|
1
|
Gupta M, Graham C, Gupta S. Immune Checkpoint Inhibitor-Associated Celiac Disease: A Retrospective Analysis and Literature Review. Diseases 2024; 12:315. [PMID: 39727645 PMCID: PMC11727056 DOI: 10.3390/diseases12120315] [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: 08/26/2024] [Revised: 10/21/2024] [Accepted: 11/16/2024] [Indexed: 12/28/2024] Open
Abstract
INTRODUCTION Immune checkpoint inhibitors (ICI) are used to treat various malignancies. They block the inhibitory signals of tumor cells and enhance the inflammatory cascade, which results in tumor killing. However, this can lead to unchecked inflammation throughout the body, leading to various adverse effects. A rare gastrointestinal adverse effect of ICI therapy is the development of immune-mediated celiac disease. This entity has a similar clinical presentation to the more common ICI-induced enterocolitis. Our study aims to determine the clinical characteristics and optimal treatment strategies for this rare ICI toxicity and differentiate it from ICI-induced enterocolitis. METHODS AND MATERIAL We conducted a retrospective analysis of eight cases of ICI-induced celiac disease and 24 cases of ICI-induced enterocolitis from the literature. Data on patient demographics, clinical history, therapeutic interventions and outcomes were collected. A comparative analysis was performed to identify the key differences between the two groups. RESULTS Patients with ICI-induced celiac disease were more likely to have a pre-existing autoimmune condition and HLA-DQ2 positivity. Significant differences in clinical manifestations, histological findings, and treatment outcomes were observed. Notably, weight loss, nutritional deficiencies and electrolyte abnormalities were more commonly associated with ICI-induced celiac disease. Regarding pathology, duodenal villous blunting was noted more commonly with ICI-induced celiac disease. Initiating a gluten-free diet led to a rapid improvement in patients with ICI-induced celiac disease, while immunosuppressive therapy did not have an impact. CONCLUSION ICI-induced celiac disease is a rare and underrecognized gastrointestinal adverse effect of ICI therapy, often misdiagnosed as ICI-induced enterocolitis. Early recognition and treatment with a gluten-free diet can lead to rapid symptom resolution, sparing patients from unnecessary systemic immunosuppression and the discontinuation of antineoplastic immunotherapy.
Collapse
Affiliation(s)
- Malvika Gupta
- Kasturba Medical College, Manipal Academy of Higher Education, Mangalore 575001, India;
| | - Christopher Graham
- Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA;
| | - Supriya Gupta
- Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA;
| |
Collapse
|
|
2
|
Verdelho Machado M. Refractory Celiac Disease: What the Gastroenterologist Should Know. Int J Mol Sci 2024; 25:10383. [PMID: 39408713 PMCID: PMC11477276 DOI: 10.3390/ijms251910383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 09/20/2024] [Accepted: 09/25/2024] [Indexed: 10/20/2024] Open
Abstract
Fewer than 1% of patients with celiac disease (CD) will develop refractory CD (RCD). As such, most gastroenterologists might never need to manage patients with RCD. However, all gastroenterologists must be familiarized with the basic concepts of RCD and non-responsive CD (NRCD), since it can present as a severe disease with high mortality, not only due to intestinal failure, but also due to progression to enteropathy-associated T cell lymphoma (EATL) and a higher susceptibility to life-threatening infections. The diagnostic workup and differential diagnosis with other causes of gastrointestinal symptoms and villous atrophy, as well as the differentiation between type I and II RCD, are complex, and may require specialized laboratories and reference hospitals. Immunosuppression is efficient in the milder RCDI; however, the treatment of RCDII falls short, with current options probably only providing transient clinical improvement and delaying EATL development. This review summarizes the current diagnostic and therapeutic approach for patients with RCD that all doctors that manage patients with CD should know.
Collapse
Affiliation(s)
- Mariana Verdelho Machado
- Gastroenterology Department, Hospital de Vila Franca de Xira, 2600-009 Lisbon, Portugal; ; Tel.: +351-912620306
- Gastroenterology Department, Faculdade de Medicina, Lisbon University, 1649-028 Lisboa, Portugal
| |
Collapse
|
|
3
|
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.
Collapse
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
| | | |
Collapse
|
|
4
|
Lapierre P, Alvarez F. Type 2 autoimmune hepatitis: Genetic susceptibility. Front Immunol 2022; 13:1025343. [PMID: 36248826 PMCID: PMC9556705 DOI: 10.3389/fimmu.2022.1025343] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 09/14/2022] [Indexed: 11/13/2022] Open
Abstract
Two types of autoimmune hepatitis (AIH) are recognized; AIH-1 is characterized by the presence of anti-nuclear and/or anti-smooth muscle autoantibodies, while AIH-2 is associated with the presence of anti-Liver kidney microsome and/or anti-Liver Cytosol antibodies. The autoantigens targeted by AIH-2 autoantibodies are the cytochrome P450 2D6 and Formiminotransferase-cyclodeaminase for anti-LKM1 and anti-LC1 respectively. Both autoantigens are expressed in hepatocytes at higher levels than in any other cell type. Therefore, compared to AIH-1, the autoantigens targeted in AIH-2 are predominantly tissue-specific. Distinct clinical features are specific to AIH-2 compared to AIH-1, including diagnosis in younger patients (mean age 6.6 years), onset as fulminant hepatitis in very young patients (3 years of age or less), higher frequency in children than in adults and is frequently associated with extrahepatic T cell-mediated autoimmune diseases. AIH-2 is also often diagnosed in patients with primary immunodeficiency. AIH-2 is associated with specific HLA class II susceptibility alleles; DQB1*0201 is considered the main determinant of susceptibility while DRB1*07/DRB1*03 is associated with the type of autoantibody present. HLA DQB1*0201 is in strong linkage disequilibrium with both HLA DRB1*03 and DRB1*07. Interestingly, as in humans, MHC and non-MHC genes strongly influence the development of the disease in an animal model of AIH-2. Altogether, these findings suggest that AIH-2 incidence is likely dependent on specific genetic susceptibility factors combined with distinct environmental triggers.
Collapse
Affiliation(s)
- Pascal Lapierre
- Laboratoire d’hépatologie cellulaire, Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de médecine, Université de Montréal, Montréal, QC, Canada
| | - Fernando Alvarez
- Service de gastroentérologie, hépatologie et nutrition, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Montréal, QC, Canada
- Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada
- *Correspondence: Fernando Alvarez,
| |
Collapse
|
|
5
|
Chye A, Allen I, Barnet M, Burnett DL. Insights Into the Host Contribution of Endocrine Associated Immune-Related Adverse Events to Immune Checkpoint Inhibition Therapy. Front Oncol 2022; 12:894015. [PMID: 35912205 PMCID: PMC9329613 DOI: 10.3389/fonc.2022.894015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 06/10/2022] [Indexed: 12/12/2022] Open
Abstract
Blockade of immune checkpoints transformed the paradigm of systemic cancer therapy, enabling substitution of a cytotoxic chemotherapy backbone to one of immunostimulation in many settings. Invigorating host immune cells against tumor neo-antigens, however, can induce severe autoimmune toxicity which in many cases requires ongoing management. Many immune-related adverse events (irAEs) are clinically and pathologically indistinguishable from inborn errors of immunity arising from genetic polymorphisms of immune checkpoint genes, suggesting a possible shared driver for both conditions. Many endocrine irAEs, for example, have analogous primary genetic conditions with varied penetrance and severity despite consistent genetic change. This is akin to onset of irAEs in response to immune checkpoint inhibitors (ICIs), which vary in timing, severity and nature despite a consistent drug target. Host contribution to ICI response and irAEs, particularly those of endocrine origin, such as thyroiditis, hypophysitis, adrenalitis and diabetes mellitus, remains poorly defined. Improved understanding of host factors contributing to ICI outcomes is essential for tailoring care to an individual’s unique genetic predisposition to response and toxicity, and are discussed in detail in this review.
Collapse
Affiliation(s)
- Adrian Chye
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, Australia
- Department of Medical Oncology, The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia
| | - India Allen
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, Australia
| | - Megan Barnet
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, Australia
- Department of Medical Oncology, The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia
- *Correspondence: Megan Barnet, ; Deborah L. Burnett,
| | - Deborah L. Burnett
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, Australia
- *Correspondence: Megan Barnet, ; Deborah L. Burnett,
| |
Collapse
|
|
6
|
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
|
|
7
|
D'Avino P, Serena G, Kenyon V, Fasano A. An updated overview on celiac disease: from immuno-pathogenesis and immuno-genetics to therapeutic implications. Expert Rev Clin Immunol 2021; 17:269-284. [PMID: 33472447 DOI: 10.1080/1744666x.2021.1880320] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Celiac disease (CD) is an autoimmune enteropathy triggered by ingestion of gluten. While presenting many similarities with other autoimmune diseases, celiac disease is unique in that the external trigger, gluten, and the genetic background necessary for disease development (HLA DQ2/DQ8) are well described. The prevalence of celiac disease is dramatically increasing over the years and new epidemiologic data show changes regarding age of onset and symptoms. A better understanding of CD-pathogenesis is fundamental to highlight the reasons of this rise of celiac diagnoses. AREAS COVERED In this review we describe CD-pathogenesis by dissecting all the components necessary to lose tolerance to gluten (ingestion of gluten, genetic predisposition, loss of barrier function and immune response). Additionally, we also highlight the role that microbiome plays in celiac disease as well as new proposed therapies and experimental tools. EXPERT OPINION Prevalence of autoimmune diseases is increasing around the world. As a result, modern society is strongly impacted by a social and economic burden. Given the unique characteristics of celiac disease, a better understanding of its pathogenesis and the factors that contribute to it may shed light on other autoimmune diseases for which external trigger and genetic background are not known.
Collapse
Affiliation(s)
- Paolo D'Avino
- Division of Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Mucosal Immunology and Biology Research Center, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Celiac Research Program, Harvard Medical School, Boston, MA, USA.,Vita-Salute San Raffaele University, Milan, Italy
| | - Gloria Serena
- Division of Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Mucosal Immunology and Biology Research Center, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Celiac Research Program, Harvard Medical School, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Victoria Kenyon
- Division of Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Mucosal Immunology and Biology Research Center, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Celiac Research Program, Harvard Medical School, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Alessio Fasano
- Division of Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Mucosal Immunology and Biology Research Center, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Celiac Research Program, Harvard Medical School, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA.,European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy
| |
Collapse
|
|
8
|
Ismail NA, Toraih EA, Ameen HM, Gomaa AHA, Marie RESM. Association of Rs231775 Genetic Variant of Cytotoxic T-lymphocyte Associated Protein 4 with Alopecia Areata Disease in Males: A Case-Control Study. Immunol Invest 2020; 50:977-986. [PMID: 32731768 DOI: 10.1080/08820139.2020.1796700] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
BACKGROUND Alopecia Areata (AA) is a common inflammatory immune-mediated non-scarring hair loss; however, the exact genetic susceptibility remains to be clarified. Cytotoxic T-lymphocyte Associated Protein 4 (CTLA4) has emerged as a central and critically important modulator of immune responses and is believed to play a crucial rule in AA pathogenesis. OBJECTIVES To investigate the association of CTLA4 variant (rs231775) within codon 17 with AA risk and outcomes. METHODS Genetic analyses of the rs231775 SNP of CTLA4 gene were performed in 186 males (93 AA patients and 93 controls). RESULTS The rs231775 CTLA4 variant was significantly higher in AA patients in comparison with control subjects especially among heterozygous and dominant model. This association varied significantly with disease severity. CONCLUSIONS Individuals with homozygosity of rs231775 CTLA4 variant represented AA disease risk and increased severity than their counterparts.Abbreviations: AA: Alopecia areata; CTLA4: Cytotoxic T-lymphocyte Associated Protein 4; SNP: Single nucleotide polymorphism; LADA: Latent autoimmune diabetes in adults; SLE: Systemic lupus erythematosus; SCU: Suez Canal University; SALT: Severity of Alopecia Tool; DNA: Deoxyribonucleic acid; RT-PCR: Real-time polymerase chain reaction, HWE: Hardy-Weinberg equation; RA: rheumatoid arthritis.
Collapse
Affiliation(s)
- Nader Ali Ismail
- Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Eman Ali Toraih
- Medical Genetics Unit, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.,Department of Surgery, School of Medicine, Tulane University, New Orleans, LA, USA
| | - Hatem Mohamed Ameen
- Department of Dermatology, Ministry of Health and Population, Al Qantara East Central Hospital, Ismailia, Egypt
| | - Amal Hussein Ahmed Gomaa
- Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Radwa El-Sayed Mahmoud Marie
- Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| |
Collapse
|
|
9
|
Brown SA, Ray JC, Herrmann J. Precision Cardio-Oncology: a Systems-Based Perspective on Cardiotoxicity of Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors. J Cardiovasc Transl Res 2020; 13:402-416. [PMID: 32253744 PMCID: PMC8855704 DOI: 10.1007/s12265-020-09992-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 03/18/2020] [Indexed: 02/07/2023]
Abstract
Cancer therapies have been evolving from conventional chemotherapeutics to targeted agents. This has fulfilled the hope of greater efficacy but unfortunately not of greater safety. In fact, a broad spectrum of toxicities can be seen with targeted therapies, including cardiovascular toxicities. Among these, cardiomyopathy and heart failure have received greatest attention, given their profound implications for continuation of cancer therapies and cardiovascular morbidity and mortality. Prediction of risk has always posed a challenge and even more so with the newer targeted agents. The merits of accurate risk prediction, however, are very evident, e.g. facilitating treatment decisions even before the first dose is given. This is important for agents with a long half-life and high potential to induced life-threatening cardiac complications, such as myocarditis with immune checkpoint inhibitors. An opportunity to address these needs in the field of cardio-oncology is provided by the expanding repertoire of "-omics" and other tools in precision medicine and their integration in a systems biology approach. This may allow for new insights into patho-mechanisms and the creation of more precise and cost-effective risk prediction tools with the ultimate goals of improved therapy decisions and prevention of cardiovascular complications. Herein, we explore this topic as a future approach to translating the complexity of cardio-oncology to the reality of patient care.
Collapse
Affiliation(s)
- Sherry-Ann Brown
- Department of Cardiovascular Diseases, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA
| | - Jordan C Ray
- Department of Cardiovascular Diseases, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA
| | - Joerg Herrmann
- Department of Cardiovascular Diseases, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA.
| |
Collapse
|
|
10
|
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.
Collapse
|
|
11
|
Chang LS, Barroso-Sousa R, Tolaney SM, Hodi FS, Kaiser UB, Min L. Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints. Endocr Rev 2019; 40:17-65. [PMID: 30184160 PMCID: PMC6270990 DOI: 10.1210/er.2018-00006] [Citation(s) in RCA: 333] [Impact Index Per Article: 55.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 06/07/2018] [Indexed: 12/13/2022]
Abstract
Immune checkpoints are small molecules expressed by immune cells that play critical roles in maintaining immune homeostasis. Targeting the immune checkpoints cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) with inhibitory antibodies has demonstrated effective and durable antitumor activity in subgroups of patients with cancer. The US Food and Drug Administration has approved several immune checkpoint inhibitors (ICPis) for the treatment of a broad spectrum of malignancies. Endocrinopathies have emerged as one of the most common immune-related adverse events (irAEs) of ICPi therapy. Hypophysitis, thyroid dysfunction, insulin-deficient diabetes mellitus, and primary adrenal insufficiency have been reported as irAEs due to ICPi therapy. Hypophysitis is particularly associated with anti-CTLA-4 therapy, whereas thyroid dysfunction is particularly associated with anti-PD-1 therapy. Diabetes mellitus and primary adrenal insufficiency are rare endocrine toxicities associated with ICPi therapy but can be life-threatening if not promptly recognized and treated. Notably, combination anti-CTLA-4 and anti-PD-1 therapy is associated with the highest incidence of ICPi-related endocrinopathies. The precise mechanisms underlying these endocrine irAEs remain to be elucidated. Most ICPi-related endocrinopathies occur within 12 weeks after the initiation of ICPi therapy, but several have been reported to develop several months to years after ICPi initiation. Some ICPi-related endocrinopathies may resolve spontaneously, but others, such as central adrenal insufficiency and primary hypothyroidism, appear to be persistent in most cases. The mainstay of management of ICPi-related endocrinopathies is hormone replacement and symptom control. Further studies are needed to determine (i) whether high-dose corticosteroids in the treatment of ICPi-related endocrinopathies preserves endocrine function (especially in hypophysitis), and (ii) whether the development of ICPi-related endocrinopathies correlates with tumor response to ICPi therapy.
Collapse
Affiliation(s)
- Lee-Shing Chang
- Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Romualdo Barroso-Sousa
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Sara M Tolaney
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - F Stephen Hodi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Ursula B Kaiser
- Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Le Min
- Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| |
Collapse
|
|
12
|
Walker MD, Zylberberg HM, Green PHR, Katz MS. Endocrine complications of celiac disease: a case report and review of the literature. Endocr Res 2019; 44:27-45. [PMID: 30198791 DOI: 10.1080/07435800.2018.1509868] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE The purpose of this article is to review recent literature regarding endocrine disorders related to celiac disease (CD). METHODS We describe a case report and review existing literature on the endocrine manifestations of CD. RESULTS CD is an autoimmune disorder characterized by intestinal inflammation in response to gluten. CD can cause a wide range of extra-intestinal complications, including endocrine manifestations. Metabolic bone disease including osteoporosis and osteopenia, vitamin D deficiency, secondary hyperparathyroidism and less frequently osteomalacia can be seen. In CD, fracture risk is increased by 30-40%, while risk for hip fracture is approximately doubled. The risk for other endocrine disorders, particularly autoimmune endocrinopathies, is also increased in those with CD compared to the general population. Epidemiologic data indicate the risk for hypothyroidism is 3-4 times higher among those with CD, while risk of type 1 diabetes is greater than double. Risk for primary adrenal insufficiency is a striking 11-fold higher in those with versus without CD, though the absolute risk is low. Fertility is reduced in women with CD before diagnosis by 37% while male fertility in the absence of hypogonadism does not appear to be affected. Other endocrine conditions including hyperthyroidism, ovarian failure, androgen insensitivity, impaired growth and growth hormone deficiency and autoimmune polyendocrine syndromes have also been associated with CD. CONCLUSIONS CD is associated with a wide range of endocrine manifestations.
Collapse
Affiliation(s)
- Marcella D Walker
- a Department of Medicine , Columbia University , New York , NY , USA
| | | | - Peter H R Green
- a Department of Medicine , Columbia University , New York , NY , USA
| | - Michael S Katz
- c Department of Medicine , University of Texas Health Science Center at San Antonio , San Antonio , TX , USA
| |
Collapse
|
|
13
|
Chaouali M, Carvalho A, Tezeghdenti A, Ben Azaiez M, Cunha C, Ghazouani E, Kochkar R. Cytotoxic T lymphocyte antigen-4 gene polymorphisms and susceptibility to type 1 autoimmune hepatitis in the Tunisian population. Genes Dis 2017; 5:256-262. [PMID: 30320190 PMCID: PMC6176120 DOI: 10.1016/j.gendis.2017.12.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2017] [Accepted: 12/15/2017] [Indexed: 02/06/2023] Open
Abstract
Genetic factors and gene polymorphisms leading to the onset of autoimmune response in autoimmune hepatitis (AIH) are still not full elucidated. Since the CTLA-4 molecule is a key modulator of the lymphocytes responses we hypothezied that deficiencies or mutations in the gene encoding CTLA4 protein may be involved in AIH susceptibility and trigger the autoimmune response. We investigated 3 distinct polymorphic sites (+49A > G, CT60 G > A and -318C > T) of the CTLA4 gene in 50 AIH patients and 100 healthy controls using the KASP genotyping technology. A significant positive association with AIH susceptibility was found for the GG genotype in +49 position of the CTLA4 gene which was significantly higher in AIH patients compared to controls (28% vs 9%, p = 0.003, OR = 3.93 [1.56-9.88]). The CTLA4 A/A genotype in position CT60 was more significantly frequent in controls comparing to AIH patients and could be considered as a protective genotype for the tunisian patients. CTLA4 genotyping in position -318 did not show any statistically significant difference in genotype or allele distribution. The CTLA4 gene polymorphism in position +49 is associated to AIH susceptibility in the Tunisian population. Mutation in the CTLA4 gene may lead to a modification of the CTLA4 protein structure that could have functional relevance in AIH pathogenesis and onset.
Collapse
Key Words
- AIH, Autoimmune hepatitis
- AMA-M2, Anti-mitochondrial antibody-M2
- ANA, Anti-nuclear antibodies
- Autoimmune hepatitis
- CMV, Cytomegalovirus
- CTLA4 gene polymorphisms
- CTLA4, Cytotoxic T-lymphocyte antigen 4
- Cytotoxic T-lymphocyte antigen 4
- EBV, Epstein–Barr virus
- HLA, Human leucocyte antigen
- KASP PCR, Competitive allele-specific real-time PCR
- LKM1, Anti-Liver/Kidney Microsomal Antibodies Type 1
- PBC, Primary biliary cirrhosis
- PSC, Primary sclerosing cholangitis
- SLA, Antibodies against soluble liver antigen
- SMA, Smooth-muscle antibodies
Collapse
Affiliation(s)
- Marwa Chaouali
- Department of Immunology, Military Hospital of Tunis, Montfleury 1008, Tunis, Tunisia.,El Manar University, Laboratory of Mycology, Pathologies and Biomarkers 1092, Tunis, Tunisia
| | - Agostinho Carvalho
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar 4710-057, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Aymen Tezeghdenti
- Department of Immunology, Military Hospital of Tunis, Montfleury 1008, Tunis, Tunisia
| | - Mouna Ben Azaiez
- Department of Immunology, Military Hospital of Tunis, Montfleury 1008, Tunis, Tunisia
| | - Cristina Cunha
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar 4710-057, Braga, Portugal
| | - Ezzeddine Ghazouani
- Department of Immunology, Military Hospital of Tunis, Montfleury 1008, Tunis, Tunisia
| | - Radhia Kochkar
- Department of Immunology, Military Hospital of Tunis, Montfleury 1008, Tunis, Tunisia
| |
Collapse
|
|
14
|
The incidence of HLA-DQ2/DQ8 in Turkish children with celiac disease and a comparison of the geographical distribution of HLA-DQ. GASTROENTEROLOGY REVIEW 2017; 12:256-261. [PMID: 29358994 PMCID: PMC5771449 DOI: 10.5114/pg.2017.72099] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 08/20/2016] [Indexed: 12/31/2022]
Abstract
Introduction Celiac disease (CD) is an auto-immune enteropathy that occurs in genetically pre-disposed people as a result of the consumption of gluten-containing foods. Aim To identify the incidence of HLA-DQ2 and HLA-DQ8 observed in children with CD. Material and methods In this study, we focused on children ranging in age from 2 to 18 years and diagnosed with celiac disease. In our patients diagnosed with CD, in addition to tissue transglutaminase antibodies (anti-tTG), we also evaluated HLA-DQ2 B1 and HLA-DQ8 B1 alleles using the method of polymerase chain reaction (PCR)/sequence-specific oligonucleotide probes (Luminex®). The detection of 0201/0202 for HLA-DQ2 allele and 0302 for HLA-DQ8 allele was accepted as a positive result. Results The mean age of our patients with celiac disease was 7.42 ±3.18 years, and the female/male ratio was 1.5/1. Seventy-six percent of our patients were HLA-DQ2 and/or HLA-DQ8 positive, 67% were HLA-DQ2 positive, and 25% were HLA-DQ8 positive. Nevertheless, 24% of them were HLA-DQ2 and HLA-DQ8 negative. The incidence of HLA-DQ2 in the control group was 18.8% with a significant difference compared to the HLA-DQ2 incidence in the patient group (67%) (p < 0.05). Similarly the HLA-DQ8 incidence in the control group (5.7%) was significantly lower than the incidence in the patient group (25%) (p < 0.05). Conclusions The incidence of the patients diagnosed with CD, who are HLA-DQ2 and HLA-DQ8 negative, varies among different populations.
Collapse
|
|
15
|
Abstract
The response of peripheral T lymphocytes (T cell) is controlled by multiple checkpoints to avoid unwanted activation against self-tissues. Two opposing costimulatory receptors, CD28 and CTLA-4, on T cells bind to the same ligands (CD80 and CD86) on antigen-presenting cells (APCs), and provide positive and negative feedback for T-cell activation, respectively. Early studies suggested that CTLA-4 is induced on activated T cells and binds to CD80/CD86 with much stronger affinity than CD28, providing a competitive inhibition. Subsequent studies by many researchers revealed the more complex mode of T-cell inhibition by CTLA-4. After T-cell activation, CTLA-4 is stored in the intracellular vesicles, and recruited to the immunological synapse formed between T cells and APCs, and inhibits further activation of T cells by blocking signals initiated by T-cell receptors and CD28. CTLA-4-positive cells can also provide cell-extrinsic regulation on other autoreactive T cells, and are considered to provide an essential regulatory mechanism for FoxP3+ regulatory T cells. Genetic deficiency of CTLA-4 leads to CD28-mediated severe autoimmunity in mice and humans, suggesting its function as a fundamental brake that restrains the expansion and activation of self-reactive T cells. In cancer, therapeutic approaches targeting CTLA-4 by humanized blocking antibodies has been demonstrated to be an effective immunotherapy by reversing T-cell tolerance against tumors. This chapter introduces CTLA-4 biology, including its discovery and mechanism of action, and discusses questions related to CTLA-4.
Collapse
Affiliation(s)
- Shunsuke Chikuma
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan.
| |
Collapse
|
|
16
|
Rasti Z, Nasiri M. Association of the +49 A/G Polymorphism of CTLA4 Gene with Idiopathic Recurrent Spontaneous Abortion in Women in Southwest of Iran. J Reprod Infertil 2016; 17:151-6. [PMID: 27478768 PMCID: PMC4947202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 11/01/2015] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Survival of the semi-allograft fetus during pregnancy opens a new area for the immunological based causes of recurrent spontaneous abortion (RSA). Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is a negative regulator of the T-cell activation, which may modulate peripheral self-tolerance of the allogeneic fetus. The present study aimed to investigate the +49 A/G CTLA4 genetic polymorphism and predisposition to RSA. METHODS The total participants were 120 women with at least two miscarriages and 120 healthy post-menopausal women as the control group. The +49 A/G polymorphism was genotyped using PCR-RFLP method. Required demographic information was collected through filling out a questionnaire. The obtained data were fed into SPSS software version 16. RESULTS The results showed a significant association between the minor alleles (G) with the decreased risk of the RSA. The frequency of the G allele in controls and patients was 25% and 12%, respectively. A GG genotype in the co-dominance model (OR: 0.25, 95%CI: 0.09-0.66) and in the dominant model for allele G (GG+AG vs. AA) (OR: 0.84, 95%CI: 0.8-0.87) showed significant association with RSA by imposing the protective role. The frequency of miscarriage is significantly (p=0.04) higher among the relatives of RSA women (33.3%) in comparison with the women in the control group (21.7%). CONCLUSION It can be concluded that +49G allele may act as a dominant allele and reduce the risk of RSA. Family history of miscarriage increased the risk of RSA among women.
Collapse
Affiliation(s)
- Zarnegar Rasti
- Department of Biology, Islamic Azad University, Arsanjan branch, Arsanjan, Iran
- Young Researchers and Elite Club, Islamic Azad University, Arsanjan Branch, Arsanjan, Iran
| | - Mahboobeh Nasiri
- Department of Biology, Islamic Azad University, Arsanjan branch, Arsanjan, Iran
- Young Researchers and Elite Club, Islamic Azad University, Arsanjan Branch, Arsanjan, Iran
| |
Collapse
|
|
17
|
Webster T, Pettei M. Celiac Disease and Abnormal Pubertal Development. ABNORMAL FEMALE PUBERTY 2016:207-224. [DOI: 10.1007/978-3-319-27225-2_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
18
|
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.
Collapse
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.
| |
Collapse
|
|
19
|
Leonard MM, Serena G, Sturgeon C, Fasano A. Genetics and celiac disease: the importance of screening. Expert Rev Gastroenterol Hepatol 2015; 9:209-15. [PMID: 25294637 DOI: 10.1586/17474124.2014.945915] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The prevalence of celiac disease (CD) is increasing. Despite an increased awareness and an improvement in diagnostic testing, the majority of individuals with CD remain undiagnosed. Currently, genetic testing in screening for CD is used only to exclude a diagnosis or reinforce a strong clinical suspicion. In this paper, we review the most current literature regarding genetic testing in CD. In response to important data revealing that an individual's HLA haplotype is one of the strongest known predictors of CD, we propose genetic screening for at-risk infants to stratify individuals based on genetic risk to ultimately create genetic specific screening algorithms.
Collapse
Affiliation(s)
- Maureen M Leonard
- Center for Celiac Research, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children, 165 Cambridge St, Boston MA 02111, USA
| | | | | | | |
Collapse
|
|
20
|
Kocsis D, Béres N, Veres G, Szabó D, Müller KE, Arató A, Juhász M. [Genetic and epigenetic aspects of celiac disease]. Orv Hetil 2014; 155:83-8. [PMID: 24412945 DOI: 10.1556/oh.2014.29795] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Genetic background of coeliac disease has been subjects to intensive research since decades. However, only results of HLA phenotyping have been taken over to routine clinical practice. Meanwhile, data on the role of epigenetical factors in the manifestation of diseases have been emerging. In coeliac disease, there are several questions both in the fields of genetics and epigenetics yet to be answered. In this review, a cross section of current knowledge on these issues is presented with special interest regarding the future clinical applications.
Collapse
Affiliation(s)
- Dorottya Kocsis
- Semmelweis Egyetem, Általános Orvostudományi Kar II. Belgyógyászati Klinika Budapest Szentkirályi u. 46. 1088
| | - Nóra Béres
- Semmelweis Egyetem, Általános Orvostudományi Kar I. Gyermekgyógyászati Klinika Budapest
| | - Gábor Veres
- Semmelweis Egyetem, Általános Orvostudományi Kar I. Gyermekgyógyászati Klinika Budapest
| | - Dolóresz Szabó
- Semmelweis Egyetem, Általános Orvostudományi Kar I. Gyermekgyógyászati Klinika Budapest
| | - Katalin Eszter Müller
- Semmelweis Egyetem, Általános Orvostudományi Kar I. Gyermekgyógyászati Klinika Budapest
| | - András Arató
- Semmelweis Egyetem, Általános Orvostudományi Kar I. Gyermekgyógyászati Klinika Budapest
| | - Márk Juhász
- Semmelweis Egyetem, Általános Orvostudományi Kar II. Belgyógyászati Klinika Budapest Szentkirályi u. 46. 1088
| |
Collapse
|
|
21
|
Diosdado B, Wijmenga C. Molecular mechanisms of the adaptive, innate and regulatory immune responses in the intestinal mucosa of celiac disease patients. Expert Rev Mol Diagn 2014; 5:681-700. [PMID: 16149872 DOI: 10.1586/14737159.5.5.681] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Celiac disease is a complex genetic disorder that affects the small intestine of genetically predisposed individuals when they ingest gluten, a dietary protein. Although several genome screens have been successful in identifying susceptibility loci in celiac disease, the only genetic contributors identified so far are the human leukocyte antigen (HLA)-DQ2/DQ8 molecules. One of the most important aspects in the pathogenesis of celiac disease is the activation of a T-helper 1 immune response, when the antigen-presenting cells that express HLA-DQ2/DQ8 molecules present the toxic gluten peptides to reactive CD4(+) T-cells. Recently, new insights into the activation of an innate immune response have also been described. It is generally accepted that the immune response triggers destruction of the mucosa in the small intestine of celiac disease patients. Hence, the activation of a detrimental immune response in the intestine of celiac disease patients appears to be key in the initiation and progression of the disease. This review summarizes the immunologic pathways that have been studied in celiac disease thus far, and will point to new potential candidate genes and pathways involved in the etiopathogenesis of celiac disease, which should lead to novel alternatives for diagnosis and treatment.
Collapse
Affiliation(s)
- Begoña Diosdado
- University Medical Centre, Complex Genetics Section, Stratenum 2.117, Department of Biomedical Genetics, PO Box 85060, 3508 AB Utrecht, The Netherlands.
| | | |
Collapse
|
|
22
|
Zamani M, Karami F, Shirvani F, Kia-Lashaki L, Shahbazkhani B. The Role of CD14 and CTLA4 Gene Polymorphisms in Risk of Celiac Disease among Patients of Iranian Ethnicity. CELL JOURNAL 2014; 16:171-8. [PMID: 24567947 PMCID: PMC4072075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/16/2013] [Accepted: 12/30/2013] [Indexed: 11/22/2022]
Abstract
OBJECTIVE Celiac disease (CD) is developed via autoimmune reactions against gluten which is mainly found in grains. Although HLA DQB1 locus is the most important genetic susceptibility to CD, some other variants such as A49G and G1359T of CTLA4 and CD14 genes respectively have been proposed as CD predisposing genetic factors in many vari- ous studies. We aimed to assess possible roles of A49G and G1359T polymorphisms in CD susceptibility in the Iranian population. MATERIALS AND METHODS In this case-control, one hundred CD patients and 100 healthy matched controls with average age of 30-33 years were selected. They were genotyped for both A49G and G1359T polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS There was no association between genotypes of A49G variant of CTLA4 and risk of CD (p<0.05). The G1359T polymorphism of CD14 gene also did not show any significant association with risk of CD among the studied population. However, patients with CD14 T/T genotype were more classified in the severe form (Marsh III) of CD, showing border line significance (p<0.05). CONCLUSION No association was identified between the combination of 1359T and A49G alleles with risk of CD. These lacks of association could be due to small sample size and considering further studies in various populations and ethnicities seems to be required.
Collapse
Affiliation(s)
- Mahdi Zamani
- Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran,Department of Neurogenetics, Iranian Center of Neurological Research , Tehran University of Medical Sciences,
Tehran, Iran,P.O. Box: 14176-13151Department of NeurogeneticsIranian Center of Neurological ResearchTehran University of Medical SciencesTehranIran
| | - Fatemeh Karami
- Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fariba Shirvani
- Department of Pediatrics, Pediatric Infections Research Center, Mofid Children Hospital. Shaheed Beheshti University of
Medical Sciences and Health Services, Tehran, Iran
| | - Laleh Kia-Lashaki
- Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Bizhan Shahbazkhani
- Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
23
|
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]
|
|
24
|
Xia W, Shi R, Zheng WL, Ma WL. Lack of association between cytotoxic T-lymphocyte antigen-4 -318C/T polymorphism and cancer risk: a meta-analysis of case-control studies. Technol Cancer Res Treat 2013; 12:565-74. [PMID: 23745791 DOI: 10.7785/tcrt.2012.500350] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is important for the down regulation of T-cell activation. Number of studies assessed the association between CTLA-4 -318C/T polymorphisms and cancer in different populations. However, the studies have provided conflicting results. We performed a meta-analysis to examine the association between CTLA-4 -318C/T polymorphisms and cancer susceptibility. Eligible studies were identified by searching several databases for relevant reports published up to September 30, 2012. Sixteen eligible studies with a total of 6190 patients and 6560 controls were included to summarize the association between CTLA-4 -318C/T polymorphisms and the risk of cancer. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Overall, no significant associations were found in all genetic models when all studies were pooled into the meta-analysis (for -318C/T polymorphisms as estimated using a fixed effect model: TT vs. (CC + CT), OR = 1.02, 95% CI = 0.83-1.24; (TT + CT) vs. CC, OR = 1.20, 95% CI = 1.00-1.44; TT vs. CC, OR = 1.09, 95% CI = 0.74-1.59; CT vs. CC, OR = 1.21, 95% CI = 1.00-1.46). In further subgroup analyses for the -318C/T polymorphisms, stratified by design of ethnicity, cancer types, solid tumors to non-solid tumors, epithelial tumors to non-epithelial tumors, no significant associations were found in any subgroup of the population. This meta-analysis strongly suggests that -318C/T polymorphisms in CTLA-4 are not associated with an increased risk of cancer.
Collapse
Affiliation(s)
- Wei Xia
- Institute of Genetic Engineering, Southern Medical University, Guangzhou, People's Republic of China.
| | | | | | | |
Collapse
|
|
25
|
Romanos J, Rybak A, Wijmenga C, Wapenaar MC. Molecular diagnosis of celiac disease: are we there yet? ACTA ACUST UNITED AC 2013; 2:399-416. [PMID: 23495707 DOI: 10.1517/17530059.2.4.399] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Celiac disease (CD) is a complex genetic disorder of the small intestine resulting from aberrant cellular responses to gluten peptides. It may affect as much as 1% of the Western population and the only treatment is a lifelong gluten-free diet. Allelic variants of the HLA-DQ locus, coding for the HLA-DQ2 and HLA-DQ8 molecules, contribute to ∼ 40% of CD etiology, whereas other genes, such as MYO9B, CTLA4, IL2, IL21, PARD3 and MAGI2, have only a modest effect. Most of these genes have shown varied association among different populations and an overlap with other autoimmune or inflammatory disorders, indicating that such disorders may share common pathways. OBJECTIVES In this review, a molecular approach into diagnostics of celiac disease is shown. CONCLUSIONS Genome-wide association studies will allow more genes to be identified, and knowing how risk variants combine will help to predict better the risk for the individual. HLA typing can already be used to identify high-risk individuals.
Collapse
Affiliation(s)
- Jihane Romanos
- PhD student University of Groningen, University Medical Center Groningen, Department of Genetics, PO Box 30001, 9700 RB Groningen, The Netherlands
| | | | | | | |
Collapse
|
|
26
|
HLA class II high-resolution genotyping in Greek children with celiac disease and impact on disease susceptibility. Pediatr Res 2012; 72:625-30. [PMID: 23041663 DOI: 10.1038/pr.2012.133] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Celiac disease (CD) has been associated with HLA class II heterodimers. This study aimed at determining the HLA genotypic and allelic distribution in Greek children with CD as compared with the general population. METHODS A total of 118 children with CD and 120 healthy individuals serving as controls were included in the study. RESULTS Higher frequencies for HLA-DQB1*02:01 (40.25 vs. 9.58%, P < 0.001) and DQB1*02:02 (20.34 vs. 5.42%, P < 0.001) were observed in patients with CD, whereas HLA-DQB1*03:01 (16.53 vs. 30.42%, P < 0.001), DQB1*05:01 (0.85 vs. 10%, P < 0.001), and DQB1*05:02 (5.51 vs. 17.92%, P < 0.001) were significantly lower, as compared with the controls. DQA1*02:01 (patients with CD vs. controls: 20.76 vs. 6.67%, P < 0.001) and DQA1*05:01 (40.25 vs. 9.58%, P < 0.001) were significantly more frequent in patients. The frequencies of HLA-DQA1* 01:01, *01:02, *01:04, and *05:05 were significantly lower in patients (P < 0.001). The haplotype mainly associated with CD was DRB1*03-DQB1*02:01-DQA1*05:01; patients with CD vs. controls: 39.83 vs. 9.58%, P < 0.001. In total, 84.75% of patients carried DQ2 (vs. 21.67% in controls, P < 0.001), whereas 11.02% were DQ8 positive/DQ2 negative. CONCLUSION This study confirms the existing data and provides additional evidence supporting a strong genetic predisposition for CD associated with the class II alleles DQB1*02 and DQA1*05 encoding the serological specificity DQ2.
Collapse
|
|
27
|
e Silva MRMA, Moreira PR, da Costa GC, Saraiva AM, Souza PEAD, Amormino SAF, Costa JED, Gollob KJ, Dutra WO. Association ofCD28andCTLA-4gene polymorphisms with aggressive periodontitis in Brazilians. Oral Dis 2012; 19:568-76. [DOI: 10.1111/odi.12036] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Revised: 07/08/2012] [Accepted: 09/28/2012] [Indexed: 11/26/2022]
Affiliation(s)
- MRMA e Silva
- Laboratory of Cell-Cell Interactions; Department of Morphology; ICB; Universidade Federal de Minas Gerais; Belo Horizonte; Brazil
| | - PR Moreira
- Laboratory of Cell-Cell Interactions; Department of Morphology; ICB; Universidade Federal de Minas Gerais; Belo Horizonte; Brazil
| | - GC da Costa
- Universidade Federal de Viçosa; Belo Horizonte; Brazil
| | - AM Saraiva
- Laboratory of Cell-Cell Interactions; Department of Morphology; ICB; Universidade Federal de Minas Gerais; Belo Horizonte; Brazil
| | - PEA de Souza
- Department of Pathology; Pontifícia Universidade Católica de Minas Gerais; Belo Horizonte; Brazil
| | - SAF Amormino
- Laboratory of Cell-Cell Interactions; Department of Morphology; ICB; Universidade Federal de Minas Gerais; Belo Horizonte; Brazil
| | - JE da Costa
- Department of Clinical, Pathology and Surgery; School of Dentistry; Universidade Federal de Minas Gerais; Belo Horizonte; Brazil
| | | | | |
Collapse
|
|
28
|
Barada K, Abu Daya H, Rostami K, Catassi C. Celiac disease in the developing world. Gastrointest Endosc Clin N Am 2012; 22:773-796. [PMID: 23083993 DOI: 10.1016/j.giec.2012.07.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The prevalence of celiac disease (CD) in many developing countries is similar to that of developed areas, in both low- and high-risk groups. The disorder is underestimated because of lack of disease awareness. CD is strongly associated with HLA-DQ2 in developing countries. Clinical presentation may be characterized by chronic diarrhea, anemia, stunting and increased mortality. Few studies have addressed atypical or silent CD. Diagnosis is initially made by serologic tests and is confirmed by small intestinal biopsies. In developing countries the adherence to the treatment is still difficult because of poor availability of dedicated gluten-free food.
Collapse
Affiliation(s)
- Kassem Barada
- Division of Gastroenterology, Department of Internal Medicine, American University of Beirut Medical Center, Riad-El-Solh Beirut, Lebanon
| | | | | | | |
Collapse
|
|
29
|
Osorio C, Wen N, Gemini R, Zemetra R, von Wettstein D, Rustgi S. Targeted modification of wheat grain protein to reduce the content of celiac causing epitopes. Funct Integr Genomics 2012; 12:417-438. [PMID: 22732824 DOI: 10.1007/s10142-012-0287-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2012] [Revised: 05/15/2012] [Accepted: 05/28/2012] [Indexed: 12/15/2022]
Abstract
The prolamin peptides in wheat gluten and in the homologous storage proteins of barley and rye cause painful chronic erasure of microvilli of the small intestine epithelium in celiac patients. If untreated, it can lead to chronic diarrhea, abdominal distension, osteoporosis, weight-loss due to malabsorption of nutrients, and anemia. In addition to congenital cases, life-long exposure to gluten proteins in bread and pasta can also induce development of celiac sprue in adults. To date, the only effective treatment is life-long strict abstinence from the staple food grains. Complete exclusion of dietary gluten is, however, difficult due to use of wheat in many foods, incomplete labeling and social constraints. Thus, finding alternative therapies for this most common foodborne disease remained an active area of research, which has led to many suggestions in last few years. The pros and cons associated with these therapies were reviewed in the present communication. As different celiac patients are immunogenic to different members of the undigestible proline/glutamine rich peptides of ~149 gliadins and low molecular weight glutenin subunits as well as the six high molecular weight glutenin subunits, an exhaustive digestion of the immunogenic peptides in the stomach, duodenum, jejunum, and ileum of celiacs is required. In view of the above, we evaluated the capacity of cereal grains to synthesize and store the enzymes prolyl endopeptidase from Flavobacterium meningosepticum and the barley cysteine endoprotease B2, which in combination are capable of detoxifying immunogenic gluten peptides in a novel treatment of celiac disease.
Collapse
Affiliation(s)
- C Osorio
- Department of Crop & Soil Sciences, Washington State University, Pullman, WA 99164, USA
| | | | | | | | | | | |
Collapse
|
|
30
|
Husby S, Koletzko S, Korponay-Szabó IR, Mearin ML, Phillips A, Shamir R, Troncone R, Giersiepen K, Branski D, Catassi C, Lelgeman M, Mäki M, Ribes-Koninckx C, Ventura A, Zimmer KP. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 2012; 54:136-60. [PMID: 22197856 DOI: 10.1097/mpg.0b013e31821a23d0] [Citation(s) in RCA: 1827] [Impact Index Per Article: 140.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Diagnostic criteria for coeliac disease (CD) from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) were published in 1990. Since then, the autoantigen in CD, tissue transglutaminase, has been identified; the perception of CD has changed from that of a rather uncommon enteropathy to a common multiorgan disease strongly dependent on the haplotypes human leukocyte antigen (HLA)-DQ2 and HLA-DQ8; and CD-specific antibody tests have improved. METHODS A panel of 17 experts defined CD and developed new diagnostic criteria based on the Delphi process. Two groups of patients were defined with different diagnostic approaches to diagnose CD: children with symptoms suggestive of CD (group 1) and asymptomatic children at increased risk for CD (group 2). The 2004 National Institutes of Health/Agency for Healthcare Research and Quality report and a systematic literature search on antibody tests for CD in paediatric patients covering the years 2004 to 2009 was the basis for the evidence-based recommendations on CD-specific antibody testing. RESULTS In group 1, the diagnosis of CD is based on symptoms, positive serology, and histology that is consistent with CD. If immunoglobulin A anti-tissue transglutaminase type 2 antibody titers are high (>10 times the upper limit of normal), then the option is to diagnose CD without duodenal biopsies by applying a strict protocol with further laboratory tests. In group 2, the diagnosis of CD is based on positive serology and histology. HLA-DQ2 and HLA-DQ8 testing is valuable because CD is unlikely if both haplotypes are negative. CONCLUSIONS The aim of the new guidelines was to achieve a high diagnostic accuracy and to reduce the burden for patients and their families. The performance of these guidelines in clinical practice should be evaluated prospectively.
Collapse
Affiliation(s)
- S Husby
- Hans Christian Andersen Children's Hospital at Odense University Hospital.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Csöngei V, Járomi L, Sáfrány E, Sipeky C, Magyari L, Polgár N, Bene J, Sarlós P, Lakner L, Baricza E, Szabó M, Rappai G, Melegh B. Interaction between CTLA4 gene and IBD5 locus in Hungarian Crohn's disease patients. Int J Colorectal Dis 2011; 26:1119-25. [PMID: 21519805 DOI: 10.1007/s00384-011-1202-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/11/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUNDS AND AIMS The IGR2198a_1 and IGR2096a_1 variants of the IBD5 region were found to be associated with Crohn's disease (CD) in the Hungarian population, while IGR2230a_1 does not seem to confer risk for the disease. In the present study, our aim was to investigate the statistical interaction of these three IBD5 polymorphisms with the +49 A/G substitution within the cytotoxic T lymphocyte antigen-4 (CTLA4) gene, detected previously as neutral gene variant in Hungarian IBD patients. METHODS A total of 305 unrelated subjects with CD and 310 healthy controls were genotyped with PCR-RFLP methods. RESULTS In contrast with single gene effects, after genotype stratification, the IGR2198a_1 C and IGR2096a_1 T variants were found to confer susceptibility only in subjects with CTLA4 +49 AA genotype (P = 0.008; OR = 1.86 and P = 0.016; OR = 1.74, respectively), for IGR2230a_1 no such effect on disease risk could be demonstrated. CONCLUSION Analysis of specific genotype combinations unfolded a possible association between the CTLA4 +49 A/G substitution and two of the observed IBD5 variants with respect to disease risk.
Collapse
Affiliation(s)
- Veronika Csöngei
- Department of Medical Genetics, University of Pécs, Pécs, Szigeti út 12, H-7624, Hungary
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Gutierrez-Achury J, Coutinho de Almeida R, Wijmenga C. Shared genetics in coeliac disease and other immune-mediated diseases. J Intern Med 2011; 269:591-603. [PMID: 21401738 DOI: 10.1111/j.1365-2796.2011.02375.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Identifying disease-associated variants can improve the predictive models of disease risk and provide mechanistic insights into disease development. Coeliac disease (CD) is the only autoimmune trait with a known environmental trigger, which makes it an excellent model for studying the complexity of genetic and environmental factors in the development of autoimmunity. In this review, we will focus on the genetic loci that have recently been associated with CD and that contain genes involved in innate and adaptive immunity. Some of these loci are shared with other immune-mediated diseases, suggesting an overlap of the genetic mechanisms involved in the development of such diseases. Some therapies, e.g. tumour necrosis factor inhibitors or a gluten-free diet, are already proving effective for more than one autoimmune disease. Follow-up of individuals with a high genetic risk of CD and other autoimmune diseases could help to elucidate the role of environmental factors (such as infectious agents or alterations in the microbiome) and prevent disease development.
Collapse
Affiliation(s)
- J Gutierrez-Achury
- Department of Genetics, University Medical Centre Groningen and University of Groningen, Groningen, The Netherlands
| | | | | |
Collapse
|
|
33
|
Saverino D, Simone R, Bagnasco M, Pesce G. The soluble CTLA-4 receptor and its role in autoimmune diseases: an update. AUTO- IMMUNITY HIGHLIGHTS 2010; 1:73-81. [PMID: 26000110 PMCID: PMC4389044 DOI: 10.1007/s13317-010-0011-7] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/07/2010] [Accepted: 09/08/2010] [Indexed: 12/24/2022]
Abstract
CTLA-4, initially described as a membranebound molecule, is a costimulatory receptor transducing a potent inhibitory signal. Increasing evidence shows the CTLA-4 gene to be an important susceptibility locus for autoimmune endocrinopathies and other autoimmune disorders. A soluble form of cytotoxic T-lymphocyte-associated antigen-4 (sCTLA-4) has been established and shown to possess CD80/CD86 binding activity and in vitro immunoregulatory functions. sCTLA-4 is generated by alternatively spliced mRNA. Whereas low levels of sCTLA-4 are detected in normal human serum, increased serum levels are observed in several autoimmune diseases (e.g. Graves' disease, myasthenia gravis, systemic lupus erythematosus, type 1 diabetes, systemic sclerosis, coeliac disease, autoimmune pancreatitis and primary biliary cirrhosis). The biological significance of increased sCTLA-4 serum levels is not fully clarified yet. On the one hand, it can be envisaged that sCTLA-4 specifically inhibits early T-cell activation by blocking the interaction of CD80/CD86 with the costimulatory receptor CD28. On the other hand, higher levels of sCTLA-4 could compete for the binding of the membrane form of CTLA-4 with CD80/CD86 in the later phases of T-lymphocyte activation, causing a reduction in inhibitory signalling. This double-edged nature of sCTLA-4 to block the binding of CD28 to CD80/CD86 may result in different outcomes during the clinical course of an autoimmune disease.
Collapse
Affiliation(s)
- Daniele Saverino
- Section of Human Anatomy, Department of Experimental Medicine, University of Genova, Genova, Italy
| | - Rita Simone
- Section of Human Anatomy, Department of Experimental Medicine, University of Genova, Genova, Italy
| | - Marcello Bagnasco
- Medical and Radiometabolic Therapy Unit, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy
| | - Giampaola Pesce
- Medical and Radiometabolic Therapy Unit, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy
| |
Collapse
|
|
34
|
Castellanos-Rubio A, Santin I, Martin-Pagola A, Irastorza I, Castaño L, Vitoria JC, Bilbao JR. Long-term and acute effects of gliadin on small intestine of patients on potentially pathogenic networks in celiac disease. Autoimmunity 2010; 43:131-9. [PMID: 19814655 DOI: 10.3109/08916930903225229] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Celiac disease (CD) is a complex, immune-mediated intolerance to gliadin that develops in genetically susceptible individuals. Although the main driving force of the disease is an aberrant autoimmune response, several other pathogenic mechanisms, many still unidentified, are also involved. In order to describe at a network level the alterations provoked by a gliadin insult on the intestinal mucosa of patients, we compared the expression profiles of biopsies from 9 active and 9 treated patients (long-term effects of gliadin), and of 10 biopsies from gluten-free diet treated patients that were incubated in vitro with or without gliadin (acute effects) and integrated significantly altered transcripts into potentially pathogenic biological processes. Using information on Kyoto Encyclopedia of Genes and Genomes pathways and Gene Ontology terms represented among the differentially expressed genes, we observed important dysfunction in several complex networks, including those related to cell-cell communication, intracellular signaling, ubiquitin-proteasome system, cell cycle/apoptosis and extracellular matrix. The reconstruction of the role of these biological networks in the development of the intestinal lesion in CD provides a comprehensive picture of key events that contribute to the disease, and could point towards novel functional candidates that might be potential therapeutic targets or responsible for genetic susceptibility.
Collapse
|
|
35
|
Brophy K, Ryan AW, Turner G, Trimble V, Patel KD, O'Morain C, Kennedy NP, Egan B, Close E, Lawlor G, MacMathuna P, Stevens FM, Abuzakouk M, Feighery C, Kelleher D, McManus R. Evaluation of 6 candidate genes on chromosome 11q23 for coeliac disease susceptibility: a case control study. BMC MEDICAL GENETICS 2010; 11:76. [PMID: 20478055 PMCID: PMC2880976 DOI: 10.1186/1471-2350-11-76] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/26/2009] [Accepted: 05/17/2010] [Indexed: 11/14/2022]
Abstract
BACKGROUND Recent whole genome analysis and follow-up studies have identified many new risk variants for coeliac disease (CD, gluten intolerance). The majority of newly associated regions encode candidate genes with a clear functional role in T-cell regulation. Furthermore, the newly discovered risk loci, together with the well established HLA locus, account for less than 50% of the heritability of CD, suggesting that numerous additional loci remain undiscovered. Linkage studies have identified some well-replicated risk regions, most notably chromosome 5q31 and 11q23. METHODS We have evaluated six candidate genes in one of these regions (11q23), namely CD3E, CD3D, CD3G, IL10RA, THY1 and IL18, as risk factors for CD using a 2-phase candidate gene approach directed at chromosome 11q. 377 CD cases and 349 ethnically matched controls were used in the initial screening, followed by an extended sample of 171 additional coeliac cases and 536 additional controls. RESULTS Promotor SNPs (-607, -137) in the IL18 gene, which has shown association with several autoimmune diseases, initially suggested association with CD (P < 0.05). Follow-up analyses of an extended sample supported the same, moderate effect (P < 0.05) for one of these. Haplotype analysis of IL18-137/-607 also supported this effect, primarily due to one relatively rare haplotype IL18-607C/-137C (P < 0.0001), which was independently associated in two case-control comparisons. This same haplotype has been noted in rheumatoid arthritis. CONCLUSION Haplotypes of the IL18 promotor region may contribute to CD risk, consistent with this cytokine's role in maintaining inflammation in active CD.
Collapse
Affiliation(s)
- Karen Brophy
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin, Ireland
- Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
| | - Anthony W Ryan
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin, Ireland
- Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
| | - Graham Turner
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin, Ireland
- Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
| | - Valerie Trimble
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin, Ireland
- Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
| | - Kunal D Patel
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin, Ireland
- Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
| | - Colm O'Morain
- Department of Clinical Medicine, Trinity College, Trinity Centre for Health Sciences, The Adelaide & Meath Hospital Dublin, Incorporating The National Children's Hospital, Tallaght, Dublin, Ireland
| | - Nicholas P Kennedy
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Brian Egan
- Department of Clinical Medicine, Trinity College, Trinity Centre for Health Sciences, The Adelaide & Meath Hospital Dublin, Incorporating The National Children's Hospital, Tallaght, Dublin, Ireland
| | - Eimear Close
- Gastrointestinal Unit, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Garrett Lawlor
- Gastrointestinal Unit, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Padraic MacMathuna
- Gastrointestinal Unit, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Fiona M Stevens
- Department of Medicine, National University of Ireland, Galway, Ireland
| | - Mohamed Abuzakouk
- Department of Immunology, Trinity College, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
- Department of Immunology, Hull Royal Infirmary, Hull, UK
| | - Conleth Feighery
- Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
- Department of Immunology, Trinity College, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
| | - Dermot Kelleher
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin, Ireland
- Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
| | - Ross McManus
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin, Ireland
- Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
| |
Collapse
|
|
36
|
Barada K, Bitar A, Mokadem MAR, Hashash JG, Green P. Celiac disease in Middle Eastern and North African countries: a new burden? World J Gastroenterol 2010; 16:1449-1457. [PMID: 20333784 PMCID: PMC2846249 DOI: 10.3748/wjg.v16.i12.1449] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2009] [Revised: 11/16/2009] [Accepted: 11/23/2009] [Indexed: 02/06/2023] Open
Abstract
Celiac disease (CD) is now recognized as a common disorder among Middle Eastern (ME) and North African (NA) populations. The aim of this review is to assess the available data regarding CD in the ME and NA and to compare this information with that of Western countries. A literature review was performed using the electronic databases PubMed and Medline (1950-2008) as search engines, and "celiac disease" was used as a Mesh term. The search was limited to ME and NA countries. The prevalence of CD in ME and NA countries among low risk populations is similar to that of Western countries, but is higher in high risk populations such as those with type 1 diabetes. It is underestimated because of lack of clinical suspicion and lack of patient awareness. Clinical presentations in term of gastrointestinal, hematologic, skeletal, and liver manifestations are similar between both populations except for a high prevalence of short stature in some ME and NA countries. Few studies have addressed atypical or silent CD. As in the West, diagnosis is initially made by serological tests and is confirmed by small intestinal biopsies. Gluten-free diet is the main mode of treatment with a higher apparent adherence rate than in the West. Most disease complications result from malabsorption. The disease is strongly associated with HLA DQ2 and to a lesser extent with HLA DQ8 alleles. In conclusion, CD prevalence is underestimated, with little data available about its malignant complications. Disease parameters in the ME and NA are otherwise similar to those in Western countries.
Collapse
|
|
37
|
van de Water JMW, Cillessen SAGM, Visser OJ, Verbeek WHM, Meijer CJLM, Mulder CJJ. Enteropathy associated T-cell lymphoma and its precursor lesions. Best Pract Res Clin Gastroenterol 2010; 24:43-56. [PMID: 20206108 DOI: 10.1016/j.bpg.2009.11.002] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2009] [Accepted: 11/16/2009] [Indexed: 01/31/2023]
Abstract
Enteropathy Associated T-cell Lymphoma (EATL) is an intestinal tumour of intra-epithelial lymphocytes. Based on morphology, immunohistochemistry and genetic profile EATL can be divided into two groups. EATL type I is a large cell lymphoma which is highly associated with Coeliac Disease (CD) and mostly presents with malabsorption, weight loss and CD-related symptoms. EATL type II consists of small to medium-sized cells and presents often with obstruction or perforation of the small bowel. This type of EATL has no known association with CD. When EATL has been diagnosed a thorough diagnostic work-up is needed. This work-up preferably includes video capsule enteroscopy (VCE), double-balloon enteroscopy (DBE), computed tomography (CT) combined with 18F-fluorodeoxyglucose positron emission tomography scan (18F-FDG-PET scan) if possible and magnetic resonance enteroclysis (MRE). Nowadays, most EATL patients are treated with chemotherapy mostly preceded by resection of the tumour and followed by stem cell transplantation. Despite these therapies outcome of EATL remains very poor with a 5-year survival of 8-20%. In order to improve survival prospective multicentre trials, studying new therapies are needed. The combination of chemotherapy, monoclonal antibodies and/or apoptosis inducing small molecules might be a potential treatment for EATL in the (nearby) future.
Collapse
Affiliation(s)
- Jolanda M W van de Water
- Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, The Netherlands.
| | | | | | | | | | | |
Collapse
|
|
38
|
Xiao M, Qi F, Chen X, Luo Z, Zhang L, Zheng C, Hu S, Jiang X, Zhou M, Tang J. Functional polymorphism ofcytotoxic T-lymphocyte antigen 4and nasopharyngeal carcinoma susceptibility in a Chinese population. Int J Immunogenet 2010; 37:27-32. [DOI: 10.1111/j.1744-313x.2009.00888.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
|
|
39
|
Jabri B, Sollid LM. Tissue-mediated control of immunopathology in coeliac disease. Nat Rev Immunol 2009; 9:858-70. [PMID: 19935805 DOI: 10.1038/nri2670] [Citation(s) in RCA: 234] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Coeliac disease is an inflammatory disorder with autoimmune features that is characterized by destruction of the intestinal epithelium and remodelling of the intestinal mucosa following the ingestion of dietary gluten. A common feature of coeliac disease and many organ-specific autoimmune diseases is a central role for T cells in causing tissue destruction. In this Review, we discuss the emerging hypothesis that, in coeliac disease, intestinal tissue inflammation--induced either by infectious agents or by gluten--is crucial for activating T cells and eliciting their tissue-destructive effector functions.
Collapse
Affiliation(s)
- Bana Jabri
- Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
| | | |
Collapse
|
|
40
|
Schuppan D, Junker Y, Barisani D. Celiac disease: from pathogenesis to novel therapies. Gastroenterology 2009; 137:1912-1933. [PMID: 19766641 DOI: 10.1053/j.gastro.2009.09.008] [Citation(s) in RCA: 409] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2009] [Revised: 09/02/2009] [Accepted: 09/11/2009] [Indexed: 02/08/2023]
Abstract
Celiac disease has become one of the best-understood HLA-linked disorders. Although it shares many immunologic features with inflammatory bowel disease, celiac disease is uniquely characterized by (1) a defined trigger (gluten proteins from wheat and related cereals), (2) the necessary presence of HLA-DQ2 or HLA-DQ8, and (3) the generation of circulating autoantibodies to the enzyme tissue transglutaminase (TG2). TG2 deamidates certain gluten peptides, increasing their affinity to HLA-DQ2 or HLA-DQ8. This generates a more vigorous CD4(+) T-helper 1 T-cell activation, which can result in intestinal mucosal inflammation, malabsorption, and numerous secondary symptoms and autoimmune diseases. Moreover, gluten elicits innate immune responses that act in concert with the adaptive immunity. Exclusion of gluten from the diet reverses many disease manifestations but is usually not or less efficient in patients with refractory celiac disease or associated autoimmune diseases. Based on the advanced understanding of the pathogenesis of celiac disease, targeted nondietary therapies have been devised, and some of these are already in phase 1 or 2 clinical trials. Examples are modified flours that have been depleted of immunogenic gluten epitopes, degradation of immunodominant gliadin peptides that resist intestinal proteases by exogenous endopeptidases, decrease of intestinal permeability by blockage of the epithelial ZOT receptor, inhibition of intestinal TG2 activity by transglutaminase inhibitors, inhibition of gluten peptide presentation by HLA-DQ2 antagonists, modulation or inhibition of proinflammatory cytokines, and induction of oral tolerance to gluten. These and other experimental therapies will be discussed critically.
Collapse
Affiliation(s)
- Detlef Schuppan
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
| | | | | |
Collapse
|
|
41
|
Abstract
BACKGROUND Coeliac disease (CD) is a genetically driven immunological intolerance to dietary gluten with a wide range of clinical presentations. The aim of this study was to investigate the heritability of the phenotype in CD and the influence on the phenotype of different genes associated with the disease. PATIENTS AND METHODS One hundred and seven families with at least 2 siblings with CD were collected. The patients were grouped in symptom grades on the basis of the clinical presentation, the age at diagnosis, and sex. Stratification analyses of the human leucocyte antigen-DQA1 and human leucocyte antigen-DQB1 genotypes, the CTLA4 +49A/G polymorphism, the CTLA4 haplotype MH30*G:-1147*T:+49*A:CT60*G:CT61*A, and the 5q31-33 loci were done. RESULTS The heritability of the phenotype was estimated to be 0.45. Significant association and linkage was found between the clinical presentation and the CTLA4 +49A/G polymorphism but not for the other genotypes. No correlation was found between genotypes and age at diagnosis or sex. CONCLUSIONS Our results indicate that the heritability is determiner of the phenotype in CD. The CTLA4 +49A/G polymorphism is correlated to the clinical presentation: the AA genotype is associated with clinically silent disease.
Collapse
|
|
42
|
Malamut G, Meresse B, Cellier C, Cerf-Bensussan N. La maladie cœliaque en 2009 : un futur sans régime ? ACTA ACUST UNITED AC 2009; 33:635-47. [DOI: 10.1016/j.gcb.2009.07.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
|
|
43
|
Simone R, Brizzolara R, Chiappori A, Milintenda-Floriani F, Natale C, Greco L, Schiavo M, Bagnasco M, Pesce G, Saverino D. A functional soluble form of CTLA-4 is present in the serum of celiac patients and correlates with mucosal injury. Int Immunol 2009; 21:1037-45. [DOI: 10.1093/intimm/dxp069] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
|
|
44
|
Béland K, Lapierre P, Alvarez F. Influence of genes, sex, age and environment on the onset of autoimmune hepatitis. World J Gastroenterol 2009; 15:1025-34. [PMID: 19266593 PMCID: PMC2655185 DOI: 10.3748/wjg.15.1025] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The pathogenesis of autoimmune hepatitis (AIH) is complex. However, it is believed that a susceptible individual, owing to his genetic background, sex and age, can develop the disease following exposure to an environmental trigger. Autoimmune hepatitis does not follow a Mendelian pattern of inheritance; hence no single causative genetic locus has been identified. However, several genes, inside and outside the HLA locus, have been linked to an increased susceptibility to AIH. Epidemiological evidence also suggests that the sex and age of the patient plays a role in AIH pathogenesis as the disease onset occurs mainly in the two first decades of life and a higher disease incidence is observed in females. No environmental trigger has been identified, but several have been proposed, mainly viruses and xenobiotics. This article aims at reviewing the current knowledge on susceptibility factors leading to AIH and putative triggers, emphasizing fundamental mechanisms responsible for the break of liver immunological tolerance.
Collapse
|
|
45
|
Ben Dhifallah I, Chelbi H, Braham A, Hamzaoui K, Houman MH. CTLA-4 +49A/G polymorphism is associated with Behçet’s disease in a Tunisian population. ACTA ACUST UNITED AC 2009; 73:213-7. [DOI: 10.1111/j.1399-0039.2008.01186.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
|
|
46
|
Phelan JD, Thompson SD, Glass DN. Susceptibility to JRA/JIA: complementing general autoimmune and arthritis traits. Genes Immun 2009; 7:1-10. [PMID: 16435022 DOI: 10.1038/sj.gene.6364273] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Juvenile rheumatoid arthritis (JRA), also known as juvenile idiopathic arthritis (JIA), includes the most common chronic autoimmune arthropathies of childhood. These two nomenclatures for classification include components representing the major subclasses of disease. The chromosomal regions and the genes involved in these complex genetic traits are being elucidated, with findings often specific for a particular disease subtype. With the advent of new SNP technologies, progress is being made at an ever-increasing pace. This review discusses the difficulties of deciphering the genetic components in complex disorders, while demonstrating the similarities that JRA shares with other autoimmune disorders. Particular emphasis has been placed on positive findings either for candidate genes that have been replicated independently in JRA/JIA, or findings in JRA for which consistent results have been reported in other forms of autoimmunity.
Collapse
Affiliation(s)
- J D Phelan
- William S Rowe Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA
| | | | | |
Collapse
|
|
47
|
Celiac disease: from oral tolerance to intestinal inflammation, autoimmunity and lymphomagenesis. Mucosal Immunol 2009; 2:8-23. [PMID: 19079330 DOI: 10.1038/mi.2008.75] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Celiac disease is a multifactorial disorder and provides a privileged model to decipher how the interplay between environmental and genetic factors can alter mucosal tolerance to a food antigen, lead to chronic intestinal inflammation, and ultimately promote T-cell lymphomagenesis. Here we summarize how HLA-DQ2/8 molecules, the main genetic risk factor for this disease can orchestrate a CD4(+) T-cell adaptive immune response against gluten, and discuss recent data which shed light on the innate and adaptive immune stimuli that collaborate to induce a proinflammatory TH1 response, a massive expansion of intraepithelial lymphocytes, and a cytolytic attack of the epithelium. The intestinal immune response driven in genetically predisposed patients by chronic exposure to gluten emerges as the pathological counterpart of normal acute intestinal responses to intracellular pathogens.
Collapse
|
|
48
|
Alaya WB, Sfar I, Aouadi H, Jendoubi S, Najjar T, Filali A, Gorgi Y, Abdallah TB, Mouelhi L, Matri S, Ayed K. Association between CTLA-4 gene promoter (49 A/G) in exon 1 polymorphisms and inflammatory bowel disease in the Tunisian population. Saudi J Gastroenterol 2009; 15:29-34. [PMID: 19568552 PMCID: PMC2702943 DOI: 10.4103/1319-3767.43285] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2008] [Accepted: 06/27/2008] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND/AIM To investigate the possible association between the polymorphism of the CTLA-4 exon 1 +49 A/G and susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) in the Tunisian population. METHODS The +49 A/G dimorphism was analyzed in 119 patients with CD, 65 patients with UC, and 100 controls by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS Significantly higher frequencies of the CTLA-4 +49A allele and A/A homozygous individuals were observed in patients with CD when compared with controls (pc = 0.0023 and pc = 0.0003, respectively). Analysis of CTLA-4 A/G polymorphism with respect to sex in CD showed a significant difference in A/A genotypes between female patients and controls (pc = 0.0001 and pc = 0.038, respectively). There were no differences in the subgroups of patients with CD. CONCLUSIONS Forty-nine A alleles and AA genotype are associated with CD susceptibility in Tunisians. Other genes involved in the T-cell regulation remain strong candidates for IBD susceptibility and require further investigation.
Collapse
Affiliation(s)
- Walid Ben Alaya
- Charles Nicolle Hospital, Immunology laboratory Ch. Nicolle Hospital, Tunis-1006, Tunis, Tunisia
| | - Imen Sfar
- Charles Nicolle Hospital, Immunology laboratory Ch. Nicolle Hospital, Tunis-1006, Tunis, Tunisia
| | - Houda Aouadi
- Charles Nicolle Hospital, Immunology laboratory Ch. Nicolle Hospital, Tunis-1006, Tunis, Tunisia
| | - Saloua Jendoubi
- Charles Nicolle Hospital, Immunology laboratory Ch. Nicolle Hospital, Tunis-1006, Tunis, Tunisia
| | - Tawfik Najjar
- Charles Nicolle Hospital, Immunology laboratory Ch. Nicolle Hospital, Tunis-1006, Tunis, Tunisia
| | - Azza Filali
- Charles Nicolle Hospital, Immunology laboratory Ch. Nicolle Hospital, Tunis-1006, Tunis, Tunisia
| | - Yousr Gorgi
- Charles Nicolle Hospital, Immunology laboratory Ch. Nicolle Hospital, Tunis-1006, Tunis, Tunisia
| | - Taieb Ben Abdallah
- Charles Nicolle Hospital, Immunology laboratory Ch. Nicolle Hospital, Tunis-1006, Tunis, Tunisia
| | - Leila Mouelhi
- Charles Nicolle Hospital, Immunology laboratory Ch. Nicolle Hospital, Tunis-1006, Tunis, Tunisia
| | - Samira Matri
- Charles Nicolle Hospital, Immunology laboratory Ch. Nicolle Hospital, Tunis-1006, Tunis, Tunisia
| | - Khaled Ayed
- Charles Nicolle Hospital, Immunology laboratory Ch. Nicolle Hospital, Tunis-1006, Tunis, Tunisia
| |
Collapse
|
|
49
|
The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency. Genes Immun 2008; 10:151-61. [DOI: 10.1038/gene.2008.89] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
|
|
50
|
Berry A, Tector M, Oaks MK. Lack of association between sCTLA-4 levels in human plasma and common CTLA-4 polymorphisms. J Negat Results Biomed 2008; 7:8. [PMID: 19014504 PMCID: PMC2596078 DOI: 10.1186/1477-5751-7-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2008] [Accepted: 11/12/2008] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an important downregulatory molecule expressed on both T and B lymphocytes. Numerous population genetics studies have documented significant associations between autoimmune diseases and single nucleotide polymorphisms (SNPs) within and around the CTLA-4 region of chromosome 2 in man. Furthermore, circulating levels of a soluble form of CTLA-4 (sCTLA-4) have been reported in a variety of autoimmune mediated diseases. Despite these findings, the relationship between levels of sCTLA-4 protein, mRNA transcript levels, and SNPs within the CTLA-4 region have not been clearly defined. In order to further clarify this relationship, we have tested four different SNPs within the CTLA-4 region among subjects whom are negative (n = 53) versus positive (n = 28) for sCTLA-4. RESULTS Our data do not support a clear association between sCTLA-4 levels and any of the four SNPs tested. CONCLUSION The variation in the SNPs tested does not appear to effect sCTLA-4 protein levels, despite reports that they affect sCTLA-4 mRNA.
Collapse
Affiliation(s)
- Andrew Berry
- Transplant Research Laboratory, Aurora St, Luke's Medical Center, Milwaukee, WI 53215, USA.
| | | | | |
Collapse
|