Expression Levels of B Cell Receptor (BCR) Signaling Pathway Factors are Associated with Conversion from Clinically Isolated Syndrome to Multiple Sclerosis

Yıl 2021, Cilt: 11 Sayı: 1, 33 - 37, 03.05.2021

Zerrin Karaaslan , Ece Akbayır Elif Şanlı Melis Şen , Recai Türkoğlu , Cem İsmail Küçükali , Erdem Tüzün

https://doi.org/10.26650/experimed.2021.888583

Öz

Objective: We have previously shown altered blood B cells in the first attack blood samples of clinically isolated syndrome (CIS) pa-tients, who converted to multiple sclerosis (MS). Our aim was to investigate levels of B cell receptor (BCR)-associated genes expres-sion in converting CIS (CIS-c) and non-converting CIS patients (CIS-nc) with a 5-year follow-up.

Methods: Seven CIS-c patients, 12 CIS-nc patients and 10 age-sex matched healthy donors were enrolled in this study. RNA was extracted from frozen peripheral blood cells of subjects that were obtained in the first attack using a RNA isolation kit. Expression levels of B-cell adaptor protein with ankyrin repeats 1 (BANK1), B lymphocyte kinase (BLK) and Fc receptor-like protein 2 (FCRL2) genes were evaluated samples by real-time polymerase chain re-action (RT-PCR).

Results: CIS-nc patients showed elevated BANK1, BLK and FCRL2 gene expression levels as compared to CIS-c patients and healthy controls.

Conclusions: Expression levels of the genes that inhibit BCR signal-ing are increased in CIS-nc, suggesting that inhibiting exaggerated B cell response by optimization of B cell proliferation may prevent the progression of clinically isolated syndrome to MS.

Anahtar Kelimeler

Clinically isolated syndrome, multiple sclerosis, B cell receptor, BANK1, BLK, FCRL2

B Hücre Reseptör (BHR) Sinyal Yolağı Faktörlerinin Ekspresyon Düzeyleri Klinik İzole Sendromdan Multipl Skleroza Dönüşümle İlişkilidir

Öz

Amaç: Daha önceki çalışmalarımızda, multipl skleroza (MS) dö-nüşen klinik izole sendrom (KİS) olgularının ilk atakta alınan kan örneklerinde periferik kan B hücre düzeylerinin değiştiğini göste-rilmiştir. Bu çalışmada beş yıllık takipte MS’e dönüşen ve dönüşme-yen KİS olgularında B hücre reseptör (BHR) ilişkili genlerin ekspres-yon düzeylerinin araştırılması amaçlanmıştır.

Yöntem: Yedi MS’e dönüşen, 12 MS’e dönüşmeyen KİS olgusu ile yaş ve cinsiyet açısından eşleştirilmiş 10 sağlıklı donör çalışmaya dahil edildi. İlk atak döneminde elde edilen donmuş periferik kan mononükleer hücrelerinden (PKMH) RNA izolasyon kiti kullanılarak total RNAlar izole edildi. Örneklerden gerçek zamanlı polimeraz zincir reaksiyonu (RT-PCR) yöntemi ile ankrin tekrarlı B-hücre adap-tör proteini (BANK1), B lenfosit kinaz (BLK), Fc reseptör benzeri pro-tein 2 (FCRL2) genlerinin ekspresyonları değerlendirildi.

Bulgular: MS’e dönüşmeyen KİS olgularında BANK1, BLK ve FCRL2 gen ekspresyon düzeyleri MS’e dönüşen KİS olguları ve sağlıklı kontrollere kıyasla artmış olarak saptandı.

Sonuç: BHR sinyalizasyonunu inhibe eden gen ekspresyonlarının MS’e dönüşmeyen olgularda artması, abartılı B hücre yanıtının B hücre proliferasyonunun optimize edilmesi yoluyla baskılanması-nın KİS’ten MS’e ilerleyişi engelleyebileceğini düşündürmüştür.

Anahtar Kelimeler

Klinik izole sendrom, multipl skleroz, B hücre reseptörü, BANK1, BLK, FCRL2

Kaynakça

• 1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Mul-tiple sclerosis. N Engl J Med 2000; 343(13): 938-52. [CrossRef] google scholar
• 2. Yadav SK, Mindur JE, Ito K, Dhib-Jalbut S. Advances in the im-munopathogenesis of multiple sclerosis. Curr Opin Neurol 2015; 28(3): 206-19. [CrossRef] google scholar
• 3. Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 2004; 14(2): 164-74. [CrossRef] google scholar
• 4. Bar-Or A, Fawaz L, Fan B, Darlington PJ, Rieger A, Ghorayeb C, et al. Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS? Ann Neurol 2010; 67(4): 452-61. [CrossRef] google scholar
• 5. Fisniku LK, Brex PA, Altmann DR, Miszkiel KA, Benton CE, Lanyon R, et al. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain 2008; 131(Pt 3): 80817. [CrossRef] google scholar
• 6. Brettschneider J, Czerwoniak A, Senel M, Fang L, Kassubek J, Pinkhardt E, et al. The chemokine CXCL13 is a prognostic marker in clinically isolated syndrome (CIS). PLoS One 2010; 5(8): e11986. [CrossRef] google scholar
• 7. Aktura SD, Yilmaz V, Ozkan-Yasargun D, Ulusoy C, Tuzun E, Turko-glu R. Peripheral blood memory B cell frequency predicts conver-sion from clinically isolated syndrome to multiple sclerosis. Mult Scler Relat Disord 2018; 23: 9-14. [CrossRef] google scholar
• 8. Âkerblad P, Sigvardsson M. Early B cell factor is an activator of the B lymphoid kinase promoter in early B cell development. The Journal of Immunology 1999; 163(10): 5453-61. google scholar
• 9. Yokoyama K, Su Ih IH, Tezuka T, Yasuda T, Mikoshiba K, Tarakhovsky A, et al. BANK regulates BCR-induced calcium mobilization by pro-moting tyrosine phosphorylation of IP(3) receptor. EMBO J 2002; 21(1-2): 83-92. [CrossRef] google scholar
• 10. Chikaev NA, Bykova EA, Najakshin AM, Mechetina LV, Volkova OY, Peklo MM, et al. Cloning and characterization of the human FCRL2 gene. Genomics 2005; 85(2): 264-72. [CrossRef] google scholar
• 11. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the Mc-Donald criteria. Lancet Neurol 2018; 17(2): 162-73. [CrossRef] google scholar
• 12. Gauld SB, Dal Porto JM, Cambier JC. B cell antigen receptor sig-naling: roles in cell development and disease. Science 2002; 296(5573): 1641-2. [CrossRef] google scholar
• 13. Aiba Y, Yamazaki T, Okada T, Gotoh K, Sanjo H, Ogata M, et al. BANK negatively regulates Akt activation and subsequent B cell responses. Immunity 2006; 24(3): 259-68. [CrossRef] google scholar
• 14. Islam KB, Rabbani H, Larsson C, Sanders R, Smith CI. Molecular cloning, characterization, and chromosomal localization of a hu-man lymphoid tyrosine kinase related to murine Blk. J Immunol 1995; 154(3): 1265-72. google scholar
• 15. Bernal-Quiros M, Wu YY, Alarcon-Riquelme ME, Castillejo-Lopez C. BANK1 and BLK act through phospholipase C gamma 2 in B-cell signaling. PLoS One 2013; 8(3): e59842. [CrossRef] google scholar
• 16. Samuelson EM, Laird RM, Papillion AM, Tatum AH, Princiotta MF, Hayes SM. Reduced B lymphoid kinase (Blk) expression enhances proinflammatory cytokine production and induces nephrosis in C57BL/6-lpr/lpr mice. PLoS One 2014; 9(3): e92054. [CrossRef] google scholar
• 17. Delgado-Vega AM, Dozmorov MG, Quiros MB, Wu YY, Marti-nez-Garcia B, Kozyrev SV, et al. Fine mapping and conditional analysis identify a new mutation in the autoimmunity susceptibil-ity gene BLK that leads to reduced half-life of the BLK protein. Ann Rheum Dis 2012; 71(7): 1219-26. [CrossRef] google scholar
• 18. Matesanz-Isabel J, Sintes J, Llinas L, de Salort J, Lazaro A, Engel P. New B-cell CD molecules. Immunol Lett 2011; 134(2): 104-12. [CrossRef] google scholar
• 19. Jackson TA, Haga CL, Ehrhardt GR, Davis RS, Cooper MD. FcR-like 2 Inhibition of B cell receptor-mediated activation of B cells. J Im-munol 2010; 185(12): 7405-12. [CrossRef] google scholar
• 20. Shabani M, Bayat AA, Jeddi-Tehrani M, Rabbani H, Hojjat-Farsangi M, Ulivieri C, et al. Ligation of human Fc receptor like-2 by mono-clonal antibodies down-regulates B-cell receptor-mediated sig-nalling. Immunology 2014; 143(3): 341-53. [CrossRef] google scholar
• 21. Comabella M, Canto E, Nurtdinov R, Rio J, Villar LM, Picon C, et al. MRI phenotypes with high neurodegeneration are associated with peripheral blood B-cell changes. Hum Mol Genet 2016; 25(2): 308-16. [CrossRef] google scholar