Abstract:
:Genetic polymorphism in MECP2/IRAK1 on chromosome Xq28 is a confirmed and replicated susceptibility locus for lupus. High linkage disequilibrium in this locus suggests that both MECP2 and IRAK1 are candidate genes for the disease. DNA methylation changes in lupus T cells play a central role in the pathogenesis of lupus, and MeCp-2 (encoded by MECP2) is a master regulator of gene expression and is also known to recruit DNA methyltransferase 1 (DNMT1) during DNA synthesis. Using human T cells from normal individuals with either the lupus risk or the lupus protective haplotype in MECP2/IRAK1, we demonstrate that polymorphism in this locus increases MECP2 isoform 2 mRNA expression in stimulated but not unstimulated T cells. By assessing DNA methylation levels across over 485,000 methylation sites across the entire genome, we further demonstrate that the lupus risk variant in this locus is associated with significant DNA methylation changes, including in the HLA-DR and HLA-DQ loci, as well as interferon-related genes such as IFI6, IRF6, and BST2. Further, using a human MECP2 transgenic mouse, we show that overexpression of MECP2 alters gene expression in stimulated T cells. This includes overexpression of Eif2c2 that regulates the expression of multiple microRNAs (such as miR-21), and the histone demethylase Jhdm1d. In addition, we show that MECP2 transgenic mice develop antinuclear antibodies. Our data suggest that the lupus-associated variant in the MECP2/IRAK1 locus has the potential to affect all 3 epigenetic mechanisms: DNA methylation, microRNA expression, and histone modification. Importantly, these data support the notion that variants within the MECP2 gene can alter DNA methylation in other genetic loci including the HLA and interferon-regulated genes, thereby providing evidence for genetic-epigenetic interaction in lupus.
journal_name
J Autoimmunjournal_title
Journal of autoimmunityauthors
Koelsch KA,Webb R,Jeffries M,Dozmorov MG,Frank MB,Guthridge JM,James JA,Wren JD,Sawalha AHdoi
10.1016/j.jaut.2012.12.012subject
Has Abstractpub_date
2013-03-01 00:00:00pages
168-74eissn
0896-8411issn
1095-9157pii
S0896-8411(13)00014-0journal_volume
41pub_type
杂志文章abstract::The effector mechanisms responsible for autoimmune beta cell destruction in insulin dependent (type 1) diabetes (IDD) remain elusive. In order to investigate whether T lymphocytes bearing the gamma-delta T cell receptor (gamma delta+ T cells) could be involved in this process, we measured percentages of peripheral blo...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/0896-8411(91)90055-h
更新日期:1991-12-01 00:00:00
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更新日期:2020-12-01 00:00:00
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journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/j.jaut.2007.02.015
更新日期:2007-06-01 00:00:00
abstract::A major concept in autoimmunity is that disruption of Foxp3(+) regulatory T cells (Tregs) predisposes to breach of tolerance. This is exemplified by the Foxp3-linked disorder termed IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked) which affects newborn children. There has been considerable clinica...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/j.jaut.2013.08.010
更新日期:2014-05-01 00:00:00
abstract::Autoimmune diseases (AIDs) are believed to be multifactorial diseases that commonly involve multiple organ systems. About three fourth of the patients afflicted with AIDs are women suggesting that sex differences impact the incidence of AID. However, the proportion of females to males suffering from AID varies dependi...
journal_title:Journal of autoimmunity
pub_type: 杂志文章,评审
doi:10.1016/j.jaut.2011.12.001
更新日期:2012-05-01 00:00:00
abstract::We investigated the in vivo pathogenic potential of murine autoimmunity to peptides of the glutamate/AMPA receptor subunit 3 (GluR3). Antibodies to GluR3 are found in human epilepsy, Rasmussen's encephalitis (RE). In our accompanying paper in this issue we found that murine antibodies to the GluR3B peptide (amino acid...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1006/jaut.1999.0297
更新日期:1999-08-01 00:00:00
abstract::The Foxp3(+)CD4(+) regulatory T-cell (Treg)-deficient Scurfy (Sf) mice rapidly develop severe inflammation in the skin and lungs with expanded Th subsets bearing increased expression of various chemokine/chemoattractant/retention receptor genes (CRG). Nine different double mutants were generated to elucidate their rol...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/j.jaut.2012.02.001
更新日期:2012-06-01 00:00:00
abstract::Dysregulation of autophagy has been implicated in the development of various disease indications including autoimmune diseases. Here we identified hitherto unsuspected molecular alterations of autophagy occurring at an early stage of the macroautophagy pathway in the salivary glands and spleen of NOD.H-2h4 mice that d...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/j.jaut.2020.102418
更新日期:2020-03-01 00:00:00
abstract::Peptidomimetic compounds that bind to major histocompatibility complex class II molecules and are resistant to cathepsins can competitively inhibit the presentation of processed protein antigens. Therefore, compounds that bind to autoimmune disease-associated class II molecules are expected to compete with autoantigen...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/j.jaut.2006.09.005
更新日期:2006-11-01 00:00:00
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journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/j.jaut.2003.09.006
更新日期:2004-02-01 00:00:00
abstract::Viruses, bacteria and other infectious pathogens are the major postulated environmental triggers of autoimmunity. In the present nation-wide study we describe the association between infections and 29 autoimmune diseases. We used the Danish Civil Registration System to identify 4.5 million persons born between 1945 an...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/j.jaut.2016.05.013
更新日期:2016-11-01 00:00:00
abstract::In a proliferation assay, peripheral blood lymphocytes (PBL) from a relatively small proportion of myasthenia gravis (MG) patients and from controls responded to Torpedo acetylcholine receptor (T-AChR), which shows approximately 75% homology with the human AChR. Over 50% of MG patients responded to recombinant human A...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/0896-8411(89)90121-2
更新日期:1989-06-01 00:00:00
abstract::Bullous pemphigoid (BP) is a cutaneous autoimmune inflammatory disease associated with subepidermal blistering and autoantibodies against BP180, a transmembrane collagen and major component of the hemidesmosome. Numerous inflammatory cells infiltrate the upper dermis in BP. IgG autoantibodies in BP fix complement and ...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/j.jaut.2008.08.009
更新日期:2008-12-01 00:00:00
abstract::We compared the classical immunofluorescence test (IFT) and counterimmunoelectrophoresis method (CIE) with the new immunoblotting technique (IBT) for the detection of antinuclear antibodies (ANA). Sera from 200 patients were tested in all three assays. Patients were classified as having either rheumatic disease includ...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/0896-8411(88)90023-6
更新日期:1988-04-01 00:00:00
abstract::Systemic lupus (SLE) is characterized by a break of B cell tolerance that plays a central role in disease pathophysiology. An early checkpoint defect occurs at the transitional stage leading to the survival of autoreactive B cells and consequently the production of pathogenic autoantibodies. The main purpose of our wo...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/j.jaut.2019.05.002
更新日期:2019-08-01 00:00:00
abstract:BACKGROUND/PURPOSE:Primary Sjögren's syndrome (SS) is a chronic autoimmune disease primarily involving the exocrine glands. The clinical picture of SS ranges from exocrinopathy to systemic disease affecting the lung, kidney, liver, skin, musculockeletal and nervous systems. The morbidity of SS is mainly determined by e...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/j.jaut.2012.05.018
更新日期:2012-09-01 00:00:00
abstract::The primary immunodeficiency diseases (PIDs) include many genetic disorders that affect different components of the innate and adaptive responses. The number of distinct genetic PIDs has increased exponentially with improved methods of detection and advanced laboratory methodology. Patients with PIDs have an increased...
journal_title:Journal of autoimmunity
pub_type: 杂志文章,评审
doi:10.1016/j.jaut.2019.01.011
更新日期:2019-05-01 00:00:00
abstract::Bullous pemphigoid (BP) and linear IgA disease (LAD) are autoimmune subepidermal blistering skin diseases associated with autoantibodies against the transmembrane hemidesmosomal protein BP180/type XVII collagen. It has been demonstrated previously that BP is characterized predominantly by IgG autoantibodies, while aut...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1006/jaut.2000.0437
更新日期:2000-11-01 00:00:00
abstract::The great majority of insulin-specific T cell clones isolated from islets of NOD mice react with insulin peptide B-(9-23) (amino acids 9-23 of the insulin B chain). The T cell receptors of these clones contain diverse beta-chains but restricted alpha-chains. The dominant alpha-chain motif is a V alpha 13 segment (10 o...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1006/jaut.1997.0134
更新日期:1997-06-01 00:00:00
abstract::Systemic lupus erythematosus (SLE) is an autoimmune disorder with unknown aetiology. The major hallmark of this disease is the presence of antibodies against nuclear components, including double-stranded (ds)DNA and histones. The disease affects different organs, particularly the skin, kidneys and the nervous system. ...
journal_title:Journal of autoimmunity
pub_type: 杂志文章,评审
doi:10.1016/s0896-8411(02)00110-5
更新日期:2003-03-01 00:00:00
abstract::We have previously demonstrated, in the collagen-induced arthritis model (CIA), that repetitive injections of immature bone-marrow-derived dendritic cells (iDCs) induce the expansion of a population of CD4CD49b-expressing cells, and that their adoptive transfer results in protection against CIA in a prophylactic setti...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/j.jaut.2009.10.003
更新日期:2010-06-01 00:00:00
abstract::CD4(+) T cells specific for immunologic non-self determinants on self-IgG, idiotopes (Id), can be raised from cerebrospinal fluid (CSF) and blood of patients with multiple sclerosis (MS). To test if Id-specific CD4(+) T cells have the potential to destroy oligodendrocytes (ODCs), we analyzed their ability to induce ap...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/j.jaut.2009.01.004
更新日期:2009-03-01 00:00:00
abstract::The development of insulin dependent diabetes mellitus (IDDM) and diabetes in the diabetes prone (DP) BB rat animal model of IDDM is thought to be due to an autoimmune process. Natural killer (NK) cells have been implicated but not proven to play a pathogenetic role in BB rats due to the increased NK cell number and a...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/s0896-8411(95)80021-2
更新日期:1995-12-01 00:00:00
abstract::Since its description in 1965, Sneddon syndrome (SNS) is usually characterized by the association of an ischemic cerebrovascular disease and a widespread livedo reticularis. The presence of many other manifestations suggests that it is a systemic syndrome. The prevalence of anti-phospholipid antibodies (aPL) is highly...
journal_title:Journal of autoimmunity
pub_type: 杂志文章,评审
doi:10.1006/jaut.2000.0418
更新日期:2000-09-01 00:00:00
abstract::The role of the innate immune system has been established in the initiation and perpetuation of inflammatory disease, but less attention has been paid to its role in the resolution of inflammation and return to homeostasis. Toll-like receptor (TLR) expression profiles were analysed in tissues with differing disease st...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/j.jaut.2021.102597
更新日期:2021-01-22 00:00:00
abstract::Lupus is a systemic autoimmune disease characterized by anti-nuclear antibodies in humans and genetically susceptible NZB/W mice that can cause immune complex glomerulonephritis. T cells contribute to lupus pathogenesis by secreting pro-inflammatory cytokines such as IL-17, and by interacting with B cells and secretin...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/j.jaut.2014.01.002
更新日期:2014-05-01 00:00:00
abstract::There are two classes of autoimmune disease, organ-specific and non-organ specific or systemic. That cells producing autoantibodies are selected by antigen is strongly suggested by the presence of mutations and high affinity antibody. T-cells are pivotal in all forms of autoimmunity as evidenced by the therapeutic ben...
journal_title:Journal of autoimmunity
pub_type: 杂志文章,评审
doi:10.1016/0896-8411(92)90015-i
更新日期:1992-04-01 00:00:00
abstract::The BB rat spontaneously develops an insulin-dependent diabetes mellitus (IDDM) that closely resembles this disease in man. The pathogenesis involves autoimmune destruction of pancreatic islet beta-cells. In the present study, a single intraperitoneal injection of complete Freund's adjuvant (CFA) in diabetes-prone (DP...
journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/s0896-8411(05)80034-4
更新日期:1990-12-01 00:00:00
abstract::Allogeneic hematopoietic cell transplantation (HCT) is an increasingly widely used treatment modality in hematological malignancies. Alloreactivity mediated by donor T cells (and, in some settings, by donor natural killer cells) can produce durable immunologic control or eradication of residual malignancy after alloge...
journal_title:Journal of autoimmunity
pub_type: 杂志文章,评审
doi:10.1016/j.jaut.2007.12.002
更新日期:2008-05-01 00:00:00
abstract::Autoinflammatory diseases (AUIDs) are a genetically heterogeneous group of rheumatic diseases characterized by episodic inflammation linked with dysregulated innate immune responses. In this review, we summarize the molecular mechanisms altered by disease-associated variants in several AUIDs, including NOD2-associated...
journal_title:Journal of autoimmunity
pub_type: 杂志文章,评审
doi:10.1016/j.jaut.2017.10.012
更新日期:2018-03-01 00:00:00