Publications by authors named "Maryam Akhtari"

13 Publications

  • Page 1 of 1

Reply: Is high-dose glucocorticoid beneficial in COVID-19?

Eur Respir J 2021 04 15;57(4). Epub 2021 Apr 15.

Rheumatology Research Center, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran

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http://dx.doi.org/10.1183/13993003.00324-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898159PMC
April 2021

A comprehensive overview on the genetics of Behçet's disease.

Int Rev Immunol 2020 Dec 1:1-64. Epub 2020 Dec 1.

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

Behçet's disease (BD) is a systemic and inflammatory disease, characterized mainly by recurrent oral and genital ulcers, eye involvement, and skin lesions. Although the exact etiopathogenesis of BD remains unrevealed, a bulk of studies have implicated the genetic contributing factors as critical players in disease predisposition. In countries along the Silk Road, human leukocyte antigen (HLA)-B51 has been reported as the strongest genetically associated factor for BD. Genome-wide association studies, local genetic polymorphism studies, and meta-analysis of combined data from Turkish, Iranian, and Japanese populations have also identified new genetic associations with BD. Among these, other HLA alleles such as , , , and have been found as independent risk factors for BD, whereas and are independent protective alleles for BD. Moreover, other genes have also reached the genome-wide significance level of association with BD susceptibility, including , , , , , , , , and . Also, several rare nonsynonymous variants in , , , and genes have been reported to be involved in BD pathogenesis. According to genetic determinants in the loci outside the MHC region that are contributed to the host defense, immunity, and inflammation pathways, it is suggested that immune responses to the pathogen as an important environmental factor and mucosal immunity contribute to BD susceptibility.
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http://dx.doi.org/10.1080/08830185.2020.1851372DOI Listing
December 2020

Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial.

Eur Respir J 2020 12 24;56(6). Epub 2020 Dec 24.

Rheumatology Research Center, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran

Introduction: There are no determined treatment agents for severe COVID-19. It is suggested that methylprednisolone, as an immunosuppressive treatment, can reduce the inflammation of the respiratory system in COVID-19 patients.

Methods: We conducted a single-blind, randomised controlled clinical trial involving severe hospitalised patients with confirmed COVID-19 at the early pulmonary phase of the illness in Iran. The patients were randomly allocated in a 1:1 ratio by the block randomisation method to receive standard care with methylprednisolone pulse (intravenous injection, 250 mg·day for 3 days) or standard care alone. The study end-point was the time of clinical improvement or death, whichever came first. Primary and safety analysis was done in the intention-to-treat (ITT) population.

Results: 68 eligible patients underwent randomisation (34 patients in each group) from April 20, 2020 to June 20, 2020. In the standard care group, six patients received corticosteroids by the attending physician before the treatment and were excluded from the overall analysis. The percentage of improved patients was higher in the methylprednisolone group than in the standard care group (94.1% 57.1%) and the mortality rate was significantly lower in the methylprednisolone group (5.9% 42.9%; p<0.001). We demonstrated that patients in the methylprednisolone group had a significantly increased survival time compared with patients in the standard care group (log-rank test: p<0.001; hazard ratio 0.293, 95% CI 0.154-0.556). Two patients (5.8%) in the methylprednisolone group and two patients (7.1%) in the standard care group showed severe adverse events between initiation of treatment and the end of the study.

Conclusions: Our results suggest that methylprednisolone pulse could be an efficient therapeutic agent for hospitalised severe COVID-19 patients at the pulmonary phase.
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http://dx.doi.org/10.1183/13993003.02808-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758541PMC
December 2020

Copy number variation of IL17RA gene and its association with the ankylosing spondylitis risk in Iranian patients: a case-control study.

BMC Med Genet 2020 07 10;21(1):147. Epub 2020 Jul 10.

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

Background: Ankylosing spondylitis (AS) is considered as a subtype of spondyloarthritis (SpA) that mainly leads to fatigue, stiffness, spinal ankylosis, and impaired physical functions with reduced quality of life. Interleukin (IL)-17A provokes additional inflammatory mediators and recruits immune cells to the inflamed site. IL17 expression increased in various inflammatory disorders including psoriasis, rheumatoid arthritis, multiple sclerosis, crohn's disease, and ankylosing spondylitis. The current study aimed to evaluate the association of IL17RA copy number changes with the susceptibility to AS and their correlation to IL17RA expression in Iranian population.

Methods: IL17RA copy number genotyping assessments were carried out in 455 AS patients and 450 healthy controls, using custom TaqMan CNV assays. TaqMan primers and probe were located in Chr.22:17109553 based on pre-designed IL17RA Copy Number Assay ID, Hs02339506_cn. mRNA expression of IL17RA was also measured by SYBR Green real-time polymerase chain reaction (PCR).

Results: A IL17RA copy number loss (< 2) was associated with AS compared to 2 copies as reference (OR:2.18, 95% CI: (1.38-3.44), P-value < 0.001) and increased the risk of AS. IL17RA mRNA expression showed a significant increase in peripheral blood mononuclear cells (PBMCs) of all AS individuals than controls. The mRNA expression level of 2 copies was significantly higher in AS patients.

Conclusions: Our findings revealed that a low copy number of IL17RA might confer a susceptibility risk to AS. However, it is probably not directly involved in the regulation of IL17RA mRNA expression. Epigenetic mechanisms like DNA methylation, post-transcriptional, and -translational modifications that regulate the expression of the genes may contribute in upregulation of IL17RA mRNA expression in the loss of gene copy number condition.
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http://dx.doi.org/10.1186/s12881-020-01078-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350761PMC
July 2020

Adoptive Treg cell-based immunotherapy: Frontier therapeutic aspects in rheumatoid arthritis.

Immunotherapy 2020 08 7;12(12):933-946. Epub 2020 Jul 7.

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

The major current focus on treating rheumatoid arthritis is to put an end to long-term treatments and instead, specifically block widespread immunosuppression by developing antigen-specific tolerance, while also permitting an intact immune response toward other antigens to occur. There have been promising preclinical findings regarding adoptive Treg cells immunotherapy with a critically responsible function in the prevention of autoimmunity, tissue repair and regeneration, which make them an attractive candidate to develop effective therapeutic approaches to achieve this interesting concept in many human immune-mediated diseases, such as rheumatoid arthritis. or manipulation protocols are not only utilized to correct Treg cells defect, but also to benefit from their specific immunosuppressive properties by identifying specific antigens that are expressed in the inflamedjoint. The methods able to address these deficiencies can be considered as a target for immunity interventions to restore appropriate immune function.
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http://dx.doi.org/10.2217/imt-2020-0071DOI Listing
August 2020

Activation of adenosine A receptor induced interleukin-23 mRNA expression in macrophages of ankylosing spondylitis patients.

Cytokine 2020 04 21;128:154997. Epub 2020 Jan 21.

Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran; Inflammation Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Background: Ankylosing spondylitis (AS) is an auto-inflammatory debilitating disorder with a complex pathogenesis. The adenosinergic pathway is an immunologic regulating pathway with a potential role in AS pathophysiology. In the present study, we have aimed to investigate the influence of A adenosine receptor (AAR) activation on tumor necrosis factor-α (TNF-α) and interleukin-23 (IL-23) expression and secretion by monocyte-generated macrophages of AS patients.

Methods: Whole-blood separated monocytes were extracted from 14 AS patients and 14 healthy controls. Macrophages were differentiated by macrophage colony-stimulating factor (M-CSF), and surface markers were confirmed by flow cytometer. Cells were treated with CGS-21680 as a known agonist of AAR. Analysis of ADORA2A, TNFA, and IL23A gene expression was performed by SYBR green real-time PCR. The concentration of secreted cytokines was also measured by ELISA kits.

Results: Based on our analysis, CGS-21680 significantly decreased TNF-α secretion by monocyte-derived macrophages of AS patients. Moreover, AAR agonist increased the IL23A mRNA expression level in monocyte-derived macrophages of AS patients considerably. Whereas, CGS-21680 did not have any influence on macrophages of healthy individuals.

Conclusion: According to our results, it appears that AAR activation can increase IL-23 secretion by monocyte-derived macrophages of AS patients. Although the TNF-α reducing effect of AAR agonists can be a potential target in AS treatment, robust increasing of IL-23 should be considered as the undesirable effect of these agents.
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http://dx.doi.org/10.1016/j.cyto.2020.154997DOI Listing
April 2020

P2 receptors mRNA expression profiles in macrophages from ankylosing spondylitis patients and healthy individuals.

Int J Rheum Dis 2020 Mar 29;23(3):350-357. Epub 2019 Dec 29.

Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Background: Ankylosing spondylitis (AS) is a multifactorial rheumatic disease which mainly involves the axial skeleton. Macrophages and extracellular nucleotides have been shown to contribute to the inflammation process in autoimmune diseases. Membrane-bound purinergic P2 receptors might be involved in the modulation of immune cells in AS. Therefore, we aimed to analyze the messenger RNA (mRNA) expression of P2 receptors in the macrophages of AS patients and healthy controls.

Methods: Twenty-three AS patients and 23 age- and sex-matched healthy individuals were included in our study. Whole blood-separated monocytes of study participants were stimulated by macrophage colony-stimulating factor for 7 days and differentiated to macrophages. Monocyte and macrophage markers were analyzed by flow cytometry. SYBR green real-time polymerase chain reaction was used to measure the relative expression levels of P2RX , P2RX , P2RX , P2RX , P2RX , P2RX , P2RX , P2RY , P2RY , P2RY , P2RY , P2RY , P2RY , P2RY , P2RY , and PANX1 genes.

Results: P2RY and P2RY genes had the highest expression levels in macrophages among P2RY genes. P2RY mRNA expression was significantly down-regulated (-1.75 fold) and P2RY was up-regulated (2.6 fold) in macrophages of AS patients compared to healthy individuals. P2RX gene had the highest expression in monocyte-derived macrophages, followed by P2RX and P2RX genes. There was no significant difference in P2X receptor mRNA expression level between macrophages of AS patients and healthy individuals.

Conclusions: Our results indicate that AS patients show altered expression levels of P2 receptor genes. Moreover, these changes might be associated with disease activity and patients' status.
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http://dx.doi.org/10.1111/1756-185X.13783DOI Listing
March 2020

Association study of copy number variation in BMP8A gene with the risk of ankylosing spondylitis in Iranian population.

J Cell Biochem 2018 Nov 28. Epub 2018 Nov 28.

Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Background: Copy number variation (CNV) of DNA segments has been considered as an important component of genetic variation, affecting the quality and quantity of gene expression. Bone morphogenic protein 8A (BMP8A) has been reported to function in bone formation. With respect to the bone and joint complications in ankylosing spondylitis (AS), this investigation aimed to study the role of BMP8A gene CNV in impressing the gene expression as well as the disease risk.

Methods: A total of 900 individuals, including 450 patients with AS and 450 healthy controls were enrolled. The copy numbers of BMP8A gene were detected by TaqMan real-time polymerase chain reaction (PCR) method. BMP8A messenger RNA (mRNA) transcript level in peripheral blood mononuclear cells (PBMCs) was also measured by SYBR Green real-time gene expression PCR method.

Results: No significant association of BMP8A copy number was detected with the risk of AS. BMP8A mRNA expression level was significantly downregulated in patients compared with controls. mRNA expression level of BMP8A in both AS patients with and without syndesmophyte was significantly lower than the healthy control group. There was no correlation between the mRNA expression level of BMP8A and both demographic and clinical data of the patients.

Conclusions: Although BMP8A gene expression was downregulated in patients with AS, its copy number could not affect the transcript level of BMP8A gene in PBMCs and was not associated with susceptibility to AS in Iranian population. BMP8a may take into account as an indicator of bone formation process in AS, but it seems that mechanisms other than CNV may regulate this protein.
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http://dx.doi.org/10.1002/jcb.28120DOI Listing
November 2018

Increased inflammatory responsiveness of peripheral blood mononuclear cells (PBMCs) to NOD2 ligand stimulation in patients with ankylosing spondylitis.

Immunopharmacol Immunotoxicol 2018 Oct 28;40(5):393-400. Epub 2018 Sep 28.

b Rheumatology Research Center, Tehran University of Medical Sciences , Tehran , Iran.

Ankylosing spondylitis (AS) is a common debilitating rheumatic disease in which the innate immune components especially the Interleukin (IL)-23/IL-17 axis related genes play important role in its pathogenesis. Nucleotide binding oligomerization domain-containing protein (NOD)2, as an innate receptor, is critical for IL-23 production in cells. Therefore, we aimed to stimulate NOD2 signaling and study its effects on cytokine production in peripheral blood mononuclear cells (PBMC) of these patients. PBMCs from 18 patients with active AS and 18 healthy individuals were separated by Ficoll-Hypaque density gradient centrifugation and cultured in the presence of muramyl dipeptide (MDP), as NOD2 ligand. Quantitative expression analysis of , , , , , , , , and genes was performed using Real-time polymerase chain reaction (PCR). Finally, protein changes of and expression were validated using enzyme linked immunosorbent assay (ELISA). Apart from that tend to be downregulated in the controls, all the selected genes showed overexpression in response to MDP in cells from the studied groups. Except , all the genes had higher expression changes upon MDP stimulation in the AS population. Overexpression of and were confirmed at protein levels using ELISA. The strong positive correlation between and was decreased after stimulation but new correlations between and , and were observed after treatment. This study indicated that AS PBMCs were hyper-responsive to MDP stimulation. This observation implies an important role of NOD2 in the pathogenesis of inflammatory diseases including AS.
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http://dx.doi.org/10.1080/08923973.2018.1510963DOI Listing
October 2018

Curcumin reduces the expression of interleukin 1β and the production of interleukin 6 and tumor necrosis factor alpha by M1 macrophages from patients with Behcet's disease.

Immunopharmacol Immunotoxicol 2018 Aug 28;40(4):297-302. Epub 2018 May 28.

a Rheumatology Research Center , Tehran University of Medical Sciences , Tehran , Iran.

Objective: Behcet's disease (BD) is an auto-inflammatory disorder. Curcumin as a bio-active agent has anti-inflammatory properties. Effects of curcumin on the pathogenesis of BD are still not clear. In this study, we investigated the effect of curcumin on the inflammatory cytokines expression and production in M1 macrophages from BD patients compared with healthy controls.

Methods: Monocytes were collected from 10 healthy controls and 20 active BD patients, differentiated to macrophages by macrophage-colony stimulating factor for 7 d. Macrophages were then treated with interferon gamma, lipopolysaccharide, and curcumin (10 or 30 µg/ml) for 24 h. Analysis of tumor necrosis factor-alpha (TNFα), interleukin 1β (IL-1β), and IL-6 mRNA expression and protein production was performed using SYBR Green qPCR and ELISA method.

Results: Treatment with 30 µg/ml curcumin significantly down-regulated mRNA expression of IL-1β (p < .05) and protein production of IL-6 (p < .05) in M1 macrophages from BD patients but not in M1 macrophage from controls. Treatment with 30 µg/ml curcumin also significantly diminishes the protein production of TNFα in BD patients (p < .01) and healthy controls (p < .05) M1 macrophages.

Conclusions: We demonstrated that curcumin can inhibit the expression and production of inflammatory cytokines in M1 macrophages from BD patients. Our results suggest that curcumin can modulate inflammatory signaling more specifically in macrophages from BD patients than healthy macrophages.
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http://dx.doi.org/10.1080/08923973.2018.1474921DOI Listing
August 2018

Ankylosing spondylitis monocyte-derived macrophages express increased level of A adenosine receptor and decreased level of ectonucleoside triphosphate diphosphohydrolase-1 (CD39), A and A adenosine receptors.

Clin Rheumatol 2018 Jun 9;37(6):1589-1595. Epub 2018 Mar 9.

Rheumatology Research Center, Shariati Hospital, Tehran University of Medical Sciences, Kargar Ave., P.O. Box: 1411713137, Tehran, Iran.

Macrophages play an important role in the ankylosing spondylitis (AS) auto-inflammatory responses and fibrocartilage destruction. Adenosine is a key modulator of inflammatory conditions. The various effects of adenosine are mediated by its interaction with adenosine receptors (AR). In this study, we investigated the mRNA expression of A, A, A, and A adenosine receptors, ectonucleoside triphosphate diphosphohydrolase-1 (CD39), and ecto-5'-nucleotidase (CD73) in the monocyte-derived macrophages from AS patients in comparison to healthy controls. We also explored the correlation between analyzed gene expression and patients' clinical manifestations. Whole blood-separated monocytes from 23 healthy controls and 23 active AS patients were stimulated by macrophage colony-stimulating factor (M-CSF) for 7 days and differentiated to macrophages. Monocyte and macrophage markers were analyzed by flow cytometry. Analysis of adenosine receptors (ADORA1، ADORA2A، ADORA2B، ADORA3), CD39 and CD73 gene expression was performed by SYBR green real-time PCR. Our results demonstrated monocyte-derived macrophages from AS patients expressed increased level of AAR and reduced level of A, AAR, and CD39 mRNA compared to healthy controls. We found an inverse correlation between AAR mRNA expression and Bath Ankylosing Spondylitis Functional Index (BASFI) score in AS patients. According to our results, altered expression level of adenosine-relying system would be involved in AS macrophage dysfunction and inflammation and correlated with functional status in AS patients.
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http://dx.doi.org/10.1007/s10067-018-4055-9DOI Listing
June 2018

Macrophages from Behcet's Disease Patients Express Decreased Level of Aryl Hydrocarbon Receptor (AHR) mRNA.

Iran J Allergy Asthma Immunol 2017 Oct;16(5):418-424

Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, connecting environmental stimulators with the immune system. M1 macrophages are a part of immune system that contribute to the inflammatory events in the pathogenesis of Behcet's disease (BD). The effect of AHR on the macrophages in BD patients is still unclear. In this study, we investigated the mRNA expression of AHR in the monocyte-derived and M1 macrophages in active BD patients in comparison to healthy controls. Isolated monocytes from 10 healthy controls and 10 active BD patients were differentiated to macrophages by macrophage-colony stimulating factor (M-CSF) for 7 days. Cells were then polarized to M1 macrophages by lipopolysaccharide (LPS) and interferon-γ (IFNγ) for 24h. Monocyte purity and macrophage markers expression were analyzed by flow cytometry. Analysis of AHR mRNA expression was performed by SYBR Green real-time PCR. Our results showed that AHR expression is significantly down-regulated in M1 macrophages compare to monocyte-derived macrophages. It was shown that both monocyte-derived macrophages and M1 macrophages from BD patients significantly express lower level of AHR mRNA compared to healthy individuals. Our results demonstrate an anti-inflammatory role for AHR in macrophages, which suggest that decreased AHR expression is associated with pro-inflammatory M1 macrophage and BD susceptibility.
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October 2017

Association of Killer Cell Immunoglobulin- Like Receptor Genes in Iranian Patients with Rheumatoid Arthritis.

PLoS One 2015 11;10(12):e0143757. Epub 2015 Dec 11.

Immunology Department, Shahid Sadoughi University of Medical Sciences (International Campus), Yazd, Iran.

Objectives: Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by persistent synovitis, ultimately leading to cartilage and bone degeneration. Natural Killer cells and CD28 null T-cells are suspected as role players in RA pathogenesis. These cells are similar in feature and function, as they both exert their cytotoxic effect via Killer Cell Immunoglobulin- Like Receptors (KIR) on their surface. KIR genes have either an inhibitory or activating effect depending on their intracytoplasmic structure. Herein we genotyped 16 KIR genes, 3 pseudo genes and 6 HLA class І genes as their corresponding ligands in RA patients and control subjects.

Methods: In this case-control study, KIR and HLA genes were genotyped in 400 RA patients and 372 matched healthy controls using sequence-specific primers (SSP-PCR). Differences in the frequency of genes and haplotypes were determined by χ² test.

Results: KIR2DL2, 2DL5a, 2DL5b and activating KIR: KIR2DS5 and 3DS1 were all protective against RA. KIR2DL5 removal from a full Inhibitory KIR haplotype converted the mild protection (OR = 0.56) to a powerful predisposition to RA (OR = 16.47). Inhibitory haplotype No. 7 comprising KIR2DL5 in the absence of KIR2DL1 and KIR2DL3 confers a 14-fold protective effect against RA.

Conclusion: Individuals carrying the inhibitory KIR haplotype No. 6 have a high potential risk for developing RA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143757PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687638PMC
June 2016