Asthma is a complex disease caused by a combination of multiple genetic and environmental factors. Angiotensin-converting enzyme (ACE) is involved in the pathogenesis of asthma by inactivating bradykinin, substance P, and neurokinin A. It has been shown that the level of ACE variation in serum is associated with an insertion-deletion (I/D) polymorphism. So, this study aimed to investigate the association of these polymorphisms with asthma in western Iran.
In this case-control study, 111 asthmatic patients as a case group and 80 healthy subjects as a control group were evaluated. The ACE gene polymorphism was determined by the PCR method. The relationship between genotypes done by the χ2 test and the relative risk of disease with genetic polymorphism (Odds Ratio) was performed using logistic regression.
The frequency of I/D genotypes (included in II, ID, and DD) between patient and control groups had no significant difference. In addition, none of the genotypes in the patient and control groups show any significant differences between men and women. However, the frequency of ID and DD genotypes was considerably different between the male patient groups (over and under 40 years old). Hence, these genotypes are suggested to be a risk factor for asthma.
The results of our study indicate that ACE gene polymorphism is not significantly associated with asthma in the west of Iran.

Acute asthma exacerbations (AAE) are episodes characterized by potentially life-threatening and rapidly deteriorating asthma symptoms. Viral respiratory infections are one of the major triggers in the pathophysiology of childhood asthma exacerbations. In this study, we aimed to determine the distribution of viral agents among pediatric AAE patients.
One hundred and three AAE patients, aged 5 or older, hospitalized between from February 2017 through February 2020 at Pediatric Immunology and Allergic Diseases Unit were included in this study. Fifty patients (48.5%) were female, and the mean age of the patients was 108.2 months. Viruses were detected in 58 (%56.3) of the patients, in 5 of whom more than one virus type was detected. The most commonly detected virus was human rhinovirus (n=43, 67.1%).
Other types included respiratory syncytial virus (n=8; 12.5%), influenza (n=6; 9.3%), human metapneumovirus (n=4; 6.2%), adenovirus (n=1; 1.5%), enterovirus (n=1; 1.5%), and parainfluenza (n=1; 1.5%). Viral agents were detected in 29 out of the 47 patients with allergic asthma, with human rhinoviruses comprising the majority (18 patients). The mean length of hospital stay was 7.89 days.
Human rhinovirus is the most common virus that triggers AAE, with similar distributions in allergic and non-allergic asthma. We found no correlation between virus type and the length of hospital stay.

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.

Alternative medicine, has become popular in asthmatic patients. We evaluated the immunomodulatory effects of SINA 1.2 therapy protocol derived from Persian medicine in an asthmatic mice model.
Forty-two male BALB/c mice divided into six groups: one control (sham) and five sensitized groups (by parenteral injection of 20 μg ovalbumin in 100 μL normal saline plus 50 μL alum on days 1 and 14). Sensitized groups were as: untreated, budesonide (1 mg nebulized budesonide: 200 μg/puff every 5 min for 25 min), dry sauna (30 min, 37°C), oral oxymel (gavaged: 0.2 mL of the syrup plus 0.8 mL of water), and SINA protocol No.1.2 (oxymel followed by sauna) groups. Treatments were given for 10 days from day 23 to 33 then sacrificed.
Significant gene expression reduction of interleukin(IL)-4, IL-5, and MUC5AC and increase of interferon(IFN)-γ and IFN-γ/IL-4 ratio and decreased perivascular and peribronchial inflammation, goblet cell hyperplasia, and subsequent mucus hypersecretion in SINA group were seen compared to untreated group. SINA lowered IL-5 and MUC5AC gene expression levels similar to the budesonide and acted better than budesonide in increasing IFN-γ gene expression up to normal level. Compared with the asthma group, sauna alone only affected MUC5AC and IFN-γ gene expressions and oxymel alone, only reduced IL-4 gene expression, perivascular and peribronchial inflammation, and mucus hypersecretion.
It seems that SINA therapy alleviates asthma via immune modulation of pro-inflammatory cytokines and improvement of pathological changes in ovalbumin-induced asthma in mice, supporting the notion of innate healing power mentioned in Persian medicine literature.

Current medications to treat allergic rhinitis (AR) include antihistamines, corticosteroids, and anti-leukotrienes. In the present study, we investigated the effects of combination therapy; using these drugs, and evaluates the AR-related markers and parameters in an animal model.
After inducing BALB/c mice AR models, the animals were treated with either pranlukast, loratadine, fluticasone, loratadine + fluticasone, loratadine + pranlukast, fluticasone + pranlukast, or loratadine + fluticasone + pranlukast. Clinical symptoms, Immunoglobulin (Ig)G1, ovalbumin (OVA)-specific and total IgE, leukotriene (LT)B4, LTC4, histamine, thymic stromal lymphopoietin (TSLP) serum levels, and interleukin 4 level in the nasal lavage fluid were determined. The expressions of HRH1, CysLT1R, NLR3, Caspase-1, and MUC5a were studied.
Allergic symptoms (nasal rubbing and sneezing), serum Igs (IgG1, total and OVA-specific IgE), eicosanoids (LTB4 and LTC4), histamine, TSLP, and IL-4 as well as gene expressions of MUC5a, Caspase-1, NLR3, HRH1, and CysLT1R were reduced in the animals receiving each of the therapeutic regimens; however, more pronounced effects were seen in the group treated with the triple combined protocol (loratadine + fluticasone + pranlukast).
The combination of the loratadine, fluticasone, and pranlukast can effectively control the symptoms of AR probably via modulating several related mechanisms at early and late phases of allergic responses.

This study is designed to present an agent-based model (ABM) to simulate the interactions between tumor cells and the immune system in the melanoma model. The Myeloid-derived Suppressor Cells (MDSCs) and dendritic cells (DCs) are considered in this model as immunosuppressive and antigen-presenting agents respectively.
The animal experiment was performed on 68 B16F10 melanoma tumor-bearing C57BL/6 female mice to collect dynamic data for ABM implementation and validation. Animals were divided into 4 groups; group 1 was control (no treatment) while groups 2 and 3 were treated with DC vaccine and low-dose 5- fluorouracil (5-FU) respectively and group 4 was treated with both DC Vaccine and low-dose of 5-FU. The tumor growth rate, number of MDSC, and presence of CD8+/CD107a+ T cells in the tumor microenvironment were evaluated in each group. Firstly, the tumor cells, the effector immune cells, DCs, and the MDSCs have been considered as the agents of the ABM model and their interaction methods have been extracted from the literature and implemented in the model. Then, the model parameters were estimated by the dynamic data collected from animal experiments. 
To validate the ABM model, the simulation results were compared with the real data. The results show that the dynamics of the model agents can mimic the relations among considered immune system components to an emergent outcome compatible with real data. The simplicity of the proposed model can help to understand the results of the combinational therapy and make this model a useful tool for studying different scenarios and assessing the combinational results.
Determining the role of each component helps to find critical times during tumor progression and change the tumor and immune system balance in favor of the immune system. 

Triple-negative breast cancer (TNBC) is the most aggressive type of BC with the highest percentage of tumor-infiltrating lymphocytes (TILs). Hence, TIL therapy is considered a promising approach to target TNBC. Depletion of regulatory T cells (Tregs) in TILs can improve the antitumor function of TIL therapy. Pentoxifylline (PTXF) is a xanthine derivative that can modulate the nuclear factor kappa B (NF-κB) signaling and probably affect the Treg proportion in TILs. We aimed to evaluate the ex vivo effect of PTXF on the proportion of Treg cells in the TILs derived from a mouse model of TNBC.
The 4T1 cells were inoculated subcutaneously to BALB/c mice to induce TNBC. TILs were isolated from tumor tissue by enzymatic digestion and cultured alone or with 4T1 cells for 24, 48, and 72 h in the presence of interleukin (IL)-2 and different concentrations of PTXF. The toxicity of PTXF and its effects on Tregs proportion as well as cytokine production was evaluated using MTT assay, flow cytometry, and ELISA, respectively.
PTXF had no significant impact on the viability of TILs. Both 500 and 1000 mg/mL of PTXF decreased the proportion of Tregs in a dose-dependent manner. The level of interferon-g and tumor growth factor-b in TILs supernatant was increased and decreased, respectively.
Our data suggest that ex vivo treatment of TILs with pentoxifylline could decrease the proportion of Tregs in the conventional IL-2-mediated TIL expansion and change the cytokine balance of TILs in favor of antitumor immune response.

Up-regulation of immune checkpoint ligands is considered as one of the most important immune escape mechanisms in acute myeloid leukemia (AML). Herein, we investigate a relationship between the inhibition of PI3K/Akt/mTOR signaling pathways and the regulation of immune checkpoint ligands in AML cells.
The HL-60 cell line was treated with idelalisib as PI3K inhibitor, MK-2206 as Akt inhibitor, and everolimus as mTOR inhibitor either in a single or combined format. Cell viability and apoptosis were evaluated using MTT and flow cytometry assays, respectively. The relative expression of PD-L1, galectin-9, and CD155 was determined by real-time PCR.
Our findings demonstrated decreased proliferation and increased apoptosis of HL-60 cells after treatment with idelalisib, MK-2206, and everolimus. As expected, the combined treatment showed a more inhibiting effect than the single treatment. Interestingly, our results elucidated that the expression of PD-L1 and Gal-9 but not MK-2206 decreased after treatment with idelalisib and everolimus. Regarding CD155, the expression of this molecule was downregulated after treatment with everolimus, but not idelalisib and MK-2206. However, combined treatment of HL-60 cells with two or three inhibitors decreased the expression levels of PD-L1, Gal-9, and CD155 checkpoint ligands.
We showed that PI3K/Akt/mTOR pathway inhibitors not only serve as cytotoxic drugs but also regulate the expression of immune checkpoint ligands and interfere with the immune evasion mechanisms of AML leukemic cells. Combinational treatment approaches to block these pathways might be a promising and novel therapeutic strategy for AML patients via interfering in immune escape mechanisms.

Cystic fibrosis (CF) is the most common lethal autosomal recessive disease in white Caucasians. It affects many organs including the lung, pancreas, and liver. Whilst CF is a monogenic disease, several studies revealed a complex relationship between genotype and clinical phenotype of diseases. We examined the expression of human leukocyte antigen (HLA) class II alleles among Iranian CF patients with disease-related microbial infection.
This study was conducted on 50 hospitalized CF patients (27 males, 23 females aged 15.5±6.5 years), and 50 healthy age- and gender-matched control subjects. 5ml whole blood was harvested and after isolation of genomic DNA, HLA-DRB1 subtypes were determined by single specific primer polymerase chain reaction methods.
HLA-DRB1*10 was less frequent and HLA-DRB1*04 and HLA-DRB1*11 was the most frequent allele in CF patients, but none reached significance. HLA-DRB1*04 allele was frequently seen among16 CF patients with high serum IgE levels (430.25±219.7 IU/mL) and 27 CF patients that were positive for Pseudomonas aeruginosa colonization. A total of 31 CF patients had candida Albicans colonization in whom HLA-DRB1*11 was mostly seen. A total of 3 CF patients had allergic bronchopulmonary aspergillosis and two were diabetic.
The DR4 and DR11 serotypes that recognize the HLA-DRB1*04 and HLA-DRB1*11 gene products respectively are not significantly enriched in the Iranian CF population. Further research should be conducted on DR4 and DR11 in CF patients to understand their possible role in infection and IgE expression.

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.

Utilizing subunit vaccines is one of the strategies to address influenza infection. Recent innovations have focused on high doses of vaccine antigens and immune enhancers or adjuvant to induce more robust and long-lasting immune responses. Here, an effect of the B cell-activating factor receptor (BAFF-R) to increase the magnitude and durability of immune responses of the recombinant HA1 (rHA1) protein against the H1N1 influenza virus was studied.
The HA1 protein and the effector domain of BAFF-R were expressed in the pET-28a (+) vector. Eight-week-old BALB/c mice were equally grouped into five groups (n=20). The 15 and 25 μg/μL of rHA1 were mixed with 2 μg/μL of rBAFF-R and injected three times for vaccinated groups. Three control groups were received normal saline and two concentrations of rHA1. The ability of rBAFF-R in eliciting HA-specific antibody response and stimulating T lymphocyte proliferation to induce the cell-mediated immunity was assayed. Induction of protection was evaluated following the challenge with PR8 strain.
Analysis of immune responses showed that the co-administration of rBAFF-R with rHA1 boosted HI responses to the antigen in mice, whilst it was not able to promote the T cell proliferation responses against influenza. Compared to rHA1alone, the rBAFF-R/rHA1 generated efficient protection for the animals. There were no significant differences in eliciting the immune responses in mice immunized with the lower dose of rHA1 than that with the higher dose.
The data indicate the rBAFF-R can enhance the primary and memory immune responses to protect against influenza infection.

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 CD3⁻CD4⁺ 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.

LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency caused by a mutation in the LRBA gene. Affected individuals present with a variety of clinical symptoms including hypogammaglobulinemia, recurrent infections, splenomegaly, hepatomegaly, and autoimmune cytopenias. Except for hypogammaglobulinemia, the remaining features resemble autoimmune lymphoproliferative syndrome (ALPS). Here, we report the case of a 14-year-old boy with the ALPS phenotype, eventually diagnosed with LRBA deficiency. He presented with lymphadenopathy and hepatosplenomegaly, along with autoimmune cytopenia. Due to recurrent infections and worsening gastrointestinal symptoms, whole-exome sequencing was conducted and revealed a novel homozygous pathogenic variant in the LRBA gene (c.534del; p.9Asp179IIef*16). The patient recently suffered from clinical deterioration due to SARS-COV-2 which appears to have triggered an acute worsening of his existing Cytomegalovirus colitis leading to an eventual demise. A literature search for reported LRBA deficient patients with ALPS-like phenotype revealed 11 patients. The most common clinical presentations in LRBA patients with ALPS-like phenotype included autoimmunity (100%), splenomegaly (91%), lymphadenopathy (36.4%), and respiratory tract infections (63.6%). LRBA deficiency is unique in the fact that it encompasses immune deficiency, autoimmunity, and lymphoproliferation. In children with multiple symptoms related to these domains, a genetic diagnosis is necessary to ensure tailored and precise medical therapy.

The article is a letter to editor and does not have the abstract