Neutrophils are the forerunner in innate immunity by defending the host organisms against infectious pathogens. During such process, neutrophils reach the site of inflammation/infection and eliminate the pathogens by phagocytosis as well as by forming the neutrophil extracellular traps (NETs). NETs trap and eradicate a number of microbes including bacteria, fungi, protozoa, viruses. NETs consist of DNA which is decorated with histones and granular proteins such as neutrophil elastase (NE), gelatinase, myeloperoxidase. NETosis (a process of NETs formation) is also involved in many inflammatory and autoimmune disorders with a major contribution to acute respiratory distress syndrome, sepsis, cystic fibrosis, periodontitis. Hyper NETosis or ineffective clearance of NETs would likely increase the risk of auto-antibody generation against NETs components and contribution in auto-inflammatory diseases. The purpose of this review is intended to highlight the molecular mechanisms of NETosis and its antimicrobial effect. Furthermore, a current status of NETosis in the pathogenesis of inflammatory and autoimmune disorders has been reviewed for better understanding. 

Antioxidant, antimicrobial, anti-hyperglycaemic, anti-diabetic and anti-inflammatory effects of Allium cepa (A. cepa) have been previously shown. In this study, the effects of A. cepa aqueous-alcoholic extract on tracheal responsiveness, lung inflammatory cells and phospholipase A2 (PLA2) level in bronchoalveolar fluid (BALF) of asthmatic rats were examined. Wistar rats were randomly divided into control group (C), asthmatic group (A), asthmatic group (A) treated with A. cepa extract (AC, 0.175, 0.35, and 0.7 mg/mL) and dexamethasone (D, 1.25 μg/mL). The extract of A. cepa and dexamethasone were added to animal's drinking water during sensitization period. Tracheal responsiveness to methacholine and ovalbumin, lung inflammatory cells and PLA2 level in BALF were assessed. Tracheal responsiveness to methacholine and ovalbumin, PLA2 level, total and most differential WBC count were increased but lymphocytes was decreased in asthmatic animals compared to group C (p<0.05 to p < 0.001). Treatment of sensitized rats with dexamethasone and all concentrations of A. cepa lead to a significant decrease in total WBC and PLA2 level compared to asthmatic group (p<0.001). The two higher concentrations of A. cepa also significantly decreased tracheal responsiveness, neutrophil and eosinophil counts but led to a significant increase in lymphocytes count compared to asthmatic group (p<0.05 to p<0.001). Treatment of sensitized group with the highest concentration of A. cepa also significantly reduced monocyte count compared to asthmatic group (p< 0.001). Anti-inflammatory and preventive effects of A. cepa on tracheal responsiveness and lung inflammation in asthmatic animals may suggest its potential therapeutic effect on airway diseases such as asthma.

The exact role of fractional exhaled nitric oxide (FeNO) in older patients with chronic inflammatory diseases including asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) remains unclear. This study aimed to investigate the differences in FeNO levels of elderly patients with ACO, asthma, COPD, and chronic cough. We conducted a retrospective study analysing the data of stable outpatients from Pulmonary Department of the Second Clinical College, Jinan University. All participants (Age≥55 years) were divided into the ACO group (n=19), asthma group (n=16), COPD group (n=25), and chronic cough group (n=22). The clinical data such as peripheral eosinophil counts, serum high sensitivity C-reactive protein (hs-CRP), FeNO, and spirometry was collected, and the correlations between FeNO levels and systemic markers or spirometric indices were analyzed. Patients with ACO and asthma had significantly elevated FeNO levels (37.7±16.5, and 36.3±17.7 ppb) compared with COPD, and chronic cough patients (21.9±10.3, and 16.1±8.8 ppb). The FeNO levels were negatively associated with forced expiratory volume in 1 second (FEV1, p=0.003), FEV1% predicted (p=0.012), and FEV1/forced vital capacity (FVC, p=0.002) in all groups. However, there were no significant correlation between FeNO levels and FVC, peripheral eosinophil counts, or serum hs-CRP (p>0.05). Elderly patients with ACO have higher levels of FeNO, when compared with patients with COPD or chronic cough. These findings suggest that FeNO measurement may provide an important implication for the etiological diagnosis of ACO in the elderly patients.

Over expression of the epidermal growth factor receptor (EGFR) in many human epithelial tumors has been correlated with disease progression and poor prognosis. EGFR-inhibiting immunotherapy has already been introduced in cancer therapy. Peptide displaying phage particles in eukaryotic hosts can behave as antigen carriers, able to activate the innate immune system and to elicit adaptive immunity. Herein, the M13-pAK8-VIII phagemid plasmid was engineered to contain the sequences for an EGFR mimotope along with the L2 extracellular domain of EGFR (EM-L2) which would produce the final peptide-phage vaccine. The prophylactic and therapeutic effects of this novel vaccine were evaluated on the Lewis lung carcinoma induced mouse (C57/BL6) model. The recombinant peptide was confirmed to be displayed on the surface of M13 phage as an extension for phage’s PVIII protein. Immunization of mice with peptide-phage vaccine resulted in antibody production against EM-L2 and significant reduction of tumor growth rate by nearly 25 percent. In conclusion, EM-L2 displaying phage particles could be deemed as an encouraging strategy in contemporary cancer immunotherapy.

Tuberculosis (TB) remains a major threat to human health. Understanding the strategies mycobacteria take to overcome immune defense is important in order to control the infection. Micro (mi)RNAs are master regulators of most pathways in the human body.  Infection with mycobacterium impacts upon the host metabolic pathways as they are subverted to obtain the nutrition for intracellular TB survival. In this study, we aimed to investigate the effect of Bacillus Calmette-Guérin (BCG) infection on the expression of three miRNAs (miR-1224, -484 and -425), which are important in infection and in the regulation of metabolic pathways. Peripheral blood monocyte-derived macrophage (MDM) cultures were prepared and infected with BCG at a multiplicity of infection (MOI)=10 or left uninfected as a control. 72h post-infection, RNA was extracted from the cultured cells and cDNA synthesis and real-time PCR performed. Expression levels miRNAs were normalized to the levels of U6 snRNA (Rnu6) using the 2^–ΔΔCt method. Infection with BCG resulted in a highly significant increase in miR-1224 expression (24.4±3.8-fold induction) in human MDMs. The induction of miR-484 (1.8±0.3-fold increase) and of miR-425 (1.2±0.2-fold increase) was less increased compared to miR-1224. Mycobacterium tolerates a hostile microenvironment by escaping from lysosomal degradation and providing a lipid-rich niche by trigger with and re-pattering host metabolism. This study highlighted the potential roles of miRNAs in host responses upon mycobacterium infection.

A subset of CD4+ T cells named T helper (Th)22 cells play some pathogenic roles in some autoimmune disorders such as type 1 diabetes (T1D). We aimed to study the correlation between the circulatory number of these cells and serum levels of its related cytokines with T1D as well as diabetic complications including metabolic control, atherosclerosis, and nephropathy. Fortynine patients with T1D and 43 healthy controls underwent the assessment of circulatory number of Th22 cells (by flow cytometry), serum level of Th22 related cytokines including Interleukin-22 (IL-22), Interleukin-10 (IL-10), Transforming growth factor-β (TGF-β), Tumor necrosis factor-α (TNF-α) (by ELISA) and carotid intima-media thickness (cIMT) measurement (by doppler ultrasonography). In addition, fasting blood and urine samples were taken to measure levels of hemoglobin A1C, lipid profile, cell blood count (CBC), serum and urine creatinine and urine protein in all participants. Th22 frequency and serum levels of IL-22 and TNF-α in patients were significantly higher than those in controls (p<0.001). Serum levels of IL-10 and TGF-β in healthy individuals were higher than those in patients (p<0.001). None of the Th22 related markers had a significant correlation with diabetic complications. There was only a significant effect of IL-22 on HbA1C variations. Th22 pathway has a significant correlation with T1D but not with its complications of cIMT and Urine Albumin/Creatinine Ratio (UACR). We report that Th22 pathway is not a good prognostic as well as diagnostic marker of early macrovascular complications in T1D.

T cell exhaustion is an immunosuppressive mechanism which occurs in chronic viral infections, solid tumors and hematologic malignancies. Exhausted T cell has increased the expression of inhibitory receptors, and functional impairment. In this study, we investigated the expression from some of those inhibitory receptors being Programmed death 1 (PD-1), T cell immunoglobulin and mucin domain containing molecules 3 (TIM-3) and CD244 on T cells from Iranian acute myeloid leukemia (AML) patients. Peripheral blood samples were collected from Iranian newly diagnosed AML patients and flow cytometric analysis was accomplished for cell surface expression of PD-1, TIM-3, and CD244 on T lymphocytes. Functionality and proliferation assay were done in the presence of anti-PD-1 and anti-CD244 blocking antibodies. Immunophenotyping of T cells showed a significant increase of PD-1 and CD244 expression on CD4⁺ and CD8⁺ T cells of AML patients. Whereas blockade of PD1 and CD244 increased the proliferation of CD4⁺ and CD8⁺ T lymphocytes of AML patients but IFN-γ production was not significantly increased. In conclusion, our data indicate that CD4⁺ and CD8⁺ T cells from AML patients appeared to be exhausted and blockade of some immune checkpoints can improve the proliferation of those cells.

Recently, Long noncoding RNAs (lncRNAs) have been described as regulatory factors for several biological mechanisms through regulating the gene expression. Among them the TNF and HNRNPL related immunoregulatory (THRIL) lncRNA may be involved in the pathogenesis of immune-related and inflammatory disease through controlling the expression of the tumor necrosis factor-alpha (TNF-α) expression. In this case-control study, we investigate the THRIL expression in blood 25 samples of de novo acute myeloid leukemia (AML) cases (10 females and 15 males, mean age±SD: 35.1±3.2 years) in comparison to 50 healthy age and sex matched controls (21 females and 29 males, mean age±SD: 34.9± 3.1) using real-time quantitative reverse transcription-PCR (qRT-PCR) in order to explore any association between THRIL and AML. Our results revealed that there was no significant difference in the expression level of THRIL lncRNA between AML patients and healthy individuals (p=0.2, 95% CI=-0.129-28.35). In addition, there was no significant association between male subgroup and THRIL expression as well as females (p=0.08, 95% CI=-0.197-19.251, p=0.4, 95% CI=-0.185-12.041, respectively). In comparison between control group and FAB classification subtypes of AML patients, there was not any significant association. In conclusion, our study showed that THRIL cannot be used as an informative biomarker for AML diagnosis, however, our results need to be clarify by evolution of more cases.

Sublingual immunotherapy (SLIT) has been introduced as a noninvasive and safer approach for allergen-specific immunotherapies. In this study we investigated the efficacy of oral immunotherapy with recombinant Salsola kali 1 protein (Sal k 1) on Th1/Th2 balance in a mouse model of allergy. Female Balb/c mice were intraperitoneally sensitized with rSal k1, followed by a respiratory challenge with 1% (w/v) rSal k1. The sensitized mice were subjected to SLIT using rSal K1 expressing Lactobacillus lactis strain for three weeks. Each week the experimental group underwent SLIT protocol twice. Finally, serum levels of specific immunoglobulins including IgE, IgG1 and IgG2a, as well as secretion of different cytokines from splenocytes including IL-2, IL-4, IL-10, IFNγ and TGFβ into culture media were measured by ELISA. Following immunotherapy, the levels of specific IgE and IgG1 in mice sera as well as IL-4 level in supernatant of splenocytes were significantly lower than allergic controls. While serum IgG2a, IgG2a/IgG1 ratio as well as concentration of IL-2, IL-10, IFNγ, and TGFβ were higher in the SLIT group compared to the controls. The histopathological examination of intestinal tissues revealed no sign of inflammatory response following SLIT. This study revealed that Th2 immune responses are reduced in allergic mice after feeding them with allergen expressing probiotic bacteria as a SLIT approach. Since the safety of this procedure was previously approved, thus, it seems that a similar protocol using human based probiotics could be applied for Salsola kali sensitive patients.

Wheat is the most commonly grown cereal. Immunological reaction to wheat may be IgE or T-cell- mediated. Asthma could be induced by inhaled flour or by exposure to allergens present in bakery products. In patients with IgE-mediated allergy to wheat proteins there is no specific therapy, except oral immunotherapy (OIT). There are few data regarding OIT with wheat protein in allergic patients. We present a case of a 32-yearold female patient, who worked for 5 years in wheat and bakery products industry, who developed an occupational asthma and chronic urticaria after flour inhalation or ingestion of foods that containit. The patient underwent wheat  OIT, that  was well-tolerated with no severe reaction during treatment. We may conclude that wheat OIT is a safe therapy and may induce symptoms improvement in allergic asthma and urticaria in patients with wheat allergy. Wheat OIT may induce tolerance to allergic patients.

FEF25-75 and Asthma in Clinical Practice