Publications by authors named "Majid Zaki-Dizaji"

37 Publications

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

Clinical, immunological, and genetic features in 938 patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED): a systematic review.

Expert Rev Clin Immunol 2021 Jun 3:1-11. Epub 2021 Jun 3.

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

: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare inborn immune error characterized by a triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism (HP), and adrenal insufficiency (ADI).: Literature search was conducted in PubMed, Web of Science, and Scopus databases using related keywords, and included studies were systematically evaluated.: We reviewed 938 APECED patients and the classic triad of APECED was detected in 57.3% (460 of 803) of patients. CMC (82.5%) was reported as the earliest, HP (84.2%) as the most prevalent, and ADI (72.2%) as the latest presentation within the classic triad. A broad spectrum of non-triad involvements has also been reported; mainly included ectodermal dystrophy (64.5%), infections (58.7%), gastrointestinal disorders (52.0%), gonadal failure (42.0%), neurologic involvements (36.4%), and ocular manifestations (34.3%). A significant positive correlation was detected between certain tissue-specific autoantibodies and particular manifestations including ADI and HP. Neutralizing autoantibodies were detected in at least 60.0% of patients. Nonsense and/or frameshift insertion-deletion mutations were detected in 73.8% of patients with CMC, 70.9% of patients with HP, and 74.6% of patients with primary ADI.: Besides penetrance diversity, our review revealed a diverse affected ethnicity (mainly from Italy followed by Finland and Ireland). APECED can initially present in adolescence as 5.2% of the patients were older than 18 years at the disease onset. According to the variety of clinical conditions, which in the majority of patients appear gradually over time, clinical management deserves a separate analysis.
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http://dx.doi.org/10.1080/1744666X.2021.1925543DOI Listing
June 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

Molecular contribution of BRCA1 and BRCA2 to genome instability in breast cancer patients: review of radiosensitivity assays.

Biol Proced Online 2020 1;22:23. Epub 2020 Oct 1.

Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran.

Background: DNA repair pathways, cell cycle arrest checkpoints, and cell death induction are present in cells to process DNA damage and prevent genomic instability caused by various extrinsic and intrinsic ionizing factors. Mutations in the genes involved in these pathways enhances the ionizing radiation sensitivity, reduces the individual's capacity to repair DNA damages, and subsequently increases susceptibility to tumorigenesis.

Body: BRCA1 and BRCA2 are two highly penetrant genes involved in the inherited breast cancer and contribute to different DNA damage pathways and cell cycle and apoptosis cascades. Mutations in these genes have been associated with hypersensitivity and genetic instability as well as manifesting severe radiotherapy complications in breast cancer patients. The genomic instability and DNA repair capacity of breast cancer patients with BRCA1/2 mutations have been analyzed in different studies using a variety of assays, including micronucleus assay, comet assay, chromosomal assay, colony-forming assay, γ -H2AX and 53BP1 biomarkers, and fluorescence in situ hybridization. The majority of studies confirmed the enhanced spontaneous & radiation-induced radiosensitivity of breast cancer patients compared to healthy controls. Using G2 micronucleus assay and G2 chromosomal assay, most studies have reported the lymphocyte of healthy carriers with BRCA1 mutation are hypersensitive to invitro ionizing radiation compared to non-carriers without a history of breast cancer. However, it seems this approach is not likely to be useful to distinguish the BRCA carriers from non-carrier with familial history of breast cancer.

Conclusion: In overall, breast cancer patients are more radiosensitive compared to healthy control; however, inconsistent results exist about the ability of current radiosensitive techniques in screening BRCA1/2 carriers or those susceptible to radiotherapy complications. Therefore, developing further radiosensitivity assay is still warranted to evaluate the DNA repair capacity of individuals with BRCA1/2 mutations and serve as a predictive factor for increased risk of cancer mainly in the relatives of breast cancer patients. Moreover, it can provide more evidence about who is susceptible to manifest severe complication after radiotherapy.
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http://dx.doi.org/10.1186/s12575-020-00133-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528506PMC
October 2020

Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical and Genetic Features of 32 Iranian Patients.

J Clin Immunol 2020 08 30;40(6):872-882. Epub 2020 Jun 30.

Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare congenital condition characterized by a selective predisposition to infections caused by weakly virulent mycobacteria and other types of intra-macrophagic pathogens. The 16 genes associated with MSMD display a considerable level of allelic heterogeneity, accounting for 31 distinct disorders with variable clinical presentations and prognosis. Most of MSMD deficiencies are isolated, referred to as selective susceptibility to mycobacterial diseases. However, other deficiencies are syndromic MSMD, defined by the combination of the mycobacterial infection with another, equally common, infectious, specific phenotypes. Herein, we described a series of 32 Iranian MSMD cases identified with seven distinct types of molecular defects, all of which are involved in the interferon gamma (IFNγ) immunity, including interleukin IL-12 receptor-β1 (IL-12Rβ1) deficiency (fifteen cases), IL-12p40 deficiency (ten cases), and IL-23R deficiency (three cases), as well as IFNγ receptor 1 (IFNγR1) deficiency, IFNγ receptor 2 (IFNγR2) deficiency, interferon-stimulated gene 15 (ISG15) deficiency, and tyrosine kinase 2 (TYK2) deficiency each in one case. Since the first report of two MSMD patients in our center, we identified 30 other affected patients with similar clinical manifestations. As the number of reported Iranian cases with MSMD diagnosis has increased in recent years and according to the national vaccination protocol, all Iranian newborns receive BCG vaccination at birth, early diagnosis, and therapeutic intervention which are required for a better outcome and also prevention of similar birth defects. Therefore, we investigated the clinical and molecular features of these 32 patients. The current report also defined novel classes of pathological mutations, further expanding our knowledge of the MSMD molecular basis and associated clinical manifestations.
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http://dx.doi.org/10.1007/s10875-020-00813-7DOI Listing
August 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

Clinical, Immunological, and Genetic Features in Patients with Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) and IPEX-like Syndrome.

J Allergy Clin Immunol Pract 2020 09 16;8(8):2747-2760.e7. Epub 2020 May 16.

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

Background: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare inborn error of immunity caused by mutations in the forkhead box P3 (FOXP3) gene.

Objective: In this study, we conducted a systematic review of patients with IPEX and IPEX-like syndrome to delineate differences in these 2 major groups.

Methods: The literature search was performed in PubMed, Web of Science, and Scopus databases, and demographic, clinical, immunologic, and molecular data were compared between the IPEX and IPEX-like groups.

Results: A total of 459 patients were reported in 148 eligible articles. Major clinical differences between patients with IPEX and IPEX-like syndrome were observed in rates of pneumonia (11% vs 31%, P < .001), bronchiectasis (0.3% vs 14%, P < .001), diarrhea (56% vs 42%, P = .020), and organomegaly (10% vs 23%, P = .001), respectively. Eosinophilia (95% vs 100%), low regulatory T-cell count (68% vs 50%), and elevated IgE (87% vs 61%) were the most prominent laboratory findings in patients with IPEX and IPEX-like syndrome, respectively. In the IPEX group, a lower mortality rate was observed among patients receiving hematopoietic stem cell transplantation (HSCT) (24%) compared with other patients (43%), P = .008; however, in the IPEX-like group, it was not significant (P = .189).

Conclusions: Patients with IPEX syndrome generally suffer from enteropathy, autoimmunity, dermatitis, eosinophilia, and elevated serum IgE. Despite similarities in their clinical presentations, patients with IPEX-like syndrome are more likely to present common variable immunodeficiency-like phenotype such as respiratory tract infections, bronchiectasis, and organomegaly. HSCT is currently the only curative therapy for both IPEX and IPEX-like syndrome and may result in favorable outcome.
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http://dx.doi.org/10.1016/j.jaip.2020.04.070DOI Listing
September 2020

Dystonia in Ataxia Telangiectasia: A Case Report with Novel Mutations.

Oman Med J 2020 Jan 17;35(1):e93. Epub 2020 Feb 17.

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

Ataxia telangiectasia (A-T) is a common, genetically inherited cause of early childhood-onset ataxia that is classically characterized by progressive cerebellar malfunction, oculocutaneous telangiectasia, genome instability, and immunodeficiency. There is vast phenotype variation in patients with A-T and recently, dystonia, an extrapyramidal movement disorder. Here, we report the case of a 10-year-old girl who had experienced repeated diarrhea and mild gait ataxia since the age of two years. At age seven, ataxia and ocular telangiectasia were evident and immunoglobulin level assessment showed hyper IgM immune phenotype, thus a diagnosis of A-T was made based on clinical and laboratory findings, and she was started on intravenous immunoglobulin therapy. Generalized dystonia appeared when she was 10-years-old. Molecular analysis revealed two heterozygous mutations, c.6259delG and c.6658C>T, in the gene of which one (c.6259delG) is novel. Dystonia can be part of the clinical picture in the A-T disorder and may even mask ataxia. This should be considered as a major feature mainly in variant A-T, which may occur without general ataxia and may be misdiagnosed in adults with primary dystonia.
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http://dx.doi.org/10.5001/omj.2020.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024809PMC
January 2020

MiR-4485-3p expression reduced in spermatozoa of men with idiopathic asthenozoospermia.

Andrologia 2020 Apr 6;52(3):e13539. Epub 2020 Feb 6.

Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.

Asthenozoospermia (AZS), which characterised by reduced forward sperm motility, is a common cause of male infertility. Recently, mitochondrial dysfunction reported in AZS men came to attention for finding the molecular aetiology of AZS. Mitochondria-related microRNAs (miRNAs) are the most important regulators of mitochondrial function through post-transcriptionally modulation of gene expression. Therefore, this study aims to evaluate the expression of four recently reported mitochondrial-related miRNAs (miR-4485-3p/4484/4461 and 4463) in the sperm sample of asthenozoospermic men. RNA was extracted from spermatozoa of 74 volunteers (39 patients with idiopathic AZS and 35 controls with normal fertility), and relative gene expression analysis was performed by quantitative PCR. We used SNORD48 as a normaliser gene, and quantification was calculated by 2 method. The expression of miR-4484 and miR-4461 was not detected in the spermatozoa of cases and controls. However, miR-4485-3p (p = .006) was significantly downregulated in the AZS men compared with the controls, but the miR-4463 expression was not significantly different between the two groups (p = .5). Bioinformatic analysis identified three target genes for miR-4485-3p (DNAH1, KIT and PARK7) that are related to male infertility. In conclusion, the downregulation of miR-4485-3p was associated with idiopathic AZS, which could be a molecular link between mitochondrial dysfunction and AZS.
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http://dx.doi.org/10.1111/and.13539DOI Listing
April 2020

Influence of β-D-mannuronic Acid, as a New Member of Non-steroidal Anti- Inflammatory Drugs Family, on the Expression Pattern of Chemokines and their Receptors in Rheumatoid Arthritis.

Curr Drug Discov Technol 2021 ;18(1):65-74

Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

Background: Based on the encouraging results of phase III clinical trial of β-Dmannuronic acid (M2000) (as a new anti-inflammatory drug) in patients with RA, in this study, we aimed to evaluate the effects of this drug on the expression of chemokines and their receptors in PBMCs of RA patients.

Methods: PBMCs of RA patients and healthy controls were separated and the patients' cells were treated with low, moderate and high doses (5, 25 and 50 μg/mL) of M2000 and optimum dose (1 μg/mL) of diclofenac, as a control in RPMI-1640 medium. Real-time PCR was used for evaluating the mRNA expression of CXCR3, CXCR4, CCR2, CCR5 and CCL2/MCP-1. Cell surface expression of CCR2 was investigated using flow cytometry.

Results: CCR5 mRNA expression reduced significantly, after treatment of the patients' cells with all three doses of M2000 and optimum dose of diclofenac. CXCR3 mRNA expression was downregulated significantly followed by the treatment of these cells with moderate and high doses of M2000 and optimum dose of diclofenac. CXCR4 mRNA expression declined significantly after the treatment of these cells with moderate and high doses of M2000. CCL2 mRNA expression significantly reduced only followed by the treatment of these cells with a high dose of M2000, whereas, mRNA and cell surface expressions of CCR2 diminished significantly followed by the treatment of these cells with a high dose of M2000 and optimum dose of diclofenac.

Conclusion: According to our results, M2000 through the down-regulation of chemokines and their receptors may restrict the infiltration of immune cells into the synovium.
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http://dx.doi.org/10.2174/1570163816666191023103118DOI Listing
January 2021

Associations of Behavioral Disorders with Asthma in Iranian Children.

Iran J Allergy Asthma Immunol 2019 Jun 8;18(3):340-345. Epub 2019 Jun 8.

Department of Allergy and Clinical Immunology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Asthma is a common respiratory disease with huge economic burden leading to activity limitations, morbidity, and mortality. In this study, we aim to investigate the prevalence of Oppositional Defiant Disorder (ODD), Attention Deficit Hyperactivity Disorder (ADHD) and Conduct Disorder (CD) among children with asthma. This case-control study was performed in a pediatric referral health care center(Children's Medical CenterinTehran University of Medical Sciences) in 2017.With random selection, the 80 children with asthma and 92 controls with age range of 5 to 11 years were enrolled in this study. In addition to the demographic information and family history of allergy, asthma symptoms, and control quality evaluated with a validated Childhood Asthma Control Test (C-ACT). The mode of measurement for ADHD, ODD and CD was based on Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) psychiatric scales from clinical interviews conducted by child psychiatrists. Totally, 42.5% and 25% in the case and control groups had ADHD respectively withsignificant difference (p=0.01). Also, 25% and 5.4% in thecase and control groups had ODD respectively with significant difference (p=0.001). But conduct disorder was 10% and 10.9% in case and control groups respectively without significant difference (p=0.8). Children with asthma were associated with exhibiting ADHD and ODD but not CD. Therefore, appropriate evaluation and treatment are needed for asthmatic children with attention-deficit and ODD symptoms. Besides, further research is needed to determine the etiological approach towards ADHD, ODD and asthma.
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http://dx.doi.org/10.18502/ijaai.v18i3.1127DOI Listing
June 2019

Diagnostic Approach to the Patients with Suspected Primary Immunodeficiency.

Endocr Metab Immune Disord Drug Targets 2020 ;20(2):157-171

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

Background And Objective: Primary immunodeficiency diseases (PIDs) are a group of more than 350 disorders affecting distinct components of the innate and adaptive immune systems. In this review, the classic and advanced stepwise approach towards the diagnosis of PIDs are simplified and explained in detail.

Results: Susceptibility to recurrent infections is the main hallmark of almost all PIDs. However, noninfectious complications attributable to immune dysregulation presenting with lymphoproliferative and/or autoimmune disorders are not uncommon. Moreover, PIDs could be associated with misleading presentations including allergic manifestations, enteropathies, and malignancies.

Conclusion: Timely diagnosis is the most essential element in improving outcome and reducing the morbidity and mortality in PIDs. This wouldn't be possible unless the physicians keep the diagnosis of PID in mind and be sufficiently aware of the approach to these patients.
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http://dx.doi.org/10.2174/1871530319666190828125316DOI Listing
November 2020

Resistance of human primary mesenchymal stem cells to cytotoxic effects of nutlin-3 in vitro.

J Cell Biochem 2020 01 26;121(1):788-796. Epub 2019 Aug 26.

Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran.

Background: The small-molecule nutlin-3 was found to be an effective therapeutic compound and p53 activator, and acts as a murine double minute 2 antagonist, although these findings need to be clinically confirmed. The essential components of the bone marrow include mesenchymal stem cells (MSCs), which play a key role in protecting, regenerating, and proliferating hematopoietic stem cells (HSCs). This feature is vital for HSC after exposure to myelotoxic anticancer agents; nevertheless, the effects of nutlin-3 on MSCs remain to be disclosed. The present research study was conducted to examine the antiproliferative and proapoptotic effectiveness of nutlin-3 in bone marrow MSCs (BMSCs).

Materials And Methods: Human-derived BMSCs were cultured for different durations, that is, 24, 48, and 72 hours, and treated using various concentrations of nutlin-3, including 5, 10, 25, 50, and 100 μΜ. To investigate the effect of nutlin-3 on the apoptosis, cell vitality and proliferation in BMSCs, the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), thiazolyl blue tetrazolium bromide, propidium iodide (PI) and annexin V assay, as well as real-time polymerase chain reaction, were used.

Results: BMSCs viability significantly decreased (P < .05) in the cells treated at concentrations of 50 and 100 μM for 24 hours and concentrations of 25, 50, and 100 μM for 48 hours and at all concentrations for 72 hours. The apoptosis of BMSCs (TUNEL positive) was significantly more visible at concentrations of 25 and 50 μM compared with that in the controls (P < .05), while this increased through dose-dependent processes. Annexin V/PI staining revealed negligible dose-dependent increases in all the apoptotic cells after 72 hours of incubation, and this apoptosis elevation was significant at 25 and 50 μM (P < .05).

Conclusion: Resistance to nutlin-3 was observed in human bone marrow-derived MSCs; nevertheless, further clinical data are required to be obtained with long-duration exposure to confirm the present findings.
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http://dx.doi.org/10.1002/jcb.29324DOI Listing
January 2020

Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review.

Clin Rev Allergy Immunol 2020 Dec;59(3):323-333

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

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a novel primary immunodeficiency (PID) caused by heterozygous gain of function mutations in PI3Kδ catalytic p110δ (PIK3CD) or regulatory p85α (PIK3R1) subunits leading to APDS1 and APDS2, respectively. Patients with APDS present a spectrum of clinical manifestations, particularly recurrent respiratory infections and lymphoproliferation. We searched PubMed, Web of Science, and Scopus databases for APDS patients and screened for eligibility criteria. A total of 243 APDS patients were identified from 55 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected. Overall, 179 APDS1 and 64 APDS2 patients were identified. The most common clinical manifestations were respiratory tract infections (pneumonia (43.6%), otitis media (28.8%), and sinusitis (25.9%)), lymphoproliferation (70.4%), autoimmunity (28%), enteropathy (26.7%), failure to thrive (20.6%), and malignancy (12.8%). The predominant immunologic phenotype was hyper-IgM syndrome (48.1%). Immunologic profiling showed decreased B cells in 74.8% and CD4 T cells in 64.8% of APDS patients. The c.3061 G>A (p. E1021K) mutation in APDS1 with 85% frequency and c.1425+1 G> (A, C, T) (p.434-475del) mutation in APDS2 with 79% frequency were hotspot mutations. The majority of APDS patients were placed on long-term immunoglobulin replacement therapy. Immunosuppressive agents such as rituximab, tacrolimus, rapamycin, and leniolisib were also administered for autoimmunity and inflammatory complications. In addition, hematopoietic stem cell transplantation (HSCT) was used in 12.8% of patients. APDS has heterogynous clinical manifestations. It should be suspected in patients with history of recurrent respiratory infections, lymphoproliferation, and raised IgM levels. Moreover, HSCT should be considered in patients with severe and complicated clinical manifestations with no or insufficient response to the conventional therapies.
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http://dx.doi.org/10.1007/s12016-019-08738-9DOI Listing
December 2020

Expression Analysis of the CRISP2, CATSPER1, PATE1 and SEMG1 in the Sperm of Men with Idiopathic Asthenozoospermia.

J Reprod Infertil 2019 Apr-Jun;20(2):70-75

Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.

Background: The purpose of this study was to analyze the expression level of CRISP2, CATSPER1, PATE1 and SEMG1 genes in the sperm of men with asthenozoospermia (AZS). AZS is a cause of infertility in men in which the motility of the sperm is reduced. So far, a few genes have been associated with AZS; however, in most of the cases, its molecular etiology is unclear.

Methods: A total of 35 subjects with idiopathic AZS and 35 fertile and healthy men as control were included. In study after total RNA extraction and cDNA synthesis, relative quantification was performed. B2M was used as the normalizer gene and fold change was calculated by 2 method. Mann-Whitney test was used to compare the expression levels between the case and control groups with significance level of p<0.05.

Results: Our results showed that CRISP2 (p=0.03) and SEMG1 (p=0.03) were significantly down-and up-regulated in AZS men respectively compared to the controls. But CATSPER1 and PATE1 did not show significant changes.

Conclusion: Down-regulation of CRISP2 and up-regulation of SEMG1 were associated with AZS, which could be suggested as the potential candidate genes for the development of a diagnostic marker or potentially for more studies for treatment of AZS.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486568PMC
May 2019

MicroRNA profiling in spermatozoa of men with unexplained asthenozoospermia.

Andrologia 2019 Jul 22;51(6):e13284. Epub 2019 Apr 22.

Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.

Asthenozoospermia (AZS) which is characterised by decreased sperm motility is one of the main causes of male infertility. Recent studies demonstrated altered microRNAs (miRNAs) in total semen, seminal plasma and spermatozoa of asthenozoospermic men. In line with these studies, it was aimed to evaluate the miRNA expression profile in spermatozoa of unexplained asthenozoospermic men. Thirty-nine cases with idiopathic AZS and 35 fertile and healthy men as control were included. After total RNA extraction from spermatozoa, high-throughput sequencing technology was employed to display miRNA profiles in spermatozoa samples pooled from AZS cases and healthy controls. Relative quantification by real-time PCR was performed to validate RNA-seq results. SNORD48 was used as normaliser gene, and fold change was calculated by 2 method. Profiling results showed that 18 altered miRNAs in AZS men in comparison to controls. Subsequently, seven miRNAs were selected to validate by RT-PCR that showed MiR-888-3p significantly overexpressed in AZS cases (p = 0.014) in comparison with controls. It seems upregulation of miR-888-3p was associated with idiopathic AZS. This finding paves the way to the future investigation on the actual molecular role of miR-888-3p in aetiology of AZS.
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http://dx.doi.org/10.1111/and.13284DOI Listing
July 2019

Clinical, Immunologic, and Molecular Spectrum of Patients with LPS-Responsive Beige-Like Anchor Protein Deficiency: A Systematic Review.

J Allergy Clin Immunol Pract 2019 Sep - Oct;7(7):2379-2386.e5. Epub 2019 Apr 14.

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

Background: LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency and immune dysregulation syndrome caused by biallelic mutations in the LRBA gene. These mutations usually abrogate the protein expression of LRBA, leading to a broad spectrum of clinical phenotypes including autoimmunity, chronic diarrhea, hypogammaglobulinemia, and recurrent infections.

Objective: Our aim was to systematically collect all studies reporting on the clinical manifestations, molecular and laboratory findings, and management of patients with LRBA deficiency.

Methods: We searched in PubMed, Web of Science, and Scopus without any restrictions on study design and publication time. A total of 109 LRBA-deficient cases were identified from 45 eligible articles. For all patients, demographic information, clinical records, and immunologic and molecular data were collected.

Results: Of the patients with LRBA deficiency, 93 had homozygous and 16 had compound heterozygous mutations in LRBA. The most common clinical manifestations were autoimmunity (82%), enteropathy (63%), splenomegaly (57%), and pneumonia (49%). Reduction in numbers of CD4 T cells and regulatory T cells as well as IgG levels was recorded for 21.6%, 65.6%, and 54.2% of evaluated patients, respectively. B-cell subpopulation analysis revealed low numbers of switched-memory and increased numbers of CD21 B cells in 73.5% and 77.8% of patients, respectively. Eighteen (16%) patients underwent hematopoietic stem cell transplantation due to the severity of complications and the outcomes improved in 13 of them.

Conclusions: Autoimmune disorders are the main clinical manifestations of LRBA deficiency. Therefore, LRBA deficiency should be included in the list of monogenic autoimmune diseases, and screening for LRBA mutations should be routinely performed for patients with these conditions.
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http://dx.doi.org/10.1016/j.jaip.2019.04.011DOI Listing
October 2020

Individual Radiosensitivity Assessment of the Families of Patients by G2-Checkpoint Abrogation.

Sultan Qaboos Univ Med J 2018 Nov 28;18(4):e440-e446. Epub 2019 Mar 28.

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

Objectives: (A-T) is an autosomal recessive multisystem disorder characterised by cerebellar degeneration, , radiation sensitivity, immunodeficiency, oxidative stress and cancer susceptibility. Epidemiological research has shown that carriers of the heterozygous () gene mutation are radiosensitive to ionising irradiation and have a higher risk of cancers, type 2 diabetes and atherosclerosis. However, there is currently no fast and reliable laboratory-based method to detect heterozygous carriers for family screening and planning purposes. This study therefore aimed to evaluate the ability of a modified G2-assay to identify heterozygous carriers in the families of A-T patients.

Methods: This study took place at the Tehran University of Medical Sciences, Tehran, Iran, between February and December 2017 and included 16 A-T patients, their parents (obligate heterozygotes) and 30 healthy controls. All of the subjects underwent individual radiosensitivity (IRS) assessment using a modified caffeine-treated G2-assay with G2-checkpoint abrogation.

Results: The mean IRS of the obligate heterozygotes was significantly higher than the healthy controls (55.13% ± 5.84% versus 39.03% ± 6.95%; <0.001), but significantly lower than the A-T patients (55.13% ± 5.84% versus 87.39% ± 8.29%; = 0.001). A receiver operating characteristic (ROC) curve analysis of the G2-assay values indicated high sensitivity and specificity, with an area under the ROC curve of 0.97 (95% confidence interval: 0.95-1.00).

Conclusion: The modified G2-assay demonstrated adequate precision and relatively high sensitivity and specificity in detecting heterozygous carriers.
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http://dx.doi.org/10.18295/squmj.2018.18.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443281PMC
November 2018

G2-lymphocyte chromosomal radiosensitivity in patients with LPS responsive beige-like anchor protein (LRBA) deficiency.

Int J Radiat Biol 2019 06 13;95(6):680-690. Epub 2019 Feb 13.

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

Lipopolysaccharide-responsive, beige-like anchor protein (LRBA) deficiency is an autosomal recessive primary immunodeficiency disease characterized by a CVID-like phenotype, particularly severe autoimmunity and inflammatory bowel disease. This study was undertaken to evaluate radiation sensitivity in 11 LRBA-deficient patients. Therefore, stimulated lymphocytes of the studied subjects were exposed to a low dose γ-radiation (100 cGy) in the G phase of the cell cycle and chromosomal aberrations were scored. Lymphocytes of age-sex matched healthy individuals used in the same way as controls. Based on the G-assay, six (54.5%) of the patients had higher radiosensitivity score comparing to the healthy control group, forming the radiosensitive LRBA-deficient patients. This chromosomal radiosensitivity showed that these patients are predisposed to autoimmunity and/or malignancy, and should be protected from unnecessary diagnostic and therapeutic procedures using ionizing radiation and exposure to other DNA damaging agents.
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http://dx.doi.org/10.1080/09553002.2019.1577570DOI Listing
June 2019

The effects of Nutlin-3 on morphology, cellular proliferation, and apoptosis in rat primary mesenchymal stem cells.

J Cell Physiol 2019 07 27;234(7):11424-11430. Epub 2018 Nov 27.

Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran.

Introduction: Nutlin-3 is a powerful antagonist of murine double minute 2/p53 interaction demonstrating promising therapeutic anticancer activity, which has not been clinically approved yet. Mesenchymal stem cells (MSCs) are an important part of the bone marrow niche and support regeneration and proliferation of hematopoietic stem cells after exposure to myelotoxic anticancer agents; however, the effect of Nutlin-3 compounds on MSCs themselves remains to be elucidated.

Materials And Methods: Rat-derived bone marrow-derived MSCs (BMSCs) were cultured and treated with different concentrations (5, 10, 25, 50, and 100 μM) and times (24, 48, and 72 hr) of Nutlin-3. The microculture tetrazolium test, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and propidium iodide and annexin-V assays, and quantitative real-time reverse-transcription polymerase chain reaction were performed to assess the effects of Nutlin-3 on the cell viability, proliferation, and apoptosis in BMSCs.

Results: The viability of BMSCs in the treated cells with concentrations of 100 μM at 24 hr, 50 and 100 μM at 48 hr, and in all concentrations at 72 hr was significantly (p < 0.05) low. The apoptotic index showed that the TUNEL-positive BMSCs were significantly higher in concentrations of 25 and 50 μM in comparison to control group ( p < 0.05) and augmented in a dose-dependent manner. Annexin-V-PI staining showed after 72 hr of incubation, there was a slight dose-dependent increase in total apoptotic cells at 10 and 25 μM of Nutlin-3, but a massive significant increase at 50 μM.

Conclusion: Here, we show that rat BMSCs are relatively resistant to Nutlin-3; however, further in vivo data with long-term exposure may help to corroborate our findings.
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http://dx.doi.org/10.1002/jcp.27798DOI Listing
July 2019

The Effects of D-aspartate on Neurosteroids, Neurosteroid Receptors, and Inflammatory Mediators in Experimental Autoimmune Encephalomyelitis.

Endocr Metab Immune Disord Drug Targets 2019 ;19(3):316-325

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

Objective: Experimental autoimmune encephalomyelitis (EAE) is a widely used model for multiple sclerosis. The present study has been designed to compare the efficiencies of oral and intraperitoneal (IP) administration of D-aspartate (D-Asp) on the onset and severity of EAE, the production of neurosteroids, and the expression of neurosteroid receptors and inflammatory mediators in the brain of EAE mice.

Methods: In this study, EAE was induced in C57BL/6 mice treated with D-Asp orally (D-Asp-Oral) or by IP injection (D-Asp-IP). On the 20th day, brains (cerebrums) and cerebellums of mice were evaluated by histological analyses. The brains of mice were analyzed for: 1) Neurosteroid (Progesterone, Testosterone, 17β-estradiol) concentrations; 2) gene expressions of cytokines and neurosteroid receptors by reverse transcription polymerase chain reaction, and 3) quantitative determination of D-Asp using liquid chromatography-tandem mass spectrometry. Further, some inflammatory cytokines and matrix metalloproteinase-2 (MMP-2) were identified in the mouse serum using enzyme-linked immunosorbent assay kits.

Results: Our findings demonstrated that after D-Asp was administered, it was taken up and accumulated within the brain. Further, IP injection of D-Asp had more beneficial effects on EAE severity than oral gavage. The concentration of the testosterone and 17β-estradiol in D-Asp-IP group was significantly higher than that of the control group. There were no significant differences in the gene expression of cytokine and neurosteroid receptors between control, D-Asp-IP, and D-Asp-Oral groups. However, IP treatment with D-Asp significantly reduced C-C motif chemokine ligand 2 and MMP-2 serum levels compared to control mice.

Conclusion: IP injection of D-Asp had more beneficial effects on EAE severity, neurosteroid induction and reduction of inflammatory mediators than oral gavage.
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http://dx.doi.org/10.2174/1871530318666181005093459DOI Listing
August 2019

Genetic aspects of idiopathic asthenozoospermia as a cause of male infertility.

Hum Fertil (Camb) 2020 Jun 9;23(2):83-92. Epub 2018 Sep 9.

Reproductive Biotechnology Research Centre, Avicenna Research Institute, ACECR, Tehran, Iran.

Infertility is a worldwide problem affecting about 15% of couples trying to conceive. Asthenozoospermia (AZS) is one of the major causes of male infertility, diagnosed by reduced sperm motility, and has no effective therapeutic treatment. To date, a few genes have been found to be associated with AZS in humans and mice, but in most of cases its molecular aetiology remains unknown. Genetic causes of AZS may include chromosomal abnormalities, specific mutations of nuclear and mitochondrial genes. However recently, epigenetic factors, altered microRNAs expression signature, and proteomics have shed light on the pathophysiological basis of AZS. This review article summarises the reported genetic causes of AZS.
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http://dx.doi.org/10.1080/14647273.2018.1504325DOI Listing
June 2020

Inflammation, a significant player of Ataxia-Telangiectasia pathogenesis?

Inflamm Res 2018 Jul 26;67(7):559-570. Epub 2018 Mar 26.

Research Center for Immunodeficiencies, Children's Medical Center Hospital, Tehran University of Medical Science, 62 Qarib St., Keshavarz Blvd., Tehran, 14194, Iran.

Introduction: Ataxia-Telangiectasia (A-T) syndrome is an autosomal recessive neurodegenerative disorder characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, chromosome instability, radiosensitivity, and predisposition to malignancy. There is growing evidence that A-T patients suffer from pathologic inflammation that is responsible for many symptoms of this syndrome, including neurodegeneration, autoimmunity, cardiovascular disease, accelerated aging, and insulin resistance. In addition, epidemiological studies have shown A-T heterozygotes, somewhat like deficient patients, are susceptible to ionizing irradiation and have a higher risk of cancers and metabolic disorders.

Area Covered: This review summarizes clinical and molecular findings of inflammation in A-T syndrome.

Conclusion: Ataxia-Telangiectasia Mutated (ATM), a master regulator of the DNA damage response is the protein known to be associated with A-T and has a complex nuclear and cytoplasmic role. Loss of ATM function may induce immune deregulation and systemic inflammation.
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http://dx.doi.org/10.1007/s00011-018-1142-yDOI Listing
July 2018

Polyautoimmunity in Patients with LPS-Responsive Beige-Like Anchor (LRBA) Deficiency.

Immunol Invest 2018 Jul 12;47(5):457-467. Epub 2018 Mar 12.

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

Background: Polyautoimmunity is defined as the presence of more than one autoimmune disorder in a single patient. Lipopolysaccharide (LPS)-responsive beige-like anchor (LRBA) deficiency is one of the monogenic causes of polyautoimmunity. The aim of this study was to report the characteristics of polyautoimmunity in patients with LRBA deficiency.

Methods: A total of 14 LRBA deficiency patients with confirmed autoimmunity were enrolled in this study. For those patients with polyautoimmunity, demographic information, clinical records, laboratory, and molecular data were collected. We also compared our results with the currently reported patients with LRBA deficiency associated with polyautoimmunity.

Results: In 64.2% (9 out of 14) of patients, autoimmunity presented as polyautoimmunity. In these patients, autoimmune cytopenias were the most frequent complication, observed in seven patients. Three patients presented with four different types of autoimmune conditions. The review of the literature showed that 41 of 72 reported LRBA deficient patients (74.5%) had also polyautoimmunity, with a wide spectrum of autoimmune diseases described. Hematopoietic stem cell transplantation is increasingly used as the treatment for patients with severe polyautoimmunity associated to LRBA deficiency.

Conclusions: Mutation in LRBA gene is one of the causes of monogenic polyautoimmunity. Awareness of this association is important in order to make an early diagnosis and prompt treatment.
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http://dx.doi.org/10.1080/08820139.2018.1446978DOI Listing
July 2018

Ataxia telangiectasia syndrome: moonlighting ATM.

Expert Rev Clin Immunol 2017 12 20;13(12):1155-1172. Epub 2017 Oct 20.

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

Introduction: Ataxia-telangiectasia (A-T) a multisystem disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. Identification of the gene defective in this syndrome, ataxia-telangiectasia mutated gene (ATM), and further characterization of the disorder together with a greater insight into the function of the ATM protein have expanded our knowledge about the molecular pathogenesis of this disease. Area covered: In this review, we have attempted to summarize the different roles of ATM signaling that have provided new insights into the diverse clinical phenotypes exhibited by A-T patients. Expert commentary: ATM, in addition to DNA repair response, is involved in many cytoplasmic roles that explain diverse phenotypes of A-T patients. It seems accumulation of DNA damage, persistent DNA damage response signaling, and chronic oxidative stress are the main players in the pathogenesis of this disease.
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http://dx.doi.org/10.1080/1744666X.2017.1392856DOI Listing
December 2017

The clinical significance of complete class switching defect in Ataxia telangiectasia patients.

Expert Rev Clin Immunol 2017 05 15;13(5):499-505. Epub 2017 Feb 15.

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

Background: Ataxia telangiectasia (AT) is a primary immunodeficiency associated with recurrent infections. We aimed to investigate clinical and immunological classification in AT patients who suffer from a different spectrum of humoral immune defects.

Methods: AT patients were categorized according to the ability of class switching and patients with hyper IgM (HIgM) profile were defined as class switching defect (CSD).

Results: Serum immunoglobulin profile in 66 AT patients showed normal immunoglobulin level (22.8%), IgA deficiency (37.9%) and hypogammaglobulinemia (18.1%) in the majority of patients, while 21.2% had HIgM profile revealing CSD. CSD does not affect the frequency of infections, however, the frequency of lymphoproliferation (p < 0.001), and autoimmunity (p = 0.004) were significantly higher in this group. Neurologic symptoms in CSD patients are mild or appear after recurrent infections, therefore these patients were usually misdiagnosed as HIgM syndrome.

Conclusions: Although most of AT patients have reduced IgA levels or normal immunoglobulin levels, but a fraction of these patients may show CSD ensuing HIgM-profile. CSD poses affected individuals at higher risk of non-infectious complications.
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http://dx.doi.org/10.1080/1744666X.2017.1292131DOI Listing
May 2017

Survivin isoform expression in arsenic trioxide-treated acute promyelocytic leukemia cell line and patients: The odd expression pattern of survivin-2α.

Asia Pac J Clin Oncol 2017 Apr 22;13(2):e21-e30. Epub 2016 Oct 22.

Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Aim: Survivin, an inhibitor of apoptosis protein, is overexpressed in most cancers and is associated with chemotherapy resistance, increased tumor recurrence and shorter patient survival. Several survivin splice variants have been described, and none of their expressions have been defined in acute promyelocytic leukemia (APL).

Methods: Expression of the survivin gene isoforms (survivin, -2α, -2B, -ΔΕx3 and -3B) were analyzed in 50 peripheral blood and 19 bone marrow samples that were collected at different phases of the disease (diagnostic, remission and relapse) in APL patients treated with arsenic trioxide (ATO) as a front-line therapy. In addition, the human APL-derived cell line (NB4) was analyzed for the expression of survivin isoforms and capsase-3 in response to the ATO.

Results: Survivin and its variants were overexpressed significantly in patient's bone marrow samples compared to peripheral blood or normal samples. Their expression was decreased after ATO treatment in both NB4 cells (except survivin-2α) and APL patients along with PML-RARα copy number reduction. Downregulation of survivin isoforms was associated with an increase in both caspase-3 gene expression and its enzymatic activity levels. In a patient who did not respond to ATO treatment, expression of survivin isoforms (except survivin-2α) were highly increased during the induction therapy.

Conclusion: Survivin isoforms are upregulated in APL patients, and their expression is diminished during the ATO treatment. In addition, overexpression of survivin and its variants (except survivin-2α) are associated with unfavorable results, suggesting that they may play an important role in mechanisms underlying the resistance of APL cells to ATO.
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http://dx.doi.org/10.1111/ajco.12589DOI Listing
April 2017

Cellular and molecular mechanisms of immune dysregulation and autoimmunity.

Cell Immunol 2016 12 27;310:14-26. Epub 2016 Aug 27.

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

Primary immunodeficiencies (PIDs) constitute a large group of rare disorders that affect the function of the immune system. A specific group of PIDs entitled "diseases of immune dysregulation" are developed due to mutation in the genes which have critical roles in the regulation of immune responses and immunological tolerance. This group of PID patients develop autoimmune and inflammatory disorders as a result of their impaired immunity, therefore they could be considered as a model for analyzing the link between immune dysregulation and autoimmunity. In this article, our aim is to describe the function of the mutated gene, the molecular and cellular mechanisms underlying the immune dysregulation and review the literature in regard with the reported autoimmune disorders in the main types of immunodysregulatory diseases including genetic defects of regulatory T cells, familial hemophagocytic lymphohistiocytosis syndromes, autoimmunity without lymphoproliferation, autoimmune lymphoproliferative syndrome, immune dysregulation with colitis, and type 1 interferonopathies.
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http://dx.doi.org/10.1016/j.cellimm.2016.08.012DOI Listing
December 2016

An Mutation (c.253dupC) Caused Diverse Phenotypes of Adrenoleukodystrophy in an Iranian Consanguineous Pedigree.

J Mol Genet Med 2016 Jun 19;10(2). Epub 2016 Jun 19.

Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran; NIH Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, Maryland, USA.

Objectives: Current study was the first to report a consanguineous Iranian pedigree with mutation.

Methods: Targeted molecular analysis was initially performed in three affected individuals in one family suspected to have X-ALD due to chronic progressive spasticity. Upon confirmation of genetic diagnosis, further neurologic and genetic evaluation of all family members was done.

Results: A mutation in was identified in 35 affected individuals (out 96 pedigree members). The c. 253dup, in exon 1, leads to a frame shift and a premature stop codon at amino acid position 194 (p.Arg85Profs*110). Surprisingly, affected individuals in our cohort show some variability in phenotype, including childhood cerebral ALD, adrenomyeloneuropathy, and addison-only disease phenotypes, expanding the phenotype of X-ALD with p.Arg85Profs*110.

Conclusion: This report characterizes the clinical spectrum of an expanded Iranian pedigree with X-ALD due to an mutation. Given a high frequency of carriers in this region, we expect the prevalence of X-ALD to be higher, underscoring the importance of genetic counseling through reliable identification of heterozygous as well as homozygote females in consanguineous communities.
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http://dx.doi.org/10.4172/1747-0862.1000222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969076PMC
June 2016