Publications by authors named "Jafar Karami"

20 Publications

  • Page 1 of 1

Immune and metabolic checkpoints blockade: Dual wielding against tumors.

Int Immunopharmacol 2021 May 13;94:107461. Epub 2021 Feb 13.

Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran. Electronic address:

Recent advances in cancer immunotherapy have raised hopes for treating cancers that are resistant to conventional therapies. Among the various immunotherapy methods, the immune checkpoint (IC) blockers were more promising and have paved their way to the clinic. Tumor cells induce the expression of ICs on the immune cells and derive them to a hyporesponsive exhausted phenotype. IC blockers could hinder immune exhaustion in the tumor microenvironment and reinvigorate immune cells for an efficient antitumor response. Despite the primary success of IC blockers in the clinic, the growing numbers of refractory cases require an in-depth study of the cellular and molecular mechanisms underlying IC expression and function. Immunometabolism is recently found to be a key factor in the regulation of immune responses. Activated or exhausted immune cells exploit different metabolic pathways. Tumor cells can suppress antitumor responses via immunometabolism alteration. Therefore, it is expected that concurrent targeting of ICs and immunometabolism pathways can cause immune cells to restore their antitumor activity. In this review, we dissected the reciprocal interactions of immune cell metabolism with expression and signaling of ICs in the tumor microenvironment. Recent findings on dual targeting of ICs and metabolic checkpoints have also been discussed.
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http://dx.doi.org/10.1016/j.intimp.2021.107461DOI Listing
May 2021

Transformation of fibroblast-like synoviocytes in rheumatoid arthritis; from a friend to foe.

Auto Immun Highlights 2021 Feb 5;12(1). Epub 2021 Feb 5.

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

Swelling and the progressive destruction of articular cartilage are major characteristics of rheumatoid arthritis (RA), a systemic autoimmune disease that directly affects the synovial joints and often causes severe disability in the affected positions. Recent studies have shown that type B synoviocytes, which are also called fibroblast-like synoviocytes (FLSs), as the most commonly and chiefly resident cells, play a crucial role in early-onset and disease progression by producing various mediators. During the pathogenesis of RA, the FLSs' phenotype is altered, and represent invasive behavior similar to that observed in tumor conditions. Modified and stressful microenvironment by FLSs leads to the recruitment of other immune cells and, eventually, pannus formation. The origins of this cancerous phenotype stem fundamentally from the significant metabolic changes in glucose, lipids, and oxygen metabolism pathways. Moreover, the genetic abnormalities and epigenetic alterations have recently been implicated in cancer-like behaviors of RA FLSs. In this review, we will focus on the mechanisms underlying the transformation of FLSs to a cancer-like phenotype during RA. A comprehensive understanding of these mechanisms may lead to devising more effective and targeted treatment strategies.
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http://dx.doi.org/10.1186/s13317-020-00145-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863458PMC
February 2021

Systematic review and meta-analytic findings on the association between killer-cell immunoglobulin-like receptor genes and susceptibility to pulmonary tuberculosis.

Pathog Glob Health 2021 Feb 1;115(1):61-69. Epub 2020 Dec 1.

Department of Health Education and Health Promotion, Faculty of Health, Tabriz University of Medical Sciences , Tabriz, Iran.

Several studies have evaluated the association between killer-cell immunoglobulin-like receptors (KIR) genes and susceptibility risk to tuberculosis (TB) infection. Nonetheless, their outcomes have not been conclusive and consistent. Here we implemented a systematic review and meta-analysis of KIR genes association to susceptibility risk of pulmonary TB (PTB) infection to attain a clear understanding of the involvement of these genes in susceptibility to PTB infection. A systematic search was conducted in the MEDLINE/PubMed and Scopus databases to find case-control studies published before November 2020. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated to determine the association between KIR genes and risk of PTB infection. After comprehensive searching and implementing the inclusion and exclusion criteria, 10 case-control studies were included in the meta-analysis. Four KIR genes were found to have significant positive association with PTB susceptibility risk of infection, including (OR = 1.454, 95% CI = 1.157-1.827; = 0.001), (OR = 1.481, 95% CI = 1.334-1.837; < 0.001), (OR = 1.782, 95% CI = 1.273-2.495; = 0.001) and (OR = 1.726, 95% CI = 1.277-2.333; < 0.001). However, the results showed that the remaining KIR genes () and two pseudogenes ( and ) did not have significant associations with risk of PTB infection. This meta-analysis provides reliable evidence that the KIR genes , and may be associated with an increased risk of PTB infection.
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http://dx.doi.org/10.1080/20477724.2020.1848271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850413PMC
February 2021

Destructive Roles of Fibroblast-like Synoviocytes in Chronic Inflammation and Joint Damage in Rheumatoid Arthritis.

Inflammation 2021 Apr 28;44(2):466-479. Epub 2020 Oct 28.

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

Fibroblast-like synoviocytes (FLSs) are important non-immune cells located mostly in the inner layer of the synovium. Indeed, these cells are specialized mesenchymal cells, implicated in collagen homeostasis of the articular joint and provide extracellular matrix (ECM) materials for cartilage and contribute to joint destruction via multiple mechanisms. RA FLS interactions with immune and non-immune cells lead to the development and organization of tertiary structures such as ectopic lymphoid-like structures (ELSs), tertiary lymphoid organs (TLOs), and secretion of proinflammatory cytokines. The interaction of RA FLS cells with immune and non-immune cells leads to stimulation and activation of effector immune cells. Pathological role of RA FLS cells has been reported for many years, while molecular and cellular mechanisms are not completely understood yet. In this review, we tried to summarize the latest findings about the role of FLS cells in ELS formation, joint destruction, interactions with immune and non-immune cells, as well as potential therapeutic options in rheumatoid arthritis (RA) treatment. Our study revealed data about interactions between RA FLS and immune/non-immune cells as well as the role of RA FLS cells in joint damage, ELS formation, and neoangiogenesis, which provide useful information for developing new approaches for RA treatment.
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http://dx.doi.org/10.1007/s10753-020-01371-1DOI Listing
April 2021

Role of glucose metabolism in aggressive phenotype of fibroblast-like synoviocytes: Latest evidence and therapeutic approaches in rheumatoid arthritis.

Int Immunopharmacol 2020 Dec 8;89(Pt A):107064. Epub 2020 Oct 8.

Department of Laboratory Sciences, Khomein University of Medical Sciences, Khomein, Iran; Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. Electronic address:

Glucose metabolism is considerably increased in inflamed joints of rheumatoid arthritis (RA) patients at early stages. Fibroblast-like synoviocytes (FLSs) activation and subsequent joint damage are linked with metabolic alterations, especially glucose metabolism. It has been shown that glucose metabolism is elevated in aggressive phenotype of FLS cells. In this regard, glycolytic blockers are able to reduce aggressiveness of the FLS cells resulting in decreased joint damage in various arthritis models. Besides, metabolic changes in immune and non-immune cells such as FLS can provide important targets for therapeutic intervention. Glycolytic enzymes such as hexokinase 2 (HK2), phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB), and phosphoglycerate kinase (PGK) play essential roles in aggressive behavior of FLS cells. It has been documented that the HK2 enzyme is significantly upregulated in RA FLS cells, compared with osteoarthritis (OA) FLS cells. The HK2 is expressed in a few tissues and upregulated in the inflamed synovium of RA patients that makes it a potential target for RA treatment. Furthermore, HK2 has different roles in each cellular compartment, which offers another level of specificity and provides a specific target to reduce deleterious effects of inhibiting the enzyme in RA without affecting glycolysis in normal cells. Thus, targeting the HK2 enzyme might be an attractive potential selective target for arthritis therapy and safer than global glycolysis inhibition. Therefore, this review was aimed to summarize the current knowledge about glucose metabolism of FLS cells and suggest novel biomarkers, which are potential candidates for RA treatment.
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http://dx.doi.org/10.1016/j.intimp.2020.107064DOI Listing
December 2020

Analysis of Killer Cell Immunoglobulin-Like Receptor Genes and Their HLA Ligands in Inflammatory Bowel Diseases.

J Immunol Res 2020 19;2020:4873648. Epub 2020 Sep 19.

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

Genetic studies have illustrated that () genes could participate in various autoimmune disorders. We aimed to clarify the role of genes, ligands, HLA-KIR interactions, and their genotypes in inflammatory bowel disease (IBD) susceptibility. The study population was composed of 183 IBD subjects, comprising 100 ulcerative colitis (UC) patients, 83 Crohn's disease (CD) patients, and 274 healthy subjects. Polymerase chain reaction with sequence-specific primers (PCR-SSP) was used to evaluate the absence or presence of the 15 genes, 5 class I ligands, and 2 pseudogenes. We did not find any significant difference in allele frequency of and pseudogenes between IBD patients and healthy controls. In the case of genes, there was a significant difference in frequency between UC patients and healthy controls ( = 0.03, OR = 0.06, 95%CI = 0.008-0.4). Furthermore, we found a significant difference in frequency between CD patients and healthy controls ( = 0.04, OR = 0.49, 95% CI = 0.3-0.8). In the full-array combination of genes, there was no significant frequency difference between UC patients and healthy controls, while two KIR genotypes showed a significant susceptible association with CD. Our data do not support a strong role of NK cells in IBD susceptibility, but it does not rule out a role for KIR variability in IBD patients. However, there are some protective associations such as Bw4 alleles; these associations may be due to the interaction of the alleles to TCRs rather than KIRs.
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http://dx.doi.org/10.1155/2020/4873648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520679PMC
September 2020

Role of autophagy in the pathogenesis of rheumatoid arthritis: Latest evidence and therapeutic approaches.

Life Sci 2020 Aug 5;254:117734. Epub 2020 May 5.

Halal Research Center of IRI, FDA, Tehran, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Autophagy is considered as an important intracellular mechanism that degrades cytoplasmic components to furnish additional energy. It has cytoprotective effects through the degradation of intracellular pathogens, damaged organelles, and protein aggregates. On the other hand, there are reports of an association between autophagy and autoimmune diseases. Indeed, it has been evident that autophagy is dysregulated in various autoimmune diseases including rheumatoid arthritis (RA). Autophagy is implicated in the maturation survival and proliferation of various immune and non-immune cells, which play pivotal roles in RA pathogenesis. Additionally, autophagy seems to be involved in citrullination and presentation of citrullinated peptides to T lymphocyte cells. Presentation of citrullinated peptides through MHC compartments to the T cells leads to immune response and chronic inflammation. Evidence suggests that autophagy could be implicated in apoptosis resistance of RA fibroblast-like synoviocyte (RA FLS), osteoclastogenesis, and finally severe bone and cartilage destruction. Since autophagy could be an important phenomenon in RA pathogenesis, we summarized the roles of autophagy in citrullination, osteoclastogenesis, RA FLS cells survival, apoptosis resistance of cells, lymphocyte homeostasis and its clinical outcomes in RA disease.
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http://dx.doi.org/10.1016/j.lfs.2020.117734DOI Listing
August 2020

Breast cancer: Biology, biomarkers, and treatments.

Int Immunopharmacol 2020 Jul 29;84:106535. Epub 2020 Apr 29.

Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran. Electronic address:

During the past recent years, various therapies emerged in the era of breast cancer. Breast cancer is a heterogeneous disease in which genetic and environmental factors are involved. Breast cancer stem cells (BCSCs) are the main player in the aggressiveness of different tumors and also, these cells are the main challenge in cancer treatment. Moreover, the major obstacle to achieve an effective treatment is resistance to therapies. There are various types of treatment for breast cancer (BC) patients. Therefore, in this review, we present the current treatments, novel approaches such as antibody-drug conjugation systems (ADCs), nanoparticles (albumin-, metal-, lipid-, polymer-, micelle-based nanoparticles), and BCSCs-based therapies. Furthermore, prognostic and predictive biomarkers will be discussed also biomarkers that have been applied by some tests such as Oncotype DX, Mamm αPrint, and uPA/PAI-1 are regarded as suitable prognostic and predictive factors in breast cancer.
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http://dx.doi.org/10.1016/j.intimp.2020.106535DOI Listing
July 2020

Epigenetics in rheumatoid arthritis; fibroblast-like synoviocytes as an emerging paradigm in the pathogenesis of the disease.

Immunol Cell Biol 2020 03 26;98(3):171-186. Epub 2020 Jan 26.

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

Rheumatoid arthritis (RA) is characterized by immune dysfunctions and chronic inflammation that mainly affects diarthrodial joints. Genetics has long been surveyed in searching for the etiopathogenesis of the disease and partially clarified the conundrums within this context. Epigenetic alterations, such as DNA methylation, histone modifications, and noncoding RNAs, which have been considered to be involved in RA pathogenesis, likely explain the nongenetic risk factors. Epigenetic modifications may influence RA through fibroblast-like synoviocytes (FLSs). It has been shown that FLSs play an essential role in the onset and exacerbation of RA, and therefore, they may illustrate some aspects of RA pathogenesis. These cells exhibit a unique DNA methylation profile in the early stage of the disease that changes with disease progression. Histone acetylation profile in RA FLSs is disrupted through the imbalance of histone acetyltransferases and histone deacetylase activity. Furthermore, dysregulation of microRNAs (miRNAs) is immense. Most of these miRNAs have shown an aberrant expression in FLSs that are involved in proliferation and cytokine production. Besides, dysregulation of long noncoding RNAs in FLSs has been revealed and attributed to RA pathogenesis. Further investigations are needed to get a better view of epigenetic alterations and their interactions. We also discuss the role of these epigenetic alterations in RA pathogenesis and their therapeutic potential.
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http://dx.doi.org/10.1111/imcb.12311DOI Listing
March 2020

Cancer stem cells: A review from origin to therapeutic implications.

J Cell Physiol 2020 02 8;235(2):790-803. Epub 2019 Jul 8.

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

Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are elucidated as cells that can perpetuate themselves via autorestoration. These cells are highly resistant to current therapeutic approaches and are the main reason for cancer recurrence. Radiotherapy has made a lot of contributions to cancer treatment. However, despite continuous achievements, therapy resistance and tumor recurrence are still prevalent in most patients. This resistance might be partly related to the existence of CSCs. In the present study, recent advances in the investigation of different biological properties of CSCs, such as their origin, markers, characteristics, and targeting have been reviewed. We have also focused our discussion on radioresistance and adaptive responses of CSCs and their related extrinsic and intrinsic influential factors. In summary, we suggest CSCs as the prime therapeutic target for cancer treatment.
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http://dx.doi.org/10.1002/jcp.29044DOI Listing
February 2020

Genetic implications in the pathogenesis of rheumatoid arthritis; an updated review.

Gene 2019 Jun 20;702:8-16. Epub 2019 Mar 20.

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

Three important factors, including genetics, environment factors and autoimmunity play a role in the pathogenesis of rheumatoid arthritis (RA). The heritability of RA has been accounted to be 50-60%, while the HLA involvement in heritability of the disease has been accounted to be 10-40%. It has been documented that shared epitope (SE) alleles, such as HLA-DRB1*01 and DRB1*04, some HLA alleles like HLA-DRB1*13 and DRB1*15 are connected to RA susceptibility. An advanced classification of SE categorizes SE alleles into four main groups namely, S1, S2, S3D, and S3P. The S2 and S3P groups have been linked to susceptibility of seropositive RA. Various genome-wide association studies (GWAS) have discovered many susceptibility loci implicated in pathogenesis of RA. Some of the important single nucleotide polymorphisms (SNPs) linked to RA are TRAF1, STAT4, CTLA4, IRF5, CCR6, PTPN22, IL23R, and PADI4. HLA and non-HLA genes may discriminate anti-cyclic citrullinated peptide (anti-CCP) antibody-positive and anti-CCP-negative RA groups. Furthermore, risk of the disease has also been linked to environmental agents, mainly cigarette smoking. Pharmacogenomics has also confirmed SNPs or genetic patterns that might be linked to drugs responses. Different aspects of genetic involvement in the pathogenesis, etiology, and RA complications are reviewed in this article.
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http://dx.doi.org/10.1016/j.gene.2019.03.033DOI Listing
June 2019

Atherosclerosis and autoimmunity: a growing relationship.

Int J Rheum Dis 2018 May 19;21(5):908-921. Epub 2018 Apr 19.

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

Atherosclerosis is regarded as one of the leading causes of mortality and morbidity in the world. Nowadays, it seems that atherosclerosis cannot be defined merely through the Framingham traditional risk factors and that autoimmunity settings exert a remarkable role in its mechanobiology. Individuals with autoimmune disorders show enhanced occurrence of cardiovascular complications and subclinical atherosclerosis. The mechanisms underlying the atherosclerosis in disorders like rheumatoid arthritis, systemic lupus erythematosus, antiphospholipid syndrome, systemic sclerosis and Sjögren's syndrome, seem to be the classical risk factors. However, chronic inflammatory processes and abnormal immune function may also be involved in atherosclerosis development. Autoantigens, autoantibodies, infectious agents and pro-inflammatory mediators exert a role in that process. Being armed with the mechanisms underlying autoimmunity in the etiopathogenesis of atherosclerosis in rheumatic autoimmune disorders and the shared etiologic pathway may result in substantial developing therapeutics for these patients.
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http://dx.doi.org/10.1111/1756-185X.13309DOI Listing
May 2018

Epigenetic involvement in etiopathogenesis and implications in treatment of systemic lupus erythematous.

Inflamm Res 2017 Dec 24;66(12):1057-1073. Epub 2017 Jul 24.

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

Background: Recent researches in the field of genetics have extended our knowledge through the discovery of genetic factors associated with autoimmune diseases (AID). Genetics by itself, however, cannot elucidate all the uncertainties encountered in the etiopathology of AID. On the other hand, incomplete harmony in the prevalence of AID in identical twins suggests that non-genetic factors may play an important role in determining the disease susceptibility. Besides, epigenetics, which is defined by changes in gene expression without a corresponding change in the DNA sequences, has come in to provide new awareness in the disease etiopathology by bridging the genetic and epigenetic factors. The recent advances in the field of epigenetics provide a new insight into the understanding of the disease mechanisms, development, diagnostic and prognostic approaches, as well as the various treatment methods.

Purpose: This review paper aims to present an overview of epigenetic modifications involved in the pathogenesis of systemic lupus erythematosus (SLE) and discuss their important roles in clinical and pharmacological settings, including novel and recent therapeutic applications.

Results: Nowadays, it is believed that autoimmune diseases, such as SLE, begin when genetically susceptible factors associate with environmental triggers. The current therapeutic approaches for SLE treatment have been based on treatments with immunosuppressive drugs, which are linked to various side effects. It is difficult to develop highly effective treatments for SLE patients with minimal or no side effects, mainly due to the disease complexity. The breakthrough of pharmacoepigenetics provides a new approach to solve this problem. Epigenetic modifications can influence the efficacy of drugs by changing the gene expression through modifying chromatin remodeling. In this regard, epigenetic studies in SLE are expected to reveal novel disease biomarkers and therapeutic targets.

Conclusions: Accumulating evidence disclosed that epigenetic dysregulations are engaged in SLE pathogenesis and may be exerted as biomarkers to diagnose and as tools to treat these patients.
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http://dx.doi.org/10.1007/s00011-017-1082-yDOI Listing
December 2017

Evaluation of DNMT1 gene expression profile and methylation of its promoter region in patients with ankylosing spondylitis.

Clin Rheumatol 2016 Nov 16;35(11):2723-2731. Epub 2016 Sep 16.

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

Ankylosing spondylitis (AS) is an autoimmune disease with a chronic inflammatory arthritis. The critical role of methylation in the biology of immunocytes has increasingly been surveyed to discover disease etiology. DNA methyltransferase 1 (DNMT1) is an enzyme, which establishes and regulates patterns of methylated cytosine residues. The aim of the current investigation was to unveil if methylation circumstances of CpG sites in DNMT1 promoter could affect the mRNA expression level of this gene in peripheral blood mononuclear cells (PBMCs) from AS patients. PBMCs were isolated from whole blood of 40 AS patients and 40 healthy individuals. Total RNA and DNA contents of leukocytes were extracted. Afterward, quantitative analysis was carried out by real-time PCR using the SYBR Green PCR Master Mix. Finally, to determine the methylation level, PCR products of bisulfite-treated DNA from patients and controls were sequenced. Compared with healthy controls, expression level of DNMT1 in AS patients was significantly downregulated. Methylation of DNMT1 promoter was significantly higher in AS patients in comparison to controls. While a negative correlation between methylation and expression level of DNMT1 was observed in AS patients, both methylation and expression level of DNMT1 did not correlate with clinical manifestations. Considering the observation that decreased expression level of DNMT1 was associated with hypermethylation of DNMT1 promoter in PBMCs from AS patients, this survey suggests that dysregulation of DNMT1 expression through altered methylation level of other target genes would probably contribute to AS development.
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http://dx.doi.org/10.1007/s10067-016-3403-xDOI Listing
November 2016

New insights toward the pathogenesis of ankylosing spondylitis; genetic variations and epigenetic modifications.

Mod Rheumatol 2017 Mar 18;27(2):198-209. Epub 2016 Jul 18.

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

Ankylosing spondylitis (AS) is a chronic inflammatory autoimmune disease, characterized by typically an axial arthritis. AS is the prototype of a group of disorders called spondyloarthropathies, which is believed to have common clinical manifestations and genetic predisposition. To date, the exact etiology of AS remains unclear. Over the past few years, however, the role of genetic susceptibility and epigenetic modifications caused through environmental factors have been extensively surveyed with respect to the pathogenesis of AS, resulted in important advances. This review article focuses on the recent advances in the field of AS research, including HLA and non-HLA susceptibility genes identified in genome-wide association studies (GWAS), and aberrant epigenetic modifications of gene loci associated with AS. HLA genes most significantly linked with AS susceptibility include HLA-B27 and its subtypes. Numerous non-HLA genes such as those in ubiquitination, aminopeptidases and MHC class I presentation molecules like ERAP-1 were also reported. Moreover, epigenetic modifications occurred in AS has been summarized. Taken together, the findings presented in this review attempt to explain the circumstance by which both genetic variations and epigenetic modifications are involved in triggering and development of AS. Nonetheless, several unanswered dark sides continue to clog our exhaustive understanding of AS. Future researches in the field of epigenetics should be carried out to extend our vision of AS etiopathogenesis.
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http://dx.doi.org/10.1080/14397595.2016.1206174DOI Listing
March 2017

Epigenetic Modifications and Therapy in Multiple Sclerosis.

Neuromolecular Med 2017 Mar 6;19(1):11-23. Epub 2016 Jul 6.

Department of Pharmacology, School of Medicine, Ardabil University of Medical Science, Ardabil, Iran.

Breakthroughs in genetic studies, like whole human genome sequencing and genome-wide association studies (GWAS), have richened our knowledge of etiopathology of autoimmune diseases (AID) through discovery of genetic patterns. Nonetheless, the precise etiology of autoimmune diseases remains largely unknown. The lack of complete concordance of autoimmune disease in identical twins suggests that non-genetic factors also play a major role in determining disease susceptibility. Although there is no certain definition, epigenetics has been known as heritable alterations in gene function without changes in the nucleotide sequence. DNA methylation, histone modifications, and microRNA-associated gene expression suppression are the central mechanisms for epigenetic regulations. Multiple sclerosis (MS) is a disorder of the central nervous system (CNS), characterized by both inflammatory and neurodegenerative features. Although studies on epigenetic alterations in MS only began in the past decade, a mounting number of surveys suggest that epigenetic changes may be involved in the initiation and development of MS, probably through bridging the effects of environmental risk factors to genetics. Arming with clear understanding of epigenetic dysregulations underpins development of epigenetic therapies. Identifying agents inhibiting the enzymes controlling epigenetic modifications, particularly DNA methyltransferases and histone deacetylases, will be promising therapeutic tool toward MS. In the article underway, it is aimed to go through the recent progresses, attempting to disclose how epigenetics associates with the pathogenesis of MS and how can be used as therapeutic approach.
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http://dx.doi.org/10.1007/s12017-016-8422-xDOI Listing
March 2017

Analysis of Killer Cell Immunoglobulin-like Receptor Genes and Their HLA Ligands in Iranian Patients with Ankylosing Spondylitis.

Iran J Allergy Asthma Immunol 2016 Feb;15(1):27-38

Immunology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran AND Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Ankylosing Spondylitis (AS) is a chronic rheumatic disease which mainly involves the axial skeleton. It seems that non-HLA genes, as well as HLA-B27 gene, are linked to the etiology of the disease. Recently, it has been documented that KIRs and their HLA ligands are contributed to the Ankylosing Spondylitis. The aim of this study was to evaluate the KIR genes and their HLA ligands in Iranian AS patients and healthy individuals. The present study includes 200 AS patient samples and 200 healthy control samples. KIR genotyping was performed using the polymerase chain reaction sequence-specific primer (PCR-SSP) method to type the presence or absence of the 16 KIR genes, 6 known specific HLA class I ligands and also, two pseudogenes. Two KIR genes (KIR-2DL3 and KIR2DL5), and among the HLA ligands, two HLA ligands (HLA-C2Lys80 and HLA-B27) genes were significantly different between case and control groups. In addition, we found some interesting KIR/HLA compound genotypes, which were associated with AS susceptibility. Our results suggest that the AS patients present more activating and less inhibitory KIR genes with combination of their HLA ligands than healthy controls. Once the balance of signal transduction between activating and inhibitory receptors is disturbed, the ability of NK cells to identify and lyse the targets in immune responses will be compromised. Accordingly, imbalance of activating and inhibitory KIR genes by up-regulating the activation and losing the inhibition of KIRs signaling or combination of both might be one of the important factors which underlying the pathogenesis of AS.
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February 2016

Epigenetic alterations underlying autoimmune diseases.

Autoimmunity 2016 13;49(2):69-83. Epub 2016 Jan 13.

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

Recent breakthroughs in genetic explorations have extended our understanding through discovery of genetic patterns subjected to autoimmune diseases (AID). Genetics, on the contrary, has not answered all the conundrums to describe a comprehensive explanation of causal mechanisms of disease etiopathology with regard to the function of environment, sex, or aging. The other side of the coin, epigenetics which is defined by gene manifestation modification without DNA sequence alteration, reportedly has come in to provide new insights towards disease apprehension through bridging the genetics and environmental factors. New investigations in genetic and environmental contributing factors for autoimmunity provide new explanation whereby the interactions between genetic elements and epigenetic modifications signed by environmental agents may be responsible for autoimmune disease initiation and perpetuation. It is aimed through this article to review recent progress attempting to reveal how epigenetics associates with the pathogenesis of autoimmune diseases.
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http://dx.doi.org/10.3109/08916934.2015.1134511DOI Listing
December 2016

Methyl-CpG-Binding Protein 2 (MECP2) Polymorphism in Iranian Patients with Systemic Lupus Erythematosus.

Inflammation 2015 Dec;38(6):2185-90

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

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which involves many organs and presents with various symptoms. It has been shown that genetic and environmental factors play a major role in this disease and may affect the onset, activity, damage, and mortality of the disease. According to recent studies, methyl-CpG-binding protein 2 (MECP2) has been associated with SLE in various populations. Herein, we studied MECP2 polymorphism in Iranian lupus patients and controls. The study included a total of 884 samples of Iranian ancestry (492 independent SLE patients and 392 unrelated healthy controls). Healthy controls were gender-, ethnic-, and age-matched with the patients. Patient and control samples were genotyped for rs1734787, rs1734791, rs1734792, and rs17435 by applying the Allelic Discrimination Real-Time PCR System. Our results showed a significant association between rs1734787 and rs1734791 SNPs and the risk of SLE in the Iranian population (p = 0.028, p = 0.028), but did not show any significant association with rs1734792 and rs17435 SNPs (p = 075, p = 0.75). The rs1734787 C and the rs1734791 T allele frequencies in the patients were significantly higher than the control group (p = 0.014, p = 0.012). In addition, a significant CTAT haplotype frequency was observed in cases with SLE (p = 0.012), and a significant AAAT haplotype frequency was observed in the control group (p = 0.0003). However, there was no significant association between genotype frequencies and SLE patients. Also, there was no significant association between these SNPs and clinical features. The result of this study suggests that polymorphism in the MECP2 locus is associated with the susceptibility of Iranian SLE patients.
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http://dx.doi.org/10.1007/s10753-015-0201-6DOI Listing
December 2015