2021: In Press

Review Article(s)

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    Program cell death protein 1 (PD1) is considered as an inhibitory molecule that is expressed on the surface of activated T-cells and bound to PD-L1 and PD-L2 ligands. Several types of cancer cells express PD-L1 which can bind to PD1 on the surface of tumor-specific T-cells. PD1/PD-L1 ligation triggers a pathway to protect tumor cells from an effective response of tumor-specific T-cells. Different PD1/PD-L1 blocker antibodies are clinically used to promote the T-cell response against the cancer cells. Current studies suggest that the gut microbiome impacts the efficiency of PD1 blockade therapy in cancer patients. The association of several bacterial species with PD1 responder patients has been determined. The present study reviewed previous reports on the relation between the microbiome and immune checkpoint therapy (ICT). The results of studies were discussed considering adjuvant and molecular mimicry of microbial antigens by tumor-associated antigens and metabolic effects of microbial products on ICT.

     

Original Article(s)

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    Asthma is considered a complex disease of the respiratory system that is characterized by bronchoconstriction, airway inflammation, cough, dyspnea, and wheezing. Allergic reactions are the main reason behind asthma which is known as an important health problem with a high rate of morbidity and mortality in patients with respiratory diseases. Liquorice, the root of Glycyrrhiza, is primarily effective for asthma which is widely used in herbal medicine. In the present study, we designed nano-particles that carry Glycyrrhizic acid as the effective component of Liquorice.
    After Poly (D,L-lactide-co-glycolic acid) PLGA nanoparticle preparation and Glycyrrhizic acid loading, the morphology of the nanoparticle, the electric charge distribution, and drug-releasing ability were studied. Then the effect of Glycyrrhizic acid-PLGA on the animal model of allergic asthma was investigated.
    Glycyrrhizic acid-nanoparticle had a mean±SD size of 350±50 nm. about 67% of the effective component was released after 10 h. The interleukin (IL)-4, IL-5, IL-13, and IL-25 levels and the Muc5ac mRNA expression were decreased in the Glycyrrhizic acid-PLGA treated group. In addition, a significant decline was observed in goblet cell hyperplasia, mucus hyper-secretion, and eosinophilic inflammation around bronchi and vessels of the nano-drug treated group, compared with the asthmatic group.
    We found that Glycyrrhizic acid-PLGA nanoparticle had an anti-asthma effect which may be used as a new drug to cure asthma. It can prevent bronchial obstruction, breathlessness, and asthma attacks.

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    Purinergic receptors stimulation by adenosine triphosphate (ATP) contributes significantly to macrophage activation, and also macrophage cell death. Upon the macrophage activation, the protein load of the endoplasmic reticulum is increased which is resulted in the activation of unfolded protein response (UPR). In the current study, we aimed to evaluate the connection between prototypic P2X7 receptor agonist, extracellular 2ʹ(3ʹ)-O-(4-Benzoylbenzoyl)-ATP (BzATP), and the UPR pathway in macrophages.
    The monocyte-derived macrophages from blood samples of 14 healthy volunteers were skewed toward M1 macrophages after incubation with LPS and IFN-γ. M1 macrophages were treated with 200 µM BzATP. The expression levels of UPR genes, including CHOP, HERP, GADD34, XBP1, and ATF6 in macrophages before and after treatment were measured using real-time polymerase chain reaction.
    The results demonstrated that the expression of CHOP, HERP, and ATF6 is significantly decreased and the expression level of GADD34 and XBP1 is significantly increased after M1 polarization. BzATP not only significantly increased the expression levels of CHOP, GADD34, ATF6, and HERP but also significantly decreases the XBP1 expression level in M1 macrophages.
    The present study showed that BzATP induces cellular stress in M1 macrophages by elevating the expression levels of UPR genes including CHOP, GADD34, ATF6, and reducing cell viability.

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    The pathogenic roles of Interleukine-16 (IL-16), CCL27, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and B-cell activating factor (BAFF) have been shown in some autoimmune and inflammatory diseases. We aimed to correlate the circulatory changes of such factors with the severity of disease in patients with multiple sclerosis (MS).
    This case-control study was conducted on 84 MS patients and 83 healthy controls. We measured the serum levels of IL-16, CCL27, TRAIL, and BAFF in all participants by enzyme-linked immune sorbent assay. Using the expanded disability status scale (EDSS), we evaluated the severity of MS. Finally, we assessed the correlation between serum levels of such factors with the severity of MS.
    We found increased serum levels of CCL27, IL-16, and BAFF in patients with MS compared to those in healthy subjects. However, no difference was found in serum levels of TRAIL between the patients and controls. In addition, a significant positive correlation between serum levels of CCL27, IL-16, TRAIL, and BAFF with disease severity according to EDSS score was determined.
    We showed higher serum levels of CCL27, BAFF, TRAIL, and IL-16 in MS patients with more severe disabilities than mild forms. Such finding may represent their contribution to the pathogenesis of MS. Blocking such molecules may yield new treatments for MS.

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    Ligustrum vulgare (Privet) pollen proteins are responsible for allergies in susceptible individuals in many regions of the world. This study investigated the immunochemical characterization of Privet pollen extract and the occurrence of skin prick test reactivity to Privet and other allergenic pollen grains in allergic rhinitis patients.
    All subjects experienced a skin prick test with twenty-two allergen extracts. sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) separated Privet pollen extract, IgE-immunoblotting, and specific ELISA procedures determined the allergenic profile on forty-five Privet allergic patients.
    A positive allergic reaction to L.vulgare pollen extract was observed in forty-five (31.4%) out of 145 patients. Ten resolved protein fractions were found on SDS-PAGE, ranging from 10 to 80 kDa. IgE-specific antibodies interacted with several allergenic protein bands from Privet-allergic patients in the immunoblotting assay. The most significant interaction was observed in proteins with molecular weights of approximately15, 18, 43, and 66 kDa.
    Privet pollen is regarded as a potent allergen composed of IgE-binding constituents. Considering the high allergenicity of Privet pollen grains and since many countries are rich in this plant, identification and production of recombinant forms of common allergens in this species can be used for developing more efficient diagnostic, therapeutic, and preventive approaches.

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    Interleukin (IL)-35 and IL-37 are two anti-inflammatory cytokines. IL-35 inhibits the development of T-effector cells such as Th1, and Th17; while increasing regulatory T cells (Tregs). IL-37 causes the suppression of inflammatory cytokines. Regarding the positive impact of Helicobacter pylori (H. pylori) infection on inflammation and considering the anti-inflammatory effects of IL-35 and IL-37, this study aimed to evaluate the expression of these two cytokines in H. pylori-infected patients with gastrointestinal problems.
    The case group consisted of H. pylori-infected individuals with gastric ulcer and/or gastritis (n=50) and the control group consisted of cases with gastric ulcer and/or gastritis non-H. pylori-infected (n=50). Sampling and classification of patients were based on pathology findings. A real-time polymerase chain reaction was performed for evaluating the IL-35 and IL-37 expression levels.
    pylori-infected gastritis patients showed lower expression of IL-35 and IL-37 than the non-infected group. There was a significant difference between the expression levels of IL-35 and IL-37 in patients with gastric ulcers and/or gastritis who were infected and non-infected by H. pylori. There were no significant differences in the expression level of IL-35 and IL-37 in H. pylori-infected patients with gastric ulcer or gastritis.
    Interleukins 37 and 35 were less expressed in patients with H. pylori infection. In differentiation between patients with gastrointestinal symptoms who have H. pylori infection or with similar symptoms who do not have H. pylori infection, mentioned interleukins can be used as diagnostic markers.

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    MicroRNA-155 (miR-155) has a critical role in pro-inflammatory activation and tumor progression. In addition, miR-155 has various oncogenic effects in the tumor microenvironment by targeting the suppressor gene of cytokine signaling-1(SOCS-1) and interleukin-6 (IL-6). This study investigated the association of inflammatory changes with the variations of miR-155 expression in newly diagnosed breast cancer (NDBC) patients.
    Seventy NDBC patients were categorized as lobular and ductal subgroups and forty healthy individuals participated in this study. The expression rate of miR-155 and its downstream target gene, SOCS-1, as well as the plasma levels of IL-6, were evaluated in peripheral blood mononuclear cells of NDBC patients; using real-time PCR and enzyme-linked immunosorbent assay, respectively.
    Our results indicated an over-expression of miR-155 in the PBMCs of NDBC patients which was significantly associated with the tumor grade and the type of ductal carcinoma. In contrast, a significant downregulation of SOCS-1 was observed in NDBC patients compared to control group, however, there was no significant difference between two subtypes of BC. Furthermore, a higher concentration of plasma IL-6 was detected in NDBC patients compared to the healthy control group which had an inverse correlation with the SOCS-1 levels.
    According to the potential effects of miR-155 on regulating the expression of SOCS-1 and IL-6, we suggest this small transcript as a promising diagnostic marker for various types of BC patients.

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    Osteoarthritis (OA) is known to be the most prevalent form of joint disease. We conducted this clinical trial to investigate the effects of Krocina TM, a natural product containing crocin, on the gene expression of unique transcription factors of various T cell subsets in patients with OA.
    We collected 40 peripheral blood samples of OA patients receiving Krocina™ and the equal number of those who took a placebo. RNA extraction was performed from the cultured peripheral blood mononuclear cells of the OA patients who received Krocina™ and placebo and SYBR Green Real-time PCR technique was applied to assess the relative gene expression of T-bet, GATA3, ROR-γt, and FOXP3 as the unique transcription factors of various T cell subsets.
    The relative gene expression of T-bet and ROR-γt insignificantly decreased in the Krocina™ receiving group as compared to the placebo group. In addition, the relative gene expressions of GATA-3 and FOXP3 after the treatment with krocina TM showed a significant and insignificant increase, respectively. Moreover, an insignificant decrease was observed in the gene expression of GATA-3 and FOXP3 in the placebo group.  A significant and insignificant decrease in the gene expression of T-bet and ROR- γt was detected in the OA patients who received a placebo. GATA-3 is known as a unique transcription factor for the differentiation of T-cells to the Th2 subset.
    The significant increase in the gene expression of GATA-3 in the patients with OA treated with crocin may suggest the beneficial effect of crocin on shifting towards the Th2 subset and enhancing an anti-inflammatory condition.

  • Rheumatoid arthritis (RA) is a multisystem disorder. Various studies have shown the important role of inflammatory factors tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-22, MYD88, and toll-like receptor 2 (TLR2) in this disease. In this study, we investigated the anti-inflammatory effects of B-D-Mannuronic acid (M2000), as a new immunosuppressive drug, on the expression of these inflammatory markers in peripheral blood mononuclear cells (PBMCs) of RA patients.
    The blood samples of active RA patients and healthy volunteers were used for PBMCsl separation. The cells were cultured with LPS (1 µg/mL), low (5 µg/mL), moderate (25 µg/mL), and high (50 µg/mL) doses of M2000 and a single dose of diclofenac (1 µg/mL) to evaluate TNF-α, IL-6, IL-22, MYD88, and TLR2 genes expression by quantitative real-time (qRT-PCR). Cell surface expression and MFI of TLR2 were assessed; using flow cytometry.
    Our findings exhibited a significant reduction of TNF-α, IL-6, and MYD88 gene expressions after treatment with three doses of M2000 and an optimum dose of diclofenac. TLR2 gene expression was significantly diminished by moderate and high doses of M2000 and a single dose of diclofenac. Moreoversurface expression of TLR2 was significantly downregulated by moderate and high doses of M2000, while MFI of this receptor was significantly reduced by three doses of M2000.
    The results of this research showed that M2000 was able to significantly reduce the gene expression of inflammatory molecules  TNF-α, IL-6, MYD88, and TLR2 in patients PBMCs. factor-alpha; Rheumatoid arthritis. These data revealed a part of the molecular mechanisms of M2000 in the treatment process.

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    Asthma is a respiratory disease; involving millions of people worldwide. The main cause of asthma is allergy and immune response dysregulation. The effects of azithromycin and doxycycline as asthma-controlling drugs were evaluated in this study.
    Mice asthma model was produced and asthmatic mice were treated with azithromycin (75 mg/kg, orally) and doxycycline (20 mg/kg, orally). Eosinophils and neutrophils count, interleukin (IL)-4, IL-5, IL-12, IL-13, and total immunoglobulin E (IgE) levels were measured. Histological study and evaluating the genes expression of Muc5ac, Muc5b, IL-33, COX2, MYD88, and TRAF6 were performed.
    Azithromycin and doxycycline did not affect eosinophil and neutrophil percentage, IL-4, IL-5, IL-12, and total IgE levels, peribronchial and perivascular inflammation, goblet cell hyperplasia, and gene expression of MYD88, TRAF6, and COX2. Treatment with azithromycin significantly decreased IL-13 level, mucus secretion, and gene expression of IL-33, Muc5ac, and Muc5b; compared to the non-treated asthma group.
    Azithromycin administration controls mucus secretion and inflammation. Azithromycin therapy and not doxycycline might be an effective adjuvant option in asthma with reducing mucus in the airway.

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    Autoinflammatory diseases (AIDs) are disorders with an inborn error of innate immunity, characterized by recurrent episodes of fever and inflammatory attacks. The spectrum of AIDs is expanding, but there are no standardized clinical criteria for the diagnosis of the patients. This study aims at establishing the first autoinflammatory registry of an Iranian population focusing on the clinical and laboratory features that may help clinicians for a better understanding and diagnosis of these disorders.
    Clinical and laboratory characteristics of patients who were clinically and or genetically diagnosed with AIDs were collected during 15 years. The updated version of classification criteria from the Eurofever Registry was used for the clinical diagnosis.
    Twenty-eight patients (16 males and 12 females) with the mean±SD age of 28.03±14.49 years (from 2 to 68 years) were entered this study. About 29% were genetically diagnosed. Familial Mediterranean fever (FMF) was the most common diagnosis of the patients. Fever duration episodes were between 1-10 days. Some of the clinical manifestations from the most to the least common were as follows: arthralgia and arthritis (80%), myalgia (76%), coughs and shortness of breath (68%), fatigue (60%), abdominal pain (56%), increased erythrocyte sedimentation rate(ESR) (48%), and splenomegaly (24%).
    Here, we presented the most common clinical manifestations of Iranian AIDs who have registered in our AID registry which would be a useful guide for managing the same patients and also designing the future studies.

Brief Communication

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    Cardiovascular diseases are the most prevalent disease worldwide and pose a considerable threat to human health. Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) plays a crucial role in the maintenance of immune diseases; however, its role in the progression of cardiovascular disorders is still unknown. The present study aimed to evaluate the relationship between CTLA-4 and myocardial infarction (MI).
    The Kyoto encyclopedia of genes and genomes database and the pathway studio database has revealed the role of CTLA4 as an inhibitory receptor on activated T cells. The relative expression of the CTLA-4 gene was assessed on the peripheral blood cells in 80 MI patients and 80 healthy individuals using quantitative real-time polymerase chain reaction (qRT-PCR) and also receiver operating characteristic (ROC) analysis was performed to evaluate the sensitivity and specificity of CTLA-4.
    We noticed the decreased expression of CTLA-4 levels in patients, compared to the control group (2.73±1.55 vs. 5.36±1.34). The study revealed the sensitivity of 0.89, specificity of 0.83, the accuracy of 0.9, and the area under the ROC curve (AUC) of 0.901 (95% CI: 0.727-0.776) for CTLA-4.
    The results highlighted the critical role of CTLA-4 as an inhibitory receptor in the maintenance of cardiovascular risks.

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    Pollens have been identified as potent inducers of allergic diseases worldwide. Acer velutinum (Persian maple) tree is an important source of allergic pollens in Iran. This study aimed to identify the immunoglobulin E (IgE)-reactive components of A. velutinum pollen extract in patients with maple allergy. We aimed to evaluate its allergenic components; using IgE in the serum of patients with maple allergy.
    Twenty-two patients with a clinical history of reaction and a positive skin-prick test to maple pollen extract were included in this study. Identification of IgE-binding proteins in A. velutinum pollen extract was performed by immunoblotting using sera from sensitive patients.
    A protein band with a molecular weight of around 70 kDa was the most IgE-reactive allergen in A. velutinum pollen extract detected by this method.
    Identification of a protein with a molecular weight of about 70kDa, as the most reactive allergen of A. velutinum pollen extract, can be considered as a potential allergen for designing diagnostic kits or as a target for immunotherapy of allergic patients with maple allergy.

Case Report(s)

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    Cold-induced urticaria is considered as a subtype of physical urticaria and also the second most common type of chronic inducible urticaria. Contact with cold surfaces or the environment may cause systemic reactions, especially during aquatic activities. A 22-year-old female patient with a history of sulfa drug allergy began her condition 2 years before the presence of generalized pruritic erythema with hives as well as 2 episodes that had been characterized by facial angioedema and syncope 3-5 minutes after being in contact with cold air or surfaces.  On both events, she had just been outdoors on a cold, winter day. She was suspected to have cold-induced urticaria; thereby she had a positive reaction to the ice cube test. Due to the previous episodes of anaphylaxis, the patient was trained to administer intramuscular epinephrine. After 4 weeks of starting the treatment with antihistamines, no new events or injuries had occurred. Cold-induced urticaria may cause life-threatening reactions. The rate of anaphylaxis in these patients is low however, this case is presented to inform the importance of identifying this type of systemic reaction and preventing strategies.

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    Loss-of-function mutations in magnesium transporter 1 (MAGT1) gene cause X-linked magnesium deficiency with Epstein–Barr virus (EBV) infection and neoplasm (X-MEN), a disease with quite diverse clinical and immunological consequences. The phenotypic characteristics of the initially described patients included CD4+ T cell lymphopenia, immune deficiency, EBV viremia, and EBV-related lymphoproliferative disease. To date, a total of 25 patients have been reported. The spectrum of the MAGT1 defect ranges from other viral infections (HSV, VZV, CMV, MCV) and sinopulmonary bacterial infections, autoimmune diseases, non-EBV driven lymphoproliferative disease, Castleman disease, HHV8+ Kaposi's sarcoma, vasculitis (Kawasaki) to glycosylation defects in new patients. Here, we report 2 patients from two different families with novel MAGT1 mutations and different clinical features. The first patient presented with B cell lymphoma and low IgM level without recurrent infections. The second patient presented with recurrent upper respiratory tract infections, Kawasaki-like disease, hypogammaglobulinemia, and T cell lymphopenia. X-MEN disease is the first phenotype identified due to MAGT1 mutation. The identification of new mutations and atypical presentations will clarify whether there is a relationship between the genotype and the phenotype and the characteristics of the disease.

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    A four-year-old female patient visited the pediatric hematologic clinic due to periodic generalized edema and eosinophilia. Laboratory assessment showed an eosinophil count of 40.02×109/L (73.6% of white blood cells). A bone marrow aspirate smear film showed no signs of malignant cells but had hypercellular marrow particles with eosinophilia (45% of all nucleated cells) and 52% of eosinophils were immature. Other laboratory tests showed an increased IgM level of 827 mg/dL, and lymphocyte phenotyping by flow cytometry revealed an aberrant CD3CD4+ T-cell population of 27–53×109/L (1.9–3.6% of lymphocytes). Polymerase chain reaction analysis for the T-cell receptor gamma gene rearrangement showed a T-cell clonality peak. At the age of 13, allogeneic stem cell transplantation was performed, but with primary rejection. From the age of 17, she has continued receiving 3 mg/kg of reslizumab intravenously every 4 weeks for 21 months. Since reslizumab treatment was initiated, her eosinophil count remained consistently within the normal range. This is the first report describing the effective use of reslizumab in a Korean adolescent patient for the management of lymphocytic-variant hypereosinophilic syndrome (L-HES). Since the patient showed clinical manifestations of L-HES as well as episodic angioedema with eosinophilia (EAE), a continuous periodic examination is required given the higher risk of developing lymphoma or leukemia.