Tehran University of Medical Sciences Immunology and Genetics Journal 2645-4831 8 2 2025 03 04 124 149 Saba Tarkashvand Sina Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran; School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran; Universal Scientific Education and Research Network (USERN), Tehran, Iran Sara Hanaei Department of Neurosurgery, Imam Khomeini Hospital Complex (IKHC), Tehran University of Medical Sciences (TUMS), Tehran, Iran; Borderless Research, Advancement and Innovation in Neuroscience Network (BRAINet), Tehran, Iran 2025 02 24 2025 03 04 Multiple sclerosis (MS), an autoimmune chronic inflammatory, demyelinating disease, has affected over 2.5 million people in the world, who are mostly in young adulthood ages. As the burden of this disease would highly influence the socioeconomic status of the societies, as well as the patient’s quality of life, any progress in better understanding the pathophysiology of this disease would be valuable. MS is caused by a series of cell-mediated immune mechanisms involving CD4+ T-cell reactivation against CNS. Also, as the involvement of both innate and acquired immunities, different risk factors have been proposed for MS. Environmental factors such as smoking, Epstein-Barr virus infection, sun exposure and vitamin D, body mass index, gut microbiota, and melatonin disturbance may affect gene expression patterns through epigenetic changes, and therefore, play roles in disease occurrence. These epigenetic changes could be categorized as alterations in DNA methylation, histone modifications and non-coding RNAs. Moreover, the reversibility of these epigenetic changes could be potentially considered as therapeutic targets. Therefore, several experimental and preclinical studies have investigated medications for reversing the pathologic epigenetic changes in MS. Accordingly, the current review was conducted to gather the current findings on the role of epigenetics in the pathophysiology and also treatment of MS. https://igj.tums.ac.ir/index.php/igj/article/view/197 https://igj.tums.ac.ir/index.php/igj/article/download/197/182

Tehran University of Medical Sciences Immunology and Genetics Journal 2645-4831 8 2 2025 03 04 236 247 Shirin Moosavi Snyder Institute for Chronic Diseases, University of Calgary, Alberta, Canada; Microbiome and Microbial Ecology Interest Group (MMEIG), Universal Scientific Education and Research Network (USERN), Alberta, Canada Aaron Shanker Department of Internal Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA Maryam Sadr Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran Samaneh Soltani Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran Sepideh Shahkarami Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany; Medical Genetics Network (MeGeNe), Universal Scientific Education and Research Network (USERN), Munich, Germany Elham Farhadi Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran Nasser Ebrahimi Daryani Division of Gastroenterology, Department of Medicine, Tehran University of Medical Sciences, Tehran, Iran Behnoud Baradaran Noveiry Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, Maryland, USA; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Baltimore, Maryland, USA Farnaz Najmi Varzaneh Department of Radiology, Yale University, New Haven, Connecticut, USA; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), New Haven, Connecticut, USA Mohammad Bashashati Division of Gastroenterology, Department of Medicine, Dell Medical School at UT Austin, Austin, TX, USA Nima Rezaei Research Center for Immunodeficiencies, Children’s Medical Center Hospital, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran 2025 03 04 2025 03 04 Background: Inflammatory bowel disease (IBD) is a chronic relapsing-remitting inflammatory disease of the intestinal tract. Tumor necrosis factor-alpha (TNF-α) signaling plays a major role in the pathogenesis of IBD and is commonly targeted for therapeutic purposes. Results on the contribution of TNF-α -308 and -238 single nucleotide polymorphisms (SNP) to the susceptibility to IBD have been contradictory in different populations. Methods: Allele frequency and genotype status of TNF-α -308 and -238 SNPs were investigated in 75 unrelated patients with IBD [40 Crohn’s disease (CD) and 35 ulcerative colitis (UC)] and 140 healthy controls by polymerase chain reaction with sequence-specific primers (PCR-SSP). We also conducted a systematic review and meta-analysis of the published reports. Results: TNF-α -238 GG was detected at a higher frequency in CD and UC. TNF-α -308 GG was more frequently detected in UC compared to control. There was no significant association between TNF-α -238 or -308 gene polymorphisms and patients’ demography (i.e., gender and age) or disease phenotype (i.e., extraintestinal manifestations, treatment, activity index, age at onset, and duration of the disease). In the meta-analysis, TNF-α -238 (AA/AG) genotype tended to be less frequent in patients with UC compared to healthy controls. There was no association between TNF-α -238 gene polymorphisms (AA/AG or GG genotypes) and either form of IBD. Conclusion: TNF-α -308 and -238 SNPs are associated with IBD in Iranian patients. The TNF-α -308 AA genotype is positively correlated with UC in this meta-analysis. https://igj.tums.ac.ir/index.php/igj/article/view/202 https://igj.tums.ac.ir/index.php/igj/article/download/202/180

Tehran University of Medical Sciences Immunology and Genetics Journal 2645-4831 8 2 2025 03 04 150 188 Mahdi Rafiyan Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran Hanieh Mojtahedi Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran 2025 02 25 2025 03 04 Neuroinflammation is a critical process in Alzheimer’s disease (AD) development in which different types of cells and cytokines are involved. Proinflammatory cytokine production and the disturbance of anti-inflammatory pathways play critical roles in AD. Neuroinflammation is affected by various factors such as metabolism (metabolic diseases such as obesity), genetics, and immune cells, especially resident immune cells in the brain. Moreover, the main pro-inflammatory cytokines and inflammatory pathways have different effects on neuroinflammation, neuronal biogenesis, and neuronal apoptosis in AD. Exploration of the relationship between neuroinflammation, risk factors of neuroinflammation, and pro-inflammatory cytokines in AD helps us to understand AD pathogenesis and select therapeutic targets more efficiently. https://igj.tums.ac.ir/index.php/igj/article/view/198 https://igj.tums.ac.ir/index.php/igj/article/download/198/175

Tehran University of Medical Sciences Immunology and Genetics Journal 2645-4831 8 2 2025 03 04 248 255 Golshid Sanati Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Mehrdad Noruzinia Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran Naser Ebrahimi Daryani Department of Internal Medicine, Division of Gastroenterology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran Davood Jafari Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Mohammad Ahmadvand Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran Shahram Teimourian Department of Genetics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran Nima Rezaei Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; 5 Research Center for Immunodeficiencies, Children's Medical Center Hospital, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Boston, MA, USA 2025 03 04 2025 03 04 Background: Growing evidence supports that changes in the expression of the suppressor of cytokine signaling 3 (SOCS3) protein contribute to the pathogenesis of types of inflammatory bowel diseases (IBDs), including ulcerative colitis (UC). Despite the importance of the currently known genetic risk map, an increasing number of observations reveal that epigenetic modifications, including DNA methylation, are considered as or even more important for IBD pathogenesis than genetic predisposition. We investigated the hypothesis that alterations in DNA methylation status at the promoter region within the SOCS3 gene in colorectal tissue specimens may be involved in the susceptibility to UC. Methods: We studied extracted DNA from colorectal biopsies of 15 ulcerative colitis cases and 15 age—and sex-matched healthy controls and performed genotype analyses of the promoter methylation status of the SOCS3 gene, using the real-time quantitative multiplex methylation-specific PCR (QM-MSP) assay to show evidence of differential methylation between cases of ulcerative colitis and healthy controls. Results: Based on methylation assay data profiling, we found that the mean CpG island methylation levels at the SOCS3 gene promoter region in colorectal mucosa of patients with UC was significantly higher than mucosa from healthy controls (ulcerative colitis vs. healthy controls; 0.00007±0.0018 vs. 0.07±0.142, p<0.000). Conclusion: Our data provide an important insight into the influence of epigenetic aberrances in the SOCS3 gene such that the inactivation of the SOCS3 gene by promoter hypermethylation might be a risk factor for inflamed mucosa of UC. It might also fundamentally contribute to the initiation of the inflammatory process and development of UC. https://igj.tums.ac.ir/index.php/igj/article/view/203 https://igj.tums.ac.ir/index.php/igj/article/download/203/181

Tehran University of Medical Sciences Immunology and Genetics Journal 2645-4831 8 2 2025 03 04 189 202 Mansoureh Karimi Kakh Department of Immunology, Faculty of Medicine, Kerman University of Medical Science, Kerman, Iran; ImmunologyToday, Universal Scientific Education and Research Network (USERN), Tehran, Iran Morteza Motallebnezhad Student Research Committee, Iran University of Medical Sciences, Tehran, Iran; Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran Pooria Ghiasi Department of Immunology, Faculty of Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran Farzad Nazari ImmunologyToday, Universal Scientific Education and Research Network (USERN), Tehran, Iran 2025 01 16 2025 03 04 CD4+ T helper (Th) cells are part of the adaptive immune system and are responsible for activating other immune cells, such as B cells, CD8+ T cells, macrophages, mast cells, neutrophils, eosinophils, and basophils. Differentiation of CD4+ T cells is influenced by cytokines and stimulation of the T cell receptor by different antigens. The pattern of cytokine secretion can be altered under specific conditions from one cell line to another, indicating that Th cells have plasticity. In fact, active and master regulators collaborate with transcription factors like signal transducers, activator transducers, and activators of transcription (STATs) in developing the differentiation process. The signals provided by cytokines activate specific transcription factors in each cell line. During this process, epigenetic modifications are actively involved. Epigenetics is defined as heritable alterations in the regulation of gene expression without any change in the DNA strand and includes DNA methylation, histone modification, and non-coding RNAs. The plasticity of CD4+ T cells in differentiation to multiple subsets allows Th cells to exhibit the best immune response against the target microorganism. Failure to respond appropriately to multiple types of microorganisms can lead to disease. In this review, we have collected recent advances in understanding the role of epigenetic regulatory mechanisms in the differentiation of Th cells and, thereby, the commitment of CD4+ T cells to a particular lineage to raise an appropriate response against a variety of microorganisms. https://igj.tums.ac.ir/index.php/igj/article/view/169 https://igj.tums.ac.ir/index.php/igj/article/download/169/176

Tehran University of Medical Sciences Immunology and Genetics Journal 2645-4831 8 2 2025 03 04 203 212 Shakiba Yousefi Osteoporosis Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran Vahid Mansouri Gene Therapy Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran 2025 02 25 2025 03 04 Fibromyalgia (FM) is a complex and debilitating rheumatologic syndrome characterized by chronic widespread pain, fatigue, and cognitive disturbances. Despite extensive research, its pathogenesis remains poorly understood, and reliable biomarkers for diagnosis are lacking. Emerging evidence suggests a critical role of immune dysregulation in FM, highlighting its potential classification as an autoimmune-related disorder. This review explores the immunological aspects of FM pathogenesis, including its association with autoimmune comorbidities, the presence of autoantibodies, and the involvement of inflammatory cytokines. Additionally, we discuss recent findings that support an autoimmune basis for FM, such as the transfer of FM symptoms through patient-derived IgG in animal models. Recognizing these immunological connections may pave the way for improved diagnostic approaches and targeted therapeutic strategies for FM.   https://igj.tums.ac.ir/index.php/igj/article/view/199 https://igj.tums.ac.ir/index.php/igj/article/download/199/177

Tehran University of Medical Sciences Immunology and Genetics Journal 2645-4831 8 2 2025 03 04 213 2ies. Case Presentation: Herein, we report a 5-year-old girl with silvery-gray hair, eyebrows, and eyelashes who were referred to our primary immune deficiency clinic because of recurrent oral thrush. Further investigations were performed to uncover the probable underlying genetic disorder. Whole-exome sequencing revealed a novel mutation in the RAB27A gene (c.137T>G) and confirmed the diagnosis of Griscelli syndrome type 2. Conclusions: Due to the poor prognosis nature of this disorder and also its need for differential diagnosis with some other conditions with hypopigmentation, prompt diagnosis, genetic analysis, and proper treatment are necessary for avoiding serious complications. https://igj.tums.ac.ir/index.php/igj/article/view/163 https://igj.tums.ac.ir/index.php/igj/article/download/163/146

Tehran University of Medical Sciences Immunology and Genetics Journal 2645-4831 7 2 2024 06 22 66 71 Reza Shiari Department of Pediatric Rheumatology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran Navid Roshanzamir Department of Internal Medicine, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran Mahsa Erfanian-Salim Department of Pediatrics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran 2025 01 12 2025 01 12 Background: Systemic juvenile idiopathic arthritis (sJIA) is determined by prominent multisystemic involvements with onset before the age of 16 years of which IL-6 has a significant role in inflammatory process. Tocilizumab (TCZ) is a human anti-IL-6 receptor monoclonal antibody, which modulates IL-6 activity by blocking its binding to the soluble and membrane-bound IL-6 receptor. No comprehensive study has been done regarding the use of IL-6 inhibitor in the treatment of SJIA patients in Iran. This study was conducted with the aim of investigating the effectiveness and outcome of IL-6 inhibitor treatment in Iranian children with sJIA. Methods and Materials: This is a case-control study including twenty patients diagnosed with sJIA divided equally in two groups of case and control who received TCZ and corticosteroids respectively. Subsequently, various clinical and laboratory features were compared amongst these two groups. Results: A significant difference before and after TCZ has been seen in terms of height increase, weight gain, and decrease in leukocytosis, thrombocytosis and ESR, CRP negativity and arthritis improvement. Conclusions: Considering the favorable effects of TCZ in the control of sJIA, by producing this drug in the country and making it available to patients at a lower cost, it is possible to better control the disease and reduce the harmful effects caused by the disease and reduce the long-term use of corticosteroids. https://igj.tums.ac.ir/index.php/igj/article/view/166 https://igj.tums.ac.ir/index.php/igj/article/download/166/143

Tehran University of Medical Sciences Immunology and Genetics Journal 2645-4831 7 2 2024 06 22 72 76 Shamsolmolouk Najafi Dental Research Center, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran Farzaneh Bolandparva Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran Arezou Rezaei Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran Mohammad Javad Kharrazifard Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran Nima Rezaei Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Stockholm, Sweden