HLA-B*51 POZİTİF BEHÇET HASTALARINDA HLA-B*51 ALLELLERİNİN ARAŞTIRILMASI

Yıl 2023, Cilt: 3 Sayı: 3, 6 - 16, 30.12.2023

Sinem Topcu Ayas , Aslı Ozkızılcık Kocyıgıt , Tulay Kılıcaslan Ayna , Kiymet Handan Kelekci , Mustafa Soyoz , Ibrahim Pırım

Öz

Amaç: 1937 yılında Türk Dermatolog Prof. Dr. Hulusi Behçet tarafından keşfedilen Behçet Hastalığının (BH) semptomları tekrar eden oral aft, genital ülserler ve üveyitti. Daha sonra bu hastalığın eklemleri, kan damarlarını, bağırsakları, akciğerleri ve beyin sistemini de kapsadığı bildirilmiştir. Hastalığın seyrini yaş, cinsiyet, fizyolojik faktörler, enfeksiyöz ajanlar, immün yanıt ve genetik geçişler etkiler. En yaygın görülen genetik risk faktörü İnsan Lökosit Antijeni (HLA)-B*51’dir. Bu çalışmada HLA-B*51 alt alleleri ile hastalık etyolojisi arasındaki ilişki irdelenmesi amaçlanmıştır.
Gereç ve Yöntem: BH hastaları ile kontrol grubu arasında HLA-B*51 alt allellerinin prevalanslarını karşılaştırdık. Sekans spesifik primer polimeraz zincir reaksiyonu (SSP-PZR) yöntemiyle HLA-B*51 pozitif olan 24 kişinin doku tiplemesi yapılmıştır. Kontrol grubunda ise kemik iliği donörü olan 73 sağlıklı bireyin HLA-B*51 alt allel tiplemesi DNA dizi analizi yöntemiyle belirlenmiştir.
Bulgular: Hasta grubunda HLA-B*51:01 ve 51:08 alt allellerinin prevalansı sırasıyla %80 ve %20 bulunmuştur. HLA-B*51:01, 02, 05, 07 ve 08 alt allellerinin kontrol grubundaki sıklıkları sırasıyla %90,4, %4,1, %2,7 %1,4 ve %1,4 olarak bulunmuştur. Hasta ve control grubu arasında HLA-B*51:01 alt allelinin sıklığı bakımından istatistiksel olarak anlamlı bir farklılık bulunmamıştır (p>0.05; p=0.457 RR<1). İstatistiksel olarak anlamlı sonuçlar HLA-B*51:08 alt alleli için bulunmuştur (p<0.05; p=0.003 RR=18.8). HLA-B*51:01 ve HLA-B*51:08 alt allelleri ile klinik semptomlar arasında anlamlı bir ilişki bulunmamıştır.
Sonuç: HLA-B*51:08 alt allelinin BH gelişiminde önemli bir faktör olabilir. Yapılacak çalışmalarla hastalığın patofizyolojisi açısından önemi gösterilebilir.

Anahtar Kelimeler

Behçet hastalığı, HLA-B*51 alt alleli, organ tutulumu, PZR, gen

Proje Numarası

2017-TYL-SABE-0043

INVESTIGATION OF HLA-B*51 SUB-ALLELES IN HLA-B*51 POSITIVE BEHCET PATIENTS

Öz

Aim: The initial identification of Behçet's disease (BD) occurred in 1937, credited to the Turkish dermatologist Prof. Dr. Hulusi Behçet. Symptoms included repeated oral aphthae, genital ulcers, and uveitis. Then, it was revealed that the illness involves the joints, blood vessels, intestines, lungs, and brain system. Age, gender, psychological factors, infectious agents, immune responses, and genetic predispositions affect illness progression. The most common genetic risk factor is HLA-B*51. This study aimed to examine the relationship between HLA-B*51 sub-alleles and illness etiology.
Materials and Method: We compared the prevalence of two HLA-B*51 sub-alleles (HLA-B*51:01 and HLA-B*51:08) in patients with BD versus healthy individuals. The samples of 24 HLA-B*51 positive individuals were typed by Polymerase Chain Reaction with Sequence-Specific Primers (PCR-SSP). In the control group, 73 healthy bone marrow donors were HLA-B*51 subtyped by DNA sequencing.
Results: The prevalence of HLA-B*51:01 and 51:08 sub-alleles in patients was 80% and 20%, respectively. The frequencies of HLA-B*51:01, 02, 05, 07, and 08 in the control group were 90.4%, 4.1%, 2.7%, 1.4%, and 1.4%, respectively. There was no significant difference in HLA-B*51:01 allele frequency between patient and control groups (p>0.05; p=0.457 RR<1). Statistically significant differences were seen for the HLA-B*51:08 allele (p<0.05; p=0.003 RR=18.8). No statistically significant correlation was found between HLA-B*51:01 and HLA-B*51:08 sub-alleles and clinical symptoms (p-value > 0.05).
Conclusion: HLA-B*51:08 sub-allele may be an important risk factor for BD development. Future investigations can further highlight the significance of its role in the pathophysiology of the disease.

Anahtar Kelimeler

Behçet’s disease, HLA-B*51 sub-alleles, organ involvement, PCR, gene

Etik Beyan

Signed Informed Consents were obtained from all patients. In compliance with the Declaration of Helsinki, our Institutional Non-Interventional Clinical Research Ethics Committee approved the study (Decision No: 17, 09.02.2017).

Destekleyen Kurum

Izmir Katip Celebi University Coordination of Scientific Research Projects

Proje Numarası

2017-TYL-SABE-0043

Teşekkür

The authors have no financial or other conflict of interest. This study was financially supported by Izmir Katip Celebi University Coordination of Scientific Research Projects (Project no: 2017-TYL-SABE-0043). This study was presented as a poster presentation (P213) in 32nd European Federation of Immunogenetics Congress in Venice, Italy in 2018.

Kaynakça

• Kaklamani VG, Vaiopoulos G, Kaklamanis PG. Behçet’s Disease. Semin Arthritis Rheum. 1998;27(4):197–217. doi: 10.1016/s0049-0172(98)80001-2.
• Skef W, Hamilton MJ, Arayssi T. Gastrointestinal Behçet’s disease: A review. World J Gastroentero 2015 Apr 4;21(13):3801. doi: 10.3748/wjg.v21.i13.3801
• Azizlerli G, Köse AA, Sarica R, et al. Prevalence of Behçet’s disease in Istanbul, Turkey. Int J Dermatol. 2003 Jan 1;42(10):803–6. doi: 10.1046/j.1365-4362.2003.01893.x.
• Gürler A, Boyvat A, Türsen Ü. Clinical manifestations of Behçet’s disease: an analysis of 2147 patients. Yonsei Med J. 1997;38(6):423–7. doi: 10.3349/ymj.1997.38.6.423.
• Alpsoy E, Constantin Zouboulis C, Ehrlich GE. Mucocutaneous Lesions of Behçet’s disease. Yonsei Med J. 2007;48(4):573–85. Available from: https://synapse.koreamed.org/upload/synapsedata/pdfdata/0069ymj/ymj-48-573.pdf
• Ohno S, Ohguchi M, Hirose S, Matsuda H, Wakisaka A, Aizawa M. Close association of HLA-Bw51 with Behçet’s disease. Arch Ophthalmol. 1982;100(9):1455–8. Doi: 10.1001/archopht.1982.01030040433013
• Kotake S, Namba K, Higashi K, et al. The change of clinical manifestations of patients with Behçet’s disease in Japan. Adv Exp Med Biol. 2003;528:83–4. doi: 10.1007/0-306-48382-3_16.
• Turna I, Pabuççuoğlu U, Akin C, Lebe B, Gunes AT. Histopathologic and direct immunofluorescence findings of the papulopustular lesions in Behçet’s disease. Eur J Dermatol. 2006;16(2):146–50. Available from: https://pubmed.ncbi.nlm.nih.gov/16581565/
• Kulkarni S, Martin MP, Carrington M. The Yin and Yang of HLA and KIR in human disease. Semin Immunol. 2008 Dec;20(6):343–52. doi: 10.1016/j.smim.2008.06.003.
• Shafi S, Vantourout P, Wallace G, et al. An NKG2D-mediated human lymphoid stress surveillance response with high interindividual variation. Sci Transl Med. 2011 Dec 14;3(113). doi: 10.1126/scitranslmed.3002922.
• Song YW, Kang EH. Behçet’s disease and genes within the major histocompatibility complex region. Mod Rheumatol. 2012 Apr;22(2):178–85. doi: 10.1007/s10165-011-0542-4
• Takeuchi M, Kastner DL, Remmers EF. The immunogenetics of Behçet’s disease: A comprehensive review. J Autoimmun. 2015 Nov 1;64:137–48. doi: 10.1016/j.jaut.2015.08.013.
• Arayssi T, Hamdan A. New insights into the pathogenesis and therapy of Behçet’s disease. Curr Opin Pharmacol. 2004 Apr;4(2):183–8. doi: 10.1016/j.coph.2003.10.009.
• Marshall SE. Behçet’s disease. Best Pract Res Clin Rheumatol. 2004 Jun;18(3):291–311. doi: 10.1016/j.berh.2004.02.008.
• Mizuki N, Inoko H, Ando H, et al. Behçet’s disease associated with one of the HLA-B51 subantigens, HLA-B* 5101. Am J Ophthalmol. 1993;116(4):406–9. doi: 10.1016/s0002-9394(14)71396-0.
• Guasp P, Alvarez-Navarro C, Gomez-Molina P, et al. The Peptidome of Behçet’s Disease-Associated HLA-B*51:01 Includes Two Subpeptidomes Differentially Shaped by Endoplasmic Reticulum Aminopeptidase 1. Arthritis Rheumatol. 2016 Feb 1;68(2):505–15. doi: 10.1002/art.39430.
• Gül A, Hajeer AH, Worthington J, Barrett JH, Ollier WER, Silman AJ. Evidence for linkage of the HLA–B locus in Behçet’s disease, obtained using the transmission disequilibrium test. Arthritis Rheum. 2001;44(1):239–41. doi: 10.1002/1529-0131(200101)44:1<239::AID-ANR31>3.0.CO;2-X.
• Choo SY. The HLA system: genetics, immunology, clinical testing, and clinical implications. Yonsei Med J. 2007 Feb;48(1):11–23. doi: 10.3349/ymj.2007.48.1.11.
• BOYVAT A. Behçet Hastalığında Tanı ve Ayırıcı Tanı. Türkiye Klinikleri J Dermatol - Özel Konular. 2017;10(4):315–20. Available from: https://www.turkiyeklinikleri.com/article/tr-Behçet-hastaliginda-tani-ve-ayirici-tani-80555.html
• Ohno S, Asanuma T, Sugiura S, Wakisaka A, Aizawa M, Itakura K. HLA-Bw51 and Behçet’s Disease. JAMA. 1978 Aug 11;240(6):529–529. doi:10.1001/jama.1978.03290060031006
• Yazici H, Tuzun Y, Pazarli H, Yalcin B, Yurdakul S, Muftuoglu A. The combined use of HLA-B5 and the pathergy test as diagnostic markers of Behçet’s disease in Turkey - PubMed. J Rheumatol. 1980 Mar-Apr; 7(2):206-10. Available from: https://pubmed.ncbi.nlm.nih.gov/7373623/
• Soylu M, Ersöz TR, Erken E. The association between HLA B5 and ocular involvement in Behçet’s disease in southern Turkey. Acta Ophthalmol. 1992 Dec 1;70(6):786–9. Doi: 10.1111/j.1755-3768.1992.tb04888.x
• Erkılıç K, Patıroğlu T, Doğan H, Mirza E, Çağıl N. HLA Antigenes and Their Associations with Organ Lesions in Behçet’s Disease. Journal of Retina-Vitreous. 1996;4(3). Available from: https://retinavitreus.com/abstract.php?lang=tr&id=322
• Azizlerli G, Aksungur VL, Sarica R, Akyol E, Övül C. The association of HLA-B5 antigen with specific manifestations of Behçet’s disease. Dermatology. 1994;188(4):293–5. doi: 10.1159/000247169.
• Zierhut M, Saal J, Pleyer U, Kötter I, Dürk H, Fierlbeck G. Behçet’s disease: epidemiology and eye manifestations in German and Mediterranian patients - PubMed. Ger J Ophtalmol. 1995;446–51. Available from: https://pubmed.ncbi.nlm.nih.gov/7492938/
• Mizuki N, Inoko H, Ohno S. Molecular Genetics (HLA) of Behçet’s disease. Yonsei Med J. 1997;38(6):333–9. Available from: https://www.eymj.org/Synapse/Data/PDFData/0069YMJ/ymj-38-333.pdf
• Balkan E, Eyerci N, Keleş S, et al. Evaluation of HLA-B*51 Subtypes in Behçet’s Patients with Uveitis Behçet Üveitli Hastalarda HLA-B*51 Alt Tipinin Değerlendirilmesi. Kafkas J Med Sci. 2017;7(3):193–6. doi: 10.5505/kjms.2017.39306
• Müller CA, Günaydın İ, Stübiger N, et al. 2003. Association of HLA-B51 Suballeles with Behçet’s Disease in Patients of German and Turkish Origin, In: Ohno S, Zierhut M, editors. Immunology of Behçet’s Disease. 1st Edition. Lisse: Swets and Zeitlinger Publishers; pp. 121. Available from: https://books.google.com.tr/books?id=3TCHv9RqFwcC&printsec=frontcover&hl=tr&source=gbs_ge_summary_r&cad=0#v=onepage&q=Association%20of%20HLA-B51%20Suballeles%20with%20Beh%C3%A7et%E2%80%99s%20Disease%20in%20Patients%20of&f=false
• Pirim I, Atasoy M, Ikbal M, Erdem T, Aliagaoglu C. HLA class I and class II genotyping in patients with Behçet’s disease: a regional study of eastern part of Turkey. Tissue Antigens. 2004 Sep;64(3):293–7. doi: 10.1111/j.1399-0039.2004.00280.x.
• Demirseren DD, Ceylan GG, Akoglu G, et al. HLA-B51 subtypes in Turkish patients with Behçet’s disease and their correlation with clinical manifestations. Genet Mol Res. 2014 Jul 2;13(3):4788–96. doi: 10.4238/2014.July.2.8.
• Kötter I, Günaydin I, Stübiger N, et al. Comparative analysis of the association of HLA-B*51 suballeles with Behçet’s disease in patients of German and Turkish origin. Tissue Antigens. 2001;58(3):166–70. doi: 10.1034/j.1399-0039.2001.580304.x.
• Kaya-Atalay A. Behçet Hastalarında HLA-B51 Genotiplerinin İncelenmesi [PhD thesis]. [Istanbul, Turkey]:Marmara University;1998. Available from: https://www.proquest.com/docview/2564506524?pq-origsite=gscholar&fromopenview=true
• Belem JMFM, Fraga AM, Andrade LEC, de Souza AWS. HLA-B*51 and its main subtypes in Brazilian patients with Behçet’s disease. Clin Exp Rheumatol. 2020;38:53–9. PMID: 33124572.
• De Menthon M, LaValley MP, Maldini C, Guillevin L, Mahr A. HLA–B51/B5 and the Risk of Behçet’s Disease: A Systematic Review and Meta-Analysis of Case–Control Genetic Association Studies. Arthritis Rheum. 2009 Oct 10;61(10):1287–96. doi: 10.1002/art.24642.
• Davatchi F, Shahram F, Chams C, et al. 2003. Non-Ocular Manifestations. In: Ohno S, Zierhut M, editors. Immunology of Behçet’s Disease. 1st Edition. Lisse: Swets and Zeitlinger Publishers; pp. 21. Available from: https://books.google.com.tr/books?hl=tr&lr=&id=3TCHv9RqFwcC&oi=fnd&pg=PP11&dq=Non-Ocular+Manifestations+zierhut&ots=MUm2Cm6wCN&sig=VQZzIPEt2CSQVC07-_C-cbdveTc&redir_esc=y#v=onepage&q=Non-Ocular%20Manifestations&f=false