Evaluation of MicroRNA-125b-5p and Transcription Factors BLIMP1 and IRF4 Expression in Unsolved Common Variable Immunodeficiency Patients

Common variable immunodeficiency (CVID) is the most prevalent form of symptomatic primary humoral immunodeficiencies characterized by failure in the final differentiation of B lymphocytes. The majority of CVID cases have no identified genetic defect, and epigenetic alteration could be involved in the pathogenesis of CVID. Hence, we aimed to evaluate the expression of hsa-miR-125b-5p -and, B lymphocyte-induced maturation protein-1(BLIMP-1) and interferon regulatory protein-4 (IRF-4) in a group of CVID patients with no definitive genetic diagnosis in comparison with healthy individuals. Ten CVID patients (all known genes excluded) and 10 age and sex-matched healthy controls participated in the study. B lymphocytes were isolated and expression of miR-125b-5p, IRF4, and BLIMP1 were evaluated by real-time polymerase chain reaction (RT-PCR). Moreover, B cell subsets were analyzed by flow cytometry. The results showed that the relative expression of miR-125b-5p in CVID patients was increased while it was decreased for the BLIMP1 and IRF4 transcription factors compared with the healthy controls. Although a reduction was observed in switched and non-switched memory B cells among all high-miR patients, these subsets were decreased in patients with normal miR expression (71.0% and 85.0%, respectively). Our results suggest that overexpression of miR-125b-5p affects the terminal differentiation of B cells in a selected group of CVID patients by downregulating the BLIMP-1 gene and more intensively for the IRF-4 gene expressions.

Disseminated Intravascular Coagulation Associated with Large Deletion of Immunoglobulin Heavy Chain

Although the majority of monogenic defects underlying primary immunodeficiency are microlesions, large lesions like large deletions are rare and constitute less than 10% of these patients. The immunoglobulin heavy chain (IGH) locus is one of the common regions for such genetic alterations. This study describes a rare case of autosomal recessive agammaglobulinemia with a homozygous large deletion in chromosome 14q32.33 (106067756-106237742) immunoglobulin heavy chain clusters with an unusual and severe skin infection and disseminated intravascular coagulopathy.

Dysregulation of Angiogenesis and Inflammatory Genes in Endometrial Mesenchymal Stem Cells and Their Contribution to Endometriosis

Endometriosis is a common, chronic, inflammatory disorder in women, characterized by the presence of endometrial tissue outside the uterus cavity. The disease affects ~10% of women during their reproductive age. There are some debates on the pathogenesis of endometriosis and its mechanism among scientists; therefore, different hypotheses have been suggested. According to Sampson's theory, a possible mechanism for seeding ectopic endometriotic lesions is a dysregulation of endometrial mesenchymal stem cells (eMSCs). In the present study, we evaluated the expression of candidate genes in eMSCs obtained from endometriosis patients and compared them with non-endometriosis female patients. In addition, bioinformatic analysis was conducted to uncover the genes in the list of our co-expression gene network in endometriosis. According to our results, the expression of vascular endothelial growth factor A, C-X-C-motif chemokine ligand 8, interleukin-6, and intercellular adhesion molecule-1 genes were up-regulated in the eMSCs isolated from endometriosis patients. There was no significant difference in the expression of the LaminB1 gene between the endometriosis and non-endometriosis patients. On the other hand, our bioinformatics analysis demonstrated that co-expressed genes were enriched in the cytokine signaling pathway. Our study provides valuable insights into the gene expression dysregulation in eMSCs derived from endometriosis patients and suggests a possible function for co-expressed networks in the pathogenesis of endometriosis. To confirm the results, more investigations are required.

Identification of Antibodies Against Neutrophil Surface Antigens in Two Iranian Patients with Autoimmune Neutropenia

Autoimmune neutropenia is a type of immune-mediated neutropenia, caused by antibody-induced neutrophil destruction. Here, we report two cases (a 3-year-old boy and a 9-year-old girl) with suspected autoimmune neutropenia. The presence of neutrophil antibodies in the sera of these two patients was investigated; using standard neutrophil antibody screening tests such as granulocyte immunofluorescence test (GIFT), granulocyte agglutination test (GAT), and lymphocyte immunofluorescence test (LIFT). A positive reactivity with two-panel cells was found in GIFT. No reactivities with panel cells were observed in GAT and LIFT. To the best of our knowledge, this is the first report for detecting the neutrophil reactive antibodies; using genotyped neutrophils in patients with autoimmune neutropenia in Iran. The final diagnosis of our patients was primary autoimmune neutropenia for the boy and autoimmune neutropenia associated with familial Mediterranean fever for the girl.

D-Pinitol Attenuated Ovalbumin-induced Allergic Rhinitis in Experimental Mice Via Balancing Th1/Th2 Response

Allergic rhinitis (AR) is a complex, chronic immunoinflammatory disorder of the membrane lining of the nasal mucosa. D-Pinitol is considered a cyclic polyol with a potential effect against various allergies. In the present study, we evaluated the anti-allergic effect of pinitol on ovalbumin (OVA)-induced AR model in mice. BALB/c mice were initially sensitized with an intraperitoneal injection of OVA and divided into 5 groups (n=18, in each group) for a treating schedule of distilled water (DW), montelukast (10 mg/kg), and pinitol (5, 10, and 20 mg/kg) through the mouth. Two saline-injected groups were considered as controls by orally administrating DW and pinitol 20. Thereafter, test and control groups were intranasally challenged by OVA and saline, respectively. Our results showed that the OVA challenge caused a marked elevation in AR symptoms like nasal rubbing, sneezing, and discharge which were remarkably diminished using pinitol (10 and 20 mg/kg) and the results were comparable with montelukast. Additionally, increased levels of total and OVA-specific serum Immunoglobulin (Ig) E and IgG1 were significantly attenuated by pinitol as compared to the control group but not the montelukast group. In AR-induced mice, pinitol had significant modulatory effects on representative markers of Th2 (GATA binding protein 3), signal transducer and activator of transcription-6, Interleukins (IL)-4, IL-5, IL-13, suppressors of cytokine signaling 1, Toll-like receptor 4, and myeloid differentiation factor 88), and Type 1 T helper (Th1) immune responses (T-box protein expressed in T cells and Interferon-gamma) as well as the histopathological aberrations induced in the nasal mucosa. In conclusion, Pinitol had potential effects on OVA-induced AR mice through amelioration of nasal symptoms and balancing the Th1/Th2 immune responses during the allergic rhinitis condition.

Pulmonary Radiological Manifestations of Humoral and Combined Immunodeficiencies in a Tertiary Pediatric Center

Respiratory diseases are considered as significant causes of morbidity and mortality in primary immunodeficiencies. This study aimed to reveal the radiologic patterns of thoracic involvement in these disorders. A total of 58 patients, including 38 cases with combined cellular-humoral and 20 cases with humoral immunodeficiencies, were enrolled in this study. The “combined” group consisted of 12 cases with severe combined immunodeficiency (SCID) and 26 cases with combined immunodeficiency. The “humoral” group included seven patients with Hyper IgM syndrome (HIGMs), seven cases with common variable immunodeficiency (CVID), three patients with X-linked agammaglobulinemia, and three patients with other types of humoral primary immunodeficiencies (PIDs). The mean age of patients at the time of evaluation was 3.3±3.8 and 5.3±3.9 years in combined and humoral groups, respectively. The findings of chest X-rays and CT scans were interpreted and compared. There was a significant difference for alveolar opacification between combined and humoral immunodeficiencies (58% vs. 30%). The bronchopneumonia-like pattern was detected as a significant finding in patients with SCID (42%) and HIGMs (43%). Atrophy of the thymus was detected significantly often in cases of SCID (67%). Two patients with CVID and lipopolysaccharide-responsive and beige-like anchor protein deficiency showed parenchymal changes of granulomatous lymphocytic interstitial lung disease. No significant difference was detected for bronchiectasis, bronchitis/bronchiolitis patterns, pleural effusion, and thoracic lymphadenopathy. lymphadenopathy. Distinct subtypes of primary immunodeficiency may provoke differing and comparable radiological patterns of thoracic involvement; which can clue the clinician and radiologist to the diagnosis of the disease.

Association of Pro-inflammatory Cytokine Gene Polymorphism with Meniere’s Disease in an Iranian Sample

Meniere’s disease (MD) is known as a rare chronic disorder of the inner ear with elevated serum levels of pro-inflammatory cytokines like tumor necrosis factor (TNF)-α, Interleukin (IL)-1, and IL-6. This study aims to evaluate genes polymorphism in some pro-inflammatory cytokines in a group of Iranian MD patients compared to the healthy controls. In this case-control study, 25 MD patients and 139 healthy controls were enrolled. DNA was extracted from blood samples, and single nucleotide polymorphisms were detected using polymerase chain reaction with sequence-specific primers assay. MD patients and controls were examined in terms of allele, genotype, and haplotype frequency of pro-inflammatory cytokine genes. Only the frequencies of alleles A/G at position -238 in the promoter of the TNF-α gene differed significantly between MD patients and healthy controls. G to A allele ratio was 23 and 3.6 in MD and controls, respectively. In individuals with MD, genotype GG was found to be significantly more prevalent at position -238 of the TNF-α gene promoter sequence. In addition, the heterozygote AG variant of -238 A/G TNF-α gene polymorphism was lower in MD patients than controls. Compared to the control group, the haplotype TNF- (-308, -238) AG was higher in MD patients, although not statistically significant. This is the first study that we know of that evaluates the frequencies of pro-inflammatory cytokine genes in an Iranian MD sample. This study shows the association between TNF-α and susceptibility to MD.

Immunomodulatory Effect of Human Umbilical Cord Blood-derived Mesenchymal Stem Cells on Activated T-lymphocyte

Many studies have been performed about regenerative and immunomodulatory properties of mesenchymal stem cells (MSCs) and their application in different treatment approaches. The present study aimed to investigate the immunomodulatory effect of umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) on the gene expression profile of cytokines in stimulated T-lymphocytes. For this purpose, MSCs were isolated from umbilical cord blood samples and cultured in Dulbecco's Modified Eagle Medium supplemented with 10% fetal bovine serum. The nature of MSCs was identified by flow cytometry analysis and differentiation to the adipocyte and osteocyte lineage. Moreover, to investigate the immunomodulatory effects of MSCs on T cells, a co-culture system was designed and expression levels of interleukin (IL)-2, IL-4, IL-6, IL-10, IL-13, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β) genes were measured; using the real-time polymerase chain reaction (RT-PCR) technique. Our results demonstrated the ability of MSCs to differentiate into adipocyte and osteocyte lineages. Further investigation also displayed that although UCB-MSCs could significantly reduce the expression of pro-inflammatory cytokines like IL-2, IL-6, IFN-γ, and TNF-α in activated T-lymphocytes, they noticeably potentiated the expression levels of IL-4, IL-10, IL-13, and TGF-β in the co-culture setting. In conclusion, UCB-MSCs have immunomodulatory effects on activated T-lymphocytes in favor of anti-inflammatory responses.

CD8+T-cells Co-expressing PD-1 and TIGIT Are Highly Frequent in Chronic Lymphocytic Leukemia

The role of immune checkpoint receptors in T-cell exhaustion has been demonstrated in several cancers. We investigated the co-expression of TIGIT/PD-1 and LAG-3/PD-1 cells in patients with chronic lymphocytic leukemia (CLL). The frequencies of TIGIT+PD-1+CD8+and LAG-3+PD-1+CD8+cells and relative mRNA expression of LSECtin and CD155 were examined in PBMCs from 33 CLL patients and 20 controls. The percentage of TIGIT+PD-1+CD8+cells was significantly higher in CLL patients than in control subjects, with the preference in advanced-stage patients. However, LAG-3+PD-1+CD8+cell percentage was significantly lower in CLL patients than in the control subjects, and no significant differences were found between the early and advanced stages of the disease. An increase in the mRNA expression level of LSECtin, but not that of CD155, was observed in CLL patients compared to the control subjects. Collectively, a higher co-expression of PD-1 and TIGIT on CD8+ T-cells in CLL compared to control subjects suggests an important role of TIGIT in T-cell exhaustion in CLL patients especially those with advanced disease.

Evaluation of NLRP3 and IL-18 Levels after Periodontal Therapy

The progression of periodontitis depends on interactions between the periodontal pathogens and the host immune cytokines, including interleukin (IL)-1β and IL-18. Production of IL-1β is regulated by NOD-like receptors family pyrin domain containing 3 (NLRP3). This study aimed to evaluate the effect of periodontal treatment on the concentrations of IL-18 and NLRP3 in patients with chronic periodontitis. In this experimental study, 18 patients with chronic periodontitis and a mean age of 46.2±8.95 years, were included. The gingival crevicular fluid (GCF) was collected at the beginning of the study, 4 weeks after non-surgical (phase I), and 4 weeks after surgical periodontal treatment. The levels of NLRP3 and IL-18 were measured; using an enzyme-linked immunosorbent assay. Pearson correlation test was used to analyze the concentration of NLRP3 and IL-18 before and after the treatments with CAL and PD. There was a significant association between the level of NLRP3 and the mean values of PD and CAL before treatment. After each treatment phase, a significant decrease was observed in the NLRP3 level. There was no significant relationship between IL-18 and clinical parameters before and after periodontal treatments. Given the possible association between the level of NLRP3 and clinical parameters, we suggest it as a possible indicator of inflammation in chronic periodontitis and an index for evaluating the treatment outcome.