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Objectives: Asthma is the most prevalent respiratory disease, caused by chronic bronchial inflammation. Cytokines are known to play an important role in the pathophysiology of asthma. This study aimed to compare interleukin-4 (IL-4) and interleukin-10 (IL-10) gene polymorphisms between Iranian pediatric asthmatic patients and healthy controls and to investigate IL4 and IL10 gene variations in children with atopic and non-atopic asthma phenotypes., Methods: In this prospective case-control study, a total of 95 unrelated pediatric asthmatic patients were recruited according to the Global Initiative for Asthma (GINA) criteria. The control group comprised two subgroups of 538 and 491 healthy individuals, undergoing IL4 and IL10 polymorphism assessments, respectively. The IL4 -589C/T (rs2243250) and IL10 -592A/C (rs1800872) gene polymorphisms were evaluated using the tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) assay., Results: The findings indicated a significant difference in IL4 gene polymorphisms at position -589 between the asthmatic and healthy control groups. However, no significant difference was found in terms of IL10 gene polymorphisms, and they were not associated with atopy in the patients., Conclusion: The IL4 -589C/T polymorphism (rs2243250) can be a risk factor for asthma susceptibility, whereas the IL10 -592A/C polymorphism (rs1800872) is not a risk factor in the Iranian pediatric population. The results also showed that these polymorphisms are not risk factors for atopy in asthmatic children., Competing Interests: None., (AJCEI Copyright © 2023.)

Asthma is one of the most prevalent chronic lung diseases that afflict genetically predisposed individuals. Certain cytokine gene polymorphisms have been associated with asthma. Tumor necrosis factor-alpha (TNF-α) is a potent inflammatory cytokine that can modulate nonspecific inflammation to influence asthma. This study aimed to define the relationship between the TNF gene polymorphism at position -308 and asthma susceptibility, as well as atopic and non-atopic asthma. Using polymerase chain reaction with sequence-specific primers, we investigated genotype frequencies and alleles of a polymorphic gene coding for TNF-α in 86 pediatric patients with asthma and 470 healthy controls of the same race. Seventy-four patients underwent a skin prick test. The homozygous AA variant (-308, rs1800629) was the most common genotype among patients, accounting for 63.3% of all cases. In contrast, homozygous GG (-308) was significantly less prevalent in the patient group compared to the control group. TNF A (-308) allele frequency was 85.5% among asthma patients and 16.6% among healthy controls. The genotype and allele frequencies of TNF (-308 A>G, rs1800629) did not differ between atopic and non-atopic asthma. In conclusion, TNF (-308) AA and AG genotypes are associated with asthma susceptibility in Iranian children, although there was no significant difference in polymorphism between atopic and non-atopic asthma and no difference in asthma severity groups.

Background: The inborn errors of immunity (IEIs) are a group of heterogeneous disorders mainly characterized by severe and recurrent infections besides other complications including autoimmune and inflammatory diseases. In this study, we aim to evaluate clinical, immunologic, and molecular data of monogenic IEI patients with and without autoimmune manifestations., Methods: We have retrospectively screened cases of monogenic IEI in the Iranian PID registry for the occurrence of autoimmunity and immune dysregulation. A questionnaire was filled for all qualified patients with monogenic defects to evaluate demographic, laboratory, clinical, and molecular data., Results: A total of 461 monogenic IEI patients (290 male and 171 female) with a median (IQR) age of 11.0 (6.0-20.0) years were enrolled in this study. Overall, 331 patients (72.1%) were born to consanguineous parents. At the time of the study, 330 individuals (75.7%) were alive and 106 (24.3%) were deceased. Autoimmunity was reported in 92 (20.0%) patients with a median (IQR) age at autoimmune diagnosis of 4.0 (2.0-7.0) years. Sixteen patients (3.5%) showed autoimmune complications (mostly autoimmune cytopenia) as the first presentation of the disease. Most of the patients with autoimmunity were diagnosed clinically with common variable immunodeficiency (42.4%). The frequency of sinusitis and splenomegaly was significantly higher in patients with autoimmunity than patients without autoimmunity. In patients with autoimmunity, the most common pathogenic variants were identified in LRBA (in 21 patients, 23.0%), ATM (in 13 patients, 14.0%), and BTK (in 9 patients, 10.0%) genes. In the evaluation of autoimmunity by different genes, 4 of 4 IL10RB (100%), 3 of 3 AIRE (100%), and 21 of 30 LRBA (70.0%) mutated genes had the highest prevalence of autoimmunity., Conclusions: Autoimmune phenomena are common features among patients with monogenic IEI and are associated with a more complicated course of the disease. Therefore, when encountering autoimmune disorders, especially in the setting of dysgammaglobulinemia, it would be appropriate to conduct next-generation sequencing to discover responsible genes for the immune dysregulation at an early stage of the disease., (© 2021 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Griscelli syndrome type 2 (GS-2) is an inborn error of immunity characterized by partial albinism and episodes of hemophagocytic lymphohistiocytosis (HLH). It is caused by RAB27A mutations that encode RAB27A, a member of the Rab GTPase family. RAB27A is expressed in many tissues and regulates vesicular transport and organelle dynamics. Occasionally, GS-2 patients with RAB27A mutation display normal pigmentation. The study of such variants provides the opportunity to map distinct binding sites for tissue-specific effectors on RAB27A. Here we present a new case of GS-2 without albinism (GS-2 sine albinism) caused by a novel missense mutation (Val143Ala) in the RAB27A and characterize its functional cellular consequences. Using pertinent animal cell lines, the Val143Ala mutation impairs both the RAB27A-SLP2-A interaction and RAB27A-MUNC13-4 interaction, but it does not affect the RAB27A-melanophilin (MLPH)/SLAC2-A interaction that is crucial for skin and hair pigmentation. We conclude that disruption of the RAB27A-MUNC13-4 interaction in cytotoxic lymphocytes leads to the HLH predisposition of the GS-2 patient with the Val143Ala mutation. Finally, we include a review of GS-2 sine albinism cases reported in the literature, summarizing their genetic and clinical characteristics., Competing Interests: SA worked as a scientific advisor for Sobi. The IRB of Children’s Medical Center affiliated to TUMS approved this study (IR.TUMS.CHMC.REC.1399.080). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer HK declared a past co-authorship with one of the authors SE to the handling editor. The reviewer AF declared a past co-authorship with one of the authors SE to the handling editor., (Copyright © 2020 Ohishi, Ammann, Ziaee, Strege, Groß, Amos, Shahrooei, Ashournia, Razaghian, Griffiths, Ehl, Fukuda and Parvaneh.)

Background: The number of inherited diseases and the spectrum of clinical manifestations of primary immunodeficiency disorders (PIDs) are ever-expanding. Molecular diagnosis using genomic approaches should be performed for all PID patients since it provides a resource to improve the management and to estimate the prognosis of patients with these rare immune disorders., Method: The current update of Iranian PID registry (IPIDR) contains the clinical phenotype of newly registered patients during last 5 years (2013-2018) and the result of molecular diagnosis in patients enrolled for targeted and next-generation sequencing., Results: Considering the newly diagnosed patients (n = 1395), the total number of registered PID patients reached 3056 (1852 male and 1204 female) from 31 medical centers. The predominantly antibody deficiency was the most common subcategory of PID (29.5%). The putative causative genetic defect was identified in 1014 patients (33.1%) and an autosomal recessive pattern was found in 79.3% of these patients. Among the genetically different categories of PID patients, the diagnostic rate was highest in defects in immune dysregulation and lowest in predominantly antibody deficiencies and mutations in the MEFV gene were the most frequent genetic disorder in our cohort., Conclusions: During a 20-year registration of Iranian PID patients, significant changes have been observed by increasing the awareness of the medical community, national PID network establishment, improving therapeutic facilities, and recently by inclusion of the molecular diagnosis. The current collective study of PID phenotypes and genotypes provides a major source for ethnic surveillance, newborn screening, and genetic consultation for prenatal and preimplantation genetic diagnosis.