Publications by authors named "Nima Rezaei"

812 Publications

X-Linked TLR7 Deficiency Underlies Critical COVID-19 Pneumonia in a Male Patient with Ataxia-Telangiectasia.

J Clin Immunol 2021 Oct 23. Epub 2021 Oct 23.

Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden.

Background: Coronavirus disease 2019 (COVID-19) exhibits a wide spectrum of clinical manifestations, ranging from asymptomatic to critical conditions. Understanding the mechanism underlying life-threatening COVID-19 is instrumental for disease prevention and treatment in individuals with a high risk.

Objectives: We aimed to identify the genetic cause for critical COVID-19 pneumonia in a patient with a preexisting inborn error of immunity (IEI).

Methods: Serum levels of specific antibodies against the virus and autoantibodies against type I interferons (IFNs) were measured. Whole exome sequencing was performed, and the impacts of candidate gene variants were investigated. We also evaluated 247 ataxia-telangiectasia (A-T) patients in the Iranian IEI registry.

Results: We report a 7-year-old Iranian boy with a preexisting hyper IgM syndrome who developed critical COVID-19 pneumonia. IgM only specific COVID-19 immune response was detected but no autoantibodies against type I IFN were observed. A homozygous deleterious mutation in the ATM gene was identified, which together with his antibody deficiency, radiosensitivity, and neurological signs, established a diagnosis of A-T. Among the 247 A-T patients evaluated, 36 had SARS-CoV-2 infection, but all had mild symptoms or were asymptomatic except the index patient. A hemizygous deleterious mutation in the TLR7 gene was subsequently identified in the patient.

Conclusions: We report a unique IEI patient with combined ATM and TLR7 deficiencies. The two genetic defects underlie A-T and critical COVID-19 in this patient, respectively.
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http://dx.doi.org/10.1007/s10875-021-01151-yDOI Listing
October 2021

Review of the recent clinical trials for PD-1/PD-L1 based lung cancer immunotherapy.

Expert Rev Anticancer Ther 2021 Oct 22. Epub 2021 Oct 22.

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

Introduction: Lung cancer is known for its high mortality rate and prevalence in the world today. For decades, chemotherapy has been used as the main treatment for this cancer, but this has changed over time. Immune checkpoint inhibitors (ICIs) such as programmed death 1 and programmed death-ligand 1 (PD-1/PD-L1) blocking agents have been assessed in numerous clinical trials as single or combination therapy and have shown overall promising results. Nevertheless, various challenges have been encountered, which cast doubts over this method.

Areas Covered: We provide an introduction to the mechanisms underlying the PD-1/PD-L1 pathway. Then, we discuss the latest results from the most leading-edge studies evaluating PD-1/PD-L1 inhibitors in different lines of lung cancer therapy (some of which have gained FDA approval), potential biomarkers, and major challenges of ICI therapy.

Expert Opinion: Currently, the standard of care (SoC) for lung cancer consists mostly of chemotherapeutics. With further studies and ongoing trials evaluating novel ICI therapy, FDA has been approving specific ICI therapeutics, including PD-1/PD-L1 inhibitors, for particular types of lung cancer. However, for ICIs to play a key role in SoC, we need to overcome the major challenges of ICI therapy.
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http://dx.doi.org/10.1080/14737140.2021.1996230DOI Listing
October 2021

The immune system and autism spectrum disorder: association and therapeutic challenges.

Acta Neurobiol Exp (Wars) 2021 ;81(3):249-263

Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, affecting communication and behavior. Historically, ASD had been described as a purely psychiatric disorder with genetic factors playing the most critical role. Recently, a growing body of literature has been emphasizing the importance of environmental and immunological factors in its pathogenesis, with the autoimmune process attracting the most attention. This study provides a review of the autoimmune involvement in the pathogenesis of ASD. The\r\nmicrobiome, the representative of the innate immune system in the central nervous system (CNS), plays a critical role in triggering inflammation. Besides, a bidirectional communicational pathway between the CNS and the intestine called the gut‑brain‑axis is linked to the development of ASD. Moreover, the higher plasma level of pro‑inflammatory cytokines in ASD patients and the higher prevalence of autoimmune disorders in the first‑degree family members of affected persons are other clues of the immune system involvement in\r\nthe pathogenesis of ASD. Furthermore, some anti‑inflammatory drugs, including resveratrol and palmitoylethanolamide have shown promising effects by relieving the manifestations of ASD. Although considerable advances have been made in elucidating the role of autoimmunity in the ASD pathogenesis, further studies with stronger methodologies are needed to apply the knowledge to the definitive treatment of ASD.
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http://dx.doi.org/10.21307/ane-2021-023DOI Listing
January 2021

In-silico study on perovskites application in capturing and distorting coronavirus.

Inform Med Unlocked 2021 10;26:100755. Epub 2021 Oct 10.

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

The COVID-19 pandemic, known as coronavirus pandemic, a global pandemic, emerged from the beginning of 2020 and became dominant in many countries. As COVID-19 is one of the deadliest pandemics in history and has a high rate of distribution, a fast and extensive reaction was needed. Considering its composition, revealing the infection mechanism is beneficial for effective decisions against the spread and attack of COVID-19. Investigating data from numerous studies confirms that the penetration of SARS-CoV-2 occurs along with bonding spike protein (S protein) and through ACE2; Therefore, these two parts were the focus of research on the suppression and control of the infection. Performing lab research on all promising candidates requires years of experimental study, which is time-consuming and not an acceptable solution. Molecular dynamic simulation can decipher the performance of nano-structures in preventing the spread of coronavirus in a shorter time. This study surveyed the effect of three nano-perovskite structures (SrTiO, CaTiO, and BaTiO), a cutting-edge group of perovskite materials with outstanding properties on coronavirus. Various computational parameters evaluate the effectiveness of these structures. Results of the simulation indicated that SrTiO performs better in SARS-CoV-2 suppression.
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http://dx.doi.org/10.1016/j.imu.2021.100755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502115PMC
October 2021

Genetic Risk Variants for Class Switching Recombination Defects in Ataxia-Telangiectasia Patients.

J Clin Immunol 2021 Oct 10. Epub 2021 Oct 10.

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 autosomal recessive disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene. A-T patients manifest considerable variability in clinical and immunological features, suggesting the presence of genetic modifying factors. A striking heterogeneity has been observed in class switching recombination (CSR) in A-T patients which cannot be explained by the severity of ATM mutations.

Methods: To investigate the cause of variable CSR in A-T patients, we applied whole-exome sequencing (WES) in 20 A-T patients consisting of 10 cases with CSR defect (CSR-D) and 10 controls with normal CSR (CSR-N). Comparative analyses on modifier variants found in the exomes of these two groups of patients were performed.

Results: For the first time, we identified some variants in the exomes of the CSR-D group that were significantly associated with antigen processing and presentation pathway. Moreover, in this group of patients, the variants in four genes involved in DNA double-strand breaks (DSB) repair signaling, in particular, XRCC3 were observed, suggesting an association with CSR defect.

Conclusion: Additional impact of certain variants, along with ATM mutations, may explain the heterogeneity in CSR defect phenotype among A-T patients. It can be concluded that genetic modulators play an important role in the course of A-T disease and its clinical severity.
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http://dx.doi.org/10.1007/s10875-021-01147-8DOI Listing
October 2021

Cardiovascular diseases burden in COVID-19.

Am J Emerg Med 2021 Oct 2. Epub 2021 Oct 2.

Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

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http://dx.doi.org/10.1016/j.ajem.2021.09.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486597PMC
October 2021

Potential therapeutic approach of intravenous immunoglobulin against COVID-19.

Allergy Asthma Clin Immunol 2021 Oct 9;17(1):105. Epub 2021 Oct 9.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, 14194, Tehran, Iran.

Since the outbreak of the novel coronavirus disease (COVID-19), the therapeutic and management options to reduce the burden of the COVID-19 disease are under investigation. IVIG therapy is used as an effective treatment for immunodeficient patients and patients with inflammatory or autoimmune conditions. The therapeutic effect of IVIG in COVID-19 patients has been investigated. But, the results are controversial and some studies reported no benefit of IVIG therapy. More clinical trials on the effect of IVIG therapy in COVID-19 patients should be performed to establish a certain conclusion about IVIG effectiveness.
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http://dx.doi.org/10.1186/s13223-021-00609-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501925PMC
October 2021

The immunologic aspects of cytokine release syndrome and graft versus host disease following CAR T cell therapy.

Int Rev Immunol 2021 Oct 5:1-20. Epub 2021 Oct 5.

Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.

Chimeric antigen receptor (CAR) T cells are the pioneers of cancer immunotherapy, which to this date have several FDA-approved products. They have been substantially improved since their first introduction in 1993 and have shown promising results regardless of their inevitable side effects. Cytokine release syndrome (CRS), the most common toxicity after CAR T cell treatment, is affiliated to a systemic inflammation through surge of cytokines, mainly IL-6, IL-1, and INF-γ. Furthermore, difference between histocompatibility antigens activates the graft versus host disease (GvHD) effect of the allogenic CAR T cells against the host cells. Immunological reactions induced by CAR T cells in the form of CRS or GvHD is necessary for fostering good responses, while excess reactions can potentially threaten patient life. In this review, we first describe the history, applications, and structure of CAR T cells, followed by a comprehensive review of CRS regarding its definition, management, and immunological aspects. Finally, we discuss about the clinical aspects of CRS and GvHD after CAR T cell therapy and how to harness anti-tumoral effects, while mitigating the adverse effects.
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http://dx.doi.org/10.1080/08830185.2021.1984449DOI Listing
October 2021

The Prognostication Potential of BRCA Genes Expression in Gliomas: A Genetic Survival Analysis Study.

World Neurosurg 2021 Oct 1. Epub 2021 Oct 1.

School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity, Universal Scientific Education and Research Network, Tehran, Iran. Electronic address:

Background: Gliomas are the most common type of central nervous system tumor in adults, and they have an extremely poor prognosis. Gliomas are classified into 4 grades, with low-grade gliomas (LGGs) constituting grades I and II and glioblastoma multiforme (GBM) constituting grade IV. Breast cancer susceptibility genes BRCA1 and BRCA2 play a role in DNA repair and are required for genome stability.

Methods: We analyzed the LGG and GBM cohorts from The Cancer Genome Atlas. We used Kaplan-Meier and log-rank analysis to determine the relationship between BRCA1 and BRCA2 expression and survival.

Results: Correlation of BRCA1 and BRCA2 expression with survival in patients with LGG was significant (P = 0.00 and P = 0.00). The higher the levels of expression were, the lower survival rates were in both LGG and GBM cohorts, but the correlation was not significant in patients with GBM (P < 0.01).

Conclusions: Our findings suggest that BRCA1 and BRCA2 can be regarded as poor prognostic factors in patients with glioma, with greater significance in patients with LGG. In the future, more in-depth experiments will enable us to elucidate the mechanism of gliomagenesis and identify potential gene therapy targets.
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http://dx.doi.org/10.1016/j.wneu.2021.09.107DOI Listing
October 2021

Effects of modified-Paleo and moderate-carbohydrate diets on body composition, serum levels of hepatokines and adipocytokines, and flow cytometric analysis of endothelial microparticles in adults with metabolic syndrome: a study protocol for a randomized clinical trial.

Trials 2021 Sep 30;22(1):673. Epub 2021 Sep 30.

Department of Cellular and Molecular Nutrition, School of Nutritional Science and Dietetics, Tehran University of Medical Sciences, Tehran, 14155-6447, Iran.

Background: Metabolic syndrome is a combination of metabolic risk factors causing a pathological condition that increases the risk of non-communicable diseases, such as diabetes and cardiovascular diseases. A variety of dietary approaches have been examined to halt this rapid trend; however, the effects of modified-Paleo diet and medium-carbohydrate diet on inflammation, adipokines, hepatokines, and the profile of endothelial microparticles in individuals with metabolic syndrome have not been investigated in detail. The present study is designed to examine the effect of modified-Paleo and moderate-carbohydrate diet with two delivery modes: "fixed diet plan" vs "calorie counting" on weight, body composition, serum levels of some hepatokines and adipocytokines, and flow cytometric analysis of endothelial microparticles in adults with metabolic syndrome.

Methods: Eighty metabolic syndrome patients will be recruited in this study. They will be randomly allocated to one of the following 4 groups: (1) receiving a modified-Paleo diet with calorie counting, (2) receiving a modified-Paleo diet with a fixed diet plan, (3) receiving a medium-carbohydrate diet with calorie counting, and (4) receiving a medium-carbohydrate diet with a fixed diet plan for 10 weeks. Weight, height, waist circumference, and body composition will be assessed at the study baseline and at the end of the trial. Serum insulin, asprosin, chemerin, FGF-21, CTRP-1, PYY, ghrelin, plasma EMPs (CD31+/CD42b- and CD144+/CD42b-), lipid profile, glycemic indices, hs-CRP, leptin, vitamin C, creatinine and satiety, hunger, fullness, and desire to eat (via visual analog scales) will be measured at the study baseline and at the end of the trial. Insulin resistance and insulin sensitivity will be determined using the HOMA-IR and QUICKI equations.

Discussion: To the best of our knowledge, this is the first randomized controlled trial that will determine the effect of modified-Paleo and moderate-carbohydrate diet on weight, body composition, serum levels of some hepatokines and adipocytokines, and the profile of EMPs in adults with metabolic syndrome. Moreover, the effects of different diet delivery modes, including "fixed diet plan" and "calorie counting" will also be analyzed. The results of this trial can provide clinical witnesses on the effectiveness of carbohydrate-restricted diets in ameliorating metabolic status and prevent the development of chronic diseases.

Trial Registration: Iranian Registry of Clinical Trials IRCT2016121925267N4 . Registered on 26 July 2017.
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http://dx.doi.org/10.1186/s13063-021-05612-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483422PMC
September 2021

[Cutaneous Manifestation of COVID-19: What have we learned an year into the pandemic?]

Actas Dermosifiliogr (Engl Ed) 2021 Sep 22. Epub 2021 Sep 22.

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

Coronavirus disease-19 (COVID-19) is an emerging health situation caused by the "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). The ongoing COVID-19 pandemic which emerged from the Chinese city of Wuhan in December 2019 has spread to over 188 countries and infected over 100 million people across the globe in over one year. Most common symptoms of COVID-19 include fever and respiratory illness. Among extrapulmonary signs associated with COVID-19, dermatological manifestations have been increasingly reported from different geographical regions. The exact incidence or prevalence of COVID-19 associated skin manifestation remains largely unknown and the pathophysiological mechanisms are still unclear. In this article, we have attempted to give a comprehensive overview of what has been learned an year into the pandemic on the epidemiology, clinical and histopathological features, pathophysiological mechanisms and clinical management of COVID-19 associated cutaneous manifestations.
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http://dx.doi.org/10.1016/j.ad.2021.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457627PMC
September 2021

Implications derived from S-protein variants of SARS-CoV-2 from six continents.

Int J Biol Macromol 2021 Sep 24;191:934-955. Epub 2021 Sep 24.

Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Institutskiy pereulok, 9, Dolgoprudny, 141700, Russia. Electronic address:

The spike (S) protein is a critical determinant of the infectivity and antigenicity of SARS-CoV-2. Several mutations in the S protein of SARS-CoV-2 have already been detected, and their effect in immune system evasion and enhanced transmission as a cause of increased morbidity and mortality are being investigated. From pathogenic and epidemiological perspectives, S proteins are of prime interest to researchers. This study focused on the unique variants of S proteins from six continents: Asia, Africa, Europe, Oceania, South America, and North America. In comparison to the other five continents, Africa had the highest percentage of unique S proteins (29.1%). The phylogenetic relationship implies that unique S proteins from North America are significantly different from those of the other five continents. They are most likely to spread to the other geographic locations through international travel or naturally by emerging mutations. It is suggested that restriction of international travel should be considered, and massive vaccination as an utmost measure to combat the spread of the COVID-19 pandemic. It is also further suggested that the efficacy of existing vaccines and future vaccine development must be reviewed with careful scrutiny, and if needed, further re-engineered based on requirements dictated by new emerging S protein variants.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.09.080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462006PMC
September 2021

The role of noncoding RNAs in pituitary adenoma.

Epigenomics 2021 Sep 24;13(17):1421-1437. Epub 2021 Sep 24.

Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran.

Pituitary adenomas (PAs) are common cranial tumors that affect the quality of life in patients. Early detection of PA is beneficial for avoiding clinical complications of this disease and increasing the quality of life. Noncoding RNAs, including long noncoding RNA, miRNA and circRNA, regulate protein expression, mostly by inhibiting the translation process. Studies have shown that dysregulation of noncoding RNAs is associated with PA. Hence understanding the expression pattern of noncoding RNAs can be considered a promising method for developing biomarkers. This article reviews data on the expression pattern of dysregulated noncoding RNAs involved in PA. Possible molecular mechanisms by which the dysregulated noncoding RNA could possibly induce PA are also described.
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http://dx.doi.org/10.2217/epi-2021-0165DOI Listing
September 2021

An overview on tumor treating fields (TTFields) technology as a new potential subsidiary biophysical treatment for COVID-19.

Drug Deliv Transl Res 2021 Sep 20. Epub 2021 Sep 20.

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

COVID-19 pandemic situation has affected millions of people with tens of thousands of deaths worldwide. Despite all efforts for finding drugs or vaccines, the key role for the survival of patients is still related to the immune system. Therefore, improving the efficacy and the functionality of the immune system of COVID-19 patients is very crucial. The potential new, non-invasive, FDA-approved biophysical technology that could be considered in this regard is tumor treating fields (TTFields) based on an alternating electric field has great biological effects. TTFields have significant effects in improving the functionality of dendritic cell, and cytotoxic T-cells, and these cells have a major role in defense against viral infection. Hence, applying TTFields could help COVID-19 patients against infection. Additionally, TTFields can reduce viral genomic replication, by reducing the expressions of some of the vital members of DNA replication complex genes from the minichromosome maintenance family (MCMs). These genes not only are involved in DNA replication but it has also been proven that they have a crucial role in viral replication. Also, TTFields suppress the formation of the network of tunneling nanotubes (TNTs) which is knows as filamentous (F)-actin-rich tubular structures. TNTs have a critical role in promoting the spread of viruses through improving viral entry and acting as a protective agent for viral components from immune cells and even pharmaceuticals. Moreover, TTFields enhance autophagy which leads to apoptosis of virally infected cells. Thus, it can be speculated that using TTFields may prove to be a promising approach as a subsidiary treatment of COVID-19.
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http://dx.doi.org/10.1007/s13346-021-01067-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451390PMC
September 2021

Preclinical studies of chimeric antigen receptor-modified natural killer cells in cancer immunotherapy: a review.

Expert Opin Biol Ther 2021 Oct 22:1-18. Epub 2021 Oct 22.

Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.

Introduction: As one of the most efficacious methods of cancer immunotherapy, chimeric antigen receptor-modified immune cells have recently drawn enormous attention. After the great success achieved with CAR-T-cells in cancer treatment both in preclinical setting and in the clinic, other types of immune cells, including natural killer (NK)-cells and macrophages, have been evaluated for their anti-cancer effects along with their potential superiority against CAR-T-cells, especially in terms of safety. First introduced by almost 26 years ago, CAR-NK-cells are now being considered as efficient immunotherapeutic modalities in various types of cancers, not only in preclinical setting but also in numerous phase I and II clinical studies.

Areas Covered: In this review, we aim to provide a comprehensive survey of the preclinical studies on CAR-NK-cells' development, with an evolutional approach on CAR structures and their associated signaling moieties. Current NK-cell sources and modes of gene transfer are also reviewed.

Expert Opinion: CAR-NK-cells have appeared as safe and effective immunotherapeutic tools in preclinical settings; however, designing CAR structures with an eye on their specific biology, along with choosing the optimal cell source and gene transfer method require further investigation to support clinical studies.
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http://dx.doi.org/10.1080/14712598.2021.1983539DOI Listing
October 2021

Central neuroinflammation in Covid-19: a systematic review of 182 cases with encephalitis, acute disseminated encephalomyelitis, and necrotizing encephalopathies.

Rev Neurosci 2021 Sep 17. Epub 2021 Sep 17.

Research Center for Immunodeficiencies, Tehran University of Medical Sciences (TUMS), Children's Medical Center Hospital, Dr. Qarib St., Keshavarz Blvd, Tehran, 14194, Iran.

Growing evidence demonstrates the association of encephalitis, meningoencephalitis or encephalomyelitis, with SARS-CoV-2 infection. This study aims to determine the profile and possible mechanisms behind CNS inflammatory diseases in the context of Covid-19. We conducted a systematic review of case reports on Covid-19-related encephalitis, meningoencephalitis, acute necrotizing encephalitis, and acute disseminated encephalomyelitis in adults, published before January 2021. A total of 182 cases (encephalitis = 109, meningoencephalitis = 26, acute disseminated encephalomyelitis = 35, acute necrotizing (hemorrhagic) encephalitis = 12) were included. While cerebrospinal fluid (CSF) pleocytosis and increased protein level was present in less than 50%, magnetic resonance imaging (MRI) and electroencephalogram (EEG) were abnormal in 78 and 93.2% of all cases, respectively. Viral particles were detected in cerebrospinal fluid of only 13 patients and autoantibodies were present in seven patients. All patients presented with altered mental status, either in the form of impaired consciousness or psychological/cognitive decline. Seizure, cranial nerve signs, motor, and reflex abnormalities were among associated symptoms. Covid-19-associated encephalitis presents with a distinctive profile requiring thorough diagnosis and thereby a comprehensive knowledge of the disease. The clinical profile of brain inflammation in Covid-19 exhibits majority of abnormal imaging and electroencephalography findings with mild/moderate pleocytosis or proteinorrhachia as prevalent as normal cerebrospinal fluid (CSF). Oligoclonal bands and autoantibody assessments are useful in further evaluating neuro-covid patients, as supported by our pooled evidence. Despite the possibility that direct viral invasion cannot be easily estimated, it is still more likely that immune-mediated or autoimmune reactions play a more important role in SARS-CoV-2 neuroinflammation.
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http://dx.doi.org/10.1515/revneuro-2021-0082DOI Listing
September 2021

Immune checkpoint inhibitors and cardiotoxicity: possible mechanisms, manifestations, diagnosis and management.

Expert Rev Anticancer Ther 2021 Sep 21:1-18. Epub 2021 Sep 21.

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

Introduction: Immune checkpoint inhibitors (ICIs) are a new class of anticancer drugs that enhance the immune system function and activate T cells against cancerous cells. Although cardiac complications are not common, they could be accompanied with high morbidity and mortality.

Areas Covered: Regarding the importance of cardiac complications and their subsequent burden on individuals and the healthcare system, this review attempts to discuss the mechanism, diagnosis, and management of myocarditis, besides recapitulating the possible mechanism of other cardiac adverse events. Moreover, we briefly discuss the concurrent administration of other chemotherapeutic agents.

Expert Opinion: Due to insufficient knowledge concerning the physiopathology of immune-related adverse events (irAEs) and their potential further complications, cardiovascular complications in particular and in the context of this paper's focus, cooperation of oncologists, immunologists, and cardiologists is necessary for the management of patients. Experimental approaches such as using corticosteroids are becoming a part of guidelines for managing cardiac irAEs. However, a unique algorithm for diagnosis and management is necessary, especially in myocarditis cases. Furthermore, more studies are required to resolve current challenges, including prevention of myocarditis, concurrent administration of other chemotherapeutic agents, and re-introducing patients with ICIs.
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http://dx.doi.org/10.1080/14737140.2021.1979396DOI Listing
September 2021

Autoimmunity roots of the thrombotic events after COVID-19 vaccination.

Autoimmun Rev 2021 Nov 9;20(11):102941. Epub 2021 Sep 9.

Department of Molecular Medicine, University of South Florida, Tampa, FL, United States. Electronic address:

Although vaccination represents the most promising way to stop or contain the coronavirus disease 2019 (COVID-19) pandemic and safety and effectiveness of available vaccines were proven, a small number of individuals who received anti-SARS-CoV-2 vaccines developed a prothrombotic syndrome. Vaccine-induced immune thrombotic thrombocytopenia (VITT) can be triggered by the adenoviral vector-based vaccine, whereas lipid nanoparticle-mRNA-based vaccines can induce rare cases of deep vein thrombosis (DVT). Although the main pathogenic mechanisms behind this rare phenomenon have not yet been identified, both host and vaccine factors might be involved, with pathology at least in part being related to the vaccine-triggered autoimmune reaction. In this review, we are considering some aspects related to pathogenesis, major risk factors, as well as peculiarities of diagnosis and treatment of this rare condition.
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http://dx.doi.org/10.1016/j.autrev.2021.102941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426137PMC
November 2021

Immune modulations and immunotherapies for Alzheimer's disease: a comprehensive review.

Rev Neurosci 2021 Sep 10. Epub 2021 Sep 10.

Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Children's Medical Center, Tehran1419733151, Iran.

Alzheimer's disease (AD), the most common cause of dementia, is characterized by progressive cognitive and memory impairment ensued from neuronal dysfunction and eventual death. Intraneuronal deposition of tau proteins and extracellular senile amyloid-β plaques have ruled as the supreme postulations of AD for a relatively long time, and accordingly, a wide range of therapeutics, especially immunotherapies have been implemented. However, none of them resulted in significant positive cognitive outcomes. Especially, the repetitive failure of anti-amyloid therapies proves the inefficiency of the amyloid cascade hypothesis, suggesting that it is time to reconsider this hypothesis. Thus, for the time being, the focus is being shifted to neuroinflammation as a third core pathology in AD. Neuroinflammation was previously considered a result of the two aforementioned phenomena, but new studies suggest that it might play a causal role in the pathogenesis of AD. Neuroinflammation can act as a double-edged sword in the pathogenesis of AD, and the activation of glial cells is indispensable for mediating such attenuating or detrimental effects. The association of immune-related genes polymorphisms with the clinical phenotype of AD as well as the protective effect of anti-inflammatory drugs like nonsteroidal anti-inflammatory drugs supports the possible causal role of neuroinflammation in AD. Here, we comprehensively review immune-based therapeutic approaches toward AD, including monoclonal antibodies and vaccines. We also discuss their efficacy and underlying reasons for shortcomings. Lastly, we highlight the capacity of modulating the neuroimmune interactions and targeting neuroinflammation as a promising opportunity for finding optimal treatments for AD.
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http://dx.doi.org/10.1515/revneuro-2021-0092DOI Listing
September 2021

COVID-19 Vaccination: What Challenges Are We Going to Face.

Acta Biomed 2021 09 2;92(4):e2021379. Epub 2021 Sep 2.

Net-work of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

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http://dx.doi.org/10.23750/abm.v92i4.11759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477080PMC
September 2021

The second brain: The connection between gut microbiota composition and multiple sclerosis.

J Neuroimmunol 2021 Nov 24;360:577700. Epub 2021 Aug 24.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran. Electronic address:

Gut microbiota composition may affect the central nervous system (CNS) and immune function. Several studies have recently examined the possible link between gut microbiota composition and multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Most of these studies agree that patients with MS suffer from dysbiosis. Moreover, an altered proportion of certain phyla of bacteria was detected in the digestive tracts of these patients compared to healthy individuals. This review article gathers information from research papers that have examined the relationship between gut microbiota composition and MS and its possible mechanisms.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577700DOI Listing
November 2021

The role of type I interferon in the treatment of COVID-19.

J Med Virol 2021 Sep 1. Epub 2021 Sep 1.

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

Although significant research has been done to find effective drugs against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), no definite effective drug exists. Thus, research has now shifted towards immunomodulatory agents other than antivirals. In this review, we aim to describe the latest findings on the role of type I interferon (IFN)-mediated innate antiviral response against SARS-CoV-2 and discuss the use of IFNs as a medication for COVID-19. A growing body of evidence has indicated a promoting active but delayed IFNs response to SARS-CoV-2 and Middle East respiratory syndrome coronavirus in infected bronchial epithelial cells. Studies have demonstrated that IFNs' administration before the viral peak and the inflammatory phase of disease could offer a highly protective effect. However, IFNs' treatment during the inflammatory and severe stages of the disease causes immunopathology and long-lasting harm for patients. Therefore, it is critical to note the best time window for IFNs' administration. Further investigation of the clinical effectiveness of interferon for patients with mild to severe COVID-19 and its optimal timing and route of administration can be beneficial in finding a safe and effective antiviral therapy for the COVID-19 disease.
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http://dx.doi.org/10.1002/jmv.27317DOI Listing
September 2021

Inhibitors of the PI3K/Akt/mTOR Pathway in Prostate Cancer Chemoprevention and Intervention.

Pharmaceutics 2021 Aug 3;13(8). Epub 2021 Aug 3.

Lake Erie Collage of Osteopathic Medicine, Bradenton, FL 34211, USA.

The phosphatidylinositol 3-kinase (PI3K)/serine-threonine kinase (Akt)/mammalian target of the rapamycin (mTOR)-signaling pathway has been suggested to have connections with the malignant transformation, growth, proliferation, and metastasis of various cancers and solid tumors. Relevant connections between the PI3K/Akt/mTOR pathway, cell survival, and prostate cancer (PC) provide a great therapeutic target for PC prevention or treatment. Recent studies have focused on small-molecule mTOR inhibitors or their usage in coordination with other therapeutics for PC treatment that are currently undergoing clinical testing. In this study, the function of the PI3K/Akt/mTOR pathway, the consequence of its dysregulation, and the development of mTOR inhibitors, either as an individual substance or in combination with other agents, and their clinical implications are discussed. The rationale for targeting the PI3K/Akt/mTOR pathway, and specifically the application and potential utility of natural agents involved in PC treatment is described. In addition to the small-molecule mTOR inhibitors, there are evidence that several natural agents are able to target the PI3K/Akt/mTOR pathway in prostatic neoplasms. These natural mTOR inhibitors can interfere with the PI3K/Akt/mTOR pathway through multiple mechanisms; however, inhibition of Akt and suppression of mTOR 1 activity are two major therapeutic approaches. Combination therapy improves the efficacy of these inhibitors to either suppress the PC progression or circumvent the resistance by cancer cells.
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http://dx.doi.org/10.3390/pharmaceutics13081195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400324PMC
August 2021

CRISPR/Cas9 revitalizes adoptive T-cell therapy for cancer immunotherapy.

J Exp Clin Cancer Res 2021 Aug 26;40(1):269. Epub 2021 Aug 26.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran.

Cancer immunotherapy has gained attention as the supreme therapeutic modality for the treatment of various malignancies. Adoptive T-cell therapy (ACT) is one of the most distinctive modalities of this therapeutic approach, which seeks to harness the potential of combating cancer cells by using autologous or allogenic tumor-specific T-cells. However, a plethora of circumstances must be optimized to produce functional, durable, and efficient T-cells. Recently, the potential of ACT has been further realized by the introduction of novel gene-editing platforms such as the CRISPR/Cas9 system; this technique has been utilized to create T-cells furnished with recombinant T-cell receptor (TCR) or chimeric antigen receptor (CAR) that have precise tumor antigen recognition, minimal side effects and treatment-related toxicities, robust proliferation and cytotoxicity, and nominal exhaustion. Here, we aim to review and categorize the recent breakthroughs of genetically modified TCR/CAR T-cells through CRISPR/Cas9 technology and address the pearls and pitfalls of each method. In addition, we investigate the latest ongoing clinical trials that are applying CRISPR-associated TCR/CAR T-cells for the treatment of cancers.
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http://dx.doi.org/10.1186/s13046-021-02076-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390258PMC
August 2021

Autoimmune complications of COVID-19.

J Med Virol 2021 Aug 24. Epub 2021 Aug 24.

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

Coronavirus disease 2019 (COVID-19) is still propagating a year after the start of the pandemic. Besides the complications patients face during the COVID-19 disease period, there is an accumulating body of evidence concerning the late-onset complications of COVID-19, of which autoimmune manifestations have attracted remarkable attention from the first months of the pandemic. Autoimmune hemolytic anemia, immune thrombocytopenic purpura, autoimmune thyroid diseases, Kawasaki disease, Guillain-Barre syndrome, and the detection of autoantibodies are the cues to the discovery of the potential of COVID-19 in inducing autoimmunity. Clarification of the pathophysiology of COVID-19 injuries to the host, whether it is direct viral injury or autoimmunity, could help to develop appropriate treatment.
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http://dx.doi.org/10.1002/jmv.27292DOI Listing
August 2021

Adverse reactions in a large cohort of patients with inborn errors of immunity receiving intravenous immunoglobulin.

Clin Immunol 2021 09 19;230:108826. Epub 2021 Aug 19.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran.

Background: Intravenous immunoglobulins (IVIg) are the major treatment in inborn errors of immunity (IEI) disorders; However, IVIg infusions show some adverse effects. We aimed to assess the adverse reactions of IVIg infusions.

Methods: Data of IVIg infusions in IEI patients were collected from 2011 to 2021. Totally, 363 IEI patients received IVIg regularly in Iran entered the study. The adverse reactions are classified regarding their severity and chronicity.

Results: 22,667 IVIg infusions were performed in the study. 157 patients (43.2%) and 1349 (5.9%) infusions were associated with at least one type of adverse reaction. The highest rates of adverse reactions were seen in severe combined immunodeficiency. Myalgia, chills, headache, fever, and hypotension were the most frequent adverse effects of IVIg.

Conclusion: The reactions affect almost half of the patients mainly in the first infusions which necessitate the close observation of IEI patients receiving IVIg.
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http://dx.doi.org/10.1016/j.clim.2021.108826DOI Listing
September 2021

The association between tumor-associated macrophages and glioblastoma: a potential target for therapy.

Curr Pharm Des 2021 Aug 16. Epub 2021 Aug 16.

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

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults, causing many deaths each year. The life expectancy of patients from the time of diagnosis does not exceed 15 months. Tumoral cells are generally surrounded by a bed of tumor microenvironment (TME), composed of various components such as different immune cells, stromal cells, and blood vessels. Previous studies on the treatment of this tumor have generally focused on cancerous cells and therefore, have introduced conventional therapies for eradicating this tumor, including maximal safe surgery, chemotherapy with temozolomide (TMZ), and radiotherapy. Despite treatment with this method, tumors almost always recur, and life expectancy has not increased much. Recently, due to the discovery of the various roles of immune cells (including tumor-associated macrophages or TAMs) in the pathogenesis of this disease, the path of studies has moved towards targeting them as a treatment for glioblastoma. In this review, we aimed to investigate recent studies on the different roles of TME components, the role of TAM in the pathogenesis, and novel methods that target TAMs, including induction of TAM repolarization, inhibition of TAM-produced cytokines, and prohibition of immune system suppression induced by TAMs. In this regard, various targets, including colony-stimulating factor-1 (CSF-1) receptors, Nuclear factor-kappa B (NF-κB), or chemokine receptor (CXCR) pathways, are investigated.
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http://dx.doi.org/10.2174/1381612827666210816114003DOI Listing
August 2021

Wiskott-Aldrich syndrome with possible congenital infection: A diagnostic dilemma.

Natl Med J India 2021 Jan-Feb;34(1):24-26

Network of Immunity in Infection, Malignancy and Autoimmunity, Universal Scientific Education and Research Network, Tehran, Iran.

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder, characterized by thrombocytopenia, eczema and recurrent infections. We report a 4-month-old boy who presented with respiratory distress, petechiae, organomegaly and eczema. He was admitted to the paediatric intensive care unit because of severe respiratory distress due to Cytomegalovirus (CMV) infection. As peripheral blood smear showed microthrombocytopenia, Sanger gene sequencing was performed, which confirmed the diagnosis of WAS. This rare combination of possible congenital CMV infection in the background of WAS, misled the initial diagnosis.
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http://dx.doi.org/10.4103/0970-258X.323441DOI Listing
August 2021

Serological tests for COVID-19: Potential opportunities.

Cell Biol Int 2021 11 24;45(11):2199-2200. Epub 2021 Aug 24.

School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

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http://dx.doi.org/10.1002/cbin.11686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426956PMC
November 2021

COVID-19 Vaccines and Thrombosis-Roadblock or Dead-End Street?

Biomolecules 2021 07 13;11(7). Epub 2021 Jul 13.

Department of Molecular Medicine and USF Health Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.

Two adenovirus-based vaccines, ChAdOx1 nCoV-19 and Ad26.COV2.S, and two mRNA-based vaccines, BNT162b2 and mRNA.1273, have been approved by the European Medicines Agency (EMA), and are invaluable in preventing and reducing the incidence of coronavirus disease-2019 (COVID-19). Recent reports have pointed to thrombosis with associated thrombocytopenia as an adverse effect occurring at a low frequency in some individuals after vaccination. The causes of such events may be related to SARS-CoV-2 spike protein interactions with different C-type lectin receptors, heparan sulfate proteoglycans (HSPGs) and the CD147 receptor, or to different soluble splice variants of the spike protein, adenovirus vector interactions with the CD46 receptor or platelet factor 4 antibodies. Similar findings have been reported for several viral diseases after vaccine administration. In addition, immunological mechanisms elicited by viral vectors related to cellular delivery could play a relevant role in individuals with certain genetic backgrounds. Although rare, the potential COVID-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) requires immediate validation, especially in risk groups, such as the elderly, chronic smokers, and individuals with pre-existing incidences of thrombocytopenia; and if necessary, a reformulation of existing vaccines.
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http://dx.doi.org/10.3390/biom11071020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301964PMC
July 2021
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