Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Clinical Reviews in Allergy & Immunology
Published in: Clinical Reviews in Allergy & Immunology 3/2016

01-06-2016

Epigenetics and Vasculitis: a Comprehensive Review

Authors: Paul Renauer, Patrick Coit, Amr H. Sawalha

Published in: Clinical Reviews in Allergy & Immunology | Issue 3/2016

Login to get access

Abstract

Vasculitides represent a group of relatively rare systemic inflammatory diseases of the blood vessels. Despite recent progress in understanding the genetic basis and the underlying pathogenic mechanisms in vasculitis, the etiology and pathogenesis of vasculitis remain incompletely understood. Epigenetic dysregulation plays an important role in immune-mediated diseases, and the contribution of epigenetic aberrancies in vasculitis is increasingly being recognized. Histone modifications in the PR3 and MPO gene loci might be mechanistically involved in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Similarly, other studies revealed important epigenetic contribution to other vasculitides, including Kawasaki disease and IgA vasculitis. More recently, genome-wide epigenomic studies have been performed in several vasculitides. A recent genome-wide DNA methylation study uncovered an important role for epigenetic remodeling of cytoskeleton-related genes in the pathogenesis of Behçet’s disease and suggested that reversal of some of these DNA methylation changes associates with disease remission. Genome-wide DNA methylation profiling characterized the inflammatory response in temporal artery tissue from patients with giant cell arteritis and showed increased activation of calcineurin/nuclear factor of activated T cells (NFAT) signaling, prompting the suggestion that a specific calcineurin/NFAT inhibitor that is well tolerated and with the added beneficial anti-platelet activity, such as dipyridamole, might be of therapeutic potential in giant cell arteritis. While epigenetic studies in systemic vasculitis are still in their infancy, currently available data clearly indicate that investigating the epigenetic mechanisms underlying these diseases will help to better understand the pathogenesis of vasculitis and provide novel targets for the development of disease biomarkers and new therapies.
Literature
1.
Jennette JC et al (2013) 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 65(1):1–11CrossRefPubMed
2.
Hoffman GS, Calabrese LH (2014) Vasculitis: determinants of disease patterns. Nat Rev Rheumatol 10(8):454–62CrossRefPubMed
3.
Carmona FD, Martin J, Gonzalez-Gay MA (2015) Genetics of vasculitis. Curr Opin Rheumatol 27(1):10–7CrossRefPubMed
4.
Miller FW et al (2012) Epidemiology of environmental exposures and human autoimmune diseases: findings from a National Institute of Environmental Health Sciences Expert Panel Workshop. J Autoimmun 39(4):259–71CrossRefPubMedPubMedCentral
5.
Selmi C et al (2012) Mechanisms of environmental influence on human autoimmunity: a National Institute of Environmental Health Sciences expert panel workshop. J Autoimmun 39(4):272–84CrossRefPubMed
6.
Stratta P et al (2001) The role of metals in autoimmune vasculitis: epidemiological and pathogenic study. Sci Total Environ 270(1–3):179–90CrossRefPubMed
7.
Lane SE et al (2003) Are environmental factors important in primary systemic vasculitis? A case–control study. Arthritis Rheum 48(3):814–23CrossRefPubMed
8.
Hogan SL et al (2007) Association of silica exposure with anti-neutrophil cytoplasmic autoantibody small-vessel vasculitis: a population-based, case–control study. Clin J Am Soc Nephrol 2(2):290–9CrossRefPubMedPubMedCentral
9.
Cartin-Ceba R, Peikert T, Specks U (2012) Pathogenesis of ANCA-associated vasculitis. Curr Rheumatol Rep 14(6):481–93CrossRefPubMed
10.
Lidar M et al (2012) Infectious serologies and autoantibodies in hepatitis C and autoimmune disease-associated mixed cryoglobulinemia. Clin Rev Allergy Immunol 42(2):238–46CrossRefPubMed
11.
Chimenti MS et al (2014) Vasculitides and the complement system: a comprehensive review. Clin Rev Allergy Immunol
12.
Konstantinov KN, Ulff-Moller CJ, Tzamaloukas AH (2015) Infections and antineutrophil cytoplasmic antibodies: triggering mechanisms. Autoimmun Rev 14(3):201–3CrossRefPubMed
13.
14.
15.
16.
Renauer PA, Coit P, Sawalha AH (2015) The DNA methylation signature of human TCRalphabeta+CD4-CD8- double negative T cells reveals CG demethylation and a unique epigenetic architecture permissive to a broad stimulatory immune response. Clin Immunol 156(1):19–27CrossRefPubMedPubMedCentral
17.
Balada E, Ordi-Ros J, Vilardell-Tarres M (2007) DNA methylation and systemic lupus erythematosus. Ann N Y Acad Sci 1108:127–36CrossRefPubMed
18.
19.
Bird AP, Wolffe AP (1999) Methylation-induced repression—belts, braces, and chromatin. Cell 99(5):451–4CrossRefPubMed
20.
Surani MA (1998) Imprinting and the initiation of gene silencing in the germ line. Cell 93(3):309–12CrossRefPubMed
21.
Zhang Y et al (2013) Impaired DNA methylation and its mechanisms in CD4(+)T cells of systemic lupus erythematosus. J Autoimmun 41:92–9CrossRefPubMed
22.
23.
Bhaumik SR, Smith E, Shilatifard A (2007) Covalent modifications of histones during development and disease pathogenesis. Nat Struct Mol Biol 14(11):1008–16CrossRefPubMed
24.
25.
Lee GR et al (2006) T helper cell differentiation: regulation by cis elements and epigenetics. Immunity 24(4):369–79CrossRefPubMed
26.
Liu Y et al (2013) Epigenetics in immune-mediated pulmonary diseases. Clin Rev Allergy Immunol 45(3):314–30CrossRefPubMed
27.
Deng X et al (2015) The role of microRNAs in autoimmune diseases with skin involvement. Scand J Immunol 81(3):153–65CrossRefPubMed
28.
29.
Fabian MR, Sonenberg N (2012) The mechanics of miRNA-mediated gene silencing: a look under the hood of miRISC. Nat Struct Mol Biol 19(6):586–93CrossRefPubMed
30.
31.
Singh RP et al (2013) The role of miRNA in inflammation and autoimmunity. Autoimmun Rev 12(12):1160–5CrossRefPubMed
32.
Zeng L et al (2014) The emerging role of circulating microRNAs as biomarkers in autoimmune diseases. Autoimmunity 47(7):419–29CrossRefPubMed
33.
Hilhorst M et al (2015) Proteinase 3-ANCA vasculitis versus myeloperoxidase-ANCA vasculitis. J Am Soc Nephrol
34.
Calafat J et al (1990) In situ localization by double-labeling immunoelectron microscopy of anti-neutrophil cytoplasmic autoantibodies in neutrophils and monocytes. Blood 75(1):242–50PubMed
35.
van der Woude FJ et al (1985) Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener’s granulomatosis. Lancet 1(8426):425–9CrossRefPubMed
36.
Falk RJ, Jennette JC (1988) Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med 318(25):1651–7CrossRefPubMed
37.
Goeken JA (1991) Antineutrophil cytoplasmic antibody—a useful serological marker for vasculitis. J Clin Immunol 11(4):161–74CrossRefPubMed
38.
Cohen Tervaert JW, Damoiseaux J (2012) Antineutrophil cytoplasmic autoantibodies: how are they detected and what is their use for diagnosis, classification and follow-up? Clin Rev Allergy Immunol 43(3):211–9CrossRefPubMed
39.
Tervaert JW et al (1990) Association of autoantibodies to myeloperoxidase with different forms of vasculitis. Arthritis Rheum 33(8):1264–72CrossRefPubMed
40.
Falk RJ et al (1990) Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A 87(11):4115–9CrossRefPubMedPubMedCentral
41.
Little MA et al (2005) Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte-microvascular interactions in vivo. Blood 106(6):2050–8CrossRefPubMed
42.
Xiao H et al (2002) Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 110(7):955–63CrossRefPubMedPubMedCentral
43.
Xiao H et al (2007) Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies. Am J Pathol 170(1):52–64CrossRefPubMedPubMedCentral
44.
Zeisberg M (2011) ANCA vasculitis meets epigenetics—closing in on the molecular roots of disease. Nephrol Dial Transplant 26(4):1146–8CrossRefPubMed
45.
Borregaard N, Cowland JB (1997) Granules of the human neutrophilic polymorphonuclear leukocyte. Blood 89(10):3503–21PubMed
46.
Cowland JB, Borregaard N (1999) The individual regulation of granule protein mRNA levels during neutrophil maturation explains the heterogeneity of neutrophil granules. J Leukoc Biol 66(6):989–95PubMed
47.
Yang JJ et al (2004) Circumvention of normal constraints on granule protein gene expression in peripheral blood neutrophils and monocytes of patients with antineutrophil cytoplasmic autoantibody-associated glomerulonephritis. J Am Soc Nephrol 15(8):2103–14CrossRefPubMed
48.
Ciavatta DJ et al (2010) Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis. J Clin Invest 120(9):3209–19CrossRefPubMedPubMedCentral
49.
Luo S et al (2013) Aberrant histone modifications in peripheral blood mononuclear cells from patients with Henoch–Schonlein purpura. Clin Immunol 146(3):165–75CrossRefPubMed
50.
Kuo HC et al (2015) Identification of an association between genomic hypomethylation of FCGR2A and susceptibility to Kawasaki disease and intravenous immunoglobulin resistance by DNA methylation array. Arthritis Rheumatol 67(3):828–36CrossRefPubMed
51.
Ryu J et al (2007) FcgammaRIIa mediates C-reactive protein-induced inflammatory responses of human vascular smooth muscle cells by activating NADPH oxidase 4. Cardiovasc Res 75(3):555–65CrossRefPubMed
52.
Hughes T et al (2014) Epigenome-wide scan identifies a treatment-responsive pattern of altered DNA methylation among cytoskeletal remodeling genes in monocytes and CD4+ T cells from patients with Behcet’s disease. Arthritis Rheumatol 66(6):1648–58CrossRefPubMedPubMedCentral
53.
54.
Audemard-Verger A et al (2015) IgA vasculitis (Henoch–Shonlein purpura) in adults: diagnostic and therapeutic aspects. Autoimmun Rev 14(7):579–585CrossRefPubMed
55.
56.
Guo MM et al (2015) Th17- and Treg-related cytokine and mRNA expression are associated with acute and resolving Kawasaki disease. Allergy 70(3):310–8CrossRefPubMed
57.
58.
Yun KW et al (2014) Elevated serum level of microRNA (miRNA)-200c and miRNA-371-5p in children with Kawasaki disease. Pediatr Cardiol 35(5):745–52CrossRefPubMed
59.
Magenta A et al (2011) miR-200c is upregulated by oxidative stress and induces endothelial cell apoptosis and senescence via ZEB1 inhibition. Cell Death Differ 18(10):1628–39CrossRefPubMedPubMedCentral
60.
61.
Zhou Q et al (2012) Decreased microRNA-155 expression in ocular Behcet’s disease but not in Vogt Koyanagi Harada syndrome. Invest Ophthalmol Vis Sci 53(9):5665–74CrossRefPubMed
62.
Tang Y et al (2009) MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum 60(4):1065–75CrossRefPubMed
63.
Zhou Q et al (2014) MicroRNA-146a and Ets-1 gene polymorphisms in ocular Behcet’s disease and Vogt–Koyanagi–Harada syndrome. Ann Rheum Dis 73(1):170–6CrossRefPubMed
64.
Qi J et al (2013) A functional variant of pre-miRNA-196a2 confers risk for Behcet’s disease but not for Vogt–Koyanagi–Harada syndrome or AAU in ankylosing spondylitis. Hum Genet 132(12):1395–404CrossRefPubMed
65.
Yu H et al (2014) Predisposition to Behcet’s disease and VKH syndrome by genetic variants of miR-182. J Mol Med (Berl) 92(9):961–7CrossRef
66.
Stittrich AB et al (2010) The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes. Nat Immunol 11(11):1057–62CrossRefPubMed
67.
Ambrose NL, Haskard DO (2013) Differential diagnosis and management of Behcet syndrome. Nat Rev Rheumatol 9(2):79–89CrossRefPubMed
68.
69.
70.
Hirohata S (2008) Histopathology of central nervous system lesions in Behcet’s disease. J Neurol Sci 267(1–2):41–7CrossRefPubMed
71.
Direskeneli H, Fujita H, Akdis CA (2011) Regulation of TH17 and regulatory T cells in patients with Behcet disease. J Allergy Clin Immunol 128(3):665–6CrossRefPubMed
72.
Geri G et al (2011) Critical role of IL-21 in modulating TH17 and regulatory T cells in Behcet disease. J Allergy Clin Immunol 128(3):655–64CrossRefPubMed
73.
Aktas Cetin E et al (2014) IL-22-secreting Th22 and IFN-gamma-secreting Th17 cells in Behcet’s disease. Mod Rheumatol 24(5):802–7CrossRefPubMed
74.
Ceppi M et al (2009) MicroRNA-155 modulates the interleukin-1 signaling pathway in activated human monocyte-derived dendritic cells. Proc Natl Acad Sci U S A 106(8):2735–40CrossRefPubMedPubMedCentral
75.
76.
77.
Yu Z et al (2007) Aberrant allele frequencies of the SNPs located in microRNA target sites are potentially associated with human cancers. Nucleic Acids Res 35(13):4535–41CrossRefPubMedPubMedCentral
78.
Paine A et al (2010) Signaling to heme oxygenase-1 and its anti-inflammatory therapeutic potential. Biochem Pharmacol 80(12):1895–903CrossRefPubMed
79.
Gonzalez-Gay MA et al (2009) Epidemiology of giant cell arteritis and polymyalgia rheumatica. Arthritis Rheum 61(10):1454–61CrossRefPubMed
80.
De Smit E, Palmer AJ, Hewitt AW (2015) Projected worldwide disease burden from giant cell arteritis by 2050. J Rheumatol 42(1):119–25CrossRefPubMed
81.
Djuretic IM et al (2007) Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Nat Immunol 8(2):145–53CrossRefPubMed
82.
Grewal IS, Flavell RA (1996) The role of CD40 ligand in costimulation and T-cell activation. Immunol Rev 153:85–106CrossRefPubMed
83.
Flanagan WM et al (1991) Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature 352(6338):803–7CrossRefPubMed
84.
Schaufelberger C et al (2006) No additional steroid-sparing effect of cyclosporine A in giant cell arteritis. Scand J Rheumatol 35(4):327–9CrossRefPubMed
85.
Naesens M, Kuypers DR, Sarwal M (2009) Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 4(2):481–508PubMed
86.
Balakumar P et al (2014) Classical and pleiotropic actions of dipyridamole: not enough light to illuminate the dark tunnel? Pharmacol Res 87:144–50CrossRefPubMed
87.
Mulero MC et al (2009) Inhibiting the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway with a regulator of calcineurin-derived peptide without affecting general calcineurin phosphatase activity. J Biol Chem 284(14):9394–401CrossRefPubMedPubMedCentral
88.
89.
Feil R, Fraga MF (2011) Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet 13(2):97–109
90.
Weyand CM, Liao YJ, Goronzy JJ (2012) The immunopathology of giant cell arteritis: diagnostic and therapeutic implications. J Neuroophthalmol 32(3):259–65CrossRefPubMedPubMedCentral
91.
Li Y et al (2010) Age-dependent decreases in DNA methyltransferase levels and low transmethylation micronutrient levels synergize to promote overexpression of genes implicated in autoimmunity and acute coronary syndromes. Exp Gerontol 45(4):312–22CrossRefPubMedPubMedCentral
Metadata
Title
Epigenetics and Vasculitis: a Comprehensive Review
Authors
Paul Renauer
Patrick Coit
Amr H. Sawalha
Publication date
01-06-2016
Publisher
Springer US
Published in
Clinical Reviews in Allergy & Immunology / Issue 3/2016
Print ISSN: 1080-0549
Electronic ISSN: 1559-0267
DOI
https://doi.org/10.1007/s12016-015-8495-6

Other articles of this Issue 3/2016

Clinical Reviews in Allergy & Immunology 3/2016 Go to the issue

ReviewPaper

The Inflammatory Response in Psoriasis: a Comprehensive Review

ReviewPaper

The Bach Family of Transcription Factors: A Comprehensive Review

ReviewPaper

Environmental Basis of Autoimmunity

ReviewPaper

OX40, OX40L and Autoimmunity: a Comprehensive Review

ReviewPaper

Epigenetics and Systemic Lupus Erythematosus: Unmet Needs

ReviewPaper

Critical Link Between Epigenetics and Transcription Factors in the Induction of Autoimmunity: a Comprehensive Review
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits