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Current Rheumatology Reviews

Editor-in-Chief

ISSN (Print): 1573-3971
ISSN (Online): 1875-6360

Review Article

Genetics and Epigenetics Mechanism in the Pathogenesis of Behçet’s Disease

Author(s): Jibran Sualeh Muhammad*, Muhammad Ishaq and Khalid Ahmed

Volume 15, Issue 1, 2019

Page: [7 - 13] Pages: 7

DOI: 10.2174/1573397114666180521090335

Price: $65

Abstract

Background: Behçet’s Disease (BD) is characterized by numerous systemic manifestations and is known for its ability to affect both, arteries and the veins. However, the etiology of BD is only partially understood, and previous studies have demonstrated a role for genetic and epigenetic factors that contribute to disease pathophysiology. Several studies have implicated T cells and monocytes in the pathogenesis of BD especially when these cells are stimulated by heat shock proteins and streptococcal antigen. Furthermore, during disease exacerbations adenosine deaminase has an important role in activating lymphocyte proliferation, maturation, and differentiation in BD. This article presents a review of the published literature mainly from the last 20 years. The topics of main concern were the role of genetic and epigenetic factors as contributing factors in disease pathophysiology.

Result and Conclusion: The authors used MeSH terms “Behçet’s disease” with “pathophysiology,” “pathogenesis,” “genetic” or “epigenetic” to search the PubMed database. All the relevant studies identified were included and are described according to the aforementioned subheadings.

Keywords: Behçet's disease, genetics, epigenetics, arteries, veins, pathogenesis.

Graphical Abstract
[1]
Sakane T, Takeno M, Suzuki N, Inaba G. Behçet’s disease. N Engl J Med 1999; 341(17): 1284-91.
[2]
Mahr A, Belarbi L, Wechsler B, et al. Population based prevalence study of Behçet’s disease: Differences by ethnic origin and low variation by age at immigration. Arthritis Rheumatol 2008; 58(12): 3951-9.
[3]
Gunesacar R, Erken E, Bozkurt B, et al. Analysis of CD28 and CTLA 4 gene polymorphisms in Turkish patients with Behcet’s disease. Int J Immunogenet 2007; 34(1): 45-9.
[4]
Mizushima Y. Skin hypersensitivity to streptococcal antigens and the induction of systemic symptoms by the antigens in Behçet’s disease- A multicenter study. J Rheumatol 1989; 16(4): 506-11.
[5]
Direskeneli H. Behçet9s disease: Infectious aetiology, new autoantigens, and HLA-B51. Ann Rheum Dis 2001; 60(11): 996-1002.
[6]
Erkiliç K, Evereklioglu C, Çekmen M, Özkiris A, Duygulu F, Dogan H. Adenosine deaminase enzyme activity is increased and negatively correlates with catalase, superoxide dismutase and glutathione peroxidase in patients with Behçet’s disease: Original contributions/clinical and laboratory investigations. Mediators Inflamm 2003; 12(2): 107-16.
[7]
Erden F, Karagoz H, Avci A, et al. Which one is best? platelet/lymphocyte ratio, neutrophil/lymphocyte ratio or both in determining deep venous thrombosis in behcet’s disease? Biomed Res 2017; 28(12)
[8]
Direskeneli H. Autoimmunity vs autoinflammation in Behcet’s disease: Do we oversimplify a complex disorder? Rheumatology 2006; 45(12): 1461-5.
[9]
Kartal Durmazlar SP, Ulkar GB, Eskioglu F, Tatlican S, Mert A, Akgul A. Significance of serum interleukin 8 levels in patients with Behcet’s disease: High levels may indicate vascular involvement. Int J Dermatol 2009; 48(3): 259-64.
[10]
Mege J, Dilsen N, Sanguedolce V, et al. Overproduction of monocyte derived tumor necrosis factor alpha, interleukin (IL) 6, IL-8 and increased neutrophil superoxide generation in Behcet’s disease. A comparative study with familial Mediterranean fever and healthy subjects. J Rheumatol 1993; 20(9): 1544-9.
[11]
Akman-Demir G, Tüzün E, İçöz S, Yeşilot N, et al. Interleukin-6 in neuro-Behçet’s disease: Association with disease subsets and long-term outcome. Cytokine 2008; 44(3): 373-6.
[12]
Ben Ahmed M, Houman H, Miled M, Dellagi K, Louzir H. Involvement of chemokines and Th1 cytokines in the pathogenesis of mucocutaneous lesions of Behçet’s disease. Arthritis Rheumatol 2004; 50(7): 2291-5.
[13]
de Chambrun MP, Wechsler B, Geri G, Cacoub P, Saadoun D. New insights into the pathogenesis of Behcet’s disease. Autoimmun Rev 2012; 11(10): 687-98.
[14]
Hamzaoui K, Hamzaoui A, Guemira F, Bessioud M, Hamza MH, Ayed K. Cytokine profile in Behçet’s disease patients. Scand J Rheumatol 2002; 31(4): 205-10.
[15]
Koné-Paut I, Geisler I, Wechsler B, et al. Familial aggregation in Behçet’s disease: High frequency in siblings and parents of pediatric probands. J Pediatr 1999; 135(1): 89-93.
[16]
Yu H, Lee D, Seo J, et al. The number of CD8+ T cells and NKT cells increases in the aqueous humor of patients with Behçet’s uveitis. Clin Exp Immunol 2004; 137(2): 437-43.
[17]
Lee YJ, Horie Y, Wallace GR, et al. Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behcet’s disease. Ann Rheum Dis 2012; 72(9): 1510-6.
[18]
Sfikakis P, Theodossiadis P, Katsiari C, Kaklamanis P, Markomichelakis N. Effect of infliximab on sight-threatening panuveitis in Behcet’s disease. Lancet 2001; 358(9278): 295-6.
[19]
Evereklioglu C. Current concepts in the etiology and treatment of Behçet disease. Surv Ophthalmol 2005; 50(4): 297-350.
[20]
Ahn JK, Yu HG, Chung H, Park YG. Intraocular cytokine environment in active Behçet uveitis. Am J Ophthalmol 2006; 142(3): 429-34.
[21]
Kurhan Yavuz S, Direskeneli H, et al. Anti MHC autoimmunity in Behçet’s disease: T cell responses to an HLA B derived peptide cross reactive with retinal S antigen in patients with uveitis. Clin Exp Immunol 2000; 120(1): 162-6.
[22]
Evereklioglu C, Turkoz Y, Er H, Inaloz HS, Ozbek E, Cekmen M. Increased nitric oxide production in patients with Behçet’s disease: Is it a new activity marker? J Am Acad Dermatol 2002; 46(1): 50-4.
[23]
de Smet MD, Dayan M. Prospective determination of T-cell responses to S-antigen in Behçet’s disease patients and controls. Invest Ophthalmol Vis Sci 2000; 41(11): 3480-4.
[24]
Balta S, Balta I, Demirkol S, Ozturk C, Demir M. Endothelial function and Behcet disease. SAGE Publications Sage CA: Los Angeles, CA 2014.
[25]
Sahin M, Arslan C, Naziroglu M, et al. Asymmetric dimethylarginine and nitric oxide levels as signs of endothelial dysfunction in Behcet’s disease. Ann Clin Lab Sci 2006; 36(4): 449-54.
[26]
Duygulu F, Evereklioglu C, Calis M, Borlu M, Çekmen M, Ascioglu O. Synovial nitric oxide concentrations are increased and correlated with serum levels in patients with active Behcet’s disease: A pilot study. Clin rheumat 2005; 24(4): 324-30.
[27]
Nakao K, Isashiki Y, Sonoda S, Uchino E, Shimonagano Y, Sakamoto T. Nitric oxide synthase and superoxide dismutase gene polymorphisms in Behcet disease. Arch Ophthalmol 2007; 125(2): 246-51.
[28]
Kiraz S. Ertenli Ih, Öztürk MA, Haznedaroğlu IbC, Çelik Is, Çalgüneri M. Pathological haemostasis and ‘prothrombotic state’in Behçet’s disease. Thromb Res 2002; 105(2): 125-33.
[29]
Üsküdar O, Erdem A, Demiroğlu H, Dikmenoğlu N. Decreased erythrocyte deformability in Behçet’s disease. Clin Hemorheol Microcirc 2005; 33(2): 89-94.
[30]
Navarro S, Ricart JM, Medina P, et al. Activated protein C levels in Behçet’s disease and risk of venous thrombosis. Br J Haematol 2004; 126(4): 550-6.
[31]
Akar S, Özcan MA, Ateş H, et al. Circulated activated platelets and increased platelet reactivity in patients with Behçet’s disease. Clin Appl Thromb Hemost 2006; 12(4): 451-7.
[32]
Tatlican S, Duran FS, Eren C, et al. Reduced erythrocyte deformability in active and untreated Behçet’s disease patients. Int J Dermatol 2010; 49(2): 167-71.
[33]
Yurdakul S, Hekim N, Soysal T, et al. Fibrinolytic activity and d-dimer levels in Behçet's syndrome. Clin Exp Rheumatol 2005; 23(4): S 53-8.
[34]
Caramaschi P, Poli G, Bonora A, et al. A study on thrombophilic factors in Italian Behcet’s patients. Joint Bone Spine 2010; 77(4): 330-4.
[35]
Ricart JM, Ramón LA, Vayá A, et al. Fibrinolytic inhibitor levels and polymorphisms in Behçet disease and their association with thrombosis. Br J Haematol 2008; 141(5): 716-9.
[36]
Leiba M, Seligsohn U, Sidi Y, et al. Thrombophilic factors are not the leading cause of thrombosis in Behçet’s disease. Ann Rheum Dis 2004; 63(11): 1445-9.
[37]
Song SH, Kim HK, Park MH, Cho H-I. Neutrophil CD64 expression is associated with severity and prognosis of disseminated intravascular coagulation. Thromb Res 2008; 121(4): 499-507.
[38]
Vaccarino L, Triolo G, Accardo-Palombo A, et al. Pathological implications of Th1/Th2 cytokine genetic variants in Behcet’s disease: Data from a pilot study in a Sicilian population. Biochem Genet 2013; 51(11-12): 967-75.
[39]
Turkmen S, Ayabakan H, Buldanlioglu S, et al. Nitric oxide, lipid peroxidation and antioxidant defence system in patients with active or inactive Behçet’s disease. Br J Dermatol 2005; 153(3): 526-30.
[40]
Saglam K, Yilmaz IM, Saglam A, Ulgey M, Bulucu F, Baykal Y. Levels of circulating intercellular adhesion molecule-1 in patients with Behçet’s disease. Rheumatol Int 2002; 21(4): 146-8.
[41]
Ateş A, Tiryaki OA, Ölmez Ü, Tutkak H. Serum-soluble selectin levels in patients with Behçet’s disease. Clin Rheumatol 2007; 26(3): 411-7.
[42]
Lee M, Hooper L, Kump L, et al. Interferon β and adhesion molecules (E selectin and s intracellular adhesion molecule 1) are detected in sera from patients with retinal vasculitis and are induced in retinal vascular endothelial cells by Toll like receptor 3 signalling. Clin Exp Immunol 2007; 147(1): 71-80.
[43]
Yamashita S, Suzuki A, Kamada M, Yanagita T, Hirohata S, Toyoshima S. Possible physiological roles of proteolytic products of actin in neutrophils of patients with Behcet’s disease. Biol Pharm Bull 2001; 24(7): 733-7.
[44]
Yoshida T, Tanaka M, Sotomatsu A, Okamoto K, Hirai S. Serum of Behqet’s Disease Enhances Super oxide Production of Normal Neutrophils. Free Radic Res 1998; 28(1): 39-44.
[45]
Kawakami T, Ohashi S, Kawa Y, et al. Elevated serum granulocyte colony-stimulating factor levels in patients with active phase of sweet syndrome and patients with active behcet disease: Implication in neutrophil apoptosis dysfunction. Arch Dermatol 2004; 140(5): 570-4.
[46]
Yazici C, Köse K, Caliş M, Demir M, Kirnap M, Ateş F. Increased advanced oxidation protein products in Behcet’s disease: A new activity marker? Br J Dermatol 2004; 151(1): 105-11.
[47]
Hamzaoui K, Maître B, Hamzaoui A. Elevated levels of MMP-9 and TIMP-1 in the cerebrospinal fluid of neuro-Behçet’s disease. Clin Exp Rheumatol 2009; 27(2): S52.
[48]
Gül A, Hajeer AH, Worthington J, Ollier WE, Silman AJ. Linkage mapping of a novel susceptibility locus for Behçet’s disease to chromosome 6p22 23. Arthritis Rheumatol 2001; 44(11): 2693-6.
[49]
Takeuchi M, Kastner DL, Remmers EF. The immunogenetics of Behcet’s disease: A comprehensive review. J Autoimmun 2015; 64: 137-48.
[50]
Wildner G, Thurau SR. Cross reactivity between an HLA B27 derived peptide and a retinal autoantigen peptide: A clue to major histocompatibility complex association with autoimmune disease. Eur J Immunol 1994; 24(11): 2579-85.
[51]
Gebreselassie D, Spiegel H, Vukmanovic S. Sampling of major histocompatibility complex class I-associated peptidome suggests relatively looser global association of HLA-B* 5101 with peptides. Human immunology 2006; 67(11): 894-906.
[52]
Kirino Y, Bertsias G, Ishigatsubo Y, et al. Genome-wide association analysis identifies new susceptibility loci for Behcet’s disease and epistasis between HLA-B [ast] 51 and ERAP1. Nat Genet 2013; 45(2): 202-7.
[53]
Salmaninejad A, Gowhari A, Hosseini S, et al. Genetics and immunodysfunction underlying Behçet’s disease and immunomodulant treatment approaches. J Immunotoxicol 2017; 14(1): 137-51.
[54]
Goldberg AD, Allis CD, Bernstein E. Epigenetics: A landscape takes shape. Cell 2007; 128(4): 635-8.
[55]
Balada E, Ordiros J, Vilardelltarrés M. DNA methylation and systemic lupus erythematosus. Ann N Y Acad Sci 2007; 1108(1): 127-36.
[56]
Deaton AM, Bird A. CpG islands and the regulation of transcription. Genes Dev 2011; 25(10): 1010-22.
[57]
Bird AP, Wolffe AP. Methylation-induced repression-belts, braces, and chromatin. Cell 1999; 99(5): 451-4.
[58]
Surani MA. Imprinting and the initiation of gene silencing in the germ line. Cell 1998; 93(3): 309-12.
[59]
Gupta B, Hawkins RD. Epigenomics of autoimmune diseases. Immunol Cell Biol 2015; 93(3): 271.
[60]
Bhaumik SR, Smith E, Shilatifard A. Covalent modifications of histones during development and disease pathogenesis. Nat Struct Mol Biol 2007; 14(11): 1008.
[61]
Kouzarides T. Chromatin modifications and their function. Cell 2007; 128(4): 693-705.
[62]
Mizuki N, Ota M, Kimura M, et al. Triplet repeat polymorphism in the transmembrane region of the MICA gene: A strong association of six GCT repetitions with Behcet disease. Proc Natl Acad Sci USA 1997; 94(4): 1298-303.
[63]
Karasneh J, Gül A, Ollier WE, Silman AJ, Worthington J. Whole genome screening for susceptibility genes in multicase families with Behçet’s disease. Arthritis Rheumatol 2005; 52(6): 1836-42.
[64]
Gül A. editor Pathogenesis of Behçet’s disease: Autoinflammatory features and beyond. Semin Immunopathol 2015; 37(4): 413-8.
[65]
Consolandi C, Turroni S, Emmi G, et al. Behçet’s syndrome patients exhibit specific microbiome signature. Autoimmun Rev 2015; 14(4): 269-76.
[66]
Ombrello MJ, Kastner DL, Remmers EF. Endoplasmic reticulum-associated amino-peptidase 1 and rheumatic disease: Genetics. Curr Opin Rheumatol 2015; 27(4): 349.
[67]
Yokota K, Hayashi S, Fujii N, et al. Antibody response to oral streptococci in Behçet’s disease. Microbiol Immunol 1992; 36(8): 815-22.
[68]
Calgüneri M, Ertenli I, Kiraz S, Erman M, Celik I. Effect of prophylactic benzathine penicillin on mucocutaneous symptoms of Behçet’s disease. Dermatology 1996; 192(2): 125-8.
[69]
Kogan A, Shinar Y, Lidar M, et al. Common MEFV mutations among Jewish ethnic groups in Israel: High frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state. Am J Med Genet A 2001; 102(3): 272-6.
[70]
Hughes T, Ture Ozdemir F, Alibaz Oner F, Coit P, Direskeneli H, Sawalha AH. 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 behçet’s disease. Arthritis Rheumatol 2014; 66(6): 1648-58.

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