Publications by authors named "Reza Yazdani"

124 Publications

Consensus Middle East and North Africa Registry on Inborn Errors of Immunity.

J Clin Immunol 2021 May 29. Epub 2021 May 29.

Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.

Background: Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis.

Methods: We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers.

Results: We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG).

Conclusions: This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation.
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http://dx.doi.org/10.1007/s10875-021-01053-zDOI Listing
May 2021

Caries incidence of the first permanent molars according to the Caries Assessment Spectrum and Treatment (CAST) index and its determinants in children: a cohort study.

BMC Oral Health 2021 05 13;21(1):259. Epub 2021 May 13.

Department of Community Oral Health, School of Dentistry, Alborz University of Medical Sciences, Karaj, Iran.

Background: There are limited information on caries incidence, especially from developing countries, the aim of the present study was to explore caries incidence in the first permanent molar teeth according to the CAST index in 7- to 8-year-old-children and its socio-demographic, oral health related and diet determinants.

Methods: A multi-stage cluster random sample of 7-8 years old children was applied in Tehran, Iran. The oral examination using the CAST index and the Oral Hygiene Index-Simplified (OHI-S) performed by trained dentists in 2017 and 2019 calibrated with an expert (Kappa of 0.89 and 0.76, respectively). A 3-day food record was used to record sugary snacks consumption. Oral health related knowledge of the parents was assessed using a valid and reliable self-administered questionnaire. The data were analyzed using the SPSS software version 23.0 and descriptive and analytical statistics including the negative binomial regression was applied.

Results: Two hundred and ninety schoolchildren aged 7-8 years old were followed up for two years. All of them had complete data obtained via oral examination and questionnaires. The annual caries incidence rate was 0.16 and 53% (95% CI 47.4-58.9) of the children developed at least one new dental caries (enamel or dentine) during two years. Multi-variate analysis revealed that the children of mothers with high school education or diploma (IRR = 1.47, 95% CI 1.02-2.12; p = 0.04) and those with low socio-economic status (IRR = 1.86, 95% CI 1.27-2.73; p < 0.001) were more likely to develop caries. There was no significant association between gender, father's educational level, child birth order, housing area per person, OHI-S score, oral health knowledge of parents, and sugary snacks consumption per day and caries increment at an individual level.

Conclusion: This 2-year longitudinal study on 7- to 8-year-old children showed that caries incidence according to the CAST index was associated with socio-economic status and mother education but not associated with having 2 or more sugary snack per day and oral hygiene status.
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http://dx.doi.org/10.1186/s12903-021-01612-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120821PMC
May 2021

Clinical, immunological, and genetic features in 780 patients with autoimmune lymphoproliferative syndrome (ALPS) and ALPS-like diseases: A systematic review.

Pediatr Allergy Immunol 2021 May 8. Epub 2021 May 8.

Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.

Background: Autoimmune lymphoproliferative syndrome (ALPS) is a group of genetic disorders characterized by early-onset lymphoproliferation, autoimmune cytopenias, and susceptibility to lymphoma. The majority of ALPS patients carry heterozygous germline mutations in the TNFRSF6 gene. In this study, we conducted a systematic review of patients with ALPS and ALPS-like syndrome.

Methods: The literature search was performed in Web of Science, Scopus, and PubMed databases to find eligible studies. Additionally, the reference list of all included papers was hand-searched for additional studies. Demographic, clinical, immunological, and molecular data were extracted and compared between the ALPS and ALPS-like syndrome.

Results: Totally, 720 patients with ALPS (532 genetically determined and 189 genetically undetermined ALPS) and 59 cases with ALPS-like phenotype due to mutations in genes other than ALPS genes were assessed. In both ALPS and ALPS-like patients, splenomegaly was the most common clinical presentation followed by autoimmune cytopenias and lymphadenopathy. Among other clinical manifestations, respiratory tract infections were significantly higher in ALPS-like patients than ALPS. The immunological analysis showed a lower serum level of IgA, IgG, and lymphocyte count in ALPS-like patients compared to ALPS. Most (85%) of the ALPS and ALPS-like cases with determined genetic defects carry mutations in the FAS gene. About one-third of patients received immunosuppressive therapy with conventional or targeted immunotherapy agents. A small fraction of patients (3.3%) received hematopoietic stem cell transplantation with successful engraftment, and all except two patients survived after transplantation.

Conclusion: Our results showed that the FAS gene with 85% frequency is the main etiological cause of genetically diagnosed patients with ALPS phenotype; therefore, the genetic defect of the majority of suspected ALPS patients could be confirmed by mutation analysis of FAS gene.
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http://dx.doi.org/10.1111/pai.13535DOI Listing
May 2021

Autoimmune manifestations among 461 patients with monogenic inborn errors of immunity.

Pediatr Allergy Immunol 2021 Mar 27. Epub 2021 Mar 27.

Department of Pediatrics, Hamedan University of Medical Sciences, Hamedan, Iran.

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.
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http://dx.doi.org/10.1111/pai.13510DOI Listing
March 2021

Evaluation of miR-210 expression in common variable immunodeficiency: patients with unsolved genetic defect.

Allergol Immunopathol (Madr) 2021 1;49(2):84-93. Epub 2021 Mar 1.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran;

Background: Common variable immunodeficiency (CVID) is one of the most prevalent forms of primary immunodeficiency diseases (PID). CVID is characterized by failure in the final differentiation of B lymphocytes and impaired antibody production but the pathogenesis is not known in the majority of patients. We postulated that the expression pattern of miRNAs in unsolved CVID patients might be the underlying epigenetic cause of the disease. Therefore, we aimed to assess the expression of hsa-miR-210-5p and FOXP3 transcription factor in CVID cases in comparison with healthy individuals.

Methods: Eleven CVID cases with no genetic defects (all PID known genes excluded) and 10 sex and age-matched healthy individuals were enrolled in the study. T lymphocytes were purified from PBMC, and expression levels of miR-210-5p and FOXP3 mRNA were evaluated by real-time PCR.

Results: We demonstrated that miR-210 expression in patients was significantly higher than the control group (P = 0.03). FOXP3 expression was slightly lower in patients compared with healthy controls (P = 0.86). There was a negative correlation between miR and gene expression (r: -0.11, P = 0.73). Among various clinical complications, autoimmunity showed a considerable rate in high-miR patients (P = 0.12, 42.8%), while autoimmunity was not observed in normal miR-210 patients.

Conclusions: Our results suggest a role for miR-210 in the pathogenesis of autoimmunity in CVID patients. Further studies would better elucidate epigenetic roles in CVID patients with no genetic defects.
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http://dx.doi.org/10.15586/aei.v49i2.39DOI Listing
March 2021

Features and roles of T helper 22 cells in immunological diseases and malignancies.

Scand J Immunol 2021 May 22;93(5):e13030. Epub 2021 Feb 22.

Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.

T helper 22 (Th22) cell populations are a newly identified subset of CD4  T cells that primarily mediate biological effects on the epithelial barrier through interleukin (IL)-22. Although, new studies showed that both Th22 and IL-22 are closely associated with the pathogenesis of inflammatory, autoimmune and allergic disease as well as malignancies. In this review, we aim to describe the development and characteristics of Th22 cells as well as their roles in the immunopathogenesis of immune-related disorders and cancer.
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http://dx.doi.org/10.1111/sji.13030DOI Listing
May 2021

The spectrum of ATM gene mutations in Iranian patients with ataxia-telangiectasia.

Pediatr Allergy Immunol 2021 Feb 6. Epub 2021 Feb 6.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran.

Background: Ataxia-telangiectasia (A-T) is a rare genetic disorder characterized by a distinct range of clinical manifestations, including progressive ataxia, immunodeficiency, and radiosensitivity.

Methods: Clinical data, laboratory results, and genetic data were collected from forty-three A-T patients. Whole-exome sequencing and Sanger sequencing were done for the patients clinically diagnosed as suffering from A-T. Based on the phenotype severity of the disease, patients were divided into severe and mild subgroups.

Results: The median (IQR) age of diagnosis in this cohort was 5 (3-7) years, and various types of clinical manifestations, including fever (P =.005), lower respiratory tract infection (P = .033), diarrhea (P = .014), and hepatosplenomegaly (P = .032), were significantly higher among patients diagnosed with the severe phenotype. Our results showed a correlation between phenotype severity and mutation type. The chance of having severe phenotype in patients who have severe mutations, including frameshift and nonsense, was 7.3 times higher than in patients who were categorized in the mild genotype group (odds ratio = 7.3, P = .006). Thirty-four types of mutations including 9 novel mutations were observed in our study.

Conclusion: Molecular analysis provides the opportunity for accurate diagnosis and timely management in A-T patients with chronic progressive disease, especially infections and the risk of malignancies. This study characterizes for the first time the broad spectrum of mutations and phenotypes in Iranian A-T patients, which is required for carrier detection and reducing the burden of disease in the future using the patients' families and for the public healthcare system.
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http://dx.doi.org/10.1111/pai.13461DOI Listing
February 2021

Primary Immunodeficiency and Thrombocytopenia.

Int Rev Immunol 2021 Jan 19:1-43. Epub 2021 Jan 19.

Research Center for Immunodeficiencies, Tehran University of Medical Sciences, Tehran, Iran.

Primary immunodeficiency (PID) or Inborn errors of immunity (IEI) refers to a heterogeneous group of disorders characterized by immune system impairment. Although patients with IEI manifest highly variable symptoms, the most common clinical manifestations are recurrent infections, autoimmunity and malignancies. Some patients present hematological abnormality including thrombocytopenia due to different pathogenic mechanisms. This review focuses on primary and secondary thrombocytopenia as a complication, which can occur in IEI. Based on the International Union of Immunological Societies phenotypic classification for IEI, the several innate and adaptive immunodeficiency disorders can lead to thrombocytopenia. This review, for the first time, describes manifestation, mechanism and therapeutic modalities for thrombocytopenia in different classes of IEI.
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http://dx.doi.org/10.1080/08830185.2020.1868454DOI Listing
January 2021

Increased Expression of B Lymphocyte Induced Maturation Protein 1 (BLIMP1) in Patients with Common Variable Immunodeficiency (CVID).

Iran J Allergy Asthma Immunol 2020 Aug 25;19(4):437-446. Epub 2020 Aug 25.

Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran AND Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.

Common variable immunodeficiency (CVID) is a primary immune deficiency disorder characterized by a failure in B cell differentiation, impaired immunoglobulin production,and defect in response to vaccines. As a result of defective B cell maturation and differentiation in CVID, the affected patients commonly present with reduced numbers of memory B cell and antibody-secreting plasma cells. B-cell lymphoma 6 protein (BCL6) and B lymphocyte induced maturation protein 1 (BLIMP1) molecules are two important transcription factors that have key roles in the maturation of B cells to plasma cells. Hence, in the current survey, we aimed to evaluate the mRNA and protein expression levels of BCL6 and BLIMP1 in B lymphocytes isolated from peripheral blood in CVID patients. We collected blood samples from 12 CVID patients and 12 healthy controls. We isolated peripheral blood mononuclear cells (PBMCs) using Ficoll density gradient separation. Then, CD19+ B cells were purified using MACS. The protein expression and transcriptional level of BCL6 and BLIMP1 were respectively measured using flow cytometry and real-time PCR. Our results showed that the BLIMP1 mRNA expression, as well as BLIMP1 protein expression, were significantly higher in CVID patients compared to control subjects (p=0.009 and p=0.007, respectively). However, we found no significant difference in mRNA and protein expression of BCL6 between patients and healthy controls. According to our findings, increased mRNA and protein expression levels of BLIMP1 could be involved in defective maturation of B cells in patients with CVID and elucidate mechanistic insights into the pathogenesis of this disorder.
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http://dx.doi.org/10.18502/ijaai.v19i4.4118DOI Listing
August 2020

The First Case Report of Kabuki Syndrome from the National Iranian Registry of Primary Immunodeficiencies.

Endocr Metab Immune Disord Drug Targets 2021 Jan 14. Epub 2021 Jan 14.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran. Iran.

Kabuki syndrome is a rare congenital anomaly/mental retardation syndrome characterized by intellectual disability, developmental delay, short stature, facial dysmorphic features including ectropion of the lateral third of the lower eyelids and long palpebral fissures, and prominent finger pads. Pathogenic variants of KMT2D (MLL2) and KDM6A are found to be the major causes of Kabuki syndrome. Here, we report the first Iranian case with Kabuki syndrome with an IQ of 79, two episodes of viral pneumonia and distinctive facial features, prominent ears and persistent fetal fingertip pads. These characteristics raised our suspicion for performing whole-exome sequencing (WES), which revealed 2 heterozygous pathogenic missense variants in the KMT2D gene: c.C10024T in exon 34 leading to p.R3342C and c.G15005A in exon 48 leading to p.R5002Q. Hence, the definitive diagnosis of Kabuki syndrome was made based on molecular findings along with the intellectual disability and characteristic facial features.
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http://dx.doi.org/10.2174/1871530321666210114153920DOI Listing
January 2021

The First Iranian Cohort of Pediatric Patients with Activated Phosphoinositide 3-Kinase-δ (PI3Kδ) Syndrome (APDS).

Immunol Invest 2021 Jan 6:1-16. Epub 2021 Jan 6.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran.

: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently defined combined primary immunodeficiency disease (PID) characterized by recurrent respiratory tract infections, lymphoproliferation, autoimmunity and lymphoma. Gain-of-function mutations in and loss-of-function of genes lead to APDS1 and APDS2, respectively.: Demographic, clinical, immunological and genetic data were collected from medical records of 15 pediatric patients, who were genetically identified using the whole-exome sequencing method.: Fifteen patients (6 APDS1 and 9 APDS2) were enrolled in this study. Recurrent respiratory tract infections followed by lymphoproliferation and autoimmunity were the most common manifestations (86.7%, 53.3% and 26.7%, respectively). Five patients (33.3%) had a Hyper-IgM-syndrome-like immunoglobulin profile. In the APDS1 group, splice site and missense mutations were found in half of the patients and the C-lobe domain of was the most affected region (50%). In the APDS2 group, splice site mutation was the most frequent mutation (77.8%) and the inter-SH2 domain was the most affected region of (66.7%). Mortality rate was significantly higher in APDS2 group ( = .02) mainly due to chronic lung infections.: Respiratory tract infections and humoral immunodeficiency are commonly the most important complication in pediatric APDS patients, and they can be fatal by ultimately causing catastrophic damage to the structure of lungs. Hence, physicians should be aware of its significance and further work-up of patients with recurrent respiratory tract infections especially in patients with lymphoproliferation. Moreover, delineation of genotype-phenotype associations with disease severity could be helpful in the timely application of appropriate management and patients' survival.
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http://dx.doi.org/10.1080/08820139.2020.1863982DOI Listing
January 2021

Impact of SARS-CoV-2 Pandemic on Patients with Primary Immunodeficiency.

J Clin Immunol 2021 02 1;41(2):345-355. Epub 2020 Dec 1.

Research Center for Primary Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Although it is estimated that COVID-19 life-threatening conditions may be diagnosed in less than 1:1000 infected individuals below the age of 50, but the real impact of this pandemic on pediatric patients with different types of primary immunodeficiency (PID) is not elucidated. The current prospective study on a national registry of PID patients showed that with only 1.23 folds higher incidence of infections, these patients present a 10-folds higher mortality rate compared to population mainly in patients with combined immunodeficiency and immune dysregulation. Therefore, further management modalities against COVID-19 should be considered to improve the survival rate in these two PID entities using hematopoietic stem cell transplantation and immunomodulatory agents.
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http://dx.doi.org/10.1007/s10875-020-00928-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707812PMC
February 2021

Autoimmunity in common variable immunodeficiency: a systematic review and meta-analysis.

Expert Rev Clin Immunol 2020 12 7;16(12):1227-1235. Epub 2020 Dec 7.

Non-communicable Diseases Research Center, Alborz University of Medical Sciences , Karaj, Iran.

: Common variable immunodeficiency (CVID) is the most common symptomatic inborn error of immunity characterized by variable clinical manifestations. : Web of Science, Scopus, and PubMed databases were searched systemically to find eligible studies from the earliest available date to February 2020 with standard keywords. Pooled estimates of the autoimmunity prevalence and the corresponding 95% confidence intervals (CI) were calculated using random-effects models. : The overall prevalence of autoimmunity was 29.8% (95% CI: 26.4-33.3; I2 = 82.8%). The prevalences of hematologic autoimmune diseases, autoimmune gastrointestinal disorders, autoimmune rheumatologic disorders, autoimmune skin disorders, and autoimmune endocrinopathy in CVID patients were 18.9%, 11.5%, 6.4%, 5.9%), and 2.5%, respectively. There were significantly higher lymphocyte, CD3 + T cell, and CD4 + T cell count among CVID patients without autoimmunity (< 0.05). Furthermore, failure to thrive, organomegaly, enteropathy, and meningitis was significantly higher in CVID patients with autoimmunity(< 0.05). : Many CVID patients could present with autoimmunity as part of the disease or even as the first or only clinical manifestation of the disease. Care providers may need to pay particular attention to the possible association of these two disorders since the co-occurrence of CVID and autoimmunity could be a misleading clue.
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http://dx.doi.org/10.1080/1744666X.2021.1850272DOI Listing
December 2020

The Potential Role of Pro-Inflammatory and Anti-Inflammatory Cytokines in Epilepsy Pathogenesis.

Endocr Metab Immune Disord Drug Targets 2020 Nov 16. Epub 2020 Nov 16.

Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj,. Iran.

Within the pathophysiology of epilepsy, as a chronic brain disorder, neuroinflammation has been extensively implied. Recurrent seizures of epilepsy have been associated with elevated levels of immune mediators that seem to play a pivotal role in triggering them. Neurons, glia, and endothelial cells of the blood-brain barrier (BBB) take part in such inflammatory processes by expressing receptors of associated mediators through autocrine and paracrine stimulation of intracellular signaling pathways. In this milieu, elevated cytokine levels in serum and brain tissue have been reported in patients with an epileptic profile. Noteworthy, interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) are the proinflammatory cytokines mostly associated, in literature, with the pathogenesis of epilepsies. In this review, we examine the function of these cytokines in connection with transforming growth factor-beta (TGF-β), IL-8, IL-12, IL-18, and macrophage inflammatory protein (MIP) as potential proinflammatory mediators in the neuropathology of epilepsy.
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http://dx.doi.org/10.2174/1871530320999201116200940DOI Listing
November 2020

Evaluation of Expression of LRBA and CTLA-4 Proteins in Common Variable Immunodeficiency Patients.

Immunol Invest 2020 Nov 15:1-14. Epub 2020 Nov 15.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Common variable immunodeficiency (CVID) is a primary immunodeficiency disease with a heterogeneous genetic background. Lipopolysaccharide-responsive beige-like anchor (LRBA), as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have important regulatory roles in the immune responses. Here, we have investigated the expression of LRBA and CTLA-4 proteins in CVID patients with at least one presentation of early-onset occurrence, autoimmunity, or enteropathy. In this study, 20 newly diagnosed CVID patients without infection only phenotype, and ten healthy individuals were enrolled. The expressions of LRBA and CTLA-4 proteins were assessed by western blotting and flow cytometry, respectively. The patients were divided into two groups of autoimmunity-positive (11 cases) and autoimmunity-negative (9 patients). LRBA and CTLA-4 expressions were significantly lower in autoimmune-positive patients than in healthy individuals ( = .03 and = .03, respectively). Autoimmune-negative patients had lower expression of LRBA and CTLA-4 than the control group, although it was not significant. There was a positive correlation between the expressions of LRBA and CTLA-4 in both groups of patients ( < .05). Furthermore, the highest frequency of LRBA (85.7%) and CTLA-4 (71.4%) defects was detected in those with concomitant presence of autoimmunity, enteropathy, and early-onset occurrence. Concurrent presence of autoimmunity, enteropathy, and early-onset occurrence in CVID patients could be indicative of a lack of expression in LRBA and CTLA-4 proteins. This could be helpful in early diagnosis and initiation of appropriate treatment in these patients prior to genetic confirmation.
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http://dx.doi.org/10.1080/08820139.2020.1833029DOI Listing
November 2020

Anti-Inflammatory Effect of KW-2449 on Autoimmune Encephalomyelitis: An Experimental Study on Mice.

Endocr Metab Immune Disord Drug Targets 2020 Nov 5. Epub 2020 Nov 5.

Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj. Iran.

Background: The KW-2449 is a novel multikinase inhibitor that inhibits FLT3, ABL, ABL-T315I, and Aurora A. FLT3 and Aurora A kinases play an important role in the pathogenesis of multiple sclerosis (MS). KW-2449 could modulate immune cells but the immunomodulatory effects of KW-2449 on experimental autoimmune encephalomyelitis (EAE) have not been investigated yet. The aim of the present study is to investigate the effects of KW-2449 on EAE mouse model.

Methods: In this study, C57BL/6 EAE mice were orally treated with (10 mg/kg/day) KW-2449 solution and compared with both EAE and control mice. Following the treatment, histological analyses were performed on brain and cerebellums to evaluate the pathological score. The gene expression levels of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and chemokine (C-C motif) ligand 2 (CCL2) were measured using qRT-PCR. The serum levels of TNF-α, IL-6, CCL-2 and MMP-2 were determined by using quantitative enzyme-linked immunosorbent assay (ELISA).

Results: The results indicated that the clinical score, the infiltration of inflammatory cells and the demyelination in EAE mice treated with KW-2449 decreased significantly compared to control groups. KW-2449 also decreased TNF-α, IL-6, CCL-2 inflammatory cytokines and MMP-2 in both brain mRNA expressions and serum levels of EAE mice.

Conclusion: The KW-2449, aging as a multi-kinase inhibitor, modulates the inflammatory responses of cytokine cascades either in brain or in plasma and reduces EAE pathogenesis manifestation.
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http://dx.doi.org/10.2174/1871530320666201106095808DOI Listing
November 2020

Evaluation of patients with primary immunodeficiency associated with Bacille Calmette-Guerin (BCG)-vaccine-derived complications.

Allergol Immunopathol (Madr) 2020 Nov - Dec;48(6):729-737. Epub 2020 Oct 25.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran, and the University of Medical Science, Tehran, Iran; Iranian Primary Immunodeficiencies Network (IPIN), Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Background: Bacille Calmette-Guerin (BCG) vaccination has a great impact on the prevention of severe complications of tuberculosis. However, in patients with primary immunodeficiencies (PID), it can lead to severe complications such as severe combined immunodeficiency, chronic granulomatous disease, and Mendelian susceptibility to mycobacterial disease. This study highlights the demographics, clinical complications and laboratory parameters among PID patients associated with BCG vaccination side effects.

Methods: One hundred and thirty-seven PID patients with BCGosis were evaluated in this study, based on the complications following BCG vaccination.

Results: The mean age of the patients with BCG complications at the time of the first visit was five years. The within-group comparison of patients showed a highly significant incidence of pneumonia and hepatomegaly in severe combined immunodeficiency patients. Furthermore, the immunologic data showed an increase in the overall rates of lymphocytes such as CD3+, CD4+ and CD8 + T cells in Mendelian susceptibility to mycobacterial disease patients. The level of immunoglobulins has also increased in chronic granulomatous disease patients.

Conclusion: The high rate of undiagnosed PIDs predisposes individuals to a high risk of severe side effects as a result of BCG vaccination, as well as infants that are less than one month of age. Therefore, there is a need for early screening and diagnosis of PIDs before exposing unknown PID status patients to BCG vaccination. The benefits of screening and early diagnosis of PID cannot be overemphasized, especially in patients with a previous family history of immunodeficiency.
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http://dx.doi.org/10.1016/j.aller.2020.04.004DOI Listing
October 2020

Variable Abnormalities in T and B Cell Subsets in Ataxia Telangiectasia.

J Clin Immunol 2021 Jan 14;41(1):76-88. Epub 2020 Oct 14.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Background: Ataxia-telangiectasia (AT) is a rare genetic condition, caused by biallelic deleterious variants in the ATM gene, and has variable immunological abnormalities. This study aimed to examine immunologic parameters reflecting cell development, activation, proliferation, and class switch recombination (CSR) and determine their relationship to the clinical phenotype in AT patients.

Methods: In this study, 40 patients with a confirmed diagnosis of AT from the Iranian immunodeficiency registry center and 28 age-sex matched healthy controls were enrolled. We compared peripheral B and T cell subsets and T cell proliferation response to CD3/CD28 stimulation in AT patients with and without CSR defects using flow cytometry.

Results: A significant decrease in naïve, transitional, switched memory, and IgM only memory B cells, along with a sharp increase in the marginal zone-like and CD21 B cells was observed in the patients. We also found CD4 and CD8 naïve, central memory, and terminally differentiated effector memory CD4 (T) T cells were decreased. CD4 and CD8 effector memory, CD8 T, and CD4 regulatory T cells were significantly elevated in our patients. CD4 T cell proliferation was markedly impaired compared to the healthy controls. Moreover, immunological investigations of 15 AT patients with CSR defect revealed a significant reduction in the marginal zone, switched memory, and more intense defects in IgM only memory B cells, CD4 naïve and central memory T cells.

Conclusion: The present study revealed that patients with AT have a broad spectrum of cellular and humoral deficiencies. Therefore, a detailed evaluation of T and B cell subsets increases understanding of the disease in patients and the risk of infection.
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http://dx.doi.org/10.1007/s10875-020-00881-9DOI Listing
January 2021

Protein Kinase C-Delta Defect in Autoimmune Lymphoproliferative Syndrome-Like Disease: First Case from the National Iranian Registry and Review of the Literature.

Immunol Invest 2020 Oct 13:1-12. Epub 2020 Oct 13.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Background: Protein kinase C is a family of serine/threonine kinases that play a key role in the adaptive immune cell signaling, as well as regulation of growth, apoptosis, and differentiation of a variety of cell types. Patients homozygous for a null mutation of the Protein Kinase C Delta gene, present clinical feature of immune dysregulation with susceptibility to Epstein-Barr virus infection. However, a minority of patients present the autoimmune lymphoproliferative syndrome (ALPS).

Methods: The data were collected by direct interview and examining the patient's clinical record. Whole-exome sequencing was performed to detect the underlying genetic mutation in the patient. We also conducted electronic searches for ALPS-like reported patients in PubMed, Web of Science, and Scopus databases.

Results: In this study, we reported a 13-year-old boy who presented with autoimmunity, lymphoproliferation, recurrent pneumonia, cardiomyopathy, and dermatological manifestations. An elevation of double-negative T cells, CD8 T cells, serum IgG level, as well as a reduction in NK cells, was observed in the patient. A homozygous frameshift mutation (c.1293_1294insA) in exon 13 of the PRKCD gene was confirmed. The literature search showed 39 ALPS-like patients with monogenic defects which only six (15.3%) of them were due to PRKCD genes.

Conclusion: PRKCD should be considered in the context of ALPS clinical manifestations with prominent dermatological involvements.
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http://dx.doi.org/10.1080/08820139.2020.1829638DOI Listing
October 2020

Infectious Complications Reporting in Common Variable Immunodeficiency: A Systematic Review and Meta-analysis.

Oman Med J 2020 Jul 30;35(4):e157. Epub 2020 Jul 30.

Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.

Objectives: Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by hypogammaglobulinemia and increased susceptibility to recurrent infections.

Methods: We searched PubMed, Web of Science, and Scopus databases to find eligible studies from the earliest available date to January 2018 with standard keywords. Pooled estimates of the infection prevalence and the corresponding 95% confidence intervals were calculated using random-effects models.

Results: We found that pneumonia (67.7%) was the most prevalent infection followed by upper respiratory tract (59.0%) and gastrointestinal infections (36.3%). Furthermore, bacterial complications (41.7%) were higher in CVID patients compared to viral (25.4%), parasitic (18.8%), or fungal (3.4%) infections. Patients with longer age at diagnosis presented with fewer disease comorbidities. There was an inverse correlation between T lymphocyte count and viral infections. Moreover, we found that immunoglobulin M (IgM) serum level was inversely correlated with hepatitis C and gastrointestinal infections, and IgG serum level was inversely correlated with infectious arthritis. Higher numbers of CD4 and CD8 T cells were associated with the lower frequencies of otitis media. CVID patients with infections had significantly lower percentages of CD3 T cells. In contrast, higher percentages of CD19 lymphocytes were found in CVID patients who had a history of infections.

Conclusions: Our findings demonstrated that in addition to hypogammaglobulinemia, patients with CVID have an imbalance in the frequency of T lymphocytes, which is in parallel with the higher frequency of infectious complications.
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http://dx.doi.org/10.5001/omj.2020.64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417520PMC
July 2020

Ataxia-telangiectasia: epidemiology, pathogenesis, clinical phenotype, diagnosis, prognosis and management.

Expert Rev Clin Immunol 2020 09 15;16(9):859-871. Epub 2020 Oct 15.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science , Tehran, Iran.

Introduction: Ataxia-telangiectasia (A-T) is a rare autosomal recessive syndrome characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, and cancer predisposition. Mutations cause A-T in the () gene encoding a serine/threonine-protein kinase.

Areas Covered: The authors reviewed the literature on PubMed, Web of Science, and Scopus databases to collect comprehensive data related to A-T. This review aims to discuss various update aspects of A-T, including epidemiology, pathogenesis, clinical manifestations, diagnosis, prognosis, and management.

Expert Opinion: A-T as a congenital disorder has phenotypic heterogeneity, and the severity of symptoms in different patients depends on the severity of mutations. This review provides a comprehensive overview of A-T, although some relevant questions about pathogenesis remain unanswered, probably owing to the phenotypic heterogeneity of this monogenic disorder. The presence of various clinical and immunologic manifestations in A-T indicates that the identification of the role of defective ATM in phenotype can be helpful in the better management and treatment of patients in the future.
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http://dx.doi.org/10.1080/1744666X.2020.1810570DOI Listing
September 2020

Global systematic review of primary immunodeficiency registries.

Expert Rev Clin Immunol 2020 07;16(7):717-732

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences , Tehran, Iran.

Introduction: During the last 4 decades, registration of patients with primary immunodeficiencies (PID) has played an essential role in different aspects of these diseases worldwide including epidemiological indexes, policymaking, quality controls of care/life, facilitation of genetic studies and clinical trials as well as improving our understanding about the natural history of the disease and the immune system function. However, due to the limitation of sustainable resources supporting these registries, inconsistency in diagnostic criteria and lack of molecular diagnosis as well as difficulties in the documentation and designing any universal platform, the global perspective of these diseases remains unclear.

Areas Covered: Published and unpublished studies from January 1981 to June 2020 were systematically reviewed on PubMed, Web of Science and Scopus. Additionally, the reference list of all studies was hand-searched for additional studies. This effort identified a total of 104614 registered patients and suggests identification of at least 10590 additional PID patients, mainly from countries located in Asia and Africa. Molecular defects in genes known to cause PID were identified and reported in 13852 (13.2% of all registered) patients.

Expert Opinion: Although these data suggest some progress in the identification and documentation of PID patients worldwide, achieving the basic requirement for the global PID burden estimation and registration of undiagnosed patients will require more reinforcement of the progress, involving both improved diagnostic facilities and neonatal screening.
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http://dx.doi.org/10.1080/1744666X.2020.1801422DOI Listing
July 2020

Application of Flow Cytometry in Predominantly Antibody Deficiencies.

Endocr Metab Immune Disord Drug Targets 2021 ;21(4):647-663

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran.

Predominantly antibody deficiencies (PADs) are a heterogeneous group of primary immunodeficiency disorders (PIDs), consisting of recurrent infections, autoimmunity, inflammation, and other immune complications. In the recent years, several immunological and genetic defects have been recognized in PADs. Currently, 45 distinct PAD disorders with 40 different genetic defects have been identified based on the 2019 IUIS classification. Genetic analysis is helpful for diagnosing PIDs; however, genetic studies are expensive, time-consuming, and unavailable everywhere. Flow cytometry is a highly sensitive tool for evaluating the immune system and diagnosing PADs. In addition to cell populations and subpopulations assay, flow cytometry can measure cell surface, intracellular and intranuclear proteins, biological changes associated with specific immune defects, and certain functional immune abnormalities. These capabilities help in rapid diagnostic and prognostic assessment as well as in evaluating the pathogenesis of PADs. For the first time, this review particularly provides an overview of the application of flow cytometry for diagnosis, immunophenotyping, and determining the pathogenesis of PADs.
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http://dx.doi.org/10.2174/1871530320666200721013312DOI Listing
January 2021

Clinical, immunological and genetic findings in patients with UNC13D deficiency (FHL3): A systematic review.

Pediatr Allergy Immunol 2021 01 24;32(1):186-197. Epub 2020 Aug 24.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Background: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive immune disorder that is caused by mutations in 6 different genes related to the formation and function of secretory lysosomes within cytotoxic T lymphocytes and natural killer (NK) cells. Thus, defect in these genes is associated with the accumulation of antigens due to defective cytotoxic function. FHL type 3 (FHL3) accounts for nearly 30-40% of FHL, and its underlying reason is mutation in UNC13D gene which encodes Munc13-4 protein.

Methods: For the first time, we aimed to systematically review clinical features, immunologic data, and genetic findings of patients with FHL3. We conducted electronic searches for English-language articles in PubMed, Web of Science, EMBASE, and Scopus databases to collect comprehensive records related to patients with UNC13D mutations.

Results: A total of 279 abstracts were initially reviewed for inclusion. Among them, 57 articles corresponding to 322 individual FHL3 patients fulfilled our selection criteria. Finally, 73 and 249 patients were considered as severe and mild feature groups, respectively. Our results confirmed that fever, hepatosplenomegaly, and hemophagocytosis are common clinical features in the disease. Moreover, reduced fibrinogen and NK cell activity, as well as increased ferritin and triglycerides, are important markers for early diagnosis of the FHL3 disease. Investigation of genotype showed that the most prevalent type and zygosity of UNC13D are splice-site errors and compound heterozygous, respectively.

Conclusion: FHL3 patients have a wide range of clinical manifestations, which makes it difficult to diagnose. Therefore, it seems that the sequencing of the entire UNC13D gene (coding and non-coding regions) is the most appropriate way to accurate diagnosis of FHL3 patients.
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http://dx.doi.org/10.1111/pai.13323DOI Listing
January 2021

A new case of congenital ficolin-3 deficiency with primary immunodeficiency.

Expert Rev Clin Immunol 2020 07 11;16(7):733-738. Epub 2020 Aug 11.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences , Tehran, Iran.

Objectives: Human Ficolin-3 () is an oligomeric-structured lectin encoded by the gene with a pivotal role in the lectin complement pathway. It has anti-microbial activities against bacterial and viral infections and restrains opportunistic pathogens. Mutation in the gene is associated with variable clinical manifestations particularly immunologic (infections and autoimmunity) and neurologic complications.

Methods: In this study, we report a 5-year-old boy with a biallelic mutation in the gene using clinical and immunological and genetic evaluations (whole exome sequencing).

Results: Our case is the first national and the eighth case worldwide with a confirmed frameshift mutation associated with Ficolin-3 deficiency. He manifested refractory seizures since early infancy, meningitis, pyelonephritis and was diagnosed with severe primary immunodeficiency.

Conclusion: Our case and literature review indicate Ficolin-3 deficiency should be considered in early-onset, premature neonate with a bacterial infection, neurological manifestation and systemic lupus erythematosus like presentations.
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http://dx.doi.org/10.1080/1744666X.2020.1792779DOI Listing
July 2020

Monogenic Primary Immunodeficiency Disorder Associated with Common Variable Immunodeficiency and Autoimmunity.

Int Arch Allergy Immunol 2020 2;181(9):706-714. Epub 2020 Jul 2.

Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency disorder mainly characterized by recurrent bacterial infections besides other immunological defects including loss of or dysfunction of B cells and decreased immunoglobulin levels. In this study, our aim is to evaluate clinical, immunological, and molecular data of patients with a primary clinical diagnosis of CVID and autoimmune phenotype with a confirmed genetic diagnosis.

Methods: Among 297 patients with CVID, who were registered in the Iranian Primary Immunodeficiency Registry at Children's Medical Center Hospital in Iran, 83 patients have been genetically examined and 27 patients with autoimmunity and confirmed genetic mutations were selected for analysis. Whole-exome sequencing and confirmatory Sanger sequencing methods were used for the study population. A questionnaire was retrospectively filled for all patients to evaluate demographic, laboratory, clinical, and genetic data.

Results: In the 27 studied patients, 11 different genetic defects were identified, and the most common mutated gene was LRBA, reported in 17 (63.0%) patients. Two patients (7.7%) showed autoimmune complications as the first presentation of immunodeficiency. Eleven patients (40.7%) developed one type of autoimmunity, and 16 patients (59.3%) progressed to poly-autoimmunity. Most of the patients with mono-autoimmunity (n = 9, 90.0%) primarily developed infectious complications, while in patients with poly-autoimmunity, the most common first presentation was enteropathy (n = 6, 37.6%). In 13 patients (61.9%), the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency. The most frequent autoimmune manifestations were hematologic (40.7%), gastrointestinal (48.1%), rheumatologic (25.9%), and dermatologic (22.2%) disorders. Patients with poly-autoimmunity had lower regulatory T cells than patients with mono-autoimmunity.

Conclusion: In our cohort, the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency in most patients. This association highlights the fact that patients referring with autoimmune manifestations should be evaluated for humoral immunity.
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http://dx.doi.org/10.1159/000508817DOI Listing
February 2021

Evaluation of protective factors in caries free preschool children: a case-control study.

BMC Oral Health 2020 06 26;20(1):177. Epub 2020 Jun 26.

Community Oral Health Department, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran.

Background: Increasing the proportion of caries-free children following the WHO's global target has led to more desirable welfare and a higher level of quality of life for children. In the present study, we aimed to evaluate the factors contributing to a caries-free condition in preschool children as a basic action towards the global goals of children's oral health.

Methods: This was a case-control study evaluating the protective factors contributing to dental caries free in 4-6-year-old children in Tehran/Iran in 2017. 500 preschool children and their mothers were selected from 22 randomly selected preschools and were enrolled in the study. The participants were divided into two case (caries-free) and control (with dental caries) groups. The data were collected using two data gathering tools; the child oral examination form and the mother's valid questionnaire. The latter included three domains; socio-demographic factors, behavioral oral health measures, and feeding practices and dietary habits. The criteria for caries detection were cavities in the enamel and dentine. A logistic regression model was applied to identify caries-free protective factors (P < 0.05).

Results: Among 230 caries-free and 270 non-caries-free children who participated in the study, boys were more caries-free (P = 0.001). The protective factors against dental caries that were identified in the study were dental check-up as the cause of dental visit, being the first child in the family, the fewer sessions night feeding of the child's, family's house ownership, and parent's university education (P < 0.05).

Conclusions: Dental health can be achieved by considering protective factors like the regular dental check-up and socio-economic factors. Communities are invited to pay close attention to these important protective factors as far as they can increase the proportion of caries-free among preschool children especially in countries with developing oral health care systems.
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http://dx.doi.org/10.1186/s12903-020-01154-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318423PMC
June 2020

Evaluation of Radiation Sensitivity in Patients with Hyper IgM Syndrome.

Immunol Invest 2020 Jun 25:1-17. Epub 2020 Jun 25.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center,Tehran University of Medical Sciences, Tehran, Iran.

Background: HIGM syndrome is a rare form of primary immunodeficiencies characterized by normal/increased amounts of serum IgM and decreased serum levels of other switched immunoglobulin classes. Since the affected patients are continuously infected with various types of pathogens and are susceptible for cancers, diagnostic and therapeutic tests including imaging techniques are recommended for the diagnosis and treatment of these patients, which predispose them to higher accumulated doses of radiation. Given the evidence of class switching recombination machinery defect and its association with an increased rate of DNA repair, we aimed to evaluate radiation sensitivity among a group of patients diagnosed with HIGM syndrome.

Methods: 19 HIGM patients (14 CD40 L and 3 AID deficiencies and 2 unsolved cases without known genetic defects) and 17 control subjects (10 healthy subjects as negative control group, 7 ataxia-telangiectasia patients as positive control group) were enrolled. G2 assay was carried out for the determination of radiosensitivity.

Results: Based on radiation-induced chromosomal changes among the studied HIGM patients and their comparison with the controls, almost all (95%) the patients had degrees of radiosensitivity: 6 patients with low to moderate, 1 patient with moderate, 11 patients with severe and 1 patient without radiation sensitivity.

Conclusion: Today, X-ray radiation plays a very important role in diagnostic and therapeutic procedures; while increased exposure has devastating effects especially in radiosensitive patients. Considering higher sensitivity in HIGM patients, utilizing radiation-free techniques could partly avoid unnecessary and high-level exposure to radiation, thus preventing or reducing its harmful effects on the affected patients.
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http://dx.doi.org/10.1080/08820139.2020.1779288DOI Listing
June 2020

Clinical, Immunologic and Molecular Spectrum of Patients with Immunodeficiency, Centromeric Instability, and Facial Anomalies (ICF) Syndrome: A Systematic Review.

Endocr Metab Immune Disord Drug Targets 2021 ;21(4):664-672

Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.

Background: Immunodeficiency, centromeric instability and facial dysmorphism (ICF) syndrome is a rare autosomal recessive immune disorder presenting with hypogammaglobulinemia, developmental delay, and facial anomalies. The ICF type 1, type 2, type 3 and type 4 are characterized by mutations in DNMT3B, ZBTB24, CDCA7 or HELLS gene, respectively. This study aimed to present a comprehensive description of the clinical, immunologic and genetic features of patients with ICF syndrome.

Methods: PubMed, Web of Science, and Scopus were searched systemically to find eligible studies.

Results: Forty-eight studies with 118 ICF patients who met the inclusion criteria were included in our study. Among these patients, 60% reported with ICF-1, 30% with ICF-2, 4% with ICF-3, and 6% with ICF-4. The four most common symptoms reported in patients with ICF syndrome were: delay in motor development, low birth weight, chronic infections, and diarrhea. Intellectual disability and preterm birth among patients with ICF-2 and failure to thrive, sepsis and fungal infections among patients with ICF-1 were also more frequent. Moreover, the median levels of all three immunoglobulins (IgA, IgG, IgM) were markedly reduced within four types of ICF syndrome.

Conclusion: The frequency of diagnosed patients with ICF syndrome has increased. Early diagnosis of ICF is important since immunoglobulin supplementation or allogeneic stem cell transplantation can improve the disease-free survival rate.
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http://dx.doi.org/10.2174/1871530320666200613204426DOI Listing
January 2021

Clinical, Immunological, and Genetic Features in 49 Patients With ZAP-70 Deficiency: A Systematic Review.

Front Immunol 2020 5;11:831. Epub 2020 May 5.

Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.

Zeta-Chain Associated Protein Kinase 70 kDa (ZAP-70) deficiency is a rare combined immunodeficiency (CID) caused by recessive homozygous/compound heterozygous loss-of-function mutations in the gene. Patients with ZAP-70 deficiency present with a variety of clinical manifestations, particularly recurrent respiratory infections and cutaneous involvements. Therefore, a systematic review of ZAP-70 deficiency is helpful to achieve a comprehensive view of this disease. We searched PubMed, Web of Science, and Scopus databases for all reported ZAP-70 deficient patients and screened against the described eligibility criteria. A total of 49 ZAP-70 deficient patients were identified from 33 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected. ZAP-70 deficient patients have been reported in the literature with a broad spectrum of clinical manifestations including recurrent respiratory infections (81.8%), cutaneous involvement (57.9%), lymphoproliferation (32.4%), autoimmunity (19.4%), enteropathy (18.4%), and increased risk of malignancies (8.1%). The predominant immunologic phenotype was low CD8+ T cell counts (97.9%). Immunologic profiling showed defective antibody production (57%) and decreased lymphocyte responses to mitogenic stimuli such as phytohemagglutinin (PHA) (95%). Mutations of the gene were located throughout the gene, and there was no mutational hotspot. However, most of the mutations were located in the kinase domain. Hematopoietic stem cell transplantation (HSCT) was applied as the major curative treatment in 25 (51%) of the patients, 18 patients survived transplantation, while two patients died and three required a second transplant in order to achieve full remission. Newborns with consanguineous parents, positive family history of CID, and low CD8+ T cell counts should be considered for ZAP-70 deficiency screening, since early diagnosis and treatment with HSCT can lead to a more favorable outcome. Based on the current evidence, there is no genotype-phenotype correlation in ZAP-70 deficient patients.
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http://dx.doi.org/10.3389/fimmu.2020.00831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214800PMC
March 2021