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Alshammary AF, BinSaif G, Ali Khan I. Efficacy of CLT4A variants as immunoregulatory molecules among Vitiligo patients in Saudi Arabia. Sci Rep 2025; 15:4407. [PMID: 39910232 PMCID: PMC11799352 DOI: 10.1038/s41598-025-88749-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 01/30/2025] [Indexed: 02/07/2025] Open
Abstract
Vitiligo is a skin depigmentation condition caused by the immune-mediated perdition of melanocytes. In vitiligo, cytotoxic T-lymphocytes damage melanocytes, causing skin depigmentation. The Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) gene has been reported to be related to vitiligo and other autoimmune diseases. The purpose of this study was to explore the molecular involvement of rs231775 and rs3087243 SNPs in the CTLA4 gene in vitiligo patients. The recruitment was based on the sample size calculation and based on it, we have recruited 300 Saudi individuals who were evenly divided into vitiligo cases and controls. Extracted genomic DNA was utilized to amplify rs231775 and rs3087243 SNPs in the CTLA4 gene, which were subsequently digested and verified using Sanger sequencing. The polymerase chain reaction and restriction fragment length polymorphism analysis laboratory data were stored in Excel and used for further statistical analysis. Although baseline details had no correlation (p > 0.05) between the two groups, Hardy-Weinberg Equilibrium analysis was in agreement with the vitiligo patients (p > 0.05). The genotype and allele frequencies were frequently associated (p < 0.05) with rs3087243, and rs231775 SNP showed a nominal association with GG genotype and G allele (p < 0.05). The specific relationship in vitiligo cases was revealed by MDR, GDMR, and linkage disequilibrium (p < 0.05), but not with haplotype analysis (p > 0.05). Thus, the study concluded that rs3087243 SNP was associated and rs231775 SNP showed a nominal association with vitiligo in the Saudi population.
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Affiliation(s)
- Amal F Alshammary
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, 11433, Saudi Arabia
| | - Ghada BinSaif
- Department of Dermatology, College of Medicine, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Imran Ali Khan
- Medical Genomics Research Department, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, 11481, Saudi Arabia.
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Long H, Espinosa L, Sawalha AH. Unraveling the immunomodulatory impact of hydroxychloroquine on peripheral T cells using single-cell RNA sequencing. J Autoimmun 2024; 149:103324. [PMID: 39405653 DOI: 10.1016/j.jaut.2024.103324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 08/28/2024] [Accepted: 10/05/2024] [Indexed: 12/15/2024]
Abstract
Hydroxychloroquine (HCQ) is widely used in the treatment of a variety of autoimmune diseases. However, the mechanisms responsible for the immunomodulatory properties of HCQ in T cells remain unclear. Here we used single-cell RNA-sequencing to examine the effect of HCQ on T cells following in vitro stimulation. HCQ treatment led to a reduction in effector CD4+ T cells and upregulation of inhibitory genes including CTLA4 and TNFAIP3 in effector and naive CD4+ T cells, respectively. HCQ induced a significant expansion of effector CD8+ T cells, and significantly upregulated key cytotoxicity genes including GZMA, GZMB, GZMH, KLRD1, NKG7, and PRF1, as well as IFNG expression. Furthermore, HCQ treatment led to a reduction in the CD38+ CD8+ T cell subset, which is characterized by defective cytotoxicity and thought to both play a pathogenic role and increase susceptibility to infections in autoimmunity. We analyzed single-cell RNA-sequencing data in effector CD8+ T cells from lupus patients with or without HCQ treatment and confirmed upregulation of key cytotoxicity genes in patients receiving HCQ. In conclusion, this work provides additional insights into the immunomodulatory effects of HCQ and indicates that HCQ improves T cell cytotoxicity, which could explain a previously suggested protective effect of HCQ against infections in patients with autoimmune diseases.
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Affiliation(s)
- Huizhong Long
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Division of Rheumatology, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA
| | - Luis Espinosa
- Division of Rheumatology, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA
| | - Amr H Sawalha
- Division of Rheumatology, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA; Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Lupus Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
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Yeo NKW, Lim CK, Yaung KN, Khoo NKH, Arkachaisri T, Albani S, Yeo JG. Genetic interrogation for sequence and copy number variants in systemic lupus erythematosus. Front Genet 2024; 15:1341272. [PMID: 38501057 PMCID: PMC10944961 DOI: 10.3389/fgene.2024.1341272] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 02/20/2024] [Indexed: 03/20/2024] Open
Abstract
Early-onset systemic lupus erythematosus presents with a more severe disease and is associated with a greater genetic burden, especially in patients from Black, Asian or Hispanic ancestries. Next-generation sequencing techniques, notably whole exome sequencing, have been extensively used in genomic interrogation studies to identify causal disease variants that are increasingly implicated in the development of autoimmunity. This Review discusses the known casual variants of polygenic and monogenic systemic lupus erythematosus and its implications under certain genetic disparities while suggesting an age-based sequencing strategy to aid in clinical diagnostics and patient management for improved patient care.
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Affiliation(s)
- Nicholas Kim-Wah Yeo
- Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
| | - Che Kang Lim
- Duke-NUS Medical School, Singapore, Singapore
- Department of Clinical Translation Research, Singapore General Hospital, Singapore, Singapore
| | - Katherine Nay Yaung
- Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
| | - Nicholas Kim Huat Khoo
- Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
| | - Thaschawee Arkachaisri
- Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
- Rheumatology and Immunology Service, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Salvatore Albani
- Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
- Rheumatology and Immunology Service, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Joo Guan Yeo
- Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
- Rheumatology and Immunology Service, KK Women’s and Children’s Hospital, Singapore, Singapore
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Vitzthum von Eckstaedt H, Singh A, Reid P, Trotter K. Immune Checkpoint Inhibitors and Lupus Erythematosus. Pharmaceuticals (Basel) 2024; 17:252. [PMID: 38399467 PMCID: PMC10892070 DOI: 10.3390/ph17020252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 01/16/2024] [Accepted: 02/01/2024] [Indexed: 02/25/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) are the standard of care for a growing number of malignancies. Unfortunately, they are associated with a broad range of unique toxicities that mimic the presentations of primary autoimmune conditions. These adverse events are termed immune-related adverse events (irAEs), of which ICI-lupus erythematosus (ICI-LE) constitutes a small percentage. Our review aims to describe the available literature on ICI-LE and ICI treatment for patients with pre-existing lupus. Most diagnoses of ICI-LE had findings of only cutaneous lupus; four diagnoses of ICI-LE had systemic lupus manifestations. Over 90% (27 of 29) of cases received anti-PD-1/PDL-1 monotherapy, 1 received combination therapy, and 1 received only anti-CTLA-4 treatment. About three-fourths (22 of 29 or 76%) of patients with ICI-lupus were managed with topical steroids, 13 (45%) received hydroxychloroquine, and 10 (34%) required oral corticosteroids. In our case series, none of the patients with pre-existing lupus receiving ICI therapy for cancer had a flare of their lupus, but few had de novo irAE manifestations, all of which were characterized as low-grade. The review of the literature yielded seven ICI-LE flares from a total of 27 patients with pre-existing lupus who received ICI. Most flares were manageable without need for ICI cessation.
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Affiliation(s)
| | - Arohi Singh
- College of the University of Chicago, University of Chicago, Chicago, IL 60637, USA;
| | - Pankti Reid
- Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago Medicine, Chicago, IL 60637, USA
- Department of Medicine, Section of Rheumatology, University of Chicago Medicine, Chicago, IL 60637, USA;
| | - Kimberly Trotter
- Department of Medicine, Section of Rheumatology, University of Chicago Medicine, Chicago, IL 60637, USA;
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Mirsharif ES, Rostamian A, Salehi M, Askari N, Ghazanfari T. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) +49A>G (rs231775) gene polymorphism is not associated with COVID-19 severity and mortality in an Iranian population. Heliyon 2024; 10:e23308. [PMID: 38116190 PMCID: PMC10726245 DOI: 10.1016/j.heliyon.2023.e23308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 11/22/2023] [Accepted: 11/30/2023] [Indexed: 12/21/2023] Open
Abstract
Introduction Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates T cell immune responses as an immune activation inhibitor. Literature reviews suggest that COVID-19 is associated with dysregulation of the inflammatory immune response. The purpose of the present hospital-based case-control study was to evaluate the genetic association of the CTLA4 +49A > G (rs231775) Single Nucleotide Polymorphism (SNP) with COVID-19 severity and mortality among the Iranian people. Method Genomic DNA of peripheral blood nuclear cells was extracted from the 794 COVID-19 patients and 167 control individuals. The polymorphic site of rs231775 was genotyped using the PCR-RFLP technique. Also, to identify whether this genetic variation was related to CTLA-4 mRNA expression, total RNA was extracted from 178 COVID-19 patients and 70 controls. The mRNA levels of CTLA-4 were determined using real-time PCR. Result There were no statistically significant differences found in the genotype and allele frequencies among the different genetic models with regards to the severity and mortality of COVID-19. Furthermore, there was no significant association between rs231775 genotypes and CTLA-4 mRNA expression in patients. Conclusion Our findings demonstrated that SARS-CoV-2 infection is not associated with rs231775 in the Iranian people. More investigations are crucial to show how this genetic variation affects other ethnic groups. Given the importance of CTLA-4 in regulating immune responses, further studies are recommended to examine other CTLA-4 SNPs and the function of this gene in COVID-19 patients.
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Affiliation(s)
| | - Abdolrahman Rostamian
- Rheumatology Research Center, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Salehi
- Department of Infectious and Tropical Medicines, Tehran University of Medical Sciences, Tehran, Iran
| | - Nayere Askari
- Immunoregulation Research Center, Shahed University, Tehran, Iran
- Department of Biology, Faculty of Basic Sciences, Shahid Bahonar, University of Kerman, Kerman, Iran
| | - Tooba Ghazanfari
- Immunoregulation Research Center, Shahed University, Tehran, Iran
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Suvankar S, Padhi S, Bagabir HA, Pati A, Wahid M, Mandal RK, Haque S, Panda AK. Cytotoxic T-lymphocyte associated protein 4 (CTLA4) polymorphisms are linked to systemic lupus erythematosus: an updated meta-analysis. Biotechnol Genet Eng Rev 2023; 39:841-858. [PMID: 36597619 DOI: 10.1080/02648725.2022.2163817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 12/26/2022] [Indexed: 01/05/2023]
Abstract
Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) molecule controls T cell immune response. Functional single nucleotide polymorphisms (SNPs) in the CTLA-4 gene have been associated with several autoimmune diseases, including systemic lupus erythematosus (SLE). However, the genetic association of the CTLA-4 variants with vulnerability to SLE remained contradictory. We have conducted a current meta-analysis by combining the findings of prior published articles in order to make a conclusive statement. Various literature databases were screened with appropriate keywords to obtain relevant articles, and eligible reports were obtained using well-defined inclusion and exclusion criteria. Meta-analysis was performed by Comprehensive Meta-analysis V 3.3, and various statistical parameters such as odds ratio, 95% confidence interval, and probability values were computed. A total of 3847 SLE patients and 5278 healthy controls were considered in the present meta-analysis from 26 individual reports. A significant association of CTLA-4 +49 A/G (G vs. A: p=0.03, OR=1.47) and -1722 T/C (p=0.02, OR=0.87) polymorphisms were observed with susceptibility and resistance against the development of SLE, respectively. However, the other two SNPs in the CTLA-4 gene (-318 C/T and -1661 A/G) failed to establish a connection. Interestingly, subgroup analysis revealed an association of CTLA-4 +49 A/G with a predisposition to SLE only in the Asian population (G vs. A: p=0.04, OR=1.26, GG vs. AA: p=0.02, OR=1.84, AG vs AA: p=0.01, OR=1.44, GG+AG vs AA: p=0.01, OR=1.52) and not in Caucasians. The current meta-analysis suggests a significant CTLA-4 +49 A/G variant association with susceptibility to SLE development in overall and Asian populations. In contrast, the other variant, -1722 T/C, is linked with protection against SLE. However, further case-control studies in diverse ethnic populations are requisite.
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Affiliation(s)
- Subham Suvankar
- Department of Biotechnology, Berhampur University, Bhanja bihar, Berhampur, Odisha, India
| | - Sunali Padhi
- Department of Biotechnology, Berhampur University, Bhanja bihar, Berhampur, Odisha, India
| | - Hala Abubaker Bagabir
- Department of Physiology, Faculty of Medicine, King Abdulaziz University, Rabigh, Saudi Arabia
| | - Abhijit Pati
- Department of Biotechnology, Berhampur University, Bhanja bihar, Berhampur, Odisha, India
| | - Mohd Wahid
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
| | - Raju K Mandal
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
- Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Aditya K Panda
- Department of Biotechnology, Berhampur University, Bhanja bihar, Berhampur, Odisha, India
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Musabak U, Erdoğan T, Ceylaner S, Özbek E, Suna N, Özdemir BH. Efficacy of abatacept treatment in a patient with enteropathy carrying a variant of unsignificance in CTLA4 gene: A case report. World J Clin Cases 2023; 11:6176-6182. [PMID: 37731560 PMCID: PMC10507547 DOI: 10.12998/wjcc.v11.i26.6176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 07/18/2023] [Accepted: 08/15/2023] [Indexed: 09/08/2023] Open
Abstract
BACKGROUND Cytotoxic T Lymphocyte Antigen-4 (CTLA4) deficiency is a genetic defect that causes a common variable immunodeficiency (CVID) clinical phenotype. Several studies have reported an association between CTLA mutations or variants and various autoimmune diseases. Targeted therapy models, which have become increasingly popular in recent years, have been successful in treating CTLA4 deficiency. In this article, we discuss the clinical outcomes of abatacept treatment in a patient with CTLA4 and lipopolysaccharide-responsive beige-like anchor (LRBA) variants that was previously diagnosed with CVID. CASE SUMMARY A 25-year-old female patient, who was visibly cachectic, visited our clinic over the course of five years, complaining of diarrhea. The patient was diagnosed with ulcerative colitis in the centers she had visited previously, and various treatments were administered; however, clinical improvement could not be achieved. Severe hypokalemia was detected during an examination. Her serum immunoglobulin levels, CD19+ B-cell percentage, and CD4/CD8 ratio were low. An endoscopic examination revealed erosive gastritis, nodular duodenitis, and pancolitis. Histopathological findings supported the presence of immune mediated enteropathy. When the patient was examined carefully, she was diagnosed with CVID, and intravenous immunoglobulin treatment was initiated. Peroral and rectal therapeutic drugs including steroid therapy episodes were administered to treat the immune mediated enteropathy. Strict follow-ups and treatment were performed due to the hypokalemia. After conducting genetic analyses, the CTLA4 and LRBA variants were identified and abatacept treatment was initiated. With targeted therapy, the patient's clinical and laboratory findings rapidly regressed, and there was an increase in weight. CONCLUSION The heterozygous CTLA4 variant identified in the patient has been previously shown to be associated with various autoimmune diseases. The successful clinical outcome of abatacept treatment in this patient supports the idea that this variant plays a role in the immunopathogenesis of the disease. In the presence of severe disease, abatacept therapy should be considered until further testing can be conducted.
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Affiliation(s)
- Ugur Musabak
- Department of Immunology and Allergy, Baskent University School of Medicine, Ankara 06490, Ankara, Turkey
| | - Tuba Erdoğan
- Department of Immunology and Allergy, Baskent University School of Medicine, Ankara 06490, Ankara, Turkey
| | - Serdar Ceylaner
- Department of Medical Genetics, Lokman Hekim University, Ankara 06000, Turkey
- Department of Medical Genetics, Intergen Genetic and Rare Disease Diagnosis and Reseach Center, Ankara 06000, Turkey
| | - Emre Özbek
- Department of Immunology-Allergy, Etlik City Hospital, Ankara 06490, Ankara, Turkey
| | - Nuretdin Suna
- Division of Gastroenterology, Baskent University School of Medicine, Ankara 06000, Turkey
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Xiao XY, Chen Q, Shi YZ, Li LW, Hua C, Zheng H. Risk factors of systemic lupus erythematosus: an overview of systematic reviews and Mendelian randomization studies. Adv Rheumatol 2023; 63:42. [PMID: 37596678 DOI: 10.1186/s42358-023-00323-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 08/02/2023] [Indexed: 08/20/2023] Open
Abstract
BACKGROUND The etiology of systemic lupus erythematosus is complex and incurable. A large number of systematic reviews have studied the risk factors of it. Mendelian randomization is an analytical method that uses genetic data as tool variables to evaluate the causal relationship between exposure and outcome. OBJECTIVE To review the systematic reviews and Mendelian randomization studies that focused on the risk factors of systemic lupus erythematosus and shed light on the development of treatments for its prevention and intervention. METHODS From inception to January 2022, we systematically searched MEDLINE (via PubMed) and Embase for related systematic reviews and Mendelian randomization studies. Extract relevant main data for studies that meet inclusion criteria. The quality of systematic reviews was assessed by using Assessment of Multiple Systematic Reviews 2 (AMSTAR-2). Finally, the risk factors are scored comprehensively according to the results' quantity, quality, and consistency. RESULTS Our study involved 64 systematic reviews and 12 Mendelian randomization studies. The results of systematic reviews showed that diseases (endometriosis, atopic dermatitis, allergic rhinitis), lifestyle (smoking, drinking, vaccination), and gene polymorphism influenced the incidence of systemic lupus erythematosus. The results of Mendelian randomization studies identified the role of disease (periodontitis, celiac disease), trace elements (selenium, iron), cytokines (growth differentiation factor 15), and gut microbiome in the pathogenesis of systemic lupus erythematosus. CONCLUSION We should pay attention to preventing and treating systemic lupus erythematosus in patients with endometriosis, celiac disease, and periodontitis. Take appropriate dietary supplements to increase serum iron and selenium levels to reduce the risk of systemic lupus erythematosus. There should be no excessive intervention in lifestyles such as smoking and drinking.
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Affiliation(s)
- Xin-Yu Xiao
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, No.1166 Liutai Avenue, Wenjiang District, Chengdu, 610000, China
| | - Qian Chen
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, No.1166 Liutai Avenue, Wenjiang District, Chengdu, 610000, China
| | - Yun-Zhou Shi
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, No.1166 Liutai Avenue, Wenjiang District, Chengdu, 610000, China
| | - Li-Wen Li
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, No.1166 Liutai Avenue, Wenjiang District, Chengdu, 610000, China
| | - Can Hua
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, No.1166 Liutai Avenue, Wenjiang District, Chengdu, 610000, China
| | - Hui Zheng
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, No.1166 Liutai Avenue, Wenjiang District, Chengdu, 610000, China.
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Hossen MM, Ma Y, Yin Z, Xia Y, Du J, Huang JY, Huang JJ, Zou L, Ye Z, Huang Z. Current understanding of CTLA-4: from mechanism to autoimmune diseases. Front Immunol 2023; 14:1198365. [PMID: 37497212 PMCID: PMC10367421 DOI: 10.3389/fimmu.2023.1198365] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 06/19/2023] [Indexed: 07/28/2023] Open
Abstract
Autoimmune diseases (ADs) are characterized by the production of autoreactive lymphocytes, immune responses to self-antigens, and inflammation in related tissues and organs. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is majorly expressed in activated T cells and works as a critical regulator in the inflammatory response. In this review, we first describe the structure, expression, and how the signaling pathways of CTLA-4 participate in reducing effector T-cell activity and enhancing the immunomodulatory ability of regulatory T (Treg) cells to reduce immune response, maintain immune homeostasis, and maintain autoimmune silence. We then focused on the correlation between CTLA-4 and different ADs and how this molecule regulates the immune activity of the diseases and inhibits the onset, progression, and pathology of various ADs. Finally, we summarized the current progress of CTLA-4 as a therapeutic target for various ADs.
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Affiliation(s)
- Md Munnaf Hossen
- Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
- Department of Immunology, Biological Therapy Institute, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Health Science Center, Shenzhen University, Shenzhen, China
- Joint Research Laboratory for Rheumatology of Shenzhen University Health Science Center and Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
| | - Yanmei Ma
- Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
- Department of Immunology, Biological Therapy Institute, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Health Science Center, Shenzhen University, Shenzhen, China
- Joint Research Laboratory for Rheumatology of Shenzhen University Health Science Center and Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
| | - Zhihua Yin
- Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
- Joint Research Laboratory for Rheumatology of Shenzhen University Health Science Center and Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
| | - Yuhao Xia
- Department of Immunology, Biological Therapy Institute, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Health Science Center, Shenzhen University, Shenzhen, China
- Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen, China
| | - Jing Du
- Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen, China
| | - Jim Yi Huang
- Department of Psychology, University of Oklahoma, Norman, OK, United States
| | - Jennifer Jin Huang
- Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK, United States
| | - Linghua Zou
- Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
- Department of Rehabilitation Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
| | - Zhizhong Ye
- Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
- Joint Research Laboratory for Rheumatology of Shenzhen University Health Science Center and Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
| | - Zhong Huang
- Department of Immunology, Biological Therapy Institute, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Health Science Center, Shenzhen University, Shenzhen, China
- Joint Research Laboratory for Rheumatology of Shenzhen University Health Science Center and Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
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Liu TY, Liao WL, Wang TY, Chan CJ, Chang JG, Chen YC, Lu HF, Yang HH, Chen SY, Tsai FJ. Genome-wide association study of hyperthyroidism based on electronic medical record from Taiwan. Front Med (Lausanne) 2022; 9:830621. [PMID: 35991636 PMCID: PMC9390483 DOI: 10.3389/fmed.2022.830621] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Excess thyroid hormones have complex metabolic effects, particularly hyperthyroidism, and are associated with various cardiovascular risk factors. Previous candidate gene studies have indicated that genetic variants may contribute to this variable response. Electronic medical record (EMR) biobanks containing clinical and genomic data on large numbers of individuals have great potential to inform the disease comorbidity development. In this study, we combined electronic medical record (EMR) -derived phenotypes and genotype information to conduct a genome-wide analysis of hyperthyroidism in a 35,009-patient cohort in Taiwan. Diagnostic codes were used to identify 2,767 patients with hyperthyroidism. Our genome-wide association study (GWAS) identified 44 novel genomic risk markers in 10 loci on chromosomes 2, 6, and 14 (P < 5 × 10–14), including CTLA4, HCP5, HLA-B, POU5F1, CCHCR1, HLA-DRA, HLA-DRB9, TSHR, RPL17P3, and CEP128. We further conducted a comorbidity analysis of our results, and the data revealed a strong correlation between hyperthyroidism patients with thyroid storm and stroke. In this study, we demonstrated application of the PheWAS using large EMR biobanks to inform the comorbidity development in hyperthyroidism patients. Our data suggest significant common genetic risk factors in patients with hyperthyroidism. Additionally, our results show that sex, body mass index (BMI), and thyroid storm are associated with an increased risk of stroke in subjects with hyperthyroidism.
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Affiliation(s)
- Ting-Yuan Liu
- Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan
- Million-Person Precision Medicine Initiative, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Wen-Ling Liao
- College of Chinese Medicine, Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
- Center for Personalized Medicine, China Medical University Hospital, Taichung, Taiwan
- Genetics Center, Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Tzu-Yuan Wang
- Department of Internal Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Division of Endocrinology, China Medical University Hospital, Taichung, Taiwan
| | - Chia-Jung Chan
- Genetics Center, Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Jan-Gowth Chang
- Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Yu-Chia Chen
- Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan
- Million-Person Precision Medicine Initiative, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Hsing-Fang Lu
- Million-Person Precision Medicine Initiative, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | | | - Shih-Yin Chen
- Genetics Center, Medical Research, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
- *Correspondence: Shih-Yin Chen
| | - Fuu-Jen Tsai
- Genetics Center, Medical Research, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
- Department of Medical Genetics, China Medical University Hospital, Taichung, Taiwan
- Fuu-Jen Tsai
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Immunogenetics of Lupus Erythematosus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1367:213-257. [DOI: 10.1007/978-3-030-92616-8_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Kailashiya J, Kailashiya V, Singh U. CTLA4 gene polymorphism and its association with disease occurrence, clinical manifestations, serum markers and cytokine levels in SLE patients from North India. Indian J Dermatol 2022; 67:311. [DOI: 10.4103/ijd.ijd_82_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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Kishk RM, Abdellatif MA, Eldesouki RE, Fawzy M, Abdelhady SA, Fouad MM. Cytotoxic T Lymphocyte Antigen 4 Gene +49 A/G (rs231775) Polymorphism and Susceptibility to Systemic Lupus Erythematosus. Curr Rheumatol Rev 2021; 17:247-251. [PMID: 33213350 DOI: 10.2174/1573397116666201119145153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 07/07/2020] [Accepted: 09/21/2020] [Indexed: 11/22/2022]
Abstract
AIM To assess the probable role of +49AG polymorphism in susceptibility to SLE in an Egyptian population. BACKGROUND Systemic lupus erythematosus (SLE) is a compound inflammatory chronic disease distinguished through the release of autoantibodies. Cytotoxic T lymphocyte associated antigen-4 is a main down controller of T-cell response; its dysregulation could affect SLE pathogenesis by altered T cells activation to self-antigens. OBJECTIVES To evaluate the CTLA-4 +49AG allelic and genotype frequency in a sample of the Egyptian population and correlate them with disease susceptibility and clinical severity. MATERIALS AND METHODS Including 100 patients with SLE and 100 healthy controls (age and gender matched), CTLA-4 exon 1 49 A>G Genotyping was done using Real-Time PCR. RESULTS No difference was noticed in genotype or allele distributions of the studied polymorphism between both groups. Similar genotypes and allele frequencies were established for the 2 groups after their stratification by the age of disease onset, clinical course, or severity. CONCLUSION CTLA-4 +49AG gene polymorphism is not linked with the liability to develop SLE in the studied Egyptian population. Yet it is significantly related to disease severity.
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Affiliation(s)
- Rania Mohammed Kishk
- Microbiology and Immunology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Maii Abdelraheem Abdellatif
- Physical Medicine, Rheumatology & Rehabilitation Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Raghda Elsawi Eldesouki
- Genetics Unit, Histology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Mohamed Fawzy
- Internal Medicine Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | | | - Marwa Mohamed Fouad
- Microbiology and Immunology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
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Yu L, Shao M, Zhou T, Xie H, Wang F, Kong J, Xu S, Shuai Z, Pan F. Association of CTLA-4 (+49 A/G) polymorphism with susceptibility to autoimmune diseases: A meta-analysis with trial sequential analysis. Int Immunopharmacol 2021; 96:107617. [PMID: 33866246 DOI: 10.1016/j.intimp.2021.107617] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/13/2021] [Accepted: 03/24/2021] [Indexed: 10/21/2022]
Abstract
OBJECTIVES In recent years, more and more studies have been focusing on the association between Cytotoxic T lymphocyte antigen-4 (CTLA-4) (+49 A/G) gene polymorphism and autoimmune diseases. However, the results of previous studies are still controversial. The meta-analysis is aiming at determining the association in CTLA-4 (+49 A/G) gene rs231775 polymorphism and ankylosing spondylitis (AS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE). METHODS We searched PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI) and Chinese Biomedical Database (CBM) up to November 2020, use random or fixed-effect models to perform meta-analysis to compare alleles and other genetic models, including homozygous, heterozygous, recessive and dominant models. The odds ratio (OR) with a 95% confidence interval (95% CI) was used to assess the correlation between CTLA-4 (+49 A/G) gene polymorphism and the genetic affectability of AS, RA, and SLE. Meanwhile, we used sequential trial analysis (TSA) to analyze the reliability of the results. Finally, we searched the relevant data of genome-wide association studies (GWAS) to further verify the accuracy of the experimental results. RESULTS 47 studies with 11,893 cases and 12,032 healthy controls were included. The rs231775 G allele was relevant to high risk of autoimmune disease over all people (P < 0.05). The G allele of rs231775 was significantly related to RA susceptibility (P < 0.05), but not with AS or SLE. Subgroup analysis by ethnicity indicated that rs231775 G allele was closely related to RA in Caucasian populations and Mongolian populations (P < 0.05). A strong connection within rs231775 G allele and AS affectability was uncovered in Caucasian populations (P < 0.05). The analysis of the TSA shows that the meta-analysis can draw the conclusion. CONCLUSION CTLA-4 (+49 A/G) gene rs231775 G allele increases the risk of autoimmune diseases in Caucasian populations. And it also increases the risk of RA in Caucasian and Mongolian populations. More sample size and more elaborately designed studies are needed to elucidate the relationship in CTLA-4 (+49 A/G) gene rs231775 G allele and autoimmune diseases, especially AS, SLE.
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Affiliation(s)
- Lingxiang Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Ming Shao
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Tingting Zhou
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Huimin Xie
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Feier Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Jiangping Kong
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Shenqian Xu
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Zongwen Shuai
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Faming Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China.
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Alghamdi SA, Kattan SW, Toraih EA, Alrowaili MG, Fawzy MS, Elshazli RM. Association of AIRE (rs2075876), but not CTLA4 (rs231775) polymorphisms with systemic lupus erythematosus. Gene 2021; 768:145270. [PMID: 33122082 DOI: 10.1016/j.gene.2020.145270] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 09/26/2020] [Accepted: 10/21/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND The AIRE (rs2075876) and CTLA4 (rs231775) variants have a crucial function in controlling the negative selection and suppression of T lymphocytes. Numerous reports studied the association of AIRE and CTLA4 variants with different autoimmune disorders, but with inconclusive conclusions. The main purpose of this work is to evaluate the association of these two variants with SLE susceptibility among Egyptian patients. SUBJECTS AND METHODS A total of 247 participants (100 SLE patients and 147 healthy controls) were enrolled in this case-controlled study. The genomic DNA of these dual variants was genotyped using the TaqMan genotyping method. RESULTS The AIRE (rs2075876) variant conferred protection against developing SLE disease under allelic [A allele vs. G allele; OR = 0.16, 95%CI = 0.09-0.28], and dominant [GA + AA vs. GG; OR = 0.14, 95%CI = 0.05-0.34] models. Moreover, patients with AIRE rs2075876 (A/A) genotype revealed a statistically significant with lower levels of complement 3 (p-value = 0.007). Nonetheless, the CTLA4 (rs231775) variant was not associated with increased risk of SLE under all genetic association models (p-value > 0.05). However, CTLA4 rs231775 (G/G) genotype observed significant difference with recurrent infection and hematuria. CONCLUSIONS Our findings indicated that the AIRE (rs2075876) variant conferred protection against developing SLE disease, but not the CTLA4 (rs231775) variant.
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Affiliation(s)
- Saleh A Alghamdi
- Medical Genetics, Clinical Laboratory Department, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia.
| | - Shahad W Kattan
- Department of Medical Laboratory, College of Applied Medical Sciences, Taibah University, Yanbu, Saudi Arabia
| | - Eman A Toraih
- Department of Surgery, Tulane University, School of Medicine, New Orleans, LA, USA; Genetics Unit, Histology and Cell Biology Department, Faculty of Medicine, Suez Canal University, Egypt
| | - Majed G Alrowaili
- Department of Surgery (Orthopedic Division), Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
| | - Manal S Fawzy
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
| | - Rami M Elshazli
- Biochemistry and Molecular Genetics Unit, Department of Basic Sciences, Faculty of Physical Therapy, Horus University - Egypt, New Damietta 34518, Egypt.
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Cai GM, Gao Z, Yue YX, Xie YC, Gao X, Hao HJ, Zhang XJ, Wang Q, Liang B, Li HF. Association between CTLA-4 gene polymorphism and myasthenia gravis in a Chinese cohort. J Clin Neurosci 2019; 69:31-37. [PMID: 31473094 DOI: 10.1016/j.jocn.2019.08.079] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 04/13/2019] [Accepted: 08/10/2019] [Indexed: 01/13/2023]
Abstract
Abnormal CTLA-4 expression is involved in the development of myasthenia gravis (MG), and serum CTLA-4 levels are positively correlated with serum anti-AChR antibody concentration, which might be related with the severity of MG. Polymorphism in CTLA-4 gene is associated with various autoimmune disorders. We investigated the association of polymorphism in CTLA-4 gene with the clinical variables and severity of MG. The frequencies of alleles and genotypes were compared between 480 MG patients and 487 healthy controls, as well as among subgroups of MG patients. The frequency of rs733618*C allele is significantly higher in MG group and several subgroups than in control group. Genotype is not found as independent factor for essential clinical variables of MG. The frequency of rs231775*A allele is significantly lower in ocular onset subgroup than in control group, and the frequencies of rs231775*A allele and rs3087243*A allele are significantly lower in ocular onset subgroup than in generalized onset subgroup. Genotypes of the two SNPs are found as independent factors for ocular onset. The frequency of rs231775*A allele is significantly lower in mild subgroup than that in control group. Genotype is not found as independent factor for mild severity. A haplotype containing rs733618*C, rs231775*G and rs3087243*G is identified to increase the general risk of MG by 1.278-fold and ocular onset MG subgroup by 1.362-fold. There is association of rs733618 with the general susceptibility of MG, and association of rs231775 and rs3087243 with the susceptibility of ocular onset MG, but no association with the severity of MG.
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Affiliation(s)
- Gao-Mei Cai
- Department of Neurology, Affiliated Hospital of Jining Medical College, No. 89 Guhuai Road, Jining 272000, China
| | - Zhe Gao
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266003, China
| | - Yao-Xian Yue
- Department of Neurology, Qilu Hospital of Shandong University, No. 107 Wenhua West Road, Jinan 250012, China
| | - Yan-Chen Xie
- Department of Neurology, Beijing Friendship Hospital, Capital Medical University, No. 95 Yongan Road, Beijing 100050, China
| | - Xiang Gao
- Department of Neurology, Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266003, China
| | - Hong-Jun Hao
- Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, Beijing 100034, China
| | - Xian-Jun Zhang
- Department of Neurology, Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266003, China
| | - Qi Wang
- Department of Neurology, Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266003, China
| | - Bing Liang
- Department of Neurology, Qilu Hospital of Shandong University, No. 107 Wenhua West Road, Jinan 250012, China
| | - Hai-Feng Li
- Department of Neurology, Xuanwu Hospital, Capital Medical University, No. 45, Changchun Street, Beijing 100053, China.
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Kailashiya V, Sharma HB, Kailashiya J. Role of CTLA4 A49G polymorphism in systemic lupus erythematosus and its geographical distribution. J Clin Pathol 2019; 72:659-662. [DOI: 10.1136/jclinpath-2019-206013] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 07/03/2019] [Accepted: 07/11/2019] [Indexed: 01/15/2023]
Abstract
CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) or CD152 is an inhibitory receptor expressed constitutively on CD4+ CD25+ T regulatory lymphocytes and transiently on activated CD4+ and CD8+ T lymphocytes. Its inhibitory function promotes long-lived anergy in immune cells and prevents autoimmunity. Therefore, it plays a crucial role in T cell-mediated autoimmunity, and thus in susceptibility to autoimmune diseases, including systemic lupus erythematosus (SLE). It is encoded by CTLA4 gene in humans. AtoG polymorphism at position +49 of CTLA4 gene is the only polymorphism which changes amino acid sequence from alanine to threonine in the leader sequence, which may affect the function of CTLA-4. Association of CTLA4 polymorphisms with SLE has been investigated in several reports in different ethnic populations from different countries, which have shown highly inconsistent findings. In this review, we have compiled previous studies which have reported the association of CTLA4 A49G polymorphism in SLE and its geographical distribution.
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Amaya-Uribe L, Rojas M, Azizi G, Anaya JM, Gershwin ME. Primary immunodeficiency and autoimmunity: A comprehensive review. J Autoimmun 2019; 99:52-72. [PMID: 30795880 DOI: 10.1016/j.jaut.2019.01.011] [Citation(s) in RCA: 119] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 01/24/2019] [Accepted: 01/28/2019] [Indexed: 02/06/2023]
Abstract
The primary immunodeficiency diseases (PIDs) include many genetic disorders that affect different components of the innate and adaptive responses. The number of distinct genetic PIDs has increased exponentially with improved methods of detection and advanced laboratory methodology. Patients with PIDs have an increased susceptibility to infectious diseases and non-infectious complications including allergies, malignancies and autoimmune diseases (ADs), the latter being the first manifestation of PIDs in several cases. There are two types of PIDS. Monogenic immunodeficiencies due to mutations in genes involved in immunological tolerance that increase the predisposition to develop autoimmunity including polyautoimmunity, and polygenic immunodeficiencies characterized by a heterogeneous clinical presentation that can be explained by a complex pathophysiology and which may have a multifactorial etiology. The high prevalence of ADs in PIDs demonstrates the intricate relationships between the mechanisms of these two conditions. Defects in central and peripheral tolerance, including mutations in AIRE and T regulatory cells respectively, are thought to be crucial in the development of ADs in these patients. In fact, pathology that leads to PID often also impacts the Treg/Th17 balance that may ease the appearance of a proinflammatory environment, increasing the odds for the development of autoimmunity. Furthermore, the influence of chronic and recurrent infections through molecular mimicry, bystander activation and super antigens activation are supposed to be pivotal for the development of autoimmunity. These multiple mechanisms are associated with diverse clinical subphenotypes that hinders an accurate diagnosis in clinical settings, and in some cases, may delay the selection of suitable pharmacological therapies. Herein, a comprehensively appraisal of the common mechanisms among these conditions, together with clinical pearls for treatment and diagnosis is presented.
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Affiliation(s)
- Laura Amaya-Uribe
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia
| | - Manuel Rojas
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia; Doctoral Program in Biomedical Sciences, Universidad Del Rosario, Bogota, Colombia
| | - Gholamreza Azizi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Juan-Manuel Anaya
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, School of Medicine, Davis, CA, USA.
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Determination of mir-155 and mir-146a expression rates and its association with expression level of TNF-α and CTLA4 genes in patients with Behcet’s disease. Immunol Lett 2018; 204:55-59. [DOI: 10.1016/j.imlet.2018.10.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2018] [Revised: 09/29/2018] [Accepted: 10/22/2018] [Indexed: 12/30/2022]
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Falasinnu T, Chaichian Y, Bass MB, Simard JF. The Representation of Gender and Race/Ethnic Groups in Randomized Clinical Trials of Individuals with Systemic Lupus Erythematosus. Curr Rheumatol Rep 2018; 20:20. [PMID: 29550947 PMCID: PMC5857270 DOI: 10.1007/s11926-018-0728-2] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW This review evaluated gender and race/ethnic representation in randomized controlled trials (RCTs) of patients with systemic lupus erythematosus (SLE). RECENT FINDINGS Whites comprise 33% of prevalent SLE cases and comprised 51% of RCT enrollees. Blacks encompass 43% of prevalent SLE cases, but only represented 14% of RCT enrollees. Hispanics comprise 16% of prevalent SLE cases and 21% of RCT enrollees, while Asians comprise 13% of prevalent SLE cases and 10% of RCT enrollees. Males encompass 9% of SLE cases and 7% of RCT enrollees. The reporting and representation of males have remained stable over time, although their representation in RCTs is slighter lower than the prevalence of SLE in males. The representation of Hispanics, Asians, and Native Americans increased over time. However, the representation of blacks among RCT participants has decreased since 2006-2011. RCTs among SLE patients need larger sample sizes in order to evaluate heterogeneity in outcomes among racial subgroups. It is imperative that novel strategies be developed to recruit racial minorities with SLE by identifying and improving barriers to RCT enrollment in order to better understand the disease's diverse population.
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Affiliation(s)
- Titilola Falasinnu
- Department of Health Research and Policy, Stanford School of Medicine, 150 Governor’s Lane, Stanford, CA 94305 USA
| | - Yashaar Chaichian
- Department of Medicine, Division of Immunology and Rheumatology, Stanford School of Medicine, 900 Blake Wilbur Dr, 2nd Fl, Stanford, CA 94305 USA
| | - Michelle B. Bass
- Lane Medical Library and Knowledge Management Center, Stanford University Medical Center, 300 Pasteur Drive, L109, Stanford, CA 94305 USA
| | - Julia F. Simard
- Department of Health Research and Policy, Stanford School of Medicine, 150 Governor’s Lane, Stanford, CA 94305 USA
- Division of Immunology and Rheumatology, Department of Health Research and Policy, Stanford School of Medicine, 150 Governor’s Lane, Stanford, CA 94305 USA
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Frydecka D, Beszłej JA, Pawlak-Adamska E, Misiak B, Karabon L, Tomkiewicz A, Partyka A, Jonkisz A, Szewczuk-Bogusławska M, Zawadzki M, Kiejna A. CTLA4 and CD28 Gene Polymorphisms with Respect to Affective Symptom Domain in Schizophrenia. Neuropsychobiology 2016; 71:158-67. [PMID: 25998553 DOI: 10.1159/000379751] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Accepted: 02/02/2015] [Indexed: 11/19/2022]
Abstract
BACKGROUND Accumulating evidence indicates that immune alterations in schizophrenia are due to genetic underpinnings. Here, we aimed at investigating whether polymorphisms in CTLA4 and CD28 genes, encoding molecules that regulate T-cell activity, influence schizophrenia symptomatology. METHOD We recruited 120 schizophrenia patients and 380 healthy age- and sex-matched controls. We divided the patients into two groups: one with no co-occurrence between psychotic and affective symptoms and the second one with psychotic symptoms dominating in the clinical manifestation, although also with occasional affective disturbances in the course of illness. RESULTS Among the patients with co-occurring affective symptoms, there were significantly more CTLA4 c.49A>G[A] alleles (p = 0.018, odds ratio (OR) 2.03, 95% confidence interval (CI) 1.2-3.66) and more CTLA4 g.319C>T[T] alleles (p = 0.07, OR 1.93, 95% CI 0.94-4.13) in comparison to the second group. Additionally, we have shown that CD28 c.17 + 3T>C[C+] were more significantly overrepresented among patients with co-occurring psychotic and affective symptoms (p = 0.0003, OR 3.36, 95% CI 1.69-6.68) than in patients without co-occurence between these symptoms (p = 0.012, OR 1.88, 95% CI 1.15-3.10). CONCLUSION CTLA4 and CD28 gene polymorphisms may not only act in immune deregulation observed in schizophrenia, but may also influence the course of the illness by modifying the susceptibility to the co-occurrence of psychotic and affective symptoms.
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Affiliation(s)
- Dorota Frydecka
- Department of Psychiatry, Wroclaw Medical University, Wroclaw, Poland
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Chen S, Li Y, Deng C, Li J, Wen X, Wu Z, Hu C, Zhang S, Li P, Zhang X, Zhang F, Li Y. The associations between PD-1, CTLA-4 gene polymorphisms and susceptibility to ankylosing spondylitis: a meta-analysis and systemic review. Rheumatol Int 2016; 36:33-44. [PMID: 26232179 DOI: 10.1007/s00296-015-3327-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 07/14/2015] [Indexed: 12/15/2022]
Abstract
Previous surveys had evaluated the effects of the PD-1, CTLA-4 gene polymorphisms on susceptibility to ankylosing spondylitis (AS), but the results remained controversial. To briefly examine these consequences, a comprehensive meta-analysis was conducted to estimate the relationships between PD-1 rs11568821, rs2227982, rs2227981, CTLA-4 +49 A/G and -318 C/T polymorphisms and AS risk. The available articles dated to December 2014 were searched in the PUBMED, MEDLINE and EMBASE databases. The data of the genotypes and/or alleles for the PD-1 rs11568821, rs2227982, rs2227981, CTLA-4 +49 A/G and -318 C/T polymorphisms in the AS and control subjects were extracted, and statistical analysis was conducted by STATA 11.2 software. Summary odds ratios (ORs) with their 95 % confidence intervals (95 % CIs) were calculated to determine the strength of associations with fixed-effects or random-effects models. A total of eight published studies were finally involved in this meta-analysis. Meta-analysis of PD-1 rs2227982 polymorphism under the T allele versus C allele (OR 1.744, 95 % CI 1.477-2.059, P < 0.0001), TT+TC versus CC (OR 2.292, 95 % CI 1.654-3.175, P < 0.0001), TT versus CC (OR 1.883, 95 % CI 1.299-2.729, P = 0.001) revealed a significant association with AS. Our meta-analysis demonstrated that the rs2227982 polymorphism in the PD-1 gene might contribute to AS susceptibility. However, further studies with large sample sizes and among different ethnicity populations should be required to confirm this association.
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Affiliation(s)
- Si Chen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, 41 Damucang Hutong, Xicheng District, Beijing, 100032, China
| | - Yuan Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, 41 Damucang Hutong, Xicheng District, Beijing, 100032, China
| | - Chuiwen Deng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, 41 Damucang Hutong, Xicheng District, Beijing, 100032, China
| | - Jing Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, 41 Damucang Hutong, Xicheng District, Beijing, 100032, China
| | - Xiaoting Wen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, 41 Damucang Hutong, Xicheng District, Beijing, 100032, China
| | - Ziyan Wu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, 41 Damucang Hutong, Xicheng District, Beijing, 100032, China
| | - Chaojun Hu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, 41 Damucang Hutong, Xicheng District, Beijing, 100032, China
| | - Shulan Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, 41 Damucang Hutong, Xicheng District, Beijing, 100032, China
| | - Ping Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, 41 Damucang Hutong, Xicheng District, Beijing, 100032, China
| | - Xuan Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, 41 Damucang Hutong, Xicheng District, Beijing, 100032, China
| | - Fengchun Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, 41 Damucang Hutong, Xicheng District, Beijing, 100032, China
| | - Yongzhe Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, 41 Damucang Hutong, Xicheng District, Beijing, 100032, China.
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Association of CTLA4 exon-1 polymorphism with the tumor necrosis factor-α in the risk of systemic lupus erythematosus among South Indians. Hum Immunol 2015; 77:158-64. [PMID: 26582004 DOI: 10.1016/j.humimm.2015.11.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Revised: 10/31/2015] [Accepted: 11/12/2015] [Indexed: 11/22/2022]
Abstract
Cytotoxic T lymphocyte associated-antigen (CTLA4) is a potential negative regulatory molecule of T-cells and associated with several autoimmune diseases. Several reports from different ethnic groups showed that the polymorphisms of the CTLA4 gene have been associated with autoimmune diseases including SLE. Therefore, we aimed to investigate the +49 A/G polymorphism in South Indian SLE patients and its association with disease aetiology and serological markers. A total of 534 samples were genotyped for the +49 A/G polymorphism in exon 1 of the CTLA-4 gene through PCR-RFLP method. We found significant association of genotype and allele frequencies with +49 A/G polymorphism in SLE patients. The frequency of the +49 A/G polymorphism rs231775 'GG' genotype was significantly higher in patients with SLE (12.32%) than those in healthy control subjects (4.6%) (OR: 1.797; 95% CI 1.264-2.554; p=0.001). The frequency of mutant allele 'G' also found to be significantly higher in cases (36.01%) than controls (24.92%) (OR: 1.695, 95% CI: 1.298-2.214, p<0.001). We observed significant increase in serum TNF-α, interferon-α, IL-10 and IL-12 in SLE cases compared to controls. We also found a significant association of serum TNF-α, interferon-α, IL-10 and IL-12 with SLE phenotypes. In addition there was a significant increase in serum TNF-α level in "GG" genotype SLE subjects suggesting that it might play a major role in the advancement of SLE disease.
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Lee HJ, Li CW, Hammerstad SS, Stefan M, Tomer Y. Immunogenetics of autoimmune thyroid diseases: A comprehensive review. J Autoimmun 2015; 64:82-90. [PMID: 26235382 DOI: 10.1016/j.jaut.2015.07.009] [Citation(s) in RCA: 208] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 07/15/2015] [Indexed: 12/13/2022]
Abstract
Both environmental and genetic triggers factor into the etiology of autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT). Although the exact pathogenesis and causative interaction between environment and genes are unknown, GD and HT share similar immune-mediated mechanisms of disease. They both are characterized by the production of thyroid autoantibodies and by thyroidal lymphocytic infiltration, despite being clinically distinct entities with thyrotoxicosis in GD and hypothyroidism in HT. Family and population studies confirm the strong genetic influence and inheritability in the development of AITD. AITD susceptibility genes can be categorized as either thyroid specific (Tg, TSHR) or immune-modulating (FOXP3, CD25, CD40, CTLA-4, HLA), with HLA-DR3 carrying the highest risk. Of the AITD susceptibility genes, FOXP3 and CD25 play critical roles in the establishment of peripheral tolerance while CD40, CTLA-4, and the HLA genes are pivotal for T lymphocyte activation and antigen presentation. Polymorphisms in these immune-modulating genes, in particular, significantly contribute to the predisposition for GD, HT and, unsurprisingly, other autoimmune diseases. Emerging evidence suggests that single nucleotide polymorphisms (SNPs) in the immunoregulatory genes may functionally hinder the proper development of central and peripheral tolerance and alter T cell interactions with antigen presenting cells (APCs) in the immunological synapse. Thus, susceptibility genes for AITD contribute directly to the key mechanism underlying the development of organ-specific autoimmunity, namely the breakdown in self-tolerance. Here we review the major immune-modulating genes that are associated with AITD and their potential functional effects on thyroidal immune dysregulation.
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Affiliation(s)
- Hanna J Lee
- Division of Endocrinology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Cheuk Wun Li
- Division of Endocrinology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sara Salehi Hammerstad
- Division of Endocrinology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pediatrics, Oslo University Hospital, Ullevål, Oslo, Norway
| | - Mihaela Stefan
- Division of Endocrinology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yaron Tomer
- Division of Endocrinology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Bronx VA Medical Center, Bronx, NY, USA.
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Jeffery LE, Qureshi OS, Gardner D, Hou TZ, Briggs Z, Soskic B, Baker J, Raza K, Sansom DM. Vitamin D Antagonises the Suppressive Effect of Inflammatory Cytokines on CTLA-4 Expression and Regulatory Function. PLoS One 2015; 10:e0131539. [PMID: 26134669 PMCID: PMC4489761 DOI: 10.1371/journal.pone.0131539] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 06/03/2015] [Indexed: 12/12/2022] Open
Abstract
The immune suppressive protein CTLA-4 is constitutively expressed by Tregs and induced in effector T cells upon activation. Its crucial role in adaptive immunity is apparent from the fatal autoimmune pathology seen in CTLA-4 knockout mice. However, little is known regarding factors that regulate CTLA-4 expression and their effect upon its function to remove CD80 and CD86 from antigen presenting cells by transendocytosis. Th17 cells are emerging as significant players in autoimmunity as well as other diseases. Therefore, in this study we have examined the effects of Th17 polarising conditions on CTLA-4 expression and function in human T cells and show that Th17 conditions can suppress the expression of CTLA-4 and its transendocytic function. In contrast to Th17 cells, vitamin D is inversely associated with autoimmune disease. We have previously shown a striking ability of 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) to enhance CTLA-4, however, its effects upon B7 transendocytosis and its activity in the context of inflammation remained unknown. Here we show that induction of CTLA-4 by 1,25(OH)2D3 can actually be enhanced in the presence of Th17 polarising cytokines. Furthermore, its transendocytic function was maintained such that T cells generated in the presence of Th17 conditions and 1,25(OH)2D3 were highly effective at capturing CTLA-4 ligands from antigen presenting cells and suppressing T cell division. Taken together, these data reveal an inhibitory effect of Th17 polarising conditions upon CTLA-4-mediated regulation and show that 1,25(OH)2D3 counteracts this effect. Given the importance of CTLA-4-mediated suppression in the control of autoimmune diseases, our novel data highlight the importance of vitamin D in inflammatory settings.
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Affiliation(s)
- Louisa E. Jeffery
- Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, United Kingdom
| | - Omar S. Qureshi
- Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, United Kingdom
| | - David Gardner
- Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, United Kingdom
| | - Tie Z. Hou
- UCL Institute of Immunity and Transplantation, Royal Free Campus, University College London, London, United Kingdom
| | - Zoe Briggs
- Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, United Kingdom
| | - Blagoje Soskic
- UCL Institute of Immunity and Transplantation, Royal Free Campus, University College London, London, United Kingdom
| | - Jennifer Baker
- Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, United Kingdom
| | - Karim Raza
- Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, United Kingdom
- Department of Rheumatology, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, United Kingdom
- * E-mail:
| | - David M. Sansom
- UCL Institute of Immunity and Transplantation, Royal Free Campus, University College London, London, United Kingdom
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Ruhi Ç, Sallakçi N, Yeğin O, Süleymanlar G, Ersoy FF. The influence of CTLA-4 single nucleotide polymorphisms on acute kidney allograft rejection in Turkish patients. Clin Transplant 2015; 29:612-8. [PMID: 25981560 DOI: 10.1111/ctr.12563] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2015] [Indexed: 01/06/2023]
Abstract
Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a cell surface protein, which down-regulates the immune response at CTLA-4/CD28/B7 pathway. We aimed to investigate the influence of the -318 C/T, +49 A/G, -1661 A/G and CT60A/G, and CTLA-4 gene polymorphisms on acute rejection of kidney allograft in Turkish patients. The study design was a case-control study that consists of three groups: Group 1 (n = 34) represented the kidney transplant (Ktx) recipients who experienced acute rejection, Group 2 (n = 47) was randomly assigned Ktx recipients without acute rejection, and Group 3 (n = 50) consisting of healthy volunteers to evaluate the normal genomic distribution. The polymerase chain reaction-restriction fragment length polymorphism technique was used to determine the polymorphisms. Genotype and allele frequencies among three groups denoted similar distributions for +49 A/G, -1661 A/G, and CT60A/G. Conversely, -318 C/T genotype was three times more frequent in the acute rejection group than in the non-rejection group (OR = 3.45; 95%CI = 1.18-10.1, p = 0.015) and two times more frequent than the healthy control group (OR = 2.45; 95% CI = 0.98 - 6.11, p = 0.047). Additionally, having a T allele at -318 position was significantly associated with acute rejection (0.147 vs. 0.043, OR = 3.45; 95% CI = 1.13-10.56, p = 0.02). 318C/T gene polymorphism and T allelic variant were found to be associated with increased acute rejection risk in Turkish kidney allograft recipients.
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Affiliation(s)
- Çağlar Ruhi
- Transplantation Center and Health Sciences Research Center, Akdeniz University Medical School, Antalya, Turkey
| | - Nilgün Sallakçi
- Transplantation Center and Health Sciences Research Center, Akdeniz University Medical School, Antalya, Turkey
| | - Olcay Yeğin
- Transplantation Center and Health Sciences Research Center, Akdeniz University Medical School, Antalya, Turkey
| | - Gültekin Süleymanlar
- Transplantation Center and Health Sciences Research Center, Akdeniz University Medical School, Antalya, Turkey
| | - F Fevzi Ersoy
- Transplantation Center and Health Sciences Research Center, Akdeniz University Medical School, Antalya, Turkey
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Lee YH, Bae SC, Song GG. Association between the CTLA-4, CD226, FAS polymorphisms and rheumatoid arthritis susceptibility: a meta-analysis. Hum Immunol 2015; 76:83-9. [PMID: 25645050 DOI: 10.1016/j.humimm.2015.01.023] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Revised: 10/03/2014] [Accepted: 01/15/2015] [Indexed: 12/30/2022]
Abstract
OBJECTIVE We explored whether cytotoxic T lymphocyte antigen-4 (CTLA-4) rs5742909, CD226 rs763361, FAS rs1800682, and FASL rs763110 polymorphisms are associated with rheumatoid arthritis (RA). METHODS We performed a meta-analysis on the association between the four gene polymorphisms and RA. RESULTS Nineteen studies were included in the meta-analysis. Meta-analysis of all study subjects showed no association between RA and the CTLA-4 rs5742909 T allele (OR=1.057, 95% CI=0.782-1.429, p=0.719). However, the meta-analysis revealed an association between RA and the CD226 rs763361 T allele in all study subjects (OR=1.294, 95% CI=1.063-1.576, p=0.010), and an association was found between the CD226 rs763361 TT genotype and RA in Asians (OR=1.363, 95% CI=1.126-1.651, p=0.001). Meta-analysis showed no association between RA and the FAS rs1800682 G/A polymorphism. However, meta-analysis revealed an association between RA and the FASL rs763110 T allele in all study subjects (OR=1.366, 95% CI=1.093-1.707, p=0.006) and in Asians (OR=1.402, 95% CI=1.059-1.855, p=0.014). CONCLUSIONS Our meta-analysis demonstrates that the CD226 rs763361 and FASL rs763110 polymorphisms are associated with RA, especially in Asians.
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Affiliation(s)
- Young Ho Lee
- Division of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea.
| | - Sang-Cheol Bae
- Division of Rheumatology, Department of Internal Medicine, The Hospital for Rheumatic Diseases, Hanyang University Medical Center, Seoul, South Korea
| | - Gwan Gyu Song
- Division of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea
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CTLA4 variants and haplotype contribute genetic susceptibility to myasthenia gravis in northern Chinese population. PLoS One 2014; 9:e101986. [PMID: 25003519 PMCID: PMC4086970 DOI: 10.1371/journal.pone.0101986] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Accepted: 06/13/2014] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Cytotoxic T lymphocyte-associated antigen-4 (CTLA4), a critical negative regulator of the T-cell response, has been considered a candidate for many autoimmune diseases. Evidence from Caucasians supported a genetic predisposition of CTLA4 to myasthenia gravis (MG), but the contribution in East Asians has not been established. OBJECTIVES To investigate the role of CTLA4 variants in the susceptibility to MG and the contribution to subtypes of MG. METHODS Six autoimmune disease-related risk alleles of CTLA4 (rs1863800, rs733618, rs4553808, rs5742909, rs231775, and rs3087243) were investigated for MG in northern Chinese. 168 patients with MG (mean age 37.1±20.5 years, 64 men and 104 women) and 233 healthy controls (mean age 53.3±8.7 years, 96 men and 137 women) were screened, and the contribution of CTLA4 to the general risk of MG and each subgroup was explored. RESULTS rs1863800*C, rs733618*C, and rs231775*G were significantly associated with the whole cohort of patients with MG after permutation correction for multiple-testing adjustment (P = 0.027, 0.001, and 0.032, respectively). A risk haplotype (CCACG) [odds ratio (OR) = 1.535, range = 1.150-2.059, P = 0.004)] was also identified. The stratified subtype analysis indicated that the positive contribution was possibly derived from early onset MG (EOMG), seropositive MG (SPMG), female patients, and MG without thymoma. No association was observed in juvenile MG/LOMG, and MG coupled with thymoma. CONCLUSION A predisposing effect of rs1863800*C, rs733618*C, and rs231775*G of CTLA4 gene to general risk of MG in Chinese was demonstrated for the first time, which was likely derived from EOMG, SPMG, MG without thymoma and the female patients.
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30
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AlFadhli S, Nizam R. Differential expression of alternative splice variants of CTLA4 in Kuwaiti autoimmune disease patients. Gene 2014. [DOI: 10.1016/j.gene.2013.10.034] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Ceeraz S, Nowak EC, Burns CM, Noelle RJ. Immune checkpoint receptors in regulating immune reactivity in rheumatic disease. Arthritis Res Ther 2014; 16:469. [PMID: 25606596 PMCID: PMC4289356 DOI: 10.1186/s13075-014-0469-1] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Immune checkpoint regulators are critical modulators of the immune system, allowing the initiation of a productive immune response and preventing the onset of autoimmunity. Co-inhibitory and co-stimulatory immune checkpoint receptors are required for full T-cell activation and effector functions such as the production of cytokines. In autoimmune rheumatic diseases, impaired tolerance leads to the development of diseases such as rheumatoid arthritis, systemic lupus erythematosus, and Sjogren's syndrome. Targeting the pathways of the inhibitory immune checkpoint molecules CD152 (cytotoxic T lymphocyte antigen-4) and CD279 (programmed death-1) in cancer shows robust anti-tumor responses and tumor regression. This observation suggests that, in autoimmune diseases, the converse strategy of engaging these molecules may alleviate inflammation owing to the success of abatacept (CD152-Ig) in rheumatoid arthritis patients. We review the preclinical and clinical developments in targeting immune checkpoint regulators in rheumatic disease.
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Affiliation(s)
- Sabrina Ceeraz
- />Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, 1 Medical Center Drive, Lebanon, NH 03756 USA
| | - Elizabeth C Nowak
- />Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, 1 Medical Center Drive, Lebanon, NH 03756 USA
| | - Christopher M Burns
- />Department of Medicine, Section of Rheumatology, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, 1 Medical Center Drive, Lebanon, NH 03756 USA
| | - Randolph J Noelle
- />Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, 1 Medical Center Drive, Lebanon, NH 03756 USA
- />Medical Research Council Centre of Transplantation, Guy’s Hospital, King’s College London, London, SE1 9RT UK
- />Department of Immune Regulation and Intervention, King’s College London, King’s Health Partners, London, SE1 9RT UK
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Chuang WY, Ströbel P, Bohlender-Willke AL, Rieckmann P, Nix W, Schalke B, Gold R, Opitz A, Klinker E, Inoue M, Müller-Hermelink HK, Saruhan-Direskeneli G, Bugert P, Willcox N, Marx A. Late-onset myasthenia gravis - CTLA4(low) genotype association and low-for-age thymic output of naïve T cells. J Autoimmun 2013; 52:122-9. [PMID: 24373506 DOI: 10.1016/j.jaut.2013.12.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2013] [Accepted: 12/08/2013] [Indexed: 11/28/2022]
Abstract
Late-onset myasthenia gravis (LOMG) has become the largest MG subgroup, but the underlying pathogenetic mechanisms remain mysterious. Among the few etiological clues are the almost unique serologic parallels between LOMG and thymoma-associated MG (TAMG), notably autoantibodies against acetylcholine receptors, titin, ryanodine receptor, type I interferons or IL-12. This is why we checked LOMG patients for two further peculiar features of TAMG - its associations with the CTLA4(high/gain-of-function) +49A/A genotype and with increased thymic export of naïve T cells into the blood, possibly after defective negative selection in AIRE-deficient thymomas. We analyzed genomic DNA from 116 Caucasian LOMG patients for CTLA4 alleles by PCR/restriction fragment length polymorphism, and blood mononuclear cells for recent thymic emigrants by quantitative PCR for T cell receptor excision circles. In sharp contrast with TAMG, we now find that: i) CTLA4(low) +49G(+) genotypes were more frequent (p = 0.0029) among the 69 LOMG patients with age at onset ≥60 years compared with 172 healthy controls; ii) thymic export of naïve T cells from the non-neoplastic thymuses of 36 LOMG patients was lower (p = 0.0058) at diagnosis than in 77 age-matched controls. These new findings are important because they suggest distinct initiating mechanisms in TAMG and LOMG and hint at aberrant immuno-regulation in the periphery in LOMG. We therefore propose alternate defects in central thymic or peripheral tolerance induction in TAMG and LOMG converging on similar final outcomes. In addition, our data support a 60-year-threshold for onset of 'true LOMG' and an LOMG/early-onset MG overlapping group of patients between 40 and 60.
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Affiliation(s)
- Wen-Yu Chuang
- Institute of Pathology, University of Würzburg, Würzburg, Germany; Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
| | - Philipp Ströbel
- Institute of Pathology, University of Würzburg, Würzburg, Germany; Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68135 Mannheim, Germany.
| | - Anna-Lena Bohlender-Willke
- Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68135 Mannheim, Germany.
| | - Peter Rieckmann
- Department of Neurology, University of Würzburg, Würzburg, Germany.
| | - Wilfred Nix
- Department of Neurology, University of Mainz, Langenbeckstrasse 1, D-55101 Mainz, Germany.
| | - Berthold Schalke
- Department of Neurology, University of Regensburg, Bezirkskrankenhaus, D-93042 Regensburg, Germany.
| | - Ralf Gold
- Department of Neurology, University of Bochum, Bochum, Germany.
| | - Andreas Opitz
- Department of Transfusion Medicine, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany.
| | - Erdwine Klinker
- Department of Transfusion Medicine, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany.
| | - Masayoshi Inoue
- Institute of Pathology, University of Würzburg, Würzburg, Germany.
| | | | - Güher Saruhan-Direskeneli
- Department of Physiology, University of Istanbul, Istanbul Tip Fakultesi, Temel Bilimler, 34093 CAPA-Istanbul, Turkey.
| | - Peter Bugert
- Department of Transfusion Medicine and Immunology, University Medical Centre Mannheim, University of Heidelberg, Germany.
| | - Nick Willcox
- Department of Clinical Neurology, Weatherall Institute for Molecular Medicine, University of Oxford, WIMM, Headington OX3 9DS, UK.
| | - Alexander Marx
- Institute of Pathology, University of Würzburg, Würzburg, Germany; Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68135 Mannheim, Germany.
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Efficacy of abatacept for arthritis in patients with an overlap syndrome between rheumatoid arthritis and systemic lupus erythematosus. Clin Dev Immunol 2013; 2013:697525. [PMID: 24324510 PMCID: PMC3845485 DOI: 10.1155/2013/697525] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2013] [Accepted: 10/01/2013] [Indexed: 11/19/2022]
Abstract
Introduction. This study aimed to investigate the efficacy of abatacept for arthritis in patients with rhupus, an overlap syndrome between rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Methods. Patients who fulfilled both the 2010 ACR/EULAR criteria for RA classification and the 1997 ACR revised criteria for classification of SLE and received abatacept treatment for arthritis were retrospectively studied. Results. Six rhupus patients who fulfilled the inclusion criteria above were identified. All patients had active arthritis despite receiving antirheumatic drugs including methotrexate when abatacept was initiated. Clinical Disease Activity Index (CDAI) significantly decreased between baseline and 12 weeks (P = 0.028) and remained low through 24 weeks. All patients achieved either a good or moderate response according to the EULAR response criteria at 24 weeks. Health Assessment Questionnaire-Disability Index (HAQ-DI) also significantly decreased between baseline and 24 weeks (P = 0.043). In addition, the levels of immunoglobulin G and anti-DNA antibody significantly decreased between baseline and 24 weeks (P = 0.028 and P = 0.043, resp.). Conclusions. Treatment with abatacept is likely to be efficacious in patients with rhupus whose arthritis is refractory to methotrexate. In addition, abatacept may have a moderate effect on abnormal antibody production in rhupus patients.
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Song GG, Kim JH, Kim YH, Lee YH. Association between CTLA-4 polymorphisms and susceptibility to Celiac disease: A meta-analysis. Hum Immunol 2013; 74:1214-8. [DOI: 10.1016/j.humimm.2013.05.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2012] [Revised: 04/12/2013] [Accepted: 05/29/2013] [Indexed: 10/26/2022]
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Zhai JX, Zou LW, Zhang ZX, Fan WJ, Wang HY, Liu T, Ren Z, Dai RX, Ye D. CTLA-4 polymorphisms and systemic lupus erythematosus (SLE): a meta-analysis. Mol Biol Rep 2013; 40:5213-23. [PMID: 23922195 DOI: 10.1007/s11033-012-2125-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2012] [Accepted: 10/03/2012] [Indexed: 11/25/2022]
Abstract
The aim of this study was to summarize results on the association of cytotoxic T-lymphocyte antigen-4 (CTLA-4) promoter exon-1 +49 and 1722T/C polymorphism with systemic lupus erythematosus (SLE) susceptibility by using the meta-analysis. We searched all the publications about the association between CTLA-4) promoter exon-1 +49 and 1722T/C polymorphism and SLE from PubMed, Elsevier Science Direct, Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI), and Wanfang (Chinese). Previous CTLA-4 association studies with SLE, however, have produced inconsistent results. We have performed a meta-analysis to better assess the purported associations. A total of 17 independent studies (to June 2012) testing association between one or more CTLA-4 polymorphisms and SLE were used in this analysis. We have compared allele and genotype frequencies at two polymorphic sites found in exon-1 (at +49) and the promoter region (at -1722). The data demonstrate that the exon-1 +49 polymorphism is associated with SLE susceptibility in Asian population. The overall risk, measured by odds ratio (OR), stratification by ethnicity indicates the exon-1 +49 GG+GA genotype is associated with SLE, at least in Asians (OR = 0.85, 95 % CI = 0.73-0.99, P = 0.04 for GG+GA vs. AA; OR = 0.85, 95 % CI = 0.72-1.00, P = 0.05 for AG vs. AA). Similar trends are found in allele-specific risk estimates and disease association. Overall, there was significant association between the 1722T/C polymorphism and overall SLE risks (OR = 0.78, 95 % CI = 0.63-0.97, P = 0.04 for GG+GA vs. AA, OR = 0.87, 95 % CI = 0.76-0.99, P = 0.04 for G vs. A) in Asian population.In summary, this meta-analysis demonstrates that the CTLA-4 promoter +49A/G and promoter -1722C/T polymorphism may confer susceptibility to SLE, especially in Asian-derived population.
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Affiliation(s)
- Jin-Xia Zhai
- Department of Occupational and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, China
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da Silva Fonseca AM, de Azevedo Silva J, Pancotto JAT, Donadi EA, Segat L, Crovella S, Sandrin-Garcia P. Polymorphisms in STK17A gene are associated with systemic lupus erythematosus and its clinical manifestations. Gene 2013; 527:435-9. [PMID: 23860322 DOI: 10.1016/j.gene.2013.06.074] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Revised: 06/15/2013] [Accepted: 06/21/2013] [Indexed: 01/15/2023]
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disorder with several clinical manifestations. SLE etiology has a strong genetic component, which plays a key role in disease's predisposition, as well as participation of environmental factors, such and UV light exposure. In this regard, we investigated whether polymorphisms in STK17A, a DNA repair related gene, encoding for serine/threonine-protein kinase 17A, are associated with SLE susceptibility. A total of 143 SLE patients and 177 healthy controls from Southern Brazil were genotyped for five STK17A TagSNPs. Our results indicated association of rs7805969 SNP (A and G/A genotype, OR=1.40 and OR=1.73, respectively) with SLE predisposition and the following clinical manifestations: arthritis, cutaneous and immunological alterations. When analyzing haplotypes distribution, we found association between TGGTC, TAGTC and AAGAT haplotypes and risk to develop SLE. When considering clinical manifestations, the haplotypes TGGTT and TAGTC were associated with protection against cutaneous alterations and the haplotype TAGTC to hematological alterations. We also observed association between SLE clinical manifestations and ethnicity, with the European-derived patients being more susceptible to cutaneous and hematological alterations.
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Romo-Tena J, Gómez-Martín D, Alcocer-Varela J. CTLA-4 and autoimmunity: new insights into the dual regulator of tolerance. Autoimmun Rev 2013; 12:1171-6. [PMID: 23851140 DOI: 10.1016/j.autrev.2013.07.002] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2013] [Accepted: 07/07/2013] [Indexed: 12/23/2022]
Abstract
Cytotoxic T-Lymphocye Antigen 4 (CTLA-4) or CD152 is an inhibitory molecule that plays a critical role in maintenance of tolerance to self-antigens. CTLA-4 is structurally as well as functionally related to CD28, since it shares 31% of homology and binds the B7 family molecules CD80 and CD86 with higher affinity. Nevertheless, CTLA-4 has opposing effects on T cell activation and current evidence shows that its inhibitory role goes beyond the ligand-binding interaction. CTLA-4 competes with CD28 in binding to B7, interacts within the immunological synapsis elements and with clathrin adaptor proteins and tyrosine phosphatases through its cytoplasmic domain to regulate cell trafficking and to set the activation threshold within T cells. Moreover, we have learned from the knock out model that CTLA-4 plays a key role in regulatory T cells and in central tolerance. Because of its importance in maintenance of peripheral tolerance, CTLA-4 has been implicated in several autoimmune diseases, such as systemic lupus erythematosus. Multiple single-nucleotide polymorphisms have been located to human Ctla-4 gene, and their association with autoimmune disease is still a matter of controversy. Despite the promising results of abatacept or CTLA-4-Ig in rheumatoid arthritis and murine lupus nephritis, more clinical randomized trials and standardization of outcomes are needed to prove its efficacy and safety in human lupus nephritis.
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Affiliation(s)
- Jorge Romo-Tena
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Tlalpan 14000, Mexico City, Mexico
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Ctla-4 expression and polymorphisms in lung tissue of patients with diagnosed non-small-cell lung cancer. BIOMED RESEARCH INTERNATIONAL 2013; 2013:576486. [PMID: 23936819 PMCID: PMC3722891 DOI: 10.1155/2013/576486] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Revised: 06/19/2013] [Accepted: 06/23/2013] [Indexed: 12/04/2022]
Abstract
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a potent immunoregulatory molecule that downregulates T-cell activation and thus influences the antitumor immune response. CTLA-4 polymorphisms are associated with various cancers, and CTLA-4 mRNA/protein increased expression is found in several tumor types. However, most of the studies are based on peripheral blood mononuclear cells, and much less is known about the relationship between CTLA-4 expression, especially gene expression, and its polymorphic variants in cancer tissue. In our study we assessed the distribution of CTLA-4 two polymorphisms (+49A/G and −318C/T), using TaqMan probes (rs231775 and rs5742909, resp.), and CTLA-4 gene expression in real-time PCR assay in non-small-cell lung cancer (NSCLC) tissue samples. The increased CTLA-4 expression was observed in the majority of NSCLC patients, and it was significantly correlated with TT genotype (−318C/T) and with tumor size (T2 versus T3 + T4). The presence of G allele and GG genotype in cancer tissue (+49A/G) was significantly associated with the increased NSCLC risk. Additionally, we compared genotype distributions in the corresponding tumor and blood samples and found statistically significant differences. The shift from one genotype in the blood to another in the tumor may confirm the complexity of gene functionality in cancer tissue.
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Gyu Song G, Ho Lee Y. CTLA-4 +49 A/G and −318 C/T polymorphisms and susceptibility to multiple sclerosis: a meta-analysis. Immunol Invest 2013; 42:409-22. [DOI: 10.3109/08820139.2013.803114] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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Song GG, Lee YH. The CTLA-4 and MCP-1 polymorphisms and susceptibility to systemic sclerosis: a meta-analysis. Immunol Invest 2013; 42:481-92. [PMID: 23782302 DOI: 10.3109/08820139.2013.789910] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE The aim of this study was to explore whether cytotoxic T lymphocyte antigen-4 (CTLA-4) and monocyte chemoattractant protein-1 (MCP-1) polymorphisms confer susceptibility to systemic sclerosis (SSc). METHODS MEDLINE and manual search were utilized to identify available articles. A meta-analysis was conducted on the associations between the CTLA-4 +49 A/G, -318 C/T, -1661 A/G, and -1722 C/T, and MCP-1 -2518 A/G polymorphisms, using a fixed-effect or random-effect model based on between-study heterogeneity. RESULTS Eleven comparative studies involving 959 SSc patients and 1739 controls were included in the meta-analysis. No association was found between SSc and the CTLA-4 +49 A/G polymorphism (OR for the +49 G allele = 1.032, 95% CI = 0.830-1.283, p = 0.779). However, an association between SSc and the CTLA-4 -318 TT + TC genotype (OR = 1.642, 95% CI = 1.034-2.609, p = 0.036). Meta-analyses failed to reveal an association between SSc and CTLA-4 -1722 C/T, MCP-1 -2518 A/G polymorphisms. CONCLUSIONS This meta-analysis of published data shows that the CTLA-4 -318 C/T polymorphism confers susceptibility to SSc.
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Affiliation(s)
- Gwan Gyu Song
- Division of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Seoul 136-705, Korea
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41
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Shojaa M, Javid N, Amoli M, Shakeri F, Samaei NM, Aghaie M, Khashayar P, Livani S. No evidence of association betweenCTLA-4polymorphisms and systemic lupus erythematosus in Iranian patients. Int J Rheum Dis 2013; 16:681-4. [DOI: 10.1111/1756-185x.12097] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Mahdieh Shojaa
- Protection Unit of Clinical Research Center; Golestan University of Medical Sciences; Gorgan Iran
- Endocrinology and Metabolism Research Institute; Tehran University of Medical Sciences; Tehran Iran
| | - Naemeh Javid
- Faculty of Medicine; Department of Microbiology; Infection Disease Research Center; Golestan University of Medical Sciences; Gorgan Iran
| | - Mahsa Amoli
- Endocrinology and Metabolism Research Institute; Tehran University of Medical Sciences; Tehran Iran
| | - Fatemeh Shakeri
- Department of Microbiology; Payam Noor University of Golestan; Gorgan Iran
| | - Nader M. Samaei
- Department of Genetics; Congenital Malformations Research Center; OMICS Research Center; Hematology and Oncology Research Center; Golestan University of Medical Sciences, Gorgan Iran
| | - Mehrdad Aghaie
- Faculty of Medicine; Department of Rheumatology; Bone Joint and Connective Tissue Research Center (BJCRC); Golestan University of Medical Sciences; Gorgan Iran
| | - Patricia Khashayar
- Osteoporosis Research Center; Endocrinology and Metabolism Clinical Sciences Institute; Tehran University of Medical Sciences; Tehran Iran
| | - Sedigheh Livani
- Endocrinology and Metabolism Research Institute; Tehran University of Medical Sciences; Tehran Iran
- Faculty of Medicine; Department of Microbiology; Infection Disease Research Center; Golestan University of Medical Sciences; Gorgan Iran
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42
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Hou X, Zhang P, Nie W, Tang S, Wang J, Zhang Q, Wan Z, Zhang B, Song B. Association between angiotensin-converting enzyme I/D polymorphism and sepsis: A meta-analysis. J Renin Angiotensin Aldosterone Syst 2013; 16:415-21. [PMID: 23748624 DOI: 10.1177/1470320313492361] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Accepted: 03/26/2013] [Indexed: 11/16/2022] Open
Affiliation(s)
- Xin Hou
- Department of General Surgery, The First People’s Hospital of Jingzhou, Jingzhou, China
| | - Pan Zhang
- Department of Nephrology, The First People’s Hospital of Jingzhou, Jingzhou, China
| | - Wei Nie
- Department of Respiratory Disease, Shanghai Changzheng Hospital, Shanghai, China
| | - Shunjuan Tang
- Department of General Surgery, The First People’s Hospital of Jingzhou, Jingzhou, China
| | - Jiuyan Wang
- Department of General Surgery, The First People’s Hospital of Jingzhou, Jingzhou, China
| | - Qiong Zhang
- Department of General Surgery, The First People’s Hospital of Jingzhou, Jingzhou, China
| | - Zhengdong Wan
- Department of General Surgery, The First People’s Hospital of Jingzhou, Jingzhou, China
| | - Botao Zhang
- Department of General Surgery, The First People’s Hospital of Jingzhou, Jingzhou, China
| | - Bin Song
- Department of General Surgery, The First People’s Hospital of Jingzhou, Jingzhou, China
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Xu H, Zhao M, He J, Chen Z. Association between cytotoxic T-lymphocyte associated protein 4 gene +49 A/G polymorphism and chronic infection with hepatitis B virus: a meta-analysis. J Int Med Res 2013; 41:559-67. [PMID: 23669295 DOI: 10.1177/0300060513483387] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE This meta-analysis determined the relationship between polymorphisms of the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) gene and hepatitis B virus (HBV) clearance in chronic hepatitis B. METHODS Published studies reporting associations between CTLA4 gene +49A/G polymorphisms and chronic HBV infection were reviewed. Odds ratio (OR) and 95% confidence interval (CI) were calculated to assess the risk of persistent HBV according to genotype. RESULTS Six studies, involving 1076 chronic HBV patients and 1294 controls, were included. The risk of persistent HBV in patients with a +49 GG/AG genotype decreased significantly compared with the AA genotype (OR 0.65; 95% CI 0.52, 0.82). The variant G allele was negatively associated with chronic HBV infection versus the A allele (OR 0.77; 95% CI 0.68, 0.88). When stratifying by type of study control, a significantly decreased risk was associated with CTLA4+49 variant genotypes (AG and GG) in both spontaneous recovery control group and healthy control group. CONCLUSIONS Findings of this meta-analysis suggest that A at position +49 of the CTLA4 gene may significantly increase the risk of persistent HBV infection, whereas G at position +49 may positively influence virus clearance.
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Affiliation(s)
- Hangdi Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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Ji R, Feng Y, Zhan WW. Updated analysis of studies on the cytotoxic T-lymphocyte-associated antigen-4 gene A49G polymorphism and Hashimoto's thyroiditis risk. GENETICS AND MOLECULAR RESEARCH 2013; 12:1421-30. [PMID: 23661465 DOI: 10.4238/2013.april.26.4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Published data on the association between the cytotoxic T-lymphocyte-associated antigen-4 gene A49G polymorphism and the risk for Hashimoto's thyroiditis (HT) are inconclusive. A meta-analysis was performed to derive a more precise estimation. Published case-control studies in English or Chinese were identified. In total, 24 studies with 2295 cases and 4521 controls were investigated. A random-effect model was performed irrespective of between-study heterogeneity. Study quality was assessed in duplicate, and subgroup analyses were conducted by ethnicity or age. Overall, the 49G allele was associated with an increase in HT risk [odds ratio (OR) = 1.31; 95% confidence interval (95%CI) = 1.17-1.47; P < 0.00001]. In a subgroup analysis by ethnicity, comparison of allele 49G with 49A generated a 27% increased risk among East Asians (OR = 1.48; 95%CI = 1.24-1.76; P < 0.00001) and whites (OR = 1.27; 95%CI = 1.12-1.44; P = 0.0002). We also found an increased risk among adults (OR = 1.31; 95%CI = 1.17-1.47; P < 0.00001) but not among children (OR = 1.44; 95%CI = 0.75-2.79; P = 0.27), possibly owing to the small sample sizes in children. No publication biases were observed. This meta-analysis suggested that the cytotoxic T-lymphocyte-associated antigen-4 gene 49G allele was associated with an increased HT risk, especially in adults.
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Affiliation(s)
- R Ji
- Department of Ultrasonography, School of Medicine, Ruijin Hospital, Shanghai Jiaotong University, Shanghai, China
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45
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Ichinose K, Zhang Z, Koga T, Juang YT, Kis-Tóth K, Sharpe AH, Kuchroo V, Crispín JC, Tsokos GC. Brief report: increased expression of a short splice variant of CTLA-4 exacerbates lupus in MRL/lpr mice. ACTA ACUST UNITED AC 2013. [PMID: 23203389 DOI: 10.1002/art.37790] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE CTLA-4 is a negative regulator of the immune response expressed by regulatory T (Treg) cells and activated T cells. Polymorphisms in the CTLA4 gene have been associated with autoimmune diseases, including systemic lupus erythematosus. Disease-associated polymorphisms have been shown to affect the production of the different CTLA-4 variants through an effect on alternative splicing. This study was undertaken to evaluate the role of the 1/4 CTLA-4 isoform in lupus-prone mice. METHODS We generated an MRL/lpr mouse strain that transgenically overexpresses a short isoform of CTLA-4 (1/4 CTLA-4) by backcrossing C57BL/6.1/4CTLA-4-transgenic mice to the MRL/lpr strain for 9 generations. A new antibody was generated to detect the expression of the 1/4 CTLA-4 isoform. Routine methods were used to evaluate kidney damage, humoral immunity, and cellular immunity. RESULTS Expression of the 1/4 CTLA-4 isoform accelerated autoimmune disease. Transgenic mice died earlier, had more severe renal disease, and had higher titers of anti-double-stranded DNA antibodies than wild-type MRL/lpr mice. The acceleration of autoimmunity and disease pathology associated with the presence of the short (1/4) isoform of CTLA-4 was linked to increased numbers of activated T cells and B cells and heightened interferon-γ production, but not to altered expression of the full-length CTLA-4 molecule or Treg cell numbers. CONCLUSION Our results indicate that the presence of the alternatively spliced 1/4 CTLA-4 isoform can further promote autoimmunity and autoimmune pathology in lupus-prone mice and suggest that altered splicing of CTLA4 contributes to the expression of autoimmune disease.
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Affiliation(s)
- Kunihiro Ichinose
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
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Song GG, Kim JH, Lee YH. The CTLA-4 +49 A/G, CT60 A/G and PTPN22 1858 C/T polymorphisms and susceptibility to vitiligo: a meta-analysis. Mol Biol Rep 2012; 40:2985-93. [DOI: 10.1007/s11033-012-2370-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2012] [Accepted: 12/17/2012] [Indexed: 02/07/2023]
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Gibson HM, Mishra A, Chan DV, Hake TS, Porcu P, Wong HK. Impaired proteasome function activates GATA3 in T cells and upregulates CTLA-4: relevance for Sézary syndrome. J Invest Dermatol 2012; 133:249-57. [PMID: 22951729 DOI: 10.1038/jid.2012.265] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Highly regulated expression of the negative costimulatory molecule cytotoxic T-lymphocyte antigen-4 (CTLA-4) on T cells modulates T-cell activation and proliferation. CTLA-4 is preferentially expressed in Th2 T cells, whose differentiation depends on the transcriptional regulator GATA3. Sézary syndrome (SS) is a T-cell malignancy characterized by Th2 cytokine skewing, impaired T-cell responses, and overexpression of GATA3 and CTLA-4. GATA3 is regulated by phosphorylation and ubiquitination. In SS cells, we detected increased polyubiquitinated proteins and activated GATA3. We hypothesized that proteasome dysfunction in SS T cells may lead to GATA3 and CTLA-4 overexpression. To test this hypothesis, we blocked proteasome function with bortezomib in normal T cells, and observed sustained GATA3 and CTLA-4 upregulation. The increased CTLA-4 was functionally inhibitory in a mixed lymphocyte reaction (MLR). GATA3 directly transactivated the CTLA-4 promoter, and knockdown of GATA3 messenger RNA and protein inhibited CTLA-4 induction mediated by bortezomib. Finally, knockdown of GATA3 in patient's malignant T cells suppressed CTLA-4 expression. Here we demonstrate a new T-cell regulatory pathway that directly links decreased proteasome degradation of GATA3, CTLA-4 upregulation, and inhibition of T-cell responses. We also demonstrate the requirement of the GATA3/CTLA-4 regulatory pathway in fresh neoplastic CD4+ T cells. Targeting of this pathway may be beneficial in SS and other CTLA-4-overexpressing T-cell neoplasms.
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Affiliation(s)
- Heather M Gibson
- Division of Dermatology, The Ohio State University, Columbus, OH, USA
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CTLA-4 polymorphisms and susceptibility to Behcet’s disease: a meta-analysis. Mol Biol Rep 2012; 39:9041-5. [DOI: 10.1007/s11033-012-1775-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Accepted: 06/09/2012] [Indexed: 10/28/2022]
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49
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Association between CTLA-4 exon-1 +49A/G polymorphism and systemic lupus erythematosus: an updated analysis. Mol Biol Rep 2012; 39:9159-65. [DOI: 10.1007/s11033-012-1788-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2011] [Accepted: 06/09/2012] [Indexed: 11/25/2022]
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50
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Lee YH, Choi SJ, Ji JD, Song GG. The CTLA-4 +49 A/G and -318 C/T polymorphisms and susceptibility to asthma: a meta-analysis. Mol Biol Rep 2012; 39:8525-32. [PMID: 22707194 DOI: 10.1007/s11033-012-1707-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2012] [Accepted: 06/06/2012] [Indexed: 01/19/2023]
Abstract
The aim of this study was to explore whether cytotoxic T lymphocyte antigen-4 (CTLA-4) +49 A/G, and -318 C/T polymorphisms confer susceptibility to asthma. A meta-analysis was conducted on the associations between the CTLA-4 +49 A/G, and -318 C/T polymorphisms and asthma using; (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. Eight studies on the CTLA-4 polymorphisms and asthma involving 2,330 patients with asthma and 1,743 control subjects were included in this meta-analysis. The meta-analysis revealed an association between asthma and the CTLA-4 +49 A/G polymorphism under the dominant model in Asians (OR = 0.758, 95 % CI = 0.599-0.958, p = 0.020). Stratification by age indicated an association between the CTLA-4 +49 GG+GA genotype and asthma in children (OR = 0.690, 95 % CI = 0.497-0.957, p = 0.026), but not in adults (OR = 0.837, 95 % CI = 0.598-1.172, p = 0.300). Furthermore, stratification by atopy status indicated an association between the CTLA-4 +49 G allele and atopic asthma (OR = 0.639, 95 % CI = 0.464-0.881, p = 0.006), but not non-atopic asthma (OR = 0.706, 95 % CI = 0.385-1.294, p = 0.266). There was no association between asthma and the CTLA-4 -318 C/T polymorphism for the whole population, or when stratified by ethnicity, age, or atopy status. This meta-analysis demonstrates that the CTLA-4 +49 A/G polymorphism confers susceptibility to asthma in Asians, children, patients with atopy status, but there was no association between the CTLA-4 -318 C/T polymorphism and asthma susceptibility.
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Affiliation(s)
- Young Ho Lee
- Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul 136-705, Korea.
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