|
1
|
Svitalkova T, Ambroz A, Svetla M, Misunova M, Kolesar L, Novota P. Polymorphisms of HSP70 genes are involved in the pathogenesis of idiopathic inflammatory myopathy. Reumatologia 2025; 63:12-21. [PMID: 40206231 PMCID: PMC11977503 DOI: 10.5114/reum/196740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 12/02/2024] [Indexed: 04/11/2025] Open
Abstract
Introduction Idiopathic inflammatory myopathies (IIM) are a group of rare systemic autoimmune diseases characterized by muscle weakness, histopathological signs of inflammation in muscle tissues, elevated serum levels of muscle-associated enzymes, inflammatory mononuclear cells infiltrating muscle tissue and progressive symmetrical proximal muscle weakness. The current view is that they begin by immune activation in response to environmental factors in genetically predisposed people, but despite the number of investigations into the genetic background, the detailed etiopathogenesis remains unknown. The aim of this study was to examine the relationship between select polymorphisms located in the human major histocompatibility complex (MHC) and IIM. These genetic markers may take part in the onset of the autoimmune process, and their identification could aid in the diagnosis and classification of IIM subtypes. Material and methods One hundred and fifty-two adult patients suffering from IIM (82 dermatomyositis and 70 polymyositis) and 150 healthy controls were analyzed in this study. All were from the Czech Republic. SNPs of the HSP70 genes HSPA1A (rs1008438, rs1043618), HSPA1B (rs1061581, rs539689, pentanucleotide tandem duplication rs9281590) and HSPA1L (rs2227956) were analyzed in all patients and controls. For the detection of HLA polymorphisms, we used commercial kits from CareDx. Haplotypes were created using Arlequin 3.5. Results Our results confirm the association of IIM with the ancestral haplotype HLA-DRB1*03-DQB1*02. The most important MHC haplotype related to IIM and covering all polymorphisms was HLA-DQB1*02-DRB1*03:01-T-C-C-G-C-INS (p < 0.05, OR = 1.90, 95% CI: 1.15-3.13). This haplotype is associated with the risk of IIM development. Conclusions Our results show that polymorphism typing within the MHC might be a very strong tool for recognition of IIM.
Collapse
Affiliation(s)
| | | | | | | | - Libor Kolesar
- Institute of Clinical and Experimental Medicine, Prague, Czech Republic
| | - Peter Novota
- Institute of Rheumatology, Prague, Czech Republic
| |
Collapse
|
|
2
|
Arnaiz-Villena A, Juarez I, Vaquero-Yuste C, Lledo T, Martin-Villa JM, Suarez-Trujillo F. Complex Interactions between the Human Major Histocompatibility Complex (MHC) and Microbiota: Their Roles in Disease Pathogenesis and Immune System Regulation. Biomedicines 2024; 12:1928. [PMID: 39200390 PMCID: PMC11352054 DOI: 10.3390/biomedicines12081928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 08/19/2024] [Accepted: 08/19/2024] [Indexed: 09/02/2024] Open
Abstract
The relationship between microbiota and the immune system is complex and characterized by the ways in which microbiota directs immune function interactions, both innate and acquired and also keeps activating the immune system throughout an individual's life. In this respect, the human Major Histocompatibility Complex (MHC, referred to as HLA in humans) plays a crucial role and is also established in self-defense against microbes by presenting microbial-derived peptides to the immune cells. However, this assumption has some unclear aspects that should be investigated. For example, how is the microbiota shaped by microbe species diversity, quantity and functions of the immune system, as well as the role and molecular mechanisms of the HLA complex during this process. There are autoimmune diseases related to both HLA and specific microbiota changes or alterations, many of which are mentioned in the present review. In addition, the HLA peptide presenting function should be put in a framework together with its linkage to diseases and also with HLA compatibility necessary for transplants to be successful. These are still quite an enigmatically statistical and phenomenological approach, but no firm pathogenic mechanisms have been described; thus, HLA's real functioning is still to be fully unveiled. After many years of HLA single-genes studies, firm pathogenesis mechanisms underlying disease linkage have been discovered. Finally, microbiota has been defined as conformed by bacteria, protozoa, archaea, fungi, and viruses; notwithstanding, endogenous viral sequences integrated into the human genome and other viral particles (obelisks) recently found in the digestive mucosa should be taken into account because they may influence both the microbiome and the immune system and their interactions. In this context, we propose to integrate these microbial-genetic particle components into the microbiome concept and designate it as "microgenobiota".
Collapse
Affiliation(s)
- Antonio Arnaiz-Villena
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (I.J.); (C.V.-Y.); (T.L.); (J.M.M.-V.); (F.S.-T.)
- Instituto de Investigacion Sanitaria Gegorio Marañon, 28009 Madrid, Spain
| | - Ignacio Juarez
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (I.J.); (C.V.-Y.); (T.L.); (J.M.M.-V.); (F.S.-T.)
- Instituto de Investigacion Sanitaria Gegorio Marañon, 28009 Madrid, Spain
| | - Christian Vaquero-Yuste
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (I.J.); (C.V.-Y.); (T.L.); (J.M.M.-V.); (F.S.-T.)
- Instituto de Investigacion Sanitaria Gegorio Marañon, 28009 Madrid, Spain
| | - Tomás Lledo
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (I.J.); (C.V.-Y.); (T.L.); (J.M.M.-V.); (F.S.-T.)
- Instituto de Investigacion Sanitaria Gegorio Marañon, 28009 Madrid, Spain
| | - José Manuel Martin-Villa
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (I.J.); (C.V.-Y.); (T.L.); (J.M.M.-V.); (F.S.-T.)
- Instituto de Investigacion Sanitaria Gegorio Marañon, 28009 Madrid, Spain
| | - Fabio Suarez-Trujillo
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (I.J.); (C.V.-Y.); (T.L.); (J.M.M.-V.); (F.S.-T.)
- Instituto de Investigacion Sanitaria Gegorio Marañon, 28009 Madrid, Spain
| |
Collapse
|
|
3
|
Sartoris S, Del Pozzo G. Exploring the HLA complex in autoimmunity: From the risk haplotypes to the modulation of expression. Clin Immunol 2024; 265:110266. [PMID: 38851519 DOI: 10.1016/j.clim.2024.110266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/29/2024] [Accepted: 05/30/2024] [Indexed: 06/10/2024]
Abstract
The genes mapping at the HLA region show high density, strong linkage disequilibrium and high polymorphism, which affect the association of HLA class I and class II genes with autoimmunity. We focused on the HLA haplotypes, genomic structures consisting of an array of specific alleles showing some degrees of genetic association with different autoimmune disorders. GWASs in many pathologies have identified variants in either the coding loci or the flanking regulatory regions, both in linkage disequilibrium in haplotypes, that are frequently associated with increased risk and may influence gene expression. We discuss the relevance of the HLA gene expression because the level of surface heterodimers determines the number of complexes presenting self-antigen and, thus, the strength of pathogenic autoreactive T cells immune response.
Collapse
Affiliation(s)
- Silvia Sartoris
- Dept. of Medicine, Section of Immunology University of Verona School of Medicine, Verona, Italy
| | - Giovanna Del Pozzo
- Institute of Genetics and Biophysics "Adriano Buzzati Traverso" National Research Council (CNR), Naples, Italy.
| |
Collapse
|
|
4
|
Dara L, Ghabril M, Phillips E, Kleiner D, Chalasani N. A 68-Year-Old Woman With Unexplained Liver Enzyme Elevation and Active Chronic Hepatitis: Beware of Drug-Induced Autoimmune-Like Hepatitis. Gastroenterology 2024; 166:259-266.e1. [PMID: 37797776 DOI: 10.1053/j.gastro.2023.09.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/25/2023] [Accepted: 09/28/2023] [Indexed: 10/07/2023]
Affiliation(s)
- Lily Dara
- Division of GI and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Marwan Ghabril
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Elizabeth Phillips
- Center for Drug Interactions and Immunology, Division of Infectious Diseases, Department of Medicine, Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - David Kleiner
- Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
| |
Collapse
|
|
5
|
Wang MH, Friton JJ, Rebert N, Monroe K, Nix BD, Fiocchi C, Raffals LE, Leighton JA, Pasha SF, Picco MF, Newberry RD, Achkar JP, Faubion WA. Novel Genetic Risk Variants and Clinical Predictors Associated With Primary Sclerosing Cholangitis in Patients With Ulcerative Colitis. Clin Transl Gastroenterol 2023; 14:e00615. [PMID: 37440754 PMCID: PMC10522100 DOI: 10.14309/ctg.0000000000000615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
INTRODUCTION Patients with ulcerative colitis (UC) who are likely to have primary sclerosing cholangitis (PSC) should be identified because PSC can influence UC clinical behavior and outcomes.The aim of this study was to establish a model incorporating clinical and genetic risk predictors that identifies patients with UC at risk of developing PSC. METHODS We conducted a retrospective case-control study. Inflammatory bowel disease cohorts from multiple institutions were used as discovery and replicate datasets. Quality control criteria, including minor allele frequency, call rates, Hardy-Weinberg equilibrium, cryptic relatedness, and population stratification (through principal components), were used. Discriminative accuracy was evaluated with area under the receiver operating characteristic curve. RESULTS Fifty-seven of 581 patients (9.8%) with UC had PSC. Multivariate analysis showed that patients with UC-PSC had more extensive disease (odds ratio [OR], 5.42; P = 1.57E-04), younger diagnosis age (younger than 20 years; OR, 2.22; P = 0.02), and less smoking (OR, 0.42; P = 0.02) than those with UC. After linkage disequilibrium pruning and multivariate analyses, 3 SNPs (rs3131621 at 6p21.33; rs9275596 and rs11244 at 6p21.32) at the HLA region were found associated with a 2- to 3-fold increased risk of PSC. Our model demonstrated good discriminatory power (area under the receiver operating characteristic curve, 88%). DISCUSSION Three variants in HLA (6p21.3) region significantly distinguished patients with UC-PSC from patients with UC alone. Once further validated in an independent large cohort, our model could be used to identify patients with UC at risk of PSC, and it could also help guide disease management.
Collapse
Affiliation(s)
- Ming-Hsi Wang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
- Gastroenterology, Mayo Clinic Health System, Southwest Minnesota Region, Mankato, Minnesota, USA
| | - Jessica J. Friton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Nancy Rebert
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
| | - Kelly Monroe
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Billy D. Nix
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Claudio Fiocchi
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
| | - Laura E. Raffals
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Jonathan A. Leighton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Shabana F. Pasha
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Michael F. Picco
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Rodney D. Newberry
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Jean-Paul Achkar
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, Ohio, USA
| | - William A. Faubion
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| |
Collapse
|
|
6
|
Olson E, Ceccarelli T, Raghavan M. Endo-lysosomal assembly variations among human leukocyte antigen class I (HLA class I) allotypes. eLife 2023; 12:e79144. [PMID: 36722462 PMCID: PMC9917446 DOI: 10.7554/elife.79144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 01/13/2023] [Indexed: 02/02/2023] Open
Abstract
The extreme polymorphisms of human leukocyte antigen class I (HLA class I) proteins enable the presentation of diverse peptides to cytotoxic T lymphocytes. The canonical endoplasmic reticulum (ER) HLA class I assembly pathway enables presentation of cytosolic peptides, but effective intracellular surveillance requires multi-compartmental antigen sampling. Endo-lysosomes are generally sites of HLA class II assembly, but human monocytes and monocyte-derived dendritic cells (moDCs) also contain significant reserves of endo-lysosomal HLA class I molecules. We hypothesized variable influences of HLA class I polymorphisms upon outcomes of endo-lysosomal trafficking, as the stabilities and peptide occupancies of cell surface HLA class I molecules are variable. Consistent with this model, when the endo-lysosomal pH of moDCs is disrupted, HLA-B allotypes display varying propensities for reductions in surface expression, with HLA-B*08:01 or HLA-B*35:01 being among the most resistant or sensitive, respectively, among eight tested HLA-B allotypes. Perturbations of moDC endo-lysosomal pH result in accumulation of HLA-B*35:01 in LAMP1+ compartments and increase HLA-B*35:01 peptide receptivity. These findings reveal the intersection of the vacuolar cross-presentation pathway with a constitutive assembly pathway for some HLA-B allotypes. Notably, cross-presentation of epitopes derived from two soluble antigens was also more efficient for B*35:01 compared to B*08:01, even when matched for T cell response sensitivity, and more affected by cathepsin inhibition. Thus, HLA class I polymorphisms dictate the degree of endo-lysosomal assembly, which can supplement ER assembly for constitutive HLA class I expression and increase the efficiency of cross-presentation.
Collapse
Affiliation(s)
- Eli Olson
- Department of Microbiology and Immunology, Michigan Medicine, University of Michigan-Ann ArborAnn ArborUnited States
- Graduate Program in Immunology, Michigan Medicine, University of Michigan-Ann ArborAnn ArborUnited States
| | - Theadora Ceccarelli
- Department of Microbiology and Immunology, Michigan Medicine, University of Michigan-Ann ArborAnn ArborUnited States
| | - Malini Raghavan
- Department of Microbiology and Immunology, Michigan Medicine, University of Michigan-Ann ArborAnn ArborUnited States
- Graduate Program in Immunology, Michigan Medicine, University of Michigan-Ann ArborAnn ArborUnited States
| |
Collapse
|
|
7
|
Sikorova K, Osoegawa K, Kocourkova L, Strnad A, Petrkova J, Fernández-Viña MA, Doubkova M, Petrek M. Association between sarcoidosis and HLA polymorphisms in a Czech population from Central Europe: focus on a relationship with clinical outcome and treatment. Front Med (Lausanne) 2023; 10:1094843. [PMID: 37153085 PMCID: PMC10160604 DOI: 10.3389/fmed.2023.1094843] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 03/31/2023] [Indexed: 05/09/2023] Open
Abstract
Background Sarcoidosis is an immune-mediated systemic disease with unknown etiology affecting the lung predominantly. The clinical manifestation of sarcoidosis is rather diverse ranging from Löfgren's syndrome to fibrotic disease. Also, it differs among patients with distinct geographical and ethnic origins, consistent with environmental and genetic factors' role in its pathogenesis. Of those, the polymorphic genes of the HLA system have been previously implicated in sarcoidosis. Therefore, we have performed an association study in a well-defined cohort of Czech patients aiming to define how variation in HLA genes, may contribute to disease origin and development. Materials and methods Total of the 301 Czech unrelated sarcoidosis patients were diagnosed according to international guidelines. In those, HLA typing was performed using next-generation sequencing. The allele frequencies at six HLA loci (HLA-A,-B,-C,-DRB1,-DQA1, and -DQB1) observed in the patients were compared with HLA allele distribution determined in 309 unrelated healthy Czech subjects; sub-analyses of relationships between HLA and distinct sarcoidosis clinical phenotypes were performed. Associations were assessed by two-tailed Fischer's exact test with correction for multiple comparisons. Results We report two variants, HLA-DQB1*06:02, and HLA-DQB1*06:04, as risk factors for sarcoidosis, and three variants, HLA-DRB1*01:01, HLA-DQA1*03:01, and HLA-DQB1*03:02 as protective factors. HLA-B*08:01, HLA-C*07:01, HLA-DRB1*03:01, HLA-DQA1*05:01, and HLA-DQB1*02:01 variants associated with Löfgren's syndrome, a more benign phenotype. HLA- DRB1*03:01 and HLA-DQA1*05:01 alleles were connected with better prognosis-chest X-ray (CXR) stage 1, disease remission, and non-requirement of corticosteroid treatment. The alleles HLA-DRB1*11:01 and HLA-DQA1*05:05 are associated with more advanced disease represented by the CXR stages 2-4. HLA-DQB1*05:03 associated with sarcoidosis extrapulmonary manifestation. Conclusion In our Czech cohort, we document some associations between sarcoidosis and HLA previously described in other populations. Further, we suggest novel susceptibility factors for sarcoidosis, such as HLA-DQB1*06:04, and characterize associations between HLA and sarcoidosis clinical phenotypes in Czech patients. Our study also extends the role of the 8.1 ancestral haplotype (HLA-A*01:01∼HLA-B*08:01∼HLA-C*07:01∼HLA-DRB1*03:01∼HLA-DQA1*05:01∼HLA-DQB1*02:01), already implicated in autoimmune diseases, as a possible predictor of better prognosis in sarcoidosis. The general translational application of our newly reported findings for personalized patient care should be validated by an independent study from another, international referral center.
Collapse
Affiliation(s)
- K. Sikorova
- Department of Pathological Physiology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czechia
| | - K. Osoegawa
- Histocompatibility & Immunogenetics Laboratory, Stanford Blood Center, Palo Alto, CA, United States
| | - L. Kocourkova
- Laboratory of Cardiogenomics–Experimental Medicine, University Hospital Olomouc, Olomouc, Czechia
| | - A. Strnad
- Department of Pathological Physiology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czechia
| | - J. Petrkova
- Laboratory of Cardiogenomics–Experimental Medicine, University Hospital Olomouc, Olomouc, Czechia
| | - M. A. Fernández-Viña
- Histocompatibility, Immunogenetics, and Disease Profiling Laboratory, Department of Pathology, Stanford Blood Center, Stanford University School Medicine, Palo Alto, CA, United States
| | - M. Doubkova
- Department of Pulmonary Diseases and Tuberculosis, Faculty of Medicine of Masaryk University, University Hospital Brno, Brno, Czechia
| | - M. Petrek
- Department of Pathological Physiology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czechia
- *Correspondence: M. Petrek,
| |
Collapse
|
|
8
|
Ren F, Jin Q, Liu T, Ren X, Zhan Y. Causal effects between gut microbiota and IgA nephropathy: a bidirectional Mendelian randomization study. Front Cell Infect Microbiol 2023; 13:1171517. [PMID: 37201114 PMCID: PMC10185820 DOI: 10.3389/fcimb.2023.1171517] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 04/17/2023] [Indexed: 05/20/2023] Open
Abstract
Background Therapeutic approaches that target the gut microbiota (GM) may be helpful in the potential prevention and treatment of IgA nephropathy (IgAN). Meanwhile, relevant studies demonstrated a correlation between GM and IgAN, however, these confounding evidence cannot prove a causal relationship between GM and IgAN. Methods Based on the data from the GM genome-wide association study (GWAS) of MiBioGen and the IgAN GWAS data from the FinnGen research. A bi-directional Mendelian randomization (MR) study was performed to explore the causal relationship between GM and IgAN. We used inverse variance weighted (IVW) method as the primary method to determine the causal relationship between exposure and outcome in our MR study. Besides, we used additional analysis (MR-Egger, weighted median) and sensitivity analysis (Cochrane's Q test, MR-Egger and MR-PRESSO) to select significant results, followed by Bayesian model averaging (MR-BMA) to test the results of MR study. Finally, a reverse MR analysis was conducted to estimate the probability of reverse causality. Results At the locus-wide significance level, the results of IVW method and additional analysis showed that Genus Enterorhabdus was a protective factor for IgAN [OR: 0.456, 95% CI: 0.238-0.875, p=0.023], while Genus butyricicoccus was a risk factor for IgAN [OR: 3.471, 95% CI: 1.671-7.209, p=0.0008]. In the sensitivity analysis, no significant pleiotropy or heterogeneity of the results was found. Conclusion Our study revealed the causal relationship between GM and IgAN, and expanded the variety of bacterial taxa causally related to IgAN. These bacterial taxa could become novel biomarkers to facilitate the development of targeted therapies for IgAN, developing our understanding of the "gut-kidney axis".
Collapse
Affiliation(s)
- Feihong Ren
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Qiubai Jin
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Tongtong Liu
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xuelei Ren
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yongli Zhan
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Yongli Zhan,
| |
Collapse
|
|
9
|
Xiong DK, Shi X, Han MM, Zhang XM, Wu NN, Sheng XY, Wang JN. The regulatory mechanism and potential application of IL-23 in autoimmune diseases. Front Pharmacol 2022; 13:982238. [PMID: 36176425 PMCID: PMC9514453 DOI: 10.3389/fphar.2022.982238] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 08/17/2022] [Indexed: 11/13/2022] Open
Abstract
IL-23 is a heterodimeric pro-inflammatory cytokine secreted by dendritic cells and macrophages that belongs to the IL-12 family. It has pro-inflammatory effects and is a key cytokine and upstream regulatory cytokine involved in protective immune responses, stimulating the differentiation and proliferation of downstream effectors such as Th17 cells. It is expressed in various autoimmune diseases such as psoriasis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA). The IL-23/TH17 axis formed by IL-23 and TH17 has been confirmed to participate in autoimmune diseases pathogenesis. IL-23R is the receptor for IL-23 and plays an activating role. Targeting IL-23 is currently the main strategy for the treatment of various autoimmune diseases. In this review we summarized the mechanism of action and clinical application potential of IL-23 in autoimmune diseases by summarizing the latest research results and reviewing the literature, which would help to further understand IL-23 and provide a theoretical basis for future clinical targeting and drug development.
Collapse
Affiliation(s)
- De-Kai Xiong
- School of Health Management, Anhui Medical University, Hefei, China
| | - Xiang Shi
- School of Health Management, Anhui Medical University, Hefei, China
| | - Miao-Miao Han
- School of Health Management, Anhui Medical University, Hefei, China
| | - Xing-Min Zhang
- School of Health Management, Anhui Medical University, Hefei, China
| | - Na-Na Wu
- School of Health Management, Anhui Medical University, Hefei, China
| | - Xiu-Yue Sheng
- School of Health Management, Anhui Medical University, Hefei, China
| | - Ji-Nian Wang
- School of Health Management, Anhui Medical University, Hefei, China
- Department of Education, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: Ji-Nian Wang,
| |
Collapse
|
|
10
|
Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. HLA, gut microbiome and hepatic autoimmunity. Front Immunol 2022; 13:980768. [PMID: 36059527 PMCID: PMC9433828 DOI: 10.3389/fimmu.2022.980768] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 07/25/2022] [Indexed: 12/12/2022] Open
Abstract
Genetic susceptibility to autoimmune liver diseases is conferred mainly by polymorphisms of genes encoding for the human leukocyte antigens (HLA). The strongest predisposition to autoimmune hepatitis type 1 (AIH-1) is linked to the allele DRB1*03:01, possession of which is associated with earlier disease onset and more severe course. In populations where this allele is very rare, such as in Asia, and in DRB1*03-negative patients, risk of AIH-1 is conferred by DRB1*04, which is associated with later disease onset and milder phenotype. AIH type 2 (AIH-2) is associated with DRB1*07. The pediatric condition referred to as autoimmune sclerosing cholangitis (ASC), is associated with the DRB1*13 in populations of Northern European ancestry. DRB1*1501 is protective from AIH-1, AIH-2 and ASC in Northern European populations. Possession of the DRB1*08 allele is associated with an increased risk of primary biliary cholangitis (PBC) across different populations. DRB1*03:01 and B*08:01 confer susceptibility to primary sclerosing cholangitis (PSC), as well as DRB1*13 and DRB1*15 in Europe. The hepatic blood supply is largely derived from the splanchnic circulation, suggesting a pathophysiological role of the gut microbiome. AIH appears to be associated with dysbiosis, increased gut permeability, and translocation of intestinal microbial products into the circulation; molecular mimicry between microbial and host antigens may trigger an autoaggressive response in genetically-predisposed individuals. In PBC an altered enteric microbiome may affect intestinal motility, immunological function and bile secretion. Patients with PSC have a gut microbial profile different from health as well as from patients with inflammatory bowel disease without PSC.
Collapse
Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- Faculty of Biomedical Sciences, Epatocentro Ticino and Università della Svizzera Italiana, Lugano, Switzerland
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
- *Correspondence: Benedetta Terziroli Beretta-Piccoli,
| | - Giorgina Mieli-Vergani
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
| | - Diego Vergani
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
| |
Collapse
|
|
11
|
Remuzgo-Martínez S, Atienza-Mateo B, Ocejo-Vinyals JG, Pulito-Cueto V, Prieto-Peña D, Genre F, Marquez A, Llorca J, Mora Cuesta VM, Fernández DI, Riesco L, Ortego-Centeno N, Gómez NP, Mera A, Martínez-Barrio J, López-Longo FJ, Lera-Gómez L, Moriano C, Díez E, Tomero E, Calvo-Alén J, Romero-Bueno F, Sanchez-Pernaute O, Nuño L, Bonilla G, Grafia I, Prieto-González S, Narvaez J, Trallero-Araguas E, Selva-O'Callaghan A, Gualillo O, Martín J, Cavagna L, Castañeda S, Cifrian JM, Renzoni EA, López-Mejías R, González-Gay MA. HLA association with the susceptibility to anti-synthetase syndrome. Joint Bone Spine 2021; 88:105115. [PMID: 33301929 DOI: 10.1016/j.jbspin.2020.105115] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 11/13/2020] [Indexed: 10/22/2022]
Abstract
OBJECTIVE To investigate the human leukocyte antigen (HLA) association with anti-synthetase syndrome (ASSD). METHODS We conducted the largest immunogenetic HLA-DRB1 and HLA-B study to date in a homogeneous cohort of 168 Caucasian patients with ASSD and 486 ethnically matched healthy controls by sequencing-based-typing. RESULTS A statistically significant increase of HLA-DRB1*03:01 and HLA-B*08:01 alleles in patients with ASSD compared to healthy controls was disclosed (26.2% versus 12.2%, P=1.56E-09, odds ratio-OR [95% confidence interval-CI]=2.54 [1.84-3.50] and 21.4% versus 5.5%, P=18.95E-18, OR [95% CI]=4.73 [3.18-7.05]; respectively). Additionally, HLA-DRB1*07:01 allele was significantly decreased in patients with ASSD compared to controls (9.2% versus 17.5%, P=0.0003, OR [95% CI]=0.48 [0.31-0.72]). Moreover, a statistically significant increase of HLA-DRB1*03:01 allele in anti-Jo-1 positive compared to anti-Jo-1 negative patients with ASSD was observed (31.8% versus 15.5%, P=0.001, OR [95% CI]=2.54 [1.39-4.81]). Similar findings were observed when HLA carrier frequencies were assessed. The HLA-DRB1*03:01 association with anti-Jo-1 was unrelated to smoking history. No HLA differences in patients with ASSD stratified according to the presence/absence of the most representative non-anti-Jo-1 anti-synthetase autoantibodies (anti-PL-12 and anti-PL-7), arthritis, myositis or interstitial lung disease were observed. CONCLUSIONS Our results support the association of the HLA complex with the susceptibility to ASSD.
Collapse
Affiliation(s)
- Sara Remuzgo-Martínez
- Research group on genetic epidemiology and atherosclerosis in systemic diseases and in metabolic bone diseases of the musculoskeletal system, IDIVAL, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Belén Atienza-Mateo
- Research group on genetic epidemiology and atherosclerosis in systemic diseases and in metabolic bone diseases of the musculoskeletal system, IDIVAL, Hospital Universitario Marqués de Valdecilla, Santander, Spain; 'López Albo' post-residency programme, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | | | - Verónica Pulito-Cueto
- Research group on genetic epidemiology and atherosclerosis in systemic diseases and in metabolic bone diseases of the musculoskeletal system, IDIVAL, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Diana Prieto-Peña
- Research group on genetic epidemiology and atherosclerosis in systemic diseases and in metabolic bone diseases of the musculoskeletal system, IDIVAL, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Fernanda Genre
- Research group on genetic epidemiology and atherosclerosis in systemic diseases and in metabolic bone diseases of the musculoskeletal system, IDIVAL, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Ana Marquez
- Instituto de Parasitología y Biomedicina 'López-Neyra', CSIC, PTS Granada, Granada, Spain; Systemic Autoimmune Disease Unit, Hospital Universitario Clínico San Cecilio, Instituto de Investigación Biosanitaria ibs. GRANADA, Granada, Spain
| | - Javier Llorca
- Department of Epidemiology and Computational Biology, School of Medicine, University of Cantabria, and CIBER Epidemiología y Salud Pública (CIBERESP), IDIVAL, Santander, Spain
| | - Víctor M Mora Cuesta
- Research group on genetic epidemiology and atherosclerosis in systemic diseases and in metabolic bone diseases of the musculoskeletal system, IDIVAL, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - David Iturbe Fernández
- Research group on genetic epidemiology and atherosclerosis in systemic diseases and in metabolic bone diseases of the musculoskeletal system, IDIVAL, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Laura Riesco
- Department of Immunology, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Norberto Ortego-Centeno
- Systemic Autoimmune Disease Unit, Hospital Universitario Clínico San Cecilio, Instituto de Investigación Biosanitaria ibs. GRANADA, Granada, Spain
| | - Nair Pérez Gómez
- Division of Rheumatology, Instituto de Investigación Sanitaria-Hospital Clínico Universitario de Santiago, Santiago de Compostela, A Coruña, Spain
| | - Antonio Mera
- Division of Rheumatology, Instituto de Investigación Sanitaria-Hospital Clínico Universitario de Santiago, Santiago de Compostela, A Coruña, Spain
| | - Julia Martínez-Barrio
- Department of Rheumatology, Hospital General Universitario Gregorio-Marañón, Madrid, Spain
| | | | - Leticia Lera-Gómez
- Research group on genetic epidemiology and atherosclerosis in systemic diseases and in metabolic bone diseases of the musculoskeletal system, IDIVAL, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Clara Moriano
- Division of Rheumatology, Complejo Asistencial Universitario de León, León, Spain
| | - Elvira Díez
- Division of Rheumatology, Complejo Asistencial Universitario de León, León, Spain
| | - Eva Tomero
- Department of Rheumatology, Hospital Universitario de la Princesa, Madrid, Spain
| | - Jaime Calvo-Alén
- Rheumatology Division, Hospital Universitario Araba, Vitoria/Gasteiz, Alava, Spain
| | | | - Olga Sanchez-Pernaute
- Rheumatology Department, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
| | - Laura Nuño
- Rheumatology Department, Hospital Universitario La Paz, Madrid, Spain
| | - Gema Bonilla
- Rheumatology Department, Hospital Universitario La Paz, Madrid, Spain
| | - Ignacio Grafia
- Department of Autoimmune Diseases, Hospital Clínico de Barcelona, Universidad de Barcelona, Barcelona, Spain
| | - Sergio Prieto-González
- Department of Autoimmune Diseases, Hospital Clínico de Barcelona, Universidad de Barcelona, Barcelona, Spain
| | - Javier Narvaez
- Rheumatology Department, Hospital Universitario de Bellvitge, Barcelona, Spain
| | - Ernesto Trallero-Araguas
- Department of Systemic Autoimmune Diseases, Hospital Universitario Valle de Hebron, Barcelona, Spain
| | - Albert Selva-O'Callaghan
- Department of Systemic Autoimmune Diseases, Hospital Universitario Valle de Hebron, Barcelona, Spain
| | - Oreste Gualillo
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, Santiago de Compostela, Spain
| | - Javier Martín
- Instituto de Parasitología y Biomedicina 'López-Neyra', CSIC, PTS Granada, Granada, Spain
| | - Lorenzo Cavagna
- Division of Rheumatology, University and IRCCS Policlinico S. Matteo Foundation, Pavia, Italy
| | - Santos Castañeda
- Department of Rheumatology, Hospital Universitario de la Princesa, Madrid, Spain
| | - José M Cifrian
- Research group on genetic epidemiology and atherosclerosis in systemic diseases and in metabolic bone diseases of the musculoskeletal system, IDIVAL, Hospital Universitario Marqués de Valdecilla, Santander, Spain; School of Medicine, Universidad de Cantabria, Santander, Spain
| | - Elisabetta A Renzoni
- Interstitial Lung Disease Unit, Royal Brompton Hospital, Imperial College, London, United Kingdom
| | - Raquel López-Mejías
- Research group on genetic epidemiology and atherosclerosis in systemic diseases and in metabolic bone diseases of the musculoskeletal system, IDIVAL, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
| | - Miguel A González-Gay
- Research group on genetic epidemiology and atherosclerosis in systemic diseases and in metabolic bone diseases of the musculoskeletal system, IDIVAL, Hospital Universitario Marqués de Valdecilla, Santander, Spain; School of Medicine, Universidad de Cantabria, Santander, Spain; Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
| |
Collapse
|
|
12
|
Gambino CM, Accardi G, Aiello A, Caruso C, Carru C, Gioia BG, Guggino G, Rizzo S, Zinellu A, Ciaccio M, Candore G. Uncoupling Protein 2 as genetic risk factor for systemic lupus erythematosus: association with malondialdehyde levels and intima media thickness. Minerva Cardioangiol 2020; 68:609-618. [PMID: 32492982 DOI: 10.23736/s0026-4725.20.05225-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
BACKGROUND Increased oxidative stress potentially leads to accelerated atherosclerosis and, consequently, cardiovascular diseases, the main cause of death in systemic lupus erythematous (SLE). To gain insight into these mechanisms, we studied the association of uncoupling protein (UCP) 2 genetic variants, gene involved in the mitochondrial production of reactive oxygen species, and oxidative stress with SLE and the presence of atherosclerosis. METHODS Genetic analysis of the UCP2 -866G/A and UCP2 Ins/Del polymorphisms was performed in 45 SLE patients and 36 healthy controls by RFLP-PCR. Oxidation status was determined by measuring malondialdehyde (MDA) levels. Presence of subclinical atherosclerosis was investigated by evaluation of intima-media thickness using echo-color-Doppler carotid ultrasound examination. RESULTS Allelic and genotypic frequencies of the SNPs analysed were evaluated by gene count. Significant association was found between UCP2-866A allele and susceptibility for SLE (P=0.001). Higher levels of MDA were found significantly increased in SLE patients (MDA, 5.05±3.36 µmol/L) compared to normal controls (MDA, 2.79±0.89 µmol/L) (P<0.0001). CONCLUSIONS Our results suggest that -866G/A UCP2 polymorphism is associated with SLE causing increased ROS production that, in turn, results in increased MDA levels responsible of accelerated atherosclerosis.
Collapse
Affiliation(s)
- Caterina M Gambino
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Giulia Accardi
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Anna Aiello
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Calogero Caruso
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Ciriaco Carru
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Bruno G Gioia
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Giuliana Guggino
- Unit of Rheumatology, Paolo Giaccone University Hospital, Palermo, Italy
| | - Sergio Rizzo
- Unit of Transfusion Medicine, Paolo Giaccone University Hospital, Palermo, Italy
| | - Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Marcello Ciaccio
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Giuseppina Candore
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy -
| |
Collapse
|
|
13
|
Kachuri L, Francis SS, Morrison ML, Wendt GA, Bossé Y, Cavazos TB, Rashkin SR, Ziv E, Witte JS. The landscape of host genetic factors involved in immune response to common viral infections. Genome Med 2020; 12:93. [PMID: 33109261 PMCID: PMC7590248 DOI: 10.1186/s13073-020-00790-x] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 10/07/2020] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Humans and viruses have co-evolved for millennia resulting in a complex host genetic architecture. Understanding the genetic mechanisms of immune response to viral infection provides insight into disease etiology and therapeutic opportunities. METHODS We conducted a comprehensive study including genome-wide and transcriptome-wide association analyses to identify genetic loci associated with immunoglobulin G antibody response to 28 antigens for 16 viruses using serological data from 7924 European ancestry participants in the UK Biobank cohort. RESULTS Signals in human leukocyte antigen (HLA) class II region dominated the landscape of viral antibody response, with 40 independent loci and 14 independent classical alleles, 7 of which exhibited pleiotropic effects across viral families. We identified specific amino acid (AA) residues that are associated with seroreactivity, the strongest associations presented in a range of AA positions within DRβ1 at positions 11, 13, 71, and 74 for Epstein-Barr virus (EBV), Varicella zoster virus (VZV), human herpesvirus 7, (HHV7), and Merkel cell polyomavirus (MCV). Genome-wide association analyses discovered 7 novel genetic loci outside the HLA associated with viral antibody response (P < 5.0 × 10-8), including FUT2 (19q13.33) for human polyomavirus BK (BKV), STING1 (5q31.2) for MCV, and CXCR5 (11q23.3) and TBKBP1 (17q21.32) for HHV7. Transcriptome-wide association analyses identified 114 genes associated with response to viral infection, 12 outside of the HLA region, including ECSCR: P = 5.0 × 10-15 (MCV), NTN5: P = 1.1 × 10-9 (BKV), and P2RY13: P = 1.1 × 10-8 EBV nuclear antigen. We also demonstrated pleiotropy between viral response genes and complex diseases, from autoimmune disorders to cancer to neurodegenerative and psychiatric conditions. CONCLUSIONS Our study confirms the importance of the HLA region in host response to viral infection and elucidates novel genetic determinants beyond the HLA that contribute to host-virus interaction.
Collapse
Affiliation(s)
- Linda Kachuri
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA
| | - Stephen S Francis
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
- Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
| | - Maike L Morrison
- Department of Biology, Stanford University, Stanford, CA, USA
- Summer Research Training Program, Graduate Division, University of California San Francisco, San Francisco, CA, USA
- Department of Mathematics, The University of Texas, Austin, TX, USA
| | - George A Wendt
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Yohan Bossé
- Department of Molecular Medicine, Université Laval, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, QC, Canada
| | - Taylor B Cavazos
- Program in Biological and Medical Informatics, University of California San Francisco, San Francisco, CA, USA
| | - Sara R Rashkin
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Elad Ziv
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - John S Witte
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
- Department of Biology, Stanford University, Stanford, CA, USA.
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
- Department of Urology, University of California San Francisco, San Francisco, CA, USA.
| |
Collapse
|
|
14
|
Kachuri L, Francis SS, Morrison M, Wendt GA, Bossé Y, Cavazos TB, Rashkin SR, Ziv E, Witte JS. The landscape of host genetic factors involved in immune response to common viral infections. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2020:2020.05.01.20088054. [PMID: 32511533 PMCID: PMC7273301 DOI: 10.1101/2020.05.01.20088054] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Humans and viruses have co-evolved for millennia resulting in a complex host genetic architecture. Understanding the genetic mechanisms of immune response to viral infection provides insight into disease etiology and therapeutic opportunities. METHODS We conducted a comprehensive study including genome-wide and transcriptome-wide association analyses to identify genetic loci associated with immunoglobulin G antibody response to 28 antigens for 16 viruses using serological data from 7924 European ancestry participants in the UK Biobank cohort. RESULTS Signals in human leukocyte antigen (HLA) class II region dominated the landscape of viral antibody response, with 40 independent loci and 14 independent classical alleles, 7 of which exhibited pleiotropic effects across viral families. We identified specific amino acid (AA) residues that are associated with seroreactivity, the strongest associations presented in a range of AA positions within DRβ1 at positions 11, 13, 71, and 74 for Epstein-Barr Virus (EBV), Varicella Zoster Virus (VZV), Human Herpes virus 7, (HHV7) and Merkel cell polyomavirus (MCV). Genome-wide association analyses discovered 7 novel genetic loci outside the HLA associated with viral antibody response (P<5.×10-8), including FUT2 (19q13.33) for human polyomavirus BK (BKV), STING1 (5q31.2) for MCV, as well as CXCR5 (11q23.3) and TBKBP1 (17q21.32) for HHV7. Transcriptome-wide association analyses identified 114 genes associated with response to viral infection, 12 outside of the HLA region, including ECSCR: P=5.0×10-15 (MCV), NTN5: P=1.1×10-9 (BKV), and P2RY13: P=1.1×10-8 EBV nuclear antigen. We also demonstrated pleiotropy between viral response genes and complex diseases; from autoimmune disorders to cancer to neurodegenerative and psychiatric conditions. CONCLUSIONS Our study confirms the importance of the HLA region in host response to viral infection and elucidates novel genetic determinants beyond the HLA that contribute to host-virus interaction.
Collapse
Affiliation(s)
- Linda Kachuri
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, USA
| | - Stephen S. Francis
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, USA
- Department of Neurological Surgery, University of California San Francisco, San Francisco, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, USA
- Weill Institute for Neurosciences, University of California San Francisco, San Francisco, USA
| | - Maike Morrison
- Summer Research Training Program, Graduate Division, University of California San Francisco, San Francisco, USA
- Department of Mathematics, The University of Texas at Austin, Austin, USA
| | - George A. Wendt
- Department of Neurological Surgery, University of California San Francisco, San Francisco, USA
| | - Yohan Bossé
- Institut universitaire de cardiologie et de pneumologie de Québec, Department of Molecular Medicine, Université Laval, Quebec City, Canada
| | - Taylor B. Cavazos
- Program in Biological and Medical Informatics, University of California San Francisco, San Francisco, USA
| | - Sara R. Rashkin
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, USA
- Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, Memphis, USA
| | - Elad Ziv
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, USA
- Department of Medicine, University of California, San Francisco, San Francisco, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, USA
| | - John S. Witte
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, USA
- Department of Urology, University of California San Francisco, San Francisco, USA
| |
Collapse
|
|
15
|
Ahlen MT, Heide G, Husebekk A, Skogen B, Kjeldsen-Kragh J, Stuge TB. The prevalence of HPA-1a alloimmunization and the potential risk of FNAIT depend on both the DRB3*01:01 allele and associated DR-DQ haplotypes. Scand J Immunol 2020; 92:e12890. [PMID: 32299122 DOI: 10.1111/sji.12890] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 03/24/2020] [Accepted: 04/07/2020] [Indexed: 01/08/2023]
Abstract
Alloimmunization against human platelet antigen (HPA)-1a during pregnancy can cause foetal/neonatal alloimmune thrombocytopenia (FNAIT) and severe bleeding in the foetus or newborn and likely depends on several factors. HPA-1a alloimmunization is associated with DRB3*01:01, which is associated with several DR-DQ haplotypes. However, it is not known to what extent these haplotypes contribute to the prevalence of HPA-1a alloimmunization. HPA-1a-alloimmunized women, identified in a prospective study, and random donors were typed for selected DRB3, DRB4, DRB1, DQA1 and DQB1 alleles to determine allele and DR-DQ haplotype frequencies. DRB3*01:01 was carried by 94% HPA-1a-immunized women compared to 27% in the general population. In the first population, the DR3-DQ2 haplotype was overrepresented (P < .003). The prevalence of HPA-1a alloimmunization was estimated to be about twice as frequent with DR3-DQ2 compared to DR13-DQ6, together accounting for about 90% of DRB3*01:01-positive individuals. Further, we examined DQB1*02 and DRB4*01:01 alleles for their reported association with HPA-1a alloimmunization, in the context of DR-DQ haplotypes. Since ~ 80% of DQB1*02 alleles are linked to the DR3-DQ2 haplotype, the association might be coincidental. However, the DQB1*02:02-associated DR7-DQ2 haplotype was also overrepresented in alloimmunized women, suggesting a role for this allele or haplotype in HPA-1a alloimmunization. As DRB4*01:01 is predominantly associated with the DR7-DQ2 haplotype in HPA-1a-alloimmunized individuals, the reported association with FNAIT may be coincidental. Typing for DR-DQ haplotypes revealed important genetic associations with HPA-1a alloimmunization not evident from typing individual alleles, and the presence of different DRB3-associated DR-DQ haplotypes showed different prevalence of HPA-1a alloimmunization.
Collapse
Affiliation(s)
- Maria Therese Ahlen
- Department of Laboratory Medicine, University Hospital of North Norway, Tromsø, Norway
| | - Gøril Heide
- Immunology Research Group, Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway
| | - Anne Husebekk
- Immunology Research Group, Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway
| | - Bjørn Skogen
- Department of Laboratory Medicine, University Hospital of North Norway, Tromsø, Norway.,Immunology Research Group, Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway
| | - Jens Kjeldsen-Kragh
- Department of Laboratory Medicine, University Hospital of North Norway, Tromsø, Norway.,Department of Clinical Immunology and Transfusion Medicine, University and Regional Laboratories, Lund, Sweden
| | - Tor B Stuge
- Department of Laboratory Medicine, University Hospital of North Norway, Tromsø, Norway.,Immunology Research Group, Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway
| |
Collapse
|
|
16
|
Singh J, Sharma A, Rani L, Kaur N, Anand S, Saikia B, Jha S, Nada R, Minz RW. Distinct HLA and non-HLA associations in different subtypes of ANCA-associated vasculitides in North India. Int J Rheum Dis 2020; 23:958-965. [PMID: 32297471 DOI: 10.1111/1756-185x.13837] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 02/07/2020] [Accepted: 03/22/2020] [Indexed: 12/12/2022]
Abstract
AIM Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is an autoimmune disease characterized by necrotizing small vessel vasculitis that can affect various organs and present multiple symptoms. Susceptibility to AAV is multifactorial and most likely caused by an amalgamation of genetic and environmental factors. The aim of the present study was to explore the distribution of human leukocyte antigen (HLA)-DRB1/DQB1, protein tyrosine phosphatase non-receptor type 22 (PTPN22) and cytotoxic T-Lymphocyte-associated protein 4 (CTLA-4) polymorphisms in North Indian AAV patients and their associations with clinical and pathological characteristics associated with the disease. METHODS A total of 150 AAV patients and 150 healthy controls were recruited. The clinical classification showed 128 as granulomatosis with polyangiitis (GPA) and 21 as microscopic polyangiitis. Only 1 case of eosinophilic granulomatosis with polyangiitis was encountered, which was excluded from analysis. HLA-DRB1/DQB1 alleles were determined by polymerase chain reaction-sequence-specific primer (PCR-SSP) method and single nucleotide variant genotyping for CTLA-4 and PTPN22 was done by simple probe-based SNP arrays. RESULTS A significant predispositional association of DRB1*03 and DQB1*02 alleles, were confirmed in proteinase 3 (PR3)-AAV patients, whereas DRB1*10, DRB1*14 and DQB1*05 were protective alleles in AAV, PR3-AAV and GPA patients. GG genotype of CTLA-4 + 49A/G was increased in patients as compared to controls and showed an association with AAV, PR3-AAV and GPA patients. CONCLUSION The study indicated strong genetic associations were linked with PR3 antineutrophil cytoplasmic antibody specificity and it appears that PR3-AAV and MPO-AAV have distinct genetic backgrounds.
Collapse
Affiliation(s)
- Jagdeep Singh
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Aman Sharma
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Lekha Rani
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Navchetan Kaur
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Shashi Anand
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Biman Saikia
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Saket Jha
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ritambhra Nada
- Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ranjana Walker Minz
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| |
Collapse
|
|
17
|
Lande A, Fluge Ø, Strand EB, Flåm ST, Sosa DD, Mella O, Egeland T, Saugstad OD, Lie BA, Viken MK. Human Leukocyte Antigen alleles associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Sci Rep 2020; 10:5267. [PMID: 32210306 PMCID: PMC7093502 DOI: 10.1038/s41598-020-62157-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 03/03/2020] [Indexed: 01/06/2023] Open
Abstract
The etiology and pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are unknown, and autoimmunity is one of many proposed underlying mechanisms. Human Leukocyte Antigen (HLA) associations are hallmarks of autoimmune disease, and have not been thoroughly investigated in a large ME/CFS patient cohort. We performed high resolution HLA -A, -B, -C, -DRB1, -DQB1 and -DPB1 genotyping by next generation sequencing in 426 adult, Norwegian ME/CFS patients, diagnosed according to the Canadian Consensus Criteria. HLA associations were assessed by comparing to 4511 healthy and ethnically matched controls. Clinical information was collected through questionnaires completed by patients or relatives. We discovered two independent HLA associations, tagged by the alleles HLA-C*07:04 (OR 2.1 [95% CI 1.4–3.1]) and HLA-DQB1*03:03 (OR 1.5 [95% CI 1.1–2.0]). These alleles were carried by 7.7% and 12.7% of ME/CFS patients, respectively. The proportion of individuals carrying one or both of these alleles was 19.2% in the patient group and 12.2% in the control group (OR 1.7 [95% CI 1.3–2.2], pnc = 0.00003). ME/CFS is a complex disease, potentially with a substantial heterogeneity. We report novel HLA associations pointing toward the involvement of the immune system in ME/CFS pathogenesis.
Collapse
Affiliation(s)
- Asgeir Lande
- Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway. .,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Øystein Fluge
- Department of Oncology and Medical Physics, Haukeland University Hospital and Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Elin B Strand
- National Advisory Unit on CFS/ME, Oslo University Hospital, Oslo, Norway.,Faculty of Health Science, VID Specialized University, Stavanger, Norway
| | - Siri T Flåm
- Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Daysi D Sosa
- CFS/ME Center, Oslo University Hospital, Oslo, Norway
| | - Olav Mella
- Department of Oncology and Medical Physics, Haukeland University Hospital and Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Torstein Egeland
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Immunology, Oslo University Hospital, Oslo, Norway
| | - Ola D Saugstad
- Department of Pediatric Research, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Benedicte A Lie
- Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Immunology, Oslo University Hospital, Oslo, Norway
| | - Marte K Viken
- Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway.,Department of Immunology, Oslo University Hospital, Oslo, Norway
| |
Collapse
|
|
18
|
TNF-Block Genotypes Influence Susceptibility to HIV-Associated Sensory Neuropathy in Indonesians and South Africans. Int J Mol Sci 2020; 21:ijms21020380. [PMID: 31936167 PMCID: PMC7014294 DOI: 10.3390/ijms21020380] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 12/11/2019] [Accepted: 12/26/2019] [Indexed: 11/17/2022] Open
Abstract
HIV-associated sensory neuropathy (HIV-SN) is a disabling complication of HIV disease and antiretroviral therapies (ART). Since stavudine was removed from recommended treatment schedules, the prevalence of HIV-SN has declined and associated risk factors have changed. With stavudine, rs1799964*C (TNF-1031) associated with HIV-SN in Caucasians and Indonesians but not in South Africans. Here, we investigate associations between HIV-SN and rs1799964*C and 12 other polymorphisms spanning TNF and seven neighboring genes (the TNF-block) in Indonesians (n = 202; 34/168 cases) and South Africans (n = 75; 29/75 cases) treated without stavudine. Haplotypes were derived using fastPHASE and haplotype networks built with PopART. There were no associations with rs1799964*C in either population. However, rs9281523*C in intron 10 of BAT1 (alternatively DDX39B) independently associated with HIV-SN in Indonesians after correcting for lower CD4 T-cell counts and >500 copies of HIV RNA/mL (model p = 0.0011, Pseudo R2 = 0.09). rs4947324*T (between NFKBIL1 and LTA) independently associated with reduced risk of HIV-SN and shared haplotype 1 (containing no minor alleles) associated with increased risk of HIV-SN after correcting for greater body weight, a history of tuberculosis and nadir CD4 T-cell counts (model: p = 0.0003, Pseudo R2 = 0.22). These results confirm TNF-block genotypes influence susceptibility of HIV-SN. However, critical genotypes differ between ethnicities and with stavudine use.
Collapse
|
|
19
|
Zhong C, Cozen W, Bolanos R, Song J, Wang SS. The role of HLA variation in lymphoma aetiology and survival. J Intern Med 2019; 286:154-180. [PMID: 31155783 DOI: 10.1111/joim.12911] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Epidemiologic and laboratory evidence has consistently supported a strong inflammatory and immune component for lymphoma aetiology. These studies have consistently implicated variation in the immune gene, human leucocyte antigen (HLA), to be associated with lymphoma risk. In this review, we summarize the historical and recent evidence of HLA in both lymphoma aetiology and survival. The recent momentum in uncovering HLA associations has been propelled by the conduct of genome-wide association studies (GWAS), which has permitted the evaluation of imputed HLA alleles in much larger sample sizes than historically feasible with allelotyping studies. Based on the culmination of smaller HLA typing studies and larger GWAS, we now recognize several HLA associations with Hodgkin (HL) and non-Hodgkin lymphomas (NHLs) and their subtypes. Although other genetic variants have also been implicated with lymphoma risk, it is notable that HLA associations have been reported in every NHL and HL subtype evaluated to date. Both HLA class I and class II alleles have been linked with NHL and HL risk. It is notable that the associations identified are largely specific to each lymphoma subtype. However, pleiotropic HLA associations have also been observed. For example, rs10484561, which is in linkage disequilibrium with HLA-DRB1*01:01˜DQA1*01:01˜DQB1*05:01, has been implicated in increased FL and DLBCL risk. Opposing HLA associations across subtypes have also been reported, such as for HLA-A*01:01 which is associated with increased risk of EBV-positive cHL but decreased risk of EBV-negative cHL and chronic lymphocytic leukaemia/small cell lymphoma. Due to extensive linkage disequilibrium and allele/haplotypic variation across race/ethnicities, identification of causal alleles/haplotypes remains challenging. Follow-up functional studies are needed to identify the specific immunological pathways responsible in the multifactorial aetiology of HL and NHL. Correlative studies linking HLA alleles with known molecular subtypes and HLA expression in the tumours are also needed. Finally, additional association studies investigating HLA diversity and lymphoma survival are also required to replicate initial associations reported to date.
Collapse
Affiliation(s)
- C Zhong
- Division of Health Analytics, Department of Computational and Quantitative Medicine, Beckman Research Institute and Comprehensive Cancer Center, City of Hope, Duarte, CA, USA
| | - W Cozen
- Genetic Epidemiology Center, Department of Preventive Medicine, Keck School of Medicine of USC, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - R Bolanos
- Genetic Epidemiology Center, Department of Preventive Medicine, Keck School of Medicine of USC, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - J Song
- Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA
| | - S S Wang
- Division of Health Analytics, Department of Computational and Quantitative Medicine, Beckman Research Institute and Comprehensive Cancer Center, City of Hope, Duarte, CA, USA
| |
Collapse
|
|
20
|
Shappley C, Paik JJ, Saketkoo LA. Myositis-Related Interstitial Lung Diseases: Diagnostic Features, Treatment, and Complications. CURRENT TREATMENT OPTIONS IN RHEUMATOLOGY 2019; 5:56-83. [PMID: 31984206 DOI: 10.1007/s40674-018-0110-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Courtney Shappley
- Ochsner Advanced Lung Disease Program, Ochsner Hospital Foundation, New Orleans, LA
- Tulane University Section of Pulmonary Medicine and Critical Care, New Orleans, LA
| | - Julie J Paik
- Johns Hopkins Medical Institute, Myositis Program, Baltimore, MD
| | - Lesley Ann Saketkoo
- Tulane University Section of Pulmonary Medicine and Critical Care, New Orleans, LA
- New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center
- University Medical Center Comprehensive Pulmonary Hypertension Center
| |
Collapse
|
|
21
|
Kara S, Pirela-Morillo GA, Gilliam CT, Wilson GD. Identification of novel susceptibility genes associated with seven autoimmune disorders using whole genome molecular interaction networks. J Autoimmun 2018; 97:48-58. [PMID: 30391024 DOI: 10.1016/j.jaut.2018.10.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 10/08/2018] [Accepted: 10/11/2018] [Indexed: 12/20/2022]
Abstract
Convergent evidence from multiple and independent genetics studies implicate a small number of genes that predispose individuals to multiple autoimmune disorders (AuD). These intersecting loci reinforced the hypothesis that disorders with overlapping etiology group into a cluster of closely related genes within a whole genome molecular interaction network. We tested the hypothesis that "biological network proximity" within a whole genome molecular interaction network can be used to inform the search for multigene inheritance. Using a set of nine previously published genome wide association studies (GWAS) of AuD genes, we generated AuD-specific molecular interaction networks to identify networks of associated genes. We show that all nine "seed genes" can be connected within a 35-member network via interactions with 26 connecting genes. We show that this network is more connected than expected by chance, and 13 of the connecting genes showed association with multiple AuD upon GWAS reanalysis. Furthermore, we report association of SNPs in five new genes (IL10RA, DGKA, GRB2, STAT5A, and NFATC2) which were not previously considered as AuD candidates, and show significant association in novel disease samples of Crohn's disease and systemic lupus erythematosus. Furthermore, we show that the connecting genes show no association in four non-AuD GWAS. Finally, we test the connecting genes in psoriasis GWAS, and show association to previously identified loci and report new loci. These findings support the hypothesis that molecular interaction networks can be used to inform the search for multigene disease etiology, especially for disorders with overlapping etiology.
Collapse
Affiliation(s)
- Sam Kara
- University of Chicago, Departments of Human Genetics, 920 East 58 th St., Chicago, IL 60637, USA; Radiation Oncology Department, Beaumont Health, 3811 W Thirteen Mile Road, Royal Oak, MI, 48073, USA
| | - Gerardo A Pirela-Morillo
- La Universidad del Zulia, Computer Science Department, Laboratories for Computational Models & Languages, and Bioinformatics, Edif. Grano de Oro, Planta Baja, Departamento de Computación, Ave. Universidad con Ave. 22, Maracaibo, 4002, Venezuela
| | - Conrad T Gilliam
- University of Chicago, Departments of Human Genetics, 920 East 58 th St., Chicago, IL 60637, USA
| | - George D Wilson
- Radiation Oncology Department, Beaumont Health, 3811 W Thirteen Mile Road, Royal Oak, MI, 48073, USA.
| |
Collapse
|
|
22
|
Tamouza R, Oliveira J, Etain B, Bengoufa D, Hamdani N, Manier C, Mariaselvam C, Sundaresh A, Bellivier F, Henry C, Kahn JP, Krishnamoorthy R, Charron D, Leboyer M. HLA genetics in bipolar disorder. Acta Psychiatr Scand 2018; 138:464-471. [PMID: 29869414 DOI: 10.1111/acps.12912] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/16/2018] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Bipolar Disorder (BD) is characterized by deregulated adaptive immune processes. Recent genome-wide association studies (GWAS) implicate the major histocompatibility complex (MHC) region in BD. The present study investigates the potential influence of variations in human leukocyte antigen (HLA) on BD risk and/or clinical presentations. This may have relevance to the dysregulated inflammatory processes commonly found in BD. METHOD DNAs from 475 BD patients and 195 healthy controls (HC) were genotyped for classical HLA class I and II loci. RESULTS We found that: (i) the HLA-A*02~B*44~DRB1*07 sub-haplotype is less prevalent in BD, vs. HC (pc = 2.4 × 10-2 ); (ii) the 57.1 and the 8.1-derived ancestral haplotypes i.e. HLA-A*02~B*57~Cw*06~DRB1*07~DQB1*09 and HLA-A*02~B*08~Cw*07 are associated with rapid cycling (pc = 1.9 × 10-3 and 1.05 × 10-2 , respectively); (iii) the 8.1AH-derived HLA class II-DRB*03~HLA-DQB1*02 sub-haplotype is more frequent in BD patients with a history of suicidal behaviors (pc = 2.1 × 10-2 ); and (iv) disease onset by an hypomanic episode or by psychotic symptoms are, respectively, more frequent in BD patients bearing the 7.1 AH-derived A*03~B*07~DRB1*15 sub-haplotype (pc = 8.5 × 10-3 ) and the HLA-A*02~B*07~DRB1*15 sub-haplotype (pc = 4.0 × 10-2 ). CONCLUSION Corroborating the established link between these HLA haplotypes/sub haplotypes and common immune disorders, our findings suggest possible HLA-mediated proinflammatory processes operating in BD.
Collapse
Affiliation(s)
- R Tamouza
- INSERM, U955, Translational Psychiatry, Paris-East University, School of Medicine, AP-HP, DHU PePSY, Pole of Psychiatry, Henri Mondor University Hospital, Créteil, France.,FondaMental Foundation, Créteil, France.,Cordons de Vie Association, Monaco and LabEx Transplantex, Strasbourg, France
| | - J Oliveira
- INSERM, U955, Translational Psychiatry, Paris-East University, School of Medicine, AP-HP, DHU PePSY, Pole of Psychiatry, Henri Mondor University Hospital, Créteil, France.,FondaMental Foundation, Créteil, France
| | - B Etain
- FondaMental Foundation, Créteil, France.,Department of Psychiatry & Addiction Medicine, INSERM UMR-S1144 - VariaPsy, University Paris Diderot, AP-HP, Fernand Widal Hospital, Paris, France
| | - D Bengoufa
- INSERM, U1160, Saint Louis Hospital, Paris, France
| | - N Hamdani
- INSERM, U955, Translational Psychiatry, Paris-East University, School of Medicine, AP-HP, DHU PePSY, Pole of Psychiatry, Henri Mondor University Hospital, Créteil, France.,FondaMental Foundation, Créteil, France
| | - C Manier
- INSERM, U955, Translational Psychiatry, Paris-East University, School of Medicine, AP-HP, DHU PePSY, Pole of Psychiatry, Henri Mondor University Hospital, Créteil, France.,INSERM, U1160, Saint Louis Hospital, Paris, France
| | - C Mariaselvam
- INSERM, U955, Translational Psychiatry, Paris-East University, School of Medicine, AP-HP, DHU PePSY, Pole of Psychiatry, Henri Mondor University Hospital, Créteil, France.,INSERM, U1160, Saint Louis Hospital, Paris, France
| | - A Sundaresh
- INSERM, U955, Translational Psychiatry, Paris-East University, School of Medicine, AP-HP, DHU PePSY, Pole of Psychiatry, Henri Mondor University Hospital, Créteil, France.,INSERM, U1160, Saint Louis Hospital, Paris, France
| | - F Bellivier
- FondaMental Foundation, Créteil, France.,Department of Psychiatry & Addiction Medicine, INSERM UMR-S1144 - VariaPsy, University Paris Diderot, AP-HP, Fernand Widal Hospital, Paris, France
| | - C Henry
- INSERM, U955, Translational Psychiatry, Paris-East University, School of Medicine, AP-HP, DHU PePSY, Pole of Psychiatry, Henri Mondor University Hospital, Créteil, France.,FondaMental Foundation, Créteil, France
| | - J-P Kahn
- Department of Psychiatry and Clinical Psychology, CHU of Nancy, Brabois Hospitals, Vandoeuvre Les Nancy, France
| | - R Krishnamoorthy
- INSERM, U955, Translational Psychiatry, Paris-East University, School of Medicine, AP-HP, DHU PePSY, Pole of Psychiatry, Henri Mondor University Hospital, Créteil, France.,FondaMental Foundation, Créteil, France
| | - D Charron
- FondaMental Foundation, Créteil, France
| | - M Leboyer
- INSERM, U955, Translational Psychiatry, Paris-East University, School of Medicine, AP-HP, DHU PePSY, Pole of Psychiatry, Henri Mondor University Hospital, Créteil, France.,FondaMental Foundation, Créteil, France
| |
Collapse
|
|
23
|
Ferreiro-Iglesias A, Lesseur C, McKay J, Hung RJ, Han Y, Zong X, Christiani D, Johansson M, Xiao X, Li Y, Qian DC, Ji X, Liu G, Caporaso N, Scelo G, Zaridze D, Mukeriya A, Kontic M, Ognjanovic S, Lissowska J, Szołkowska M, Swiatkowska B, Janout V, Holcatova I, Bolca C, Savic M, Ognjanovic M, Bojesen SE, Wu X, Albanes D, Aldrich MC, Tardon A, Fernandez-Somoano A, Fernandez-Tardon G, Le Marchand L, Rennert G, Chen C, Doherty J, Goodman G, Bickeböller H, Wichmann HE, Risch A, Rosenberger A, Shen H, Dai J, Field JK, Davies M, Woll P, Teare MD, Kiemeney LA, van der Heijden EHFM, Yuan JM, Hong YC, Haugen A, Zienolddiny S, Lam S, Tsao MS, Johansson M, Grankvist K, Schabath MB, Andrew A, Duell E, Melander O, Brunnström H, Lazarus P, Arnold S, Slone S, Byun J, Kamal A, Zhu D, Landi MT, Amos CI, Brennan P. Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity. Nat Commun 2018; 9:3927. [PMID: 30254314 PMCID: PMC6156406 DOI: 10.1038/s41467-018-05890-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 07/30/2018] [Indexed: 12/19/2022] Open
Abstract
The basis for associations between lung cancer and major histocompatibility complex genes is not completely understood. Here the authors further consider genetic variation within the MHC region in lung cancer patients and identify independent associations within HLA genes that explain MHC lung cancer associations in Europeans and Asian populations. Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA–tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.
Collapse
Affiliation(s)
- Aida Ferreiro-Iglesias
- International Agency for Research on Cancer, World Health Organization, Lyon, 69372 cedex 08, France
| | - Corina Lesseur
- International Agency for Research on Cancer, World Health Organization, Lyon, 69372 cedex 08, France
| | - James McKay
- International Agency for Research on Cancer, World Health Organization, Lyon, 69372 cedex 08, France
| | - Rayjean J Hung
- Lunenfeld-Tanenbaum Research Institute of Sinai Health System, University of Toronto, Toronto, M5G 1X5, Canada
| | - Younghun Han
- Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, 03755, NH, USA
| | - Xuchen Zong
- Lunenfeld-Tanenbaum Research Institute of Sinai Health System, University of Toronto, Toronto, M5G 1X5, Canada
| | - David Christiani
- Department of Environmental Health, Harvard TH Chan School of Public Health, Massachusetts General Hospital/ Harvard Medical School, Boston, 02115, MA, USA
| | - Mattias Johansson
- International Agency for Research on Cancer, World Health Organization, Lyon, 69372 cedex 08, France
| | - Xiangjun Xiao
- Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, 03755, NH, USA
| | - Yafang Li
- Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, 03755, NH, USA
| | - David C Qian
- Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, 03755, NH, USA
| | - Xuemei Ji
- Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, 03755, NH, USA
| | - Geoffrey Liu
- Lunenfeld-Tanenbaum Research Institute of Sinai Health System, University of Toronto, Toronto, M5G 1X5, Canada
| | - Neil Caporaso
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, 20892-9768, MD, USA
| | - Ghislaine Scelo
- International Agency for Research on Cancer, World Health Organization, Lyon, 69372 cedex 08, France
| | - David Zaridze
- Russian N.N. Blokhin Cancer Research Centre, Moscow, 115478, Russian Federation
| | - Anush Mukeriya
- Russian N.N. Blokhin Cancer Research Centre, Moscow, 115478, Russian Federation
| | | | - Simona Ognjanovic
- International Organization for Cancer Prevention and Research, Belgrade, 11070, Serbia
| | - Jolanta Lissowska
- M. Sklodowska-Curie Cancer Center, Institute of Oncology, Warsaw, 02-034, Poland
| | - Małgorzata Szołkowska
- Department of Pathology, National Tuberculosis and Lung Diseases Research Institute, Warsaw, 01-138, Poland
| | - Beata Swiatkowska
- Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lodz, 91-348, Poland
| | - Vladimir Janout
- Faculty of Medicine, University of Olomouc, Olomouc, 701 03, Czech Republic
| | - Ivana Holcatova
- 2nd Faculty of Medicine, Institute of Public Health and Preventive Medicine, Charles University, Prague, CZ 128 00, Czech Republic
| | - Ciprian Bolca
- Institute of Pneumology "Marius Nasta", Bucharest, RO-050159, Romania
| | - Milan Savic
- Department of Thoracic Surgery Clinical Center of Serbia Belgrade, Belgrade, 11000, Serbia
| | - Miodrag Ognjanovic
- International Organization for Cancer Prevention and Research, Belgrade, 11070, Serbia
| | - Stig Egil Bojesen
- Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen, 2730, Denmark.,Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, 2730, Denmark.,Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2730, Denmark
| | - Xifeng Wu
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA
| | - Demetrios Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, 20892-9768, MD, USA
| | - Melinda C Aldrich
- Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, 37232-4682, TA, USA
| | - Adonina Tardon
- University of Oviedo and CIBERESP, Faculty of Medicine, Oviedo, 33006, Spain
| | | | | | - Loic Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, 96813, HI, USA
| | - Gadi Rennert
- Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine, Haifa, 3525433, Israel
| | - Chu Chen
- Department of Epidemiology, University of Washington School of Public Health and Community Medicine, Seattle, 98195, WA, USA
| | - Jennifer Doherty
- Department of Epidemiology, University of Washington School of Public Health and Community Medicine, Seattle, 98195, WA, USA.,Fred Hutchinson Cancer Research Center, Seattle, 98109, WA, USA
| | | | - Heike Bickeböller
- Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, Göttingen, 37073, Germany
| | - H-Erich Wichmann
- Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig Maximilians University, Munich, D-85764, Germany.,Helmholtz Center Munich, Institute of Epidemiology 2, Munich, D-85764, Germany.,Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich, D-80333, Germany
| | - Angela Risch
- University of Salzburg and Cancer Cluster Salzburg, Salzburg, 5020, Austria.,Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, 69120, Germany.,German Center for Lung Research (DZL), Heidelberg, 69121, Germany
| | - Albert Rosenberger
- Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, Göttingen, 37073, Germany
| | - Hongbing Shen
- Department of Epidemiology and Biostatistics, Jiangsu Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Juncheng Dai
- Department of Epidemiology and Biostatistics, Jiangsu Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - John K Field
- Institute of Translational Medicine, University of Liverpool, Liverpool, L3 9TA, UK
| | - Michael Davies
- Institute of Translational Medicine, University of Liverpool, Liverpool, L3 9TA, UK
| | - Penella Woll
- Department of Oncology, University of Sheffield, Sheffield, S10 2RX, UK
| | - M Dawn Teare
- School of Health and Related Research, University Of Sheffield, England, S1 4DA, UK
| | | | | | - Jian-Min Yuan
- University of Pittsburgh Cancer Institute, Pittsburgh, 15232, PA, USA
| | - Yun-Chul Hong
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea
| | - Aage Haugen
- National Institute of Occupational Health, Oslo, N-0033, Norway
| | | | - Stephen Lam
- British Columbia Cancer Agency, Vancouver, V5Z 1M9, Canada
| | - Ming-Sound Tsao
- Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada
| | - Mikael Johansson
- Department of Radiation Sciences, Umeå University, Umeå, 901 85, Sweden
| | - Kjell Grankvist
- Department of Medical Biosciences, Umeå University, Umeå, 901 85, Sweden
| | - Matthew B Schabath
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, 33612, FL, USA
| | - Angeline Andrew
- Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, 03755, NH, USA
| | - Eric Duell
- Unit of Nutrition and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, 08908, Spain
| | - Olle Melander
- Department of Clinical Sciences Malmö, Lund University, Malmö, 221 00, Sweden.,Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden
| | - Hans Brunnström
- Laboratory Medicine Region Skåne, Department of Clinical Sciences Lund, Pathology, Lund University, Lund, 221 00, Sweden
| | - Philip Lazarus
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, 99202, WA, USA
| | - Susanne Arnold
- University of Kentucky, Markey Cancer Center, Lexington, 40536-0098, KY, USA
| | - Stacey Slone
- University of Kentucky, Markey Cancer Center, Lexington, 40536-0098, KY, USA
| | - Jinyoung Byun
- Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, 03755, NH, USA
| | - Ahsan Kamal
- Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, 03755, NH, USA
| | - Dakai Zhu
- Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, 03755, NH, USA
| | - Maria Teresa Landi
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, 20892-9768, MD, USA
| | - Christopher I Amos
- Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, 03755, NH, USA
| | - Paul Brennan
- International Agency for Research on Cancer, World Health Organization, Lyon, 69372 cedex 08, France.
| |
Collapse
|
|
24
|
Yarzabek B, Zaitouna AJ, Olson E, Silva GN, Geng J, Geretz A, Thomas R, Krishnakumar S, Ramon DS, Raghavan M. Variations in HLA-B cell surface expression, half-life and extracellular antigen receptivity. eLife 2018; 7:e34961. [PMID: 29989547 PMCID: PMC6039183 DOI: 10.7554/elife.34961] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 05/29/2018] [Indexed: 12/11/2022] Open
Abstract
The highly polymorphic human leukocyte antigen (HLA) class I molecules present peptide antigens to CD8+ T cells, inducing immunity against infections and cancers. Quality control mediated by peptide loading complex (PLC) components is expected to ensure the cell surface expression of stable peptide-HLA class I complexes. This is exemplified by HLA-B*08:01 in primary human lymphocytes, with both expression level and half-life at the high end of the measured HLA-B expression and stability hierarchies. Conversely, low expression on lymphocytes is measured for three HLA-B allotypes that bind peptides with proline at position 2, which are disfavored by the transporter associated with antigen processing. Surprisingly, these lymphocyte-specific expression and stability differences become reversed or altered in monocytes, which display larger intracellular pools of HLA class I than lymphocytes. Together, the findings indicate that allele and cell-dependent variations in antigen acquisition pathways influence HLA-B surface expression levels, half-lives and receptivity to exogenous antigens.
Collapse
Affiliation(s)
- Brogan Yarzabek
- Department of Microbiology and Immunology, Michigan MedicineUniversity of MichiganMichiganUnited States
| | - Anita J Zaitouna
- Department of Microbiology and Immunology, Michigan MedicineUniversity of MichiganMichiganUnited States
| | - Eli Olson
- Department of Microbiology and Immunology, Michigan MedicineUniversity of MichiganMichiganUnited States
- Graduate Program in Immunology, Michigan MedicineUniversity of MichiganMichiganUnited States
| | - Gayathri N Silva
- Department of Microbiology and Immunology, Michigan MedicineUniversity of MichiganMichiganUnited States
| | - Jie Geng
- Department of Microbiology and Immunology, Michigan MedicineUniversity of MichiganMichiganUnited States
| | - Aviva Geretz
- US Military HIV Research ProgramWalter Reed Army Institute of ResearchSilver SpringUnited States
- Henry M. Jackson Foundation for the Advancement of Military MedicineBethesdaUnited States
| | - Rasmi Thomas
- US Military HIV Research ProgramWalter Reed Army Institute of ResearchSilver SpringUnited States
- Henry M. Jackson Foundation for the Advancement of Military MedicineBethesdaUnited States
| | | | - Daniel S Ramon
- Department of Laboratory Medicine and PathologyMayo ClinicArizonaUnited States
| | - Malini Raghavan
- Department of Microbiology and Immunology, Michigan MedicineUniversity of MichiganMichiganUnited States
| |
Collapse
|
|
25
|
HLA -A, -C, -B, -DRB1, -DQB1 and -DPB1 allele and haplotype frequencies in 4514 healthy Norwegians. Hum Immunol 2018; 79:527-529. [DOI: 10.1016/j.humimm.2018.04.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 04/18/2018] [Accepted: 04/18/2018] [Indexed: 11/22/2022]
|
|
26
|
Liesmaa I, Paakkanen R, Järvinen A, Valtonen V, Lokki ML. Clinical features of patients with homozygous complement C4A or C4B deficiency. PLoS One 2018; 13:e0199305. [PMID: 29928053 PMCID: PMC6013154 DOI: 10.1371/journal.pone.0199305] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 06/05/2018] [Indexed: 12/28/2022] Open
Abstract
INTRODUCTION Homozygous deficiencies of complement C4A or C4B are detected in 1-10% of populations. In genome-wide association studies C4 deficiencies are missed because the genetic variation of C4 is complex. There are no studies where the clinical presentation of these patients is analyzed. This study was aimed to characterize the clinical features of patients with homozygous C4A or C4B deficiency. MATERIAL AND METHODS Thirty-two patients with no functional C4A, 87 patients with no C4B and 120 with normal amount of C4 genes were included. C4A and C4B numbers were assessed with genomic quantitative real-time PCR. Medical history was studied retrospectively from patients' files. RESULTS Novel associations between homozygous C4A deficiency and lymphoma, coeliac disease and sarcoidosis were detected. These conditions were present in 12.5%, (4/32 in patients vs. 0.8%, 1/120, in controls, OR = 17.00, 95%CI = 1.83-158.04, p = 0.007), 12.5% (4/32 in patients vs. 0%, 0/120 in controls, OR = 1.14, 95%CI = 1.00-1.30, p = 0.002) and 12.5%, respectively (4/32 in patients vs. 2.5%, 3/120 in controls, OR = 5.571, 95%CI = 1.79-2.32, p = 0.036). In addition, C4A and C4B deficiencies were both associated with adverse drug reactions leading to drug discontinuation (34.4%, 11/32 in C4A-deficient patients vs. 14.2%, 17/120 in controls, OR = 3.174, 95%CI = 1.30-7.74, p = 0.009 and 28.7%, 25/87 in C4B-deficient patients, OR = 2.44, 95%CI = 1.22-4.88, p = 0.010). CONCLUSION This reported cohort of homozygous deficiencies of C4A or C4B suggests that C4 deficiencies may have various unrecorded disease associations. C4 gene should be considered as a candidate gene in studying these selected disease associations.
Collapse
Affiliation(s)
- Inka Liesmaa
- Division of Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- * E-mail:
| | - Riitta Paakkanen
- Transplantation Laboratory, Medicum, University of Helsinki, Helsinki, Finland
- Division of Cardiology, Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Asko Järvinen
- Division of Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Ville Valtonen
- Division of Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Marja-Liisa Lokki
- Transplantation Laboratory, Medicum, University of Helsinki, Helsinki, Finland
| |
Collapse
|
|
27
|
Gambino CM, Aiello A, Accardi G, Caruso C, Candore G. Autoimmune diseases and 8.1 ancestral haplotype: An update. HLA 2018; 92:137-143. [PMID: 29877054 DOI: 10.1111/tan.13305] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 05/08/2018] [Accepted: 06/01/2018] [Indexed: 12/11/2022]
Abstract
The aim of the present review is to provide an update of the current research into the pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype. This is a common Caucasoid haplotype carried by most people who type for HLA-B8, DR3. Numerous genetic studies reported that individuals with certain HLA alleles have a higher risk of specific autoimmune disorders than those without these alleles. However, much remains to be learned about the heritability of autoimmune conditions. Recently, progress and advances in the field of genome-wide-association studies have revolutionized the capacity to perform large, economically feasible, and statistically robust analyses of HLA within 8.1 ancestral haplotype, and understand its contribute to autoimmune events. In this paper, the characteristic features of this haplotype that might give rise to diverse autoimmune phenotypes are reviewed, focusing on the contribution of the HLA-DRB1 gene, the most polymorphic sequence within the HLA II region.
Collapse
Affiliation(s)
- C M Gambino
- Department of Pathobiology and Medical Biotechnologies (Di.Bi.Med.), University of Palermo, Palermo, Italy
| | - A Aiello
- Department of Pathobiology and Medical Biotechnologies (Di.Bi.Med.), University of Palermo, Palermo, Italy
| | - G Accardi
- Department of Pathobiology and Medical Biotechnologies (Di.Bi.Med.), University of Palermo, Palermo, Italy
| | - C Caruso
- Department of Pathobiology and Medical Biotechnologies (Di.Bi.Med.), University of Palermo, Palermo, Italy
| | - G Candore
- Department of Pathobiology and Medical Biotechnologies (Di.Bi.Med.), University of Palermo, Palermo, Italy
| |
Collapse
|
|
28
|
Tratamiento antituberculoso en un paciente con enfermedad celíaca. Arch Bronconeumol 2018; 54:337-338. [DOI: 10.1016/j.arbres.2017.12.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 12/10/2017] [Accepted: 12/14/2017] [Indexed: 11/27/2022]
|
|
29
|
Gambino CM, Di Bona D, Aiello A, Carru C, Duro G, Guggino G, Ferrante A, Zinellu A, Caruso C, Candore G, Accardi G. HLA-C1 ligands are associated with increased susceptibility to systemic lupus erythematosus. Hum Immunol 2018; 79:172-177. [PMID: 29395276 DOI: 10.1016/j.humimm.2018.01.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 12/09/2017] [Accepted: 01/16/2018] [Indexed: 12/31/2022]
Abstract
Recently, the role of killer cell immunoglobulin-like receptor (KIR) in autoimmune diseases has received increasing attention. The present study was undertaken to determine the association of KIR genes and the human leukocytes antigen (HLA) ligands with Systemic Lupus Erythematosus (SLE) and accompanying oxidative stress. Presence or absence of 17 KIR and 5 HLA loci was performed using the polymerase chain reaction-sequence specific primer (PCR-SSP) method by case-control study. A total of 45 SLE patients, and 60 healthy controls, all of Sicilian descent, were enrolled. Plasma values of the anti-oxidant molecule Taurine were determined in all subjects by capillary electrophoresis UV detection. The carrier frequency of the KIR2DS2 gene was significantly increased in SLE patients compared to healthy controls (73.3 versus 45.0%; OR = 3.36; 95% CI = 1.46-7.74; p = .005) suggesting a role of KIR2DS2 gene in the susceptibility to disease. We also observed a strong positive association between the presence of HLA-C1 ligands group and the disease (82.2% in SLE patients versus 41.7% in controls; OR = 6.47, 95% CI = 2.58-16.26; p < .0001). Stepwise logistic regression analysis supported the effect of the HLA-C1 ligands in SLE patients (OR = 7.06, 95% CI = 0.07-2.19; p = .002), while the KIR genes were no longer significant. Interestingly, we found that SLE patients HLA-C1 positive showed significantly decreased plasma levels of antioxidant activity marker Taurine (69.38 ± 28.49 μmol/L) compared to SLE patients HLA-C1 negative (108.37 ± 86.09 μmol/L) (p = .03). In conclusion, HLA-C1 ligands group was significantly associated with an increased risk of SLE as well as an increased oxidative stress status overall in SLE patients.
Collapse
Affiliation(s)
- Caterina Maria Gambino
- Department of Pathobiology and Medical Biotechnologies (Di.Bi.Med.), University of Palermo, Palermo, Italy
| | - Danilo Di Bona
- School and Chair of Allergology, Department of Emergencies and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Anna Aiello
- Department of Pathobiology and Medical Biotechnologies (Di.Bi.Med.), University of Palermo, Palermo, Italy
| | - Ciriaco Carru
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Giovanni Duro
- Institute of Biomedicine and Molecular Immunology, National Research Council, Palermo, Italy
| | - Giuliana Guggino
- Department of Internal and Specialist Biomedicine, University of Palermo, Italy
| | - Angelo Ferrante
- Department of Internal and Specialist Biomedicine, University of Palermo, Italy
| | - Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Calogero Caruso
- Department of Pathobiology and Medical Biotechnologies (Di.Bi.Med.), University of Palermo, Palermo, Italy; Department of Transfusion Medicine, Azienda Universitaria-Ospedaliera Policlinico "Paolo Giaccone", Palermo, Italy.
| | - Giuseppina Candore
- Department of Pathobiology and Medical Biotechnologies (Di.Bi.Med.), University of Palermo, Palermo, Italy; Department of Transfusion Medicine, Azienda Universitaria-Ospedaliera Policlinico "Paolo Giaccone", Palermo, Italy
| | - Giulia Accardi
- Department of Pathobiology and Medical Biotechnologies (Di.Bi.Med.), University of Palermo, Palermo, Italy
| |
Collapse
|
|
30
|
Allenbach Y, Mammen AL, Benveniste O, Stenzel W. 224th ENMC International Workshop:: Clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14-16 October 2016. Neuromuscul Disord 2017; 28:87-99. [PMID: 29221629 DOI: 10.1016/j.nmd.2017.09.016] [Citation(s) in RCA: 332] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 09/25/2017] [Accepted: 09/29/2017] [Indexed: 12/17/2022]
Affiliation(s)
- Yves Allenbach
- Department of Internal Medicine, Pitie Salpetrière Hospital, AP-HP Sorbonne university, Paris, France
| | - Andrew L Mammen
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Olivier Benveniste
- Department of Internal Medicine, Pitie Salpetrière Hospital, AP-HP Sorbonne university, Paris, France
| | - Werner Stenzel
- Department of Neuropathology, Charité-Universitätsmedizin, Berlin, Germany.
| | | |
Collapse
|
|
31
|
Henriksen EKK, Viken MK, Wittig M, Holm K, Folseraas T, Mucha S, Melum E, Hov JR, Lazaridis KN, Juran BD, Chazouillères O, Färkkilä M, Gotthardt DN, Invernizzi P, Carbone M, Hirschfield GM, Rushbrook SM, Goode E, Ponsioen CY, Weersma RK, Eksteen B, Yimam KK, Gordon SC, Goldberg D, Yu L, Bowlus CL, Franke A, Lie BA, Karlsen TH. HLA haplotypes in primary sclerosing cholangitis patients of admixed and non-European ancestry. HLA 2017; 90:228-233. [PMID: 28695657 DOI: 10.1111/tan.13076] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Revised: 05/26/2017] [Accepted: 06/12/2017] [Indexed: 12/19/2022]
Abstract
Primary sclerosing cholangitis (PSC) is strongly associated with several human leukocyte antigen (HLA) haplotypes. Due to extensive linkage disequilibrium and multiple polymorphic candidate genes in the HLA complex, identifying the alleles responsible for these associations has proven difficult. We aimed to evaluate whether studying populations of admixed or non-European descent could help in defining the causative HLA alleles. When assessing haplotypes carrying HLA-DRB1*13:01 (hypothesized to specifically increase the susceptibility to chronic cholangitis), we observed that every haplotype in the Scandinavian PSC population carried HLA-DQB1*06:03. In contrast, only 65% of HLA-DRB1*13:01 haplotypes in an admixed/non-European PSC population carried this allele, suggesting that further assessments of the PSC-associated haplotype HLA-DRB1*13:01-DQA1*01:03-DQB1*06:03 in admixed or multi-ethnic populations could aid in identifying the causative allele.
Collapse
Affiliation(s)
- E K K Henriksen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - M K Viken
- K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - M Wittig
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
| | - K Holm
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - T Folseraas
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - S Mucha
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
| | - E Melum
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - J R Hov
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - K N Lazaridis
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - B D Juran
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - O Chazouillères
- Hôpital Saint-Antoine, Service d'Hépatologie, INSERM, UMR_S 938, CDR Saint-Antoine, and Sorbonne Universités, UPMC Univ Paris 06, Paris, France
| | - M Färkkilä
- Helsinki University and Clinic of Gastroenterology, Helsinki University Hospital, Helsinki, Finland
| | - D N Gotthardt
- Department of Gastroenterology, Infectious Diseases and Intoxications, University Hospital of Heidelberg, Heidelberg, Germany
| | - P Invernizzi
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - M Carbone
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - G M Hirschfield
- Centre for Liver Research and NIHR Birmingham Liver Biomedical Research Unit, Institute of Biomedical Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - S M Rushbrook
- The Department of Gastroenterology, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norfolk, UK
| | - E Goode
- Wellcome Trust Sanger Institute, Hinxton and Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | | | - C Y Ponsioen
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands
| | - R K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - B Eksteen
- Snyder Institute for Chronic Diseases, Division of Gastroenterology, University of Calgary, Calgary, Canada
| | - K K Yimam
- Division of Hepatology and Liver Transplantation, California Pacific Medical Center, San Francisco, California
| | - S C Gordon
- Division of Gastroenterology and Hepatology, Henry Ford Health System, Detroit, Michigan
| | - D Goldberg
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - L Yu
- Department of Medicine, University of Washington, Seattle, Washington
| | - C L Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento, California
| | - A Franke
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
| | - B A Lie
- K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Department of Medical Genetics, University of Oslo and Oslo University Hospital Ullevål, Oslo, Norway
| | - T H Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| |
Collapse
|
|
32
|
Słomiński B, Ławrynowicz U, Myśliwska J, Ryba-Stanisławowska M, Skrzypkowska M, Myśliwiec M, Brandt A. CCR5-Δ32 gene polymorphism is related to celiac disease and autoimmune thyroiditis coincidence in patients with type 1 diabetes. J Diabetes Complications 2017; 31:615-618. [PMID: 27894748 DOI: 10.1016/j.jdiacomp.2016.10.031] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 10/03/2016] [Accepted: 10/28/2016] [Indexed: 11/22/2022]
Abstract
AIM The aim of the study was to assess the relationship between CCR5-Δ32 polymorphism and the coincidence of celiac and autoimmune thyroid diseases with type 1 diabetes mellitus (T1D) in children. METHODS 420 children with T1D aged 15.5±3.0years and 350 healthy controls were studied. Characterization of CCR5-Δ32 genotypes (rs333) was analyzed by polymerase chain reaction (PCR). RESULTS The allele frequency was significantly different in diabetic children as compared to the healthy controls (p<0.0001). We found negative association between T1D and Δ32 allele (OR=0.383; 95% CI=0.268-0.549). Besides, we observed alterations in the frequencies of CCR5-Δ32 genotypes due to celiac and autoimmune thyroid diseases. The risk of celiac disease for patient carriers of the 32-bp deletion was more than threefold higher than for noncarriers (OR=3.490; 95% CI=1.357-8.859; p=0.009). Similar results were obtained in the case of autoimmune thyroiditis. The risk of autoimmune thyroiditis for patient carriers of the 32-bp deletion was also more than threefold higher than for noncarriers (OR=3.466; 95% CI=1.754-6.849; p=0.0004). CONCLUSIONS The findings of our studies suggest that the CCR5-Δ32 polymorphism is associated with type 1 diabetes mellitus and the Δ32 allele increases the risk of celiac disease and autoimmune thyroid disorders in patients with T1D.
Collapse
MESH Headings
- Adolescent
- Alleles
- Celiac Disease/complications
- Celiac Disease/genetics
- Celiac Disease/metabolism
- Child
- Diabetes Mellitus, Type 1/blood
- Diabetes Mellitus, Type 1/complications
- Diabetes Mellitus, Type 1/drug therapy
- Female
- Gene Deletion
- Gene Frequency
- Genetic Association Studies
- Genetic Predisposition to Disease
- Glycated Hemoglobin/analysis
- Heterozygote
- Hospitals, University
- Humans
- Hyperglycemia/prevention & control
- Hypoglycemic Agents/therapeutic use
- Insulin/therapeutic use
- Male
- Poland
- Polymorphism, Genetic
- Receptors, CCR5/genetics
- Receptors, CCR5/metabolism
- Thyroiditis, Autoimmune/complications
- Thyroiditis, Autoimmune/genetics
- Thyroiditis, Autoimmune/metabolism
Collapse
Affiliation(s)
- Bartosz Słomiński
- Department of Immunology, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk.
| | - Urszula Ławrynowicz
- Department of Immunology, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk
| | - Jolanta Myśliwska
- Department of Immunology, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk
| | | | - Maria Skrzypkowska
- Department of Immunology, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk
| | - Małgorzata Myśliwiec
- Chair & Clinics of Paediatrics, Diabetology and Endocrinology, Medical University of Gdańsk, Dębinki 7, 80-211 Gdańsk
| | - Agnieszka Brandt
- Chair & Clinics of Paediatrics, Diabetology and Endocrinology, Medical University of Gdańsk, Dębinki 7, 80-211 Gdańsk
| |
Collapse
|
|
33
|
Hov JR, Boberg KM, Taraldsrud E, Vesterhus M, Boyadzhieva M, Solberg IC, Schrumpf E, Vatn MH, Lie BA, Molberg Ø, Karlsen TH. Antineutrophil antibodies define clinical and genetic subgroups in primary sclerosing cholangitis. Liver Int 2017; 37:458-465. [PMID: 27558072 DOI: 10.1111/liv.13238] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 08/18/2016] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS The strongest genetic risk factors in primary sclerosing cholangitis (PSC) are encoded in the HLA complex. Antineutrophil cytoplasmic antibodies (ANCA) have been reported in up to 94% of PSC patients, but their clinical significance and immunogenetic basis are ill defined. We aimed to characterize clinical and genetic associations of ANCA in PSC. METHODS Antineutrophil cytoplasmic antibodies were analysed with indirect immunofluorescence in 241 Norwegian PSC patients. HLA-B and HLA-DRB1 genotyping was performed in the patients and in 368 healthy controls. Data on perinuclear ANCA (pANCA) and HLA-DRB1 were available from 274 ulcerative colitis (UC) patients without known liver disease. RESULTS Antineutrophil cytoplasmic antibodies were found in 193 (80%) of the PSC patients, with pANCA in 169 (70%). ANCA-positive patients were younger than ANCA negative at diagnosis of PSC and had a lower frequency of biliary cancer (9% vs 19%, P=.047). There were no differences between PSC patients with and without inflammatory bowel disease. Genetically, the strong PSC risk factors HLA-B*08 (frequency in healthy 13%) and DRB1*03 (14%) were more prevalent in ANCA-positive than -negative patients (43% vs 25%, P=.0012 and 43% vs 25%, P=.0015 respectively). The results were similar when restricting the analysis to pANCA-positive patients. In UC patients without liver disease, HLA-DRB1*03 was more prevalent in pANCA-positive compared with -negative patients (P=.03). CONCLUSIONS Antineutrophil cytoplasmic antibodies identified PSC patients with particular clinical and genetic characteristics, suggesting that ANCA may mark a clinically relevant pathogenetic subgroup in the PSC-UC disease spectrum.
Collapse
Affiliation(s)
- Johannes R Hov
- Division of Surgery, Department of Transplantation Medicine, Inflammatory Medicine and Transplantation, Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Section of Gastroenterology, Division of Surgery, Department of Transplantation Medicine, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Division of Surgery, Inflammatory Medicine and Transplantation, Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway.,K.G.Jebsen Inflammation Research Centre, Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Kirsten M Boberg
- Division of Surgery, Department of Transplantation Medicine, Inflammatory Medicine and Transplantation, Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Section of Gastroenterology, Division of Surgery, Department of Transplantation Medicine, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Eli Taraldsrud
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,K.G.Jebsen Inflammation Research Centre, Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Mette Vesterhus
- Division of Surgery, Department of Transplantation Medicine, Inflammatory Medicine and Transplantation, Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Oslo, Norway.,National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway
| | - Maria Boyadzhieva
- Clinical Center of Endocrinology, Medical University Sofia, Sofia, Bulgaria
| | - Inger Camilla Solberg
- Division of Medicine, Department of Gastroenterology, Oslo University Hospital Ullevål, Oslo, Norway
| | - Erik Schrumpf
- Division of Surgery, Department of Transplantation Medicine, Inflammatory Medicine and Transplantation, Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Morten H Vatn
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,EpiGen Institute, Campus AHUS, Akershus University Hospital, Nordbyhagen, Norway
| | - Benedicte A Lie
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,K.G.Jebsen Inflammation Research Centre, Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Øyvind Molberg
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Rheumatology Unit, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Tom H Karlsen
- Division of Surgery, Department of Transplantation Medicine, Inflammatory Medicine and Transplantation, Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Section of Gastroenterology, Division of Surgery, Department of Transplantation Medicine, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Division of Surgery, Inflammatory Medicine and Transplantation, Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway.,K.G.Jebsen Inflammation Research Centre, Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| |
Collapse
|
|
34
|
Abstract
The complement system is reemerging in the last few years not only as key element of innate immunity against pathogens, but also as a main regulator of local adaptive responses, affecting dendritic cells as well as T and B lymphocytes. We review data showing that leucocytes are capable of significant autocrine synthesis of complement proteins, and express a large range of complement receptors, which in turn regulate their differentiation and effector functions while cross talking with other innate receptors such as Toll-like receptors. Other unconventional roles of complement proteins are reviewed, including their impact in non-leukocytes and their intracellular cleavage by vesicular proteases, which generate critical cues required for T cell function. Thus, leucocytes are very much aware of complement-derived information, both extracellular and intracellular, to elaborate their responses, offering rich avenues for therapeutic intervention and new hypothesis for conserved major histocompatibility complex complotypes.
Collapse
|
|
35
|
Giza S, Kotanidou E, Papadopoulou-Alataki E, Antoniou MC, Maggana I, Kyrgios I, Galli-Tsinopoulou A. Prevalence of selective immunoglobulin A deficiency in Greek children and adolescents with type 1 diabetes. World J Pediatr 2016; 12:470-476. [PMID: 27286692 DOI: 10.1007/s12519-016-0039-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 02/03/2015] [Indexed: 12/18/2022]
Abstract
BACKGROUND The association of selective immunoglobulin A (IgA) deficiency with type 1 diabetes (T1D) remains unclear. This study was to evaluate serum IgA concentrations in Greek children and adolescents with T1D. METHODS In two hundred individuals with T1D, serum IgA concentrations were quantitatively determined using nephelometry. RESULTS Immunoglobulin A deficiency was detected in 6 (3.0%) of 200 patients who were subjected to immunological evaluation. Recurrent infections were not recorded, but human papilloma virus infection was clinically suspected and confirmed by laboratory examination in a 5-year-old girl. In regard to coincidence of selective IgA deficiency with autoimmune diseases, celiac disease was detected in a girl and juvenile idiopathic arthritis in a boy. Serum IgA concentrations differed significantly when patients were grouped according to age at the beginning of the study (P<0.001), age at diagnosis of T1D (P=0.015) and coincidence of celiac disease (CD) (P=0.038). However, when the age of the patients was adjusted, difference in serum IgA concentrations was not statistically significant despite CD was present or not. Moreover, serum IgA concentrations were positively correlated with serum IgG (P<0.001) and IgE (P=0.001) concentrations and negatively correlated with serum antigliadin antibody IgG (P=0.035) concentrations. There was no association or correlation of serum IgA concentrations with glycemic control. CONCLUSION The prevalence of selective IgA deficiency in Greek children and adolescents with T1D is high (3.0%). The correlation of serum IgA concentrations with serum IgG, IgE and anti-gliadin antibody IgG concentrations needs further investigation.
Collapse
Affiliation(s)
- Styliani Giza
- 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road Nea Efkarpia, 56403, Thessaloniki, Greece
| | - Eleni Kotanidou
- 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road Nea Efkarpia, 56403, Thessaloniki, Greece
| | - Efimia Papadopoulou-Alataki
- 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road Nea Efkarpia, 56403, Thessaloniki, Greece
| | - Maria Christina Antoniou
- 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road Nea Efkarpia, 56403, Thessaloniki, Greece
| | - Ioanna Maggana
- 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road Nea Efkarpia, 56403, Thessaloniki, Greece
| | - Ioannis Kyrgios
- 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road Nea Efkarpia, 56403, Thessaloniki, Greece
| | - Assimina Galli-Tsinopoulou
- 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road Nea Efkarpia, 56403, Thessaloniki, Greece.
| |
Collapse
|
|
36
|
|
|
37
|
Wang M, Liu H, Liu Z, Yi X, Bickeboller H, Hung RJ, Brennan P, Landi MT, Caporaso N, Christiani DC, Doherty JA, Amos CI, Wei Q. Genetic variant in DNA repair gene GTF2H4 is associated with lung cancer risk: a large-scale analysis of six published GWAS datasets in the TRICL consortium. Carcinogenesis 2016; 37:888-896. [PMID: 27288692 PMCID: PMC5008248 DOI: 10.1093/carcin/bgw070] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 05/27/2016] [Accepted: 06/07/2016] [Indexed: 12/15/2022] Open
Abstract
DNA repair pathways maintain genomic integrity and stability, and dysfunction of DNA repair leads to cancer. We hypothesize that functional genetic variants in DNA repair genes are associated with risk of lung cancer. We performed a large-scale meta-analysis of 123,371 single nucleotide polymorphisms (SNPs) in 169 DNA repair genes obtained from six previously published genome-wide association studies (GWASs) of 12160 lung cancer cases and 16838 controls. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) using the logistic regression model and used the false discovery rate (FDR) method for correction of multiple testing. As a result, 14 SNPs had a significant odds ratio (OR) for lung cancer risk with P FDR < 0.05, of which rs3115672 in MSH5 (OR = 1.20, 95% CI = 1.14-1.27) and rs114596632 in GTF2H4 (OR = 1.19, 95% CI = 1.12-1.25) at 6q21.33 were the most statistically significant (P combined = 3.99×10(-11) and P combined = 5.40×10(-10), respectively). The MSH5 rs3115672, but not GTF2H4 rs114596632, was strongly correlated with MSH5 rs3131379 in that region (r (2) = 1.000 and r (2) = 0.539, respectively) as reported in a previous GWAS. Importantly, however, the GTF2H4 rs114596632 T, but not MSH5 rs3115672 T, allele was significantly associated with both decreased DNA repair capacity phenotype and decreased mRNA expression levels. These provided evidence that functional genetic variants of GTF2H4 confer susceptibility to lung cancer.
Collapse
Affiliation(s)
- Meilin Wang
- Duke Cancer Institute, Duke University Medical Center, 905 Lasalle Street, Durham, NC 27710, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 21116, China
| | - Hongliang Liu
- Duke Cancer Institute, Duke University Medical Center, 905 Lasalle Street, Durham, NC 27710, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Zhensheng Liu
- Duke Cancer Institute, Duke University Medical Center, 905 Lasalle Street, Durham, NC 27710, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Xiaohua Yi
- Duke Cancer Institute, Duke University Medical Center, 905 Lasalle Street, Durham, NC 27710, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Heike Bickeboller
- Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, 37073 Göttingen, Germany
| | - Rayjean J. Hung
- Lunenfeld-Tanenbaum Research Institute of Mount Sinai hospital, Toronto, Ontario, Canada
| | - Paul Brennan
- Genetic Epidemiology Group, International Agency for Research on Cancer, 69372 Lyon, France
| | - Maria Teresa Landi
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA
| | - Neil Caporaso
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA
| | - David C. Christiani
- Department of Environmental Health and
- Department of Epidemiology, Harvard University School of Public Health, Boston, MA 02115, USA and
| | - Jennifer Anne Doherty
- Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH 03756, USA
| | - The TRICL Research Team
- Duke Cancer Institute, Duke University Medical Center, 905 Lasalle Street, Durham, NC 27710, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 21116, China
- Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, 37073 Göttingen, Germany
- Lunenfeld-Tanenbaum Research Institute of Mount Sinai hospital, Toronto, Ontario, Canada
- Genetic Epidemiology Group, International Agency for Research on Cancer, 69372 Lyon, France
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA
- Department of Environmental Health and
- Department of Epidemiology, Harvard University School of Public Health, Boston, MA 02115, USA and
- Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH 03756, USA
| | - Christopher I. Amos
- Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH 03756, USA
| | - Qingyi Wei
- Duke Cancer Institute, Duke University Medical Center, 905 Lasalle Street, Durham, NC 27710, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| |
Collapse
|
|
38
|
Stephens C, Castiella A, Gomez-Moreno EM, Otazua P, López-Nevot MÁ, Zapata E, Ortega-Alonso A, Ruiz-Cabello F, Medina-Cáliz I, Robles-Díaz M, Soriano G, Roman E, Hallal H, Moreno-Planas JM, Prieto M, Andrade RJ, Lucena MI. Autoantibody presentation in drug-induced liver injury and idiopathic autoimmune hepatitis: the influence of human leucocyte antigen alleles. Pharmacogenet Genomics 2016; 26:414-422. [PMID: 27206238 DOI: 10.1097/fpc.0000000000000230] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVES Positive autoantibody (AAB) titres are commonly encountered in autoimmune hepatitis (AIH) and in a proportion of drug-induced liver injury (DILI) patients. The underlying mechanism for selective AAB occurrence in DILI is unknown, but could be associated with variations in immune-associated genes. Hence, we aimed to analyse human leucocyte antigen (HLA) allele compositions in DILI with positive (+) and negative (-) AAB titres and in AIH patients. METHODS High-resolution genotyping of HLA class I (A, B, C) and II (DRB1, DQB1) loci was performed on 207 DILI and 50 idiopathic AIH patients and compared with 885 healthy Spanish controls. RESULTS Compared with controls, HLA-B*08:01 [44 vs. 9.7%, P=3.7E-13/corrected P-value (Pc)=1.0E-11], C*07:01 (46 vs. 24%, P=6.4E-04/Pc=0.012), DRB1*03:01 (58 vs. 21.5%, P=5.0E-09/Pc=1.0E-07) and DQB1*02:01 (56 vs. 22%, P=6.8E-08/Pc=9.0E-07) were significantly more frequent in AIH patients. The HLA-A*01:01 frequency was increased in the same population, but did not reach significance after Bonferroni's correction (34 vs. 19%, P=0.02/Pc=0.37). Fifty-eight of 207 DILI patients presented positive titres for at least one AAB (predominantly antinuclear antibody 76% and antismooth muscle antibody 28%). There was a tendency towards higher representation of DRB1*14:01 and DQB1*05:03 in DILI AAB+ compared with DILI AAB- (13.8 vs. 4.0%, P=0.02/Pc=0.5; 13.8 vs. 4.7%, P=0.04/Pc=0.5). CONCLUSION The presence of HLA alleles B*08:01, C*07:01, DRB1*03:01, DQB1*02:01 and possibly A*01:01 enhances the risk of AIH (type 1) in Spanish patients. These alleles form part of the ancestral haplotype 8.1. HLA-DRB1*14:01 and DQB1*05:03 could potentially increase the risk of positive AAB (particularly antinuclear antibody) in Spanish DILI patients.
Collapse
Affiliation(s)
- Camilla Stephens
- aUnidad de Gestión Clínica de Enfermedades Digestivas, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd, Málaga bServicio de Digestivo, Hospital Mendaro cServicio de Digestivo, Hospital Mondragón, Guipúzcoa dDepartamento de Bioquímica y Biología Molecular III/Inmunología, Instituto de Investigación Biosanitario de Granada, Hospital Universitario Virgen de las Nieves, Universidad de Granada, Granada eServicio de Gastroenterología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, CIBERehd fEscola Universitària d'Infermeria EUI-Sant Pau, Universitat Autònoma de Barcelona, Barcelona gServicio de Aparato Digestivo, Hospital Morales Meseguer, Murcia hServicio de Digestivo, Complejo Hospitalario Universitario de Albacete, Albacete iUnidad de Hepatología, Servicio de Aparato Digestivo, Hospital Universitari i Politècnic La Fe, CIBERehd, Valencia, Spain
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Sbarsi I, Falcone C, Boiocchi C, Campo I, Zorzetto M, De Silvestri A, Cuccia M. Inflammation and Atherosclerosis: The Role of TNF and TNF Receptors Polymorphisms in Coronary Artery Disease. Int J Immunopathol Pharmacol 2016; 20:145-54. [PMID: 17346438 DOI: 10.1177/039463200702000117] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Inflammation plays an important role in the pathogenesis of atherosclerosis and coronary syndromes; moreover, various lines of evidence suggest that genetic factors contribute significantly to the risk of coronary artery disease (CAD). Through its effects on endothelial function, coagulation, insulin resistance and lipid metabolism, the proinflammatory cytokine TNF could be involved in cardiovascular pathophysiology. The aim of our study is to analyze whether TNF gene promoter (-308 G/A; −857 G/A) and TNF receptor polymorphisms (TNFR1 MspA1 I exon 1 and TNFR2 Nla III exon 6) show involvement in CAD predisposition in a group of Italian patients compared with healthy controls. Genotyping was performed by PCR-RFLP. Consecutive Italian patients with angiographically proven CAD (n= 248) were compared with controls (n=241), matched for age, sex and geographical origins. CAD patients showed a higher frequency of the TNF −308 A allele than healthy controls (p=0.046). After stratification according to risk factors for CAD, our analysis revealed that CAD patients with diabetes (p=0.042) and CAD patients without hypertension (p=0.0495) displayed a higher frequency of the TNF −308 AA genotype compared with healthy controls. Our data stress the inflammatory nature of CAD and show a possible involvement of TNF −308G/A promoter polymorphisms in the predisposition to the development of this disease. The less frequent A allele seems to be a predisposing factor for development of CAD in particular pathological settings associated with the disease itself, such as diabetes.
Collapse
Affiliation(s)
- I Sbarsi
- Department of Genetics and Microbiology, University of Pavia, Italy
| | | | | | | | | | | | | |
Collapse
|
|
40
|
Wang ZX, Wang HF, Tan L, Sun FR, Tan MS, Tan CC, Jiang T, Tan L, Yu JT. HLA-A2 Alleles Mediate Alzheimer's Disease by Altering Hippocampal Volume. Mol Neurobiol 2016; 54:2469-2476. [PMID: 26979752 DOI: 10.1007/s12035-016-9832-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 03/04/2016] [Indexed: 01/22/2023]
Abstract
HLA-A is a locus of the major histocompatibility complex situated on chromosome 6p21.3. HLA-A has been shown to be associated with susceptibility to Alzheimer's disease (AD). In this study, we firstly investigated the association of gene variants in HLA-A and brain structures on MRI in a large sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to explore the effects of HLA-A on AD pathogenesis. We selected the hippocampus, parahippocampus, posterior cingulate, precuneus, middle temporal, entorhinal cortex, and amygdala as regions of interest (ROIs). In hybrid population analysis, our results showed a marginally significant association between rs9260168 and the atrophy of the left parahippocampus (P = 0.007, Pc = 0.054), rs3823342 and the atrophy of the left parahippocampus (P = 0.014, Pc = 0.054), rs76475517, which only exists in Caucasians with HLA-A23 or HLA-A24 alleles, and the atrophy of the right amygdala (P = 0.010, Pc = 0.085) at baseline. In particular, the haplotype (TGACAAGG), as a surrogate marker of HLA-A2, was founded to be positively associated with the atrophy of the right hippocampus (P = 0.047) at baseline. Furthermore, we detected the above four associations in mild cognitive impairment (MCI) subpopulation analysis. Our study provided preliminary evidences supporting HLA-A2 in Caucasians contribute to the risk of AD by modulating the alteration of hippocampal volume and HLA-A gene variants appear to play a role in altering AD-related brain structures on MRI.
Collapse
Affiliation(s)
- Zi-Xuan Wang
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No. 5 Donghai Middle Road, Qingdao, Shandong Province, 266071, China
| | - Hui-Fu Wang
- Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao, China
| | - Lin Tan
- College of Medicine and Pharmaceutics, Ocean University of China, Qingdao, 266000, China
| | - Fu-Rong Sun
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No. 5 Donghai Middle Road, Qingdao, Shandong Province, 266071, China
| | - Meng-Shan Tan
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No. 5 Donghai Middle Road, Qingdao, Shandong Province, 266071, China
| | - Chen-Chen Tan
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No. 5 Donghai Middle Road, Qingdao, Shandong Province, 266071, China
| | - Teng Jiang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Lan Tan
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No. 5 Donghai Middle Road, Qingdao, Shandong Province, 266071, China.
- Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao, China.
| | - Jin-Tai Yu
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No. 5 Donghai Middle Road, Qingdao, Shandong Province, 266071, China.
- Memory and Aging Center, Department of Neurology, University of California, 675 Nelson Rising Lane, Suite 190, Box 1207, San Francisco, CA, 94158, USA.
| |
Collapse
|
|
41
|
Kolte AM, Nielsen HS, Steffensen R, Crespi B, Christiansen OB. Inheritance of the 8.1 ancestral haplotype in recurrent pregnancy loss. EVOLUTION MEDICINE AND PUBLIC HEALTH 2015; 2015:325-31. [PMID: 26675299 PMCID: PMC4681376 DOI: 10.1093/emph/eov031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 11/15/2015] [Indexed: 12/02/2022]
Abstract
A segment of DNA called the 8.1 ancestral haplotype is hypothesized to cause fetal loss due to a ‘selfish gene’ effect. The hypothesis was not supported, although the haplotype tended to be inherited more often than expected among girls (p=0.11) in a study of 110 mother-child pairs. Further studies are warranted. Background and objectives: The 8.1 ancestral haplotype (AH) (HLA-A1, C7, B8, C4AQ0, C4B1, DR3, DQ2) is a remarkably long and conserved haplotype in the human major histocompatibility complex. It has been associated with both beneficial and detrimental effects, consistent with antagonistic pleiotropy. It has also been proposed that the survival of long, conserved haplotypes may be due to gestational drive, i.e. selective miscarriage of fetuses who have not inherited the haplotype from a heterozygous mother. Recurrent pregnancy loss (RPL) is defined as three or more consecutive pregnancy losses. The objective was to test the gestational drive theory for the 8.1AH in women with RPL and their live born children. Methodology: We investigated the inheritance of the 8.1AH from 82 heterozygous RPL women to 110 live born children. All participants were genotyped for HLA-A, -B and -DRB1 in DNA from EDTA-treated blood or buccal swaps. Inheritance was compared with a Mendelian inheritance of 50% using a two-sided exact binomial test. Results: We found that 55% of the live born children had inherited the 8.1AH, which was not significantly higher than the expected 50% (P = 0.29). Interestingly, we found a non-significant trend toward a higher inheritance of the 8.1AH in girls, 63%, P = 0.11 as opposed to boys, 50%, P = 1.00. Conclusions and implications: We did not find that the 8.1AH was significantly more often inherited by live born children of 8.1AH heterozygous RPL women. However our data suggest that there may be a sex-specific effect which would be interesting to explore further, both in RPL and in a background population.
Collapse
Affiliation(s)
- Astrid M Kolte
- Recurrent Pregnancy Loss Unit, Fertility Clinic 4071, University Hospital Copenhagen Rigshospitalet, Blegdamsvej 9, Copenhagen Ø 2100, Denmark;
| | - Henriette S Nielsen
- Recurrent Pregnancy Loss Unit, Fertility Clinic 4071, University Hospital Copenhagen Rigshospitalet, Blegdamsvej 9, Copenhagen Ø 2100, Denmark
| | - Rudi Steffensen
- Department of Clinical Immunology, Aalborg University Hospital, North, Urbansgade 32, Aalborg 9000, Denmark
| | - Bernard Crespi
- Human Evolutionary Studies Program and Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada and
| | - Ole B Christiansen
- Recurrent Pregnancy Loss Unit, Fertility Clinic 4071, University Hospital Copenhagen Rigshospitalet, Blegdamsvej 9, Copenhagen Ø 2100, Denmark; Department of Gynecology and Obstetrics, Aalborg University Hospital North, Reberbansgade 15, Aalborg 9000, Denmark
| |
Collapse
|
|
42
|
Intrahaplotypic Variants Differentiate Complex Linkage Disequilibrium within Human MHC Haplotypes. Sci Rep 2015; 5:16972. [PMID: 26593880 PMCID: PMC4655331 DOI: 10.1038/srep16972] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 10/22/2015] [Indexed: 12/21/2022] Open
Abstract
Distinct regions of long-range genetic fixation in the human MHC region, known as conserved extended haplotypes (CEHs), possess unique genomic characteristics and are strongly associated with numerous diseases. While CEHs appear to be homogeneous by SNP analysis, the nature of fine variations within their genomic structure is unknown. Using multiple, MHC-homozygous cell lines, we demonstrate extensive sequence conservation in two common Asian MHC haplotypes: A33-B58-DR3 and A2-B46-DR9. However, characterization of phase-resolved MHC haplotypes revealed unique intra-CEH patterns of variation and uncovered 127 single nucleotide variants (SNVs) which are missing from public databases. We further show that the strong linkage disequilibrium structure within the human MHC that typically confounds precise identification of genetic features can be resolved using intra-CEH variants, as evidenced by rs3129063 and rs448489, which affect expression of ZFP57, a gene important in methylation and epigenetic regulation. This study demonstrates an improved strategy that can be used towards genetic dissection of diseases.
Collapse
|
|
43
|
The Protective Role of HLA-DRB1(∗)13 in Autoimmune Diseases. J Immunol Res 2015; 2015:948723. [PMID: 26605347 PMCID: PMC4641944 DOI: 10.1155/2015/948723] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 10/20/2015] [Indexed: 12/23/2022] Open
Abstract
Autoimmune diseases (AIDs) are characterized by a multifactorial aetiology and a complex genetic background, with the MHC region playing a major role. We genotyped for HLA-DRB1 locus 1228 patients with AIDs-213 with Systemic Lupus Erythematosus (SLE), 166 with Psoriasis or Psoriatic Arthritis (Ps + PsA), 153 with Rheumatoid Arthritis (RA), 67 with Systemic Sclerosis (SSc), 536 with Multiple Sclerosis (MS), and 93 with Myasthenia Gravis (MG) and 282 unrelated controls. We confirmed previously established associations of HLA-DRB1∗15 (OR = 2.17) and HLA-DRB1∗03 (OR = 1.81) alleles with MS, HLA-DRB1∗03 with SLE (OR = 2.49), HLA-DRB1∗01 (OR = 1.79) and HLA-DRB1∗04 (OR = 2.81) with RA, HLA-DRB1∗07 with Ps + PsA (OR = 1.79), HLA-DRB1∗01 (OR = 2.28) and HLA-DRB1∗08 (OR = 3.01) with SSc, and HLA-DRB1∗03 with MG (OR = 2.98). We further observed a consistent negative association of HLA-DRB1∗13 allele with SLE, Ps + PsA, RA, and SSc (18.3%, 19.3%, 16.3%, and 11.9%, resp., versus 29.8% in controls). HLA-DRB1∗13 frequency in the AIDs group was 20.0% (OR = 0.58). Although different alleles were associated with particular AIDs, the same allele, HLA-DRB1∗13, was underrepresented in all of the six diseases analysed. This observation suggests that this allele may confer protection for AIDs, particularly for systemic and rheumatic disease. The protective effect of HLA-DRB1∗13 could be explained by a more proficient antigen presentation by these molecules, favouring efficient clonal deletion during thymic selection.
Collapse
|
|
44
|
Levin AM, Adrianto I, Datta I, Iannuzzi MC, Trudeau S, Li J, Drake WP, Montgomery CG, Rybicki BA. Association of HLA-DRB1 with Sarcoidosis Susceptibility and Progression in African Americans. Am J Respir Cell Mol Biol 2015; 53:206-16. [PMID: 25506722 DOI: 10.1165/rcmb.2014-0227oc] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
HLA-DRB1 is a sarcoidosis risk gene, and the *03:01 allele is strongly associated with disease resolution in European sarcoidosis cases. Whereas the HLA-DRB1 variation is associated with sarcoidosis susceptibility in African Americans, DRB1 risk alleles are not as well defined, and associations with disease resolution have not been studied. Associations between genotyped and imputed HLA-DRB1 alleles and disease susceptibility/resolution were evaluated in a sample of 1,277 African-American patients with sarcoidosis and 1,467 control subjects. In silico binding assays were performed to assess the functional significance of the associated alleles. Increased disease susceptibility was associated with the HLA-DRB1 alleles *12:01 (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.65-2.69; P = 3.2 × 10(-9)) and *11:01 (OR, 1.69; 95% CI, 1.42-2.01; P = 3.0 × 10(-9)). The strongest protective association was found with *03:01 (OR, 0.56; 95% CI, 0.44-0.73; P = 1.0 × 10(-5)). The African-derived allele *03:02 was associated with decreased risk of persistent radiographic disease (OR, 0.52; 95% CI, 0.37-0.72; P = 1.3 × 10(-4)), a finding consistent across the three component studies comprising the analytic sample. The DRB1*03:01 association with disease persistence was dependent upon local ancestry, with carriers of at least one European allele at DRB1 at a decreased risk of persistent disease (OR, 0.36; 95% CI, 0.14-0.94; P = 0.037). Results of in silico binding analyses showed that DRB1*03:01 consistently demonstrated the highest binding affinities for six bacterial peptides previously found in sarcoidosis granulomas, whereas *12:01 displayed the lowest binding affinities. This study has identified DRB1*03:01 and *03:02 as novel alleles associated with disease susceptibility and course in African Americans. Further investigation of DRB1*03 alleles may uncover immunologic factors that favor sarcoidosis protection and resolution among African Americans.
Collapse
Affiliation(s)
- Albert M Levin
- 1 Department of Public Health Sciences and.,2 Center for Bioinformatics, Henry Ford Health System, Detroit, Michigan
| | - Indra Adrianto
- 3 Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
| | - Indrani Datta
- 1 Department of Public Health Sciences and.,2 Center for Bioinformatics, Henry Ford Health System, Detroit, Michigan
| | - Michael C Iannuzzi
- 4 Department of Medicine, Upstate Medical University, Syracuse, New York; and
| | | | - Jia Li
- 1 Department of Public Health Sciences and.,2 Center for Bioinformatics, Henry Ford Health System, Detroit, Michigan
| | - Wonder P Drake
- 5 Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Courtney G Montgomery
- 3 Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
| | | |
Collapse
|
|
45
|
Autoimmune Conditions in 235 Hemochromatosis Probands with HFE C282Y Homozygosity and Their First-Degree Relatives. J Immunol Res 2015; 2015:453046. [PMID: 26504855 PMCID: PMC4609477 DOI: 10.1155/2015/453046] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 08/02/2015] [Indexed: 12/17/2022] Open
Abstract
We performed a retrospective study of autoimmune conditions (ACs) in 235 hemochromatosis probands at diagnosis by analyzing age, sex, ACs, history of first-degree family members with ACs (FH), diabetes, heavy ethanol consumption, elevated serum ALT/AST, nonalcoholic fatty liver disease, viral hepatitis, cirrhosis, iron removed to achieve iron depletion (QFe), and positivity for human leukocyte antigen (HLA) haplotypes A∗01, B∗08; A∗02, B∗44; A∗03, B∗07; A∗03, B∗14; and A∗29, B∗44. There were 138 men (58.7%). Median followup was 19.6 y. One or more of 19 ACs were diagnosed in each of 35 probands (14.9%). Prevalences of Hashimoto's thyroiditis, rheumatoid arthritis, and ankylosing spondylitis were 8.1% (95% CI: [5.1, 12.5]), 1.7% [0.6, 4.6], and 0.0085 [0.0015, 0.0337], respectively. Eighteen probands (7.7%) had a FH. Eight probands with ACs had 9 family members with ACs. In a logistic regression, ACs were less likely in men (odds ratio (OR) 0.3 [0.1, 0.6]) and more likely in probands with a FH (OR 4.1 [1.4, 11.8]). Overall ACs risk was not significantly associated with QFe or HLA haplotypes. Estimated survival of probands with and without ACs did not differ significantly. We conclude that ACs are common in hemochromatosis probands, especially women and probands with a FH.
Collapse
|
|
46
|
Miller FW, Chen W, O’Hanlon TP, Cooper RG, Vencovsky J, Rider LG, Danko K, Wedderburn LR, Lundberg IE, Pachman LM, Reed AM, Ytterberg SR, Padyukov L, Selva-O’Callaghan A, Radstake TR, Isenberg DA, Chinoy H, Ollier WE, Scheet P, Peng B, Lee A, Byun J, Lamb JA, Gregersen PK, Amos CI. Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes. Genes Immun 2015; 16:470-80. [PMID: 26291516 PMCID: PMC4840953 DOI: 10.1038/gene.2015.28] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2015] [Revised: 06/15/2015] [Accepted: 06/18/2015] [Indexed: 02/06/2023]
Abstract
Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5×10(-8)) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.
Collapse
Affiliation(s)
- Frederick W. Miller
- National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, Maryland 20892
| | - Wei Chen
- M.D. Anderson Cancer Center, Houston, Texas 77030
| | - Terrance P. O’Hanlon
- National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, Maryland 20892
| | - Robert G. Cooper
- MRC/ARUK Institute for Ageing and Chronic Disease, University of Liverpool, United Kingdom, L69 3GA
| | - Jiri Vencovsky
- Institute of Rheumatology, Charles University, Prague, Czech Republic; Na Slupi, 12850 Prague
| | - Lisa G. Rider
- National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, Maryland 20892
| | - Katalin Danko
- 3 Department of Internal Medicine, Division of Immunology University of Debrecen, Debrecen, Hungary H-4032
| | - Lucy R. Wedderburn
- Institute of Child Health, University College London, London, United Kingdom, WC1N 1EH
| | - Ingrid E. Lundberg
- Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden SE-171 77
| | - Lauren M. Pachman
- Department of Pediatric Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611
| | | | | | - Leonid Padyukov
- Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden SE-171 77
| | | | - Timothy R. Radstake
- Department of Rheumatology and Clinical Immunology, Laboratory for Translational Immunology, Utrecht University Medical Center; and Nijmegen Center for Molecular Life Sciences, Nijmegen, The Netherlands 6500.HB
| | - David A. Isenberg
- Division of Medicine, University College London, London, United Kingdom WC1E63T
| | - Hector Chinoy
- The National Institute for Health Research Manchester Musculoskeletal Biomedical Research Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester, United Kingdom M139PT
| | - William E.R. Ollier
- Centre for Integrated Genomic Medical Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom M13 9PT
| | - Paul Scheet
- M.D. Anderson Cancer Center, Houston, Texas 77030
| | - Bo Peng
- M.D. Anderson Cancer Center, Houston, Texas 77030
| | - Annette Lee
- Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York 11030
| | - Jinyoung Byun
- Department of Community and Family Medicine, Dartmouth College, Hanover, New Hampshire 03755
| | - Janine A. Lamb
- Centre for Integrated Genomic Medical Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom M13 9PT
| | - Peter K. Gregersen
- Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York 11030
| | - Christopher I. Amos
- Department of Community and Family Medicine, Dartmouth College, Hanover, New Hampshire 03755
| | | |
Collapse
|
|
47
|
Hov JR, Zhong H, Qin B, Anmarkrud JA, Holm K, Franke A, Lie BA, Karlsen TH. The Influence of the Autoimmunity-Associated Ancestral HLA Haplotype AH8.1 on the Human Gut Microbiota: A Cross-Sectional Study. PLoS One 2015. [PMID: 26207384 PMCID: PMC4514645 DOI: 10.1371/journal.pone.0133804] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Multiple immune-related genes are encoded in the HLA complex on chromosome 6p21. The 8.1 ancestral haplotype (AH8.1) include the classical HLA alleles HLA-B*08:01 and HLA-DRB1*03:01, and has been associated with a large number of autoimmune diseases, but the underlying mechanisms for this association are largely unknown. Given the recently established links between the gut microbiota and inflammatory diseases, we hypothesized that the AH8.1 influences the host gut microbial community composition. To study this further, healthy individuals were selected from the Norwegian Bone Marrow Donor Registry and categorized as either I. AH8.1 homozygote (n=34), II. AH8.1 heterozygote (n=38), III. Non AH8.1 heterozygote or IV. HLA-DRB1 homozygote but non AH8.1 (n=15). Bacterial DNA from stool samples were subjected to sequencing of the V3–V5 region of the 16S rRNA gene on the 454 Life Sciences platform and data analyzed using Mothur and QIIME. The results showed that the abundances of different taxa were highly variable within all pre-defined AH8.1 genotype groups. Using univariate non-parametric statistics, there were no differences regarding alpha or beta diversity between AH8.1 carriers (categories I and II) and non-carriers (categories III and IV), however four different taxa (Prevotellaceae, Clostridium XVIII, Coprococcus, Enterorhabdus) had nominally significant lower abundances in AH8.1 carriers than non-carriers. After including possible confounders in a multivariate linear regression, only the two latter genera remained significantly associated. In conclusion, the overall contribution of the AH8.1 haplotype to the variation in gut microbiota profile of stool in the present study was small.
Collapse
Affiliation(s)
- Johannes R. Hov
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine and K.G.Jebsen Inflammation Research Centre, Faculty of Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- * E-mail:
| | | | - Bingcai Qin
- BGI-Shenzhen, Shenzhen, China
- Shanghai Majorbio Bio-pharm Technology Co. Ltd., Shanghai, China
| | - Jarl Andreas Anmarkrud
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Kristian Holm
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Andre Franke
- Christian-Albrechts-University of Kiel, Institute of Clinical Molecular Biology, Kiel, Germany
| | - Benedicte A. Lie
- Institute of Clinical Medicine and K.G.Jebsen Inflammation Research Centre, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway
- Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Tom H. Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine and K.G.Jebsen Inflammation Research Centre, Faculty of Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| |
Collapse
|
|
48
|
Kruis T, Jöhrens K, Moos V, Puls I, Siegmund B, Daum S, Schumann M. A case series in patients with enteropathy and granulomatous diseases. BMC Gastroenterol 2015; 15:62. [PMID: 26001889 PMCID: PMC4493942 DOI: 10.1186/s12876-015-0292-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 05/18/2015] [Indexed: 12/13/2022] Open
Abstract
Background Although sarcoidosis and celiac disease are both chronic immunologic disorders involving multiple organ systems, reports about association of diseases in individual patients are sparse. While sarcoidosis is a chronic granulomatous disease presumably reflecting an exaggerated response to an unknown antigen, celiac disease is a T cell-driven disease triggered by ingestion of gluten, a protein composite found in wheat and related grains. Case presentation We present three cases with a longstanding history of sarcoidosis that have been additionally diagnosed with celiac-like enteropathy. In two cases, celiac disease was established applying celiac-specific serology and duodenal histology, while one case was revealed as an AIE-75-positive autoimmune enteropathy. The HLA-DR3/DQ2 haplotype was confirmed in both celiac patients, hence confirming previous data of linkage disequilibrium as a cause for disease association. Remarkably, one celiac patient presented with granulomatous nodulae in the ileum, thus reflecting an intestinal sarcoid manifestation. In contrast the patient with an autoimmune enteropathy, was HLA-DQ9/DQ6-positive, also arguing against CD. Conclusions Associations of sarcoidosis and celiac disease are rare but do occur. Determining the HLA status in patients with complex autoimmune associations might help classifying involved disease entities.
Collapse
Affiliation(s)
- Tassilo Kruis
- Medical Department I (Gastroenterology, Infectious Diseases, Rheumatology), Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin, 12200, Germany.
| | - Korinna Jöhrens
- Institute for Pathology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
| | - Verena Moos
- Medical Department I (Gastroenterology, Infectious Diseases, Rheumatology), Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin, 12200, Germany.
| | - Imke Puls
- Department for Psychiatry, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
| | - Britta Siegmund
- Medical Department I (Gastroenterology, Infectious Diseases, Rheumatology), Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin, 12200, Germany.
| | - Severin Daum
- Medical Department I (Gastroenterology, Infectious Diseases, Rheumatology), Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin, 12200, Germany.
| | - Michael Schumann
- Medical Department I (Gastroenterology, Infectious Diseases, Rheumatology), Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin, 12200, Germany.
| |
Collapse
|
|
49
|
Lonati D, Zancan A, Pasi A, Schreiber A, Giampreti A, Pignatti P, Stella M, Locatelli CA, Manzo L, Martinetti M. SJS/TEN overlap associated with lomefloxacin: case report and molecular typing studies. Dermatology 2014; 229:319-23. [PMID: 25359191 DOI: 10.1159/000365188] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 06/04/2014] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) may develop in susceptible patients after administration of different drugs. Only mild cutaneous reactions have been related to lomefloxacin. A correlation between human leucocyte antigen (HLA) and cutaneous adverse reaction has been identified. CASE REPORT Twenty-four hours after intake of lomefloxacin, a 30-year-old Caucasian woman developed a severe skin reaction with symptoms suggesting SJS/TEN. The fast onset reaction worsened with skin blisters and 20% body surface area skin detachment within 48 h. Burn unit admittance was required; corticosteroids and human immunoglobulins were administered. Complete recovery occurred within 3 months, except for epidermal discoloration. Molecular studies showed a peculiar profile characterized by HLA class I genotype rich of ligands for natural killer cell immunoglobulin-like receptors (KIR) and HLA class II haplotype, HLA-DRB1*03:01,DQB1*02:01, prone to autoimmunity. CONCLUSION While the HLA profile approaches our case to other well-documented drug-induced SJS/TEN, KIR involvement still remains puzzling.
Collapse
Affiliation(s)
- Davide Lonati
- Pavia Poison Control Centre and National Toxicology Information Centre, IRCCS Maugeri Foundation Clinical Institute and University of Pavia, Italy
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Genetic basis of myasthenia gravis – A comprehensive review. J Autoimmun 2014; 52:146-53. [DOI: 10.1016/j.jaut.2013.12.001] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Accepted: 12/02/2013] [Indexed: 11/24/2022]
|