Iranian Journal of Allergy, Asthma and Immunology
Volume:18 Issue: 2, Apr 2019

CD4+T cells are composed of different subpopulations that differ in developmental pathways, surface markers, and their products. Among the catalog of these cells is Th9 cell subset that has a great capacity of Interleukin (IL)-9 production. They could be involved in the pathogenic or protective immune responses. Therefore, it is important to know how Th9 cells and cytokines influence the function of the human immune system as multitasking machinery, both in isolation or after the interaction with other surrounding cells. Since an important characteristic of Th9 cells is their tropism for skin, this article reviews the physiological and pathophysiological functions of Th9 and its cytokines under normal conditions and inflammatory skin disorders.

The Chronic granulomatous disease (CGD) is a primary immunodeficiency that characterized by mutations in phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, resulting in deficient antimicrobial activity of phagocytic cells and recurrent childhood infections. Hematopoietic stem cell transplantation (HSCT) is a curative option for patients with human leukocyte antigen (HLA) matched donor, when conventional cares and therapies fail. However, in many cases when the patients have not an HLA-matched donor, they need to a method to recapitulate the function of the affected gene within the patient’s own cells. Gene therapy is a promising approach for CGD. While, the success of retroviral or lentiviral vectors in gene therapy for CGD has been hampered by random integration and insertional activation of proto-oncogenes. These serious adverse events led to improvement and generations of viral vectors with increased safety characteristics. Gene therapy continues to progress and the advent of new technologies, such as engineered endonucleases that have shown a great promise for the treatment of genetic disease. This review focuses on the application of gene therapy for the CGD, the limitations encountered in current clinical trials, advantages and disadvantages of endonucleases in gene correction and modeling with CRISPR/Cas9 approach.

Assessment of the number of T-cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC) copies has been recently described as biomarkers of newly formed T and B cells respectively. In this study, we aimed to explore the effects of demographic variables including age, gender, weight, height and ethnicity on these two episomal DNA molecules. Second, for the first time in our country, we determined the reference values of TREC and KREC copy numbers in different age groups of Iranian healthy individuals as a threshold for identifying T cell and B cell lymphopenia. The TREC and KREC copy numbers were evaluated in 251 dried blood spot (DBS) samples from healthy volunteers (age range: 0-60 years). Six primary immunodeficiency (PID) patients were included as disease controls. TREC and KREC copies were markedly reduced with increasing age. Although the levels of TREC and KREC were higher in females than males, this difference did not reach statistical significance. These findings suggest that demographic variables including age should be considered for interpretation results of the TREC/KREC assay.

Tumor cells rely on glycolysis for their energy supply with the production of lactate even in normoxia condition, which is named aerobic glycolysis or Warburg effect. Therefore, high glucose (HG) concentration provides a favorable condition for increasing proliferation, angiogenesis and decreasing apoptosis, but its molecular mechanisms are still unknown. The objective of this study is to investigate HG condition on tumor cells behavior including proliferation, apoptosis, and an angiogenesis mediator. In this study, MCF-7 derived from human breast adenocarcinoma, were cultured in DMEM with two different concentrations of glucose for 48 h (5.5 mM as normal glucose (NG) condition and 25 mM as HG condition). We used Zingiber officinale extraction for the inhibition of NF-κB. Cell proliferation assay was done by direct counting, cell viability by MTT method, bcl-2 by Immunocytochemistry, apoptosis by Hoechst/PI double staining and vascular endothelium growth factor (VEGF) by ELISA. Results showed that HG increased lactate production, significantly. HG increased cell proliferation, cell viability, VEGF secretion, and bcl-2 expression while it decreased apoptosis. However, when HG was combined with Zingiber officinale extraction, cell proliferation, cell viability, VEGF secretion and bcl-2 expression decreased and apoptosis increased significantly due to inhibition of NF-κB. Results revealed that HG increased cell proliferation, angiogenesis and decreased apoptosis due to activation of NF-κB pathway. Moreover, the probable mechanism of the activation of NF-κB in HG is increasing reactive oxygen species (ROS) in this condition that can activate NF-κB directly.

Unexplained infertility (UI) is one of the most common diagnoses in the fertility care. Seminal plasma (SP) plays a crucial role in the regulation of female immune responses and the success of a pregnancy. In vitro fertilization (IVF) is a well-known method for the treatment of UI. In this study, we aimed to investigate the effect of SP on the differentiation of T helper (Th) cell subsets and the relationship between these subsets with the rate of IVF success in a group of women complicated with UI compared to those with normal pregnancy. This study was conducted on 20 UI couples (ten with successful and ten with unsuccessful IVF outcome) and 10 fertile couples as the control group. Four color flow cytometry technique was used to detect Th cell subsets in the peripheral blood mononuclear cells (PBMC) with or without stimulation by SP. Results indicated that the frequencies of IL-17+ and Foxp3+ T cells after incubation with SP was significantly increased in couples with unsuccessful IVF outcome as compared to successful and healthy groups (p<0.05). Additionally, a positive correlation was observed between Th1 and Th2 cells in the unsuccessful IVF group (R=0.6, p=0.03). In summary, the results of the present study demonstrated that exposure to SP might increase Th17 and Treg cell frequencies in infertile women with unsuccessful IVF, and might also balance inflammatory to regulatory responses to finally tune-up the Th1/Th2/Th17/Treg balance and support the success of IVF.

Systemic sclerosis (SSc) is characterized by excessive production of collagens by fibroblasts that leads to vast fibrosis. Resistance to apoptosis is one of the possible underlying mechanisms of fibrosis in these patients. Survivinis involved in inhibition of apoptosis and aberrantly functions in SSc. Since dysregulation of survivin-targeting microRNAs (miRNAs) has frequently been observed in cancer and some autoimmune disorders, this study aimed to investigate their expression status in dermal fibroblasts from SSc patients. DiffuseSSc patients were selected according to American College of Rheumatology criteria. Isolated fibroblasts from 10 SSc and 10 healthy skin biopsies were cultured. After examining purity of the cells, mRNA and miRNAs extraction was performed followed by complementary DNA (cDNA) synthesis. Relative expressions ofsurvivin mRNA, miR-16-5p, miR-320a, miR-218-5p, miR-708-5p and miR-542-3p were analyzed using real time PCR. Survivin mRNA expression was significantly 1.85-fold upregulated in fibroblasts from SSc patients compared with healthy controls (p=0.046). Among the studied miRNAs, miR-542-3p expression was significantly decreased (p=0.033), while enhanced expression of miR-708-5p was observed in SSc fibroblasts (p=0.05) in comparison to healthy subjects. Downregulation of miR-542-3p significantly correlated with survivin overexpression (r=˗0.45, p=0.049). Downregulation of miR-542-3p that is correlated with higher surviving expression levels might be a possible cause of apoptosis resistance in SSc fibroblasts, hence providing a new understanding of the disease pathogenesis.

Systemic sclerosis is a fibrotic autoimmune disease in which aberrant remodeling of the extracellular matrix in organs disturbs their functionalities. The aim of this study was to investigate the expression of gelatinases on systemic sclerosis. Consequently, a mouse model of systemic sclerosis was employed and the gelatinolytic activity of gelatinases was evaluated on the fibrotic tissues of this model. Two groups of ten mice were considered in this work: a group of systemic sclerosis model and control group. For the generation of systemic sclerosis model, mice received bleomycin, while the control group was subjected to phosphate buffered saline (PBS) reception. Mice were tested for fibrosis by using trichrome staining, hydroxyproline measurement and α-SMA detection in tissue sections. Additionally, the gelatinolytic activity of matrix metalloproteinase 2 and matrix metalloproteinase 9 were measured using gelatin zymography in lungs and skin tissue homogenates. The obtained results indicated that subcutaneous injection of bleomycin-induced fibrosis in skin and lung tissues of mice. Pro and active forms of matrix methaloproteinase 9 were increased in fibrotic lung tissues (p<0.05 and p<0.01, respectively), while, the gelatinolytic activity of MMP2 was unaffected in these tissues. Additionally, in skin tissues of bleomycin-treated animals, both pro and active forms of MMP9 and MMP2 were increased (p<0.05). Pro and active forms of gelatinases increase differently in skin and lung tissues of bleomycin-induced scleroderma.

Contrasting studies are reported on the induction of IL-10 and IFN-γ via chitin microparticles (CMPs) during immune stimulation. Our previous studies have shown marked protection among CMP treated Leishmania-infected mice via regulated IL-10/IFN-γ response, at the present study, once more, examined the inconsistent responses regarding the immunologic response of CMPS. To verify whether CMPs could indeed up-regulate IL-10/IFN-γ axis, isolated spleen cells from the myelin oligodendrocyte glycoprotein (MOG) induced experimental autoimmune encephalomyelitis (EAE) mice were cultured in the presence of MOG peptide and/or CMPs. The effects of CMPs on IL-10, IFN-γ and IL-17 production were evaluated by Enzyme-linked Immunosorbent Assay (ELISA). Moreover, GATA binding protein 3 (Gata3), T-box transcription factor TBX21 (Tbx21), and RAR-related orphan receptor gamma (RORγT) expressions (real-time PCR) were investigated. MOG alone stimulated the production of IFN-γ (p≤0.004) but not, IL-10 (p≤0.140). MOG/chitin stimulation resulted in a significant increase in IFN-γ and IL-10 levels, respectively; (p≤0.004 and p≤0.003) rather than MOG. Additionally, the expression of Tbx21 (p≤0.001), but not Gata3 (p≤0.08), was increased in the MOG/chitin-treated spleen cells. All in all, CMP supports Gata3 independent IL-10 production and promotes Tbx21 dependent IFN-γ induction. These results, alongside our previous data, indicate that CMPs has particular adjuvant effects.

Unstable angina pectoris (USAP) is a complex condition in which widespread coronary inflammatory processes have important implications for clearer understanding of its pathogenesis and also its treatment. This study aimed at evaluating the diagnostic as well as prognostic value of serum inflammatory markers of pentraxin-3 (PTX-3), Von Willebrand Factor (vWf) and C-X-C Motif Chemokine Ligand 13 (CXCL13) in such patients. Out of sixty-nine patients, thirty-nine had USAP, thirty had stable angina pectoris (SAP), and thirty-nine were healthy controls. For all participants, serum PTX-3, vWf and CXCL13 levels were measured using ELISA. For each patient with USAP, the Thrombolysis in Myocardial Infarction (TIMI) and the scores of Global Registry of Acute Coronary Events (GRACE) were calculated to determine the severity of the disease. We, then, analyzed the relation of PTX-3, vWf and CXCL13 levels with TIMI and GRACE scores in patients with USAP. Serum PTX-3, vWf and CXCL13 levels were significantly higher in USAP group than those in either SAP or control groups (p˂0.001). Strong correlation was observed between CXCL13 level and TIMI risk score (p=0.019). In receiver operating characteristic (ROC) curves, area under the curve (AUC) values of PTX3, vWf and CXCL13 for detection of USAP were 0.755, 0.751, and 0.906, respectively. The levels of serum PTX3, vWf and CXCL13 increased in patients with USAP. The notable correlation implied that CXCL13 might be a sensitive and specific biomarker for the diagnosis of USAP as well as its severity. It might also show additional diagnostic values when measured in combination with vWf.

Asthma is a chronic inflammatory disease of the airways of the lungs. Pomalidomide (POM) a therapy for multiple myeloma has been stated to have an anti-inflammatory effect. The main goal of the present study was to assess its possible effect on airway contraction and inflammation in a rat model of ovalbumin-induced asthma. Different groups of rats received saline or pomalidomide (0.4, 0.8 mg/kg) or dexamethasone (0.6 mg/kg). The asthma was induced by ovalbumin (OVA). Trachea contraction was assayed by organ bath system. Airway histology was assessed using hematoxylin and eosin method. Serum Tumor necrosis factor alpha (TNF-α) level was analyzed by Enzyme-Linked Immunosorbent Assay and Platelet-derived growth factor (PDGFα) Gene expressions were evaluated by Real-time PCR. Pomalidomide prevented ovalbumin-induced airway contraction and histopathological damage. In addition serum, TNF-α level was significantly (p<0.05) decreased in POM treated animals compared to control (asthmatic animals that received POM vehicle). Results indicate that POM prevented the PDGF expression induced by ovalbumin. In conclusion, we found that pomalidomide ameliorated the symptoms, histopathological changes and inflammatory markers induced by ovalbumin in asthmatic rats and these effects might be related to its anti-inflammatory properties.

The mustard lung is a late consequence of exposure to sulfur mustard (SM) in veterans who had participated in the Iraq-Iran war. Three mechanisms are contributed in the pathogenesis of mustard lung including oxidative stress, protease-antiprotease imbalance, and dysregulated immune response. In the context of the immune response, the role of the inflammasome complex and their inflammatory cytokines are important. This study aims to investigate the inflammasome pathway and their inflammatory cytokine (i.e IL-1 and IL-18) in the peripheral blood of mustard lung patients as well as chronic obstructive pulmonary disease (COPD) patients. This research was conducted as a cross-sectional analytical study on 15 SM patients and was compared with 15 COPD patients and 15 healthy controls. The real-time polymerase chain reaction was used to assess gene expression levels of inflammasome components (NLRP1, NLRP3, NLRC4, and ASC), inflammatory cytokines (IL-1β, IL-18, and IL-1βR), and IL-37 as an anti-inflammatory cytokine. Finally, the data were analyzed by SPSS version 21 software. The gene expression level of molecules involved in inflammasome pathway showed a slight increase in the peripheral blood of SM and COPD patients compared to the control group. However, this difference was not statistically significant. Only IL-37 and NLRP1 had a significant increase in mustard lung and COPD patients; compared to healthy controls (p<0.05). Due to the normal expression of genes involved in the inflammasome pathway, it can be stated that the inflammasome pathway is not active in the blood of mustard lung patients.

Hyperimmunoglobulin E syndrome (HIGE) is considered as a phagocytic or a newly classified complex and heterogeneous primary immunodeficiency disease with symptoms such as increased levels of immunoglobulin E, eczema, and, recurrent lung and skin infections. In this paper, we have presented a rare case of this syndrome. A 9-year-old Iranian girl presented with a history of pruritic maculopapular rash who was eventually diagnosed as a case of HIGE. In her recent admission, she had dysphonia, stridor and huge cauliflower cutaneous lesions on her neck, finger and vocal cords, which did not respond to intravenous antibiotics, and ultimately required surgical removal.