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Peripheral blood mononuclear cell proteome profile in Behçet’s syndrome

  • Observational Research
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Abstract

Behçet’s syndrome (BS) is a systemic inflammatory disorder with unknown etiology. Investigation of proteome profiles of disease specific cells facilitates our understanding of the processes and related molecular pathways, especially in disorders like BS with complex inheritance pattern and clinical heterogeneity. In the current study, we evaluated the peripheral blood mononuclear cells (PBMCs) proteome of 59 patients with BS (33 in active and 26 in inactive phases) and of 28 healthy controls using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Differentially expressed protein spots with at least twofold and/or statistically significant change (p ≤ 0.05) between active BS vs inactive BS, and also active BS vs healthy controls were identified by mass spectrometry (MALDI-TOF/TOF). Bioinformatic analyses revealed 16 differentially expressed proteins (12 of them in active vs inactive BS comparison, whereas 11 of them for active BS vs healthy control comparison) belonging to glycolysis, cytoskeleton organization, protein folding, and regulation of blood coagulation pathways. Stathmin (active BS vs inactive BS; fourfold, active BS vs healthy control; 4.7-fold) and WD repeat-containing protein-1 (active BS vs inactive BS; 2.7-fold, active BS vs healthy control; 2.7-fold), which are cytoskeleton-related proteins, were found to be lower in active patients compared to inactive patients and healthy control. Decreased levels of calreticulin (active BS vs inactive BS; 1.29-fold) and heat shock 70 kDa protein 8 (active BS vs healthy control; 1.5-fold) which are involved in protein folding and endoplasmic reticulum (ER) stress process, were observed in patients with active phase of BS. Down-regulation of protein folding and ER stress process proteins in BS patients may further support the involvement of ER stress in BS.

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Abbreviations

2D-DIGE:

Two-dimensional fluorescence difference gel electrophoresis

ALDOC:

Fructose-bisphosphate aldolase C

BS:

Behçet’s syndrome

CALR:

Calreticulin

CRP:

C-reactive protein

ER:

Endoplasmic reticulum

FCN1:

Ficolin 1

FGA:

Fibrinogen alpha chain

FGB:

Fibrinogen beta chain

FLNA:

Filamin A

FUBP1:

Far upstream element-binding protein 1

HNRNPM:

Heterogeneous nuclear ribonucleoprotein M

HSPA8:

Heat shock 70 kDa protein 8

IEF:

Isoelectric focusing

MALDI-TOF/TOF MS:

Matrix-assisted laser desorption ionization time of flight mass spectrometry

MYL6:

Myosin light polypeptide 6

PBMC:

Peripheral blood mononuclear cell

PGK1:

Phosphoglycerate kinase 1

STMN:

Stathmin

TLN1:

Talin 1

TPM3:

Tropomyosin alpha-3 chain

WDR1:

WD repeat-containing protein 1

VCL:

Vinculin

References

  1. Yazici H, Seyahi E, Hatemi G, Yazici Y (2018) Behçet syndrome: a contemporary view. Nat Rev Rheumatol 14(2):107–119. https://doi.org/10.1038/nrrheum.2017.208

    Article  CAS  PubMed  Google Scholar 

  2. Akkoç N (2018) Update on the epidemiology, risk factors and disease outcomes of Behçet’s disease. Best Pract Res Clin Rheumatol 32(2):261–270. https://doi.org/10.1016/j.berh.2018.08.010

    Article  PubMed  Google Scholar 

  3. Calamia KT, Wilson FC, Icen M, Crowson CS, Gabriel SE, Kremers HM (2009) Epidemiology and clinical characteristics of Behçet’s disease in the US: a population-based study. Arthritis Rheum 61(5):600–604. https://doi.org/10.1002/art.24423

    Article  PubMed  PubMed Central  Google Scholar 

  4. Karasneh J, Gül A, Ollier WE, Silman AJ, Worthington J (2005) Whole-genome screening for susceptibility genes in multicase families with Behçet’s disease. Arthritis Rheum 52(6):1836–1842. https://doi.org/10.1002/art.21060

    Article  CAS  PubMed  Google Scholar 

  5. Fei Y, Webb R, Cobb BL, Direskeneli H, Saruhan-Direskeneli G, Sawalha AH (2009) Identification of novel genetic susceptibility loci for Behçet’s disease using a genome-wide association study. Arthritis Res Ther 11(3):R66. https://doi.org/10.1186/ar2695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Remmers EF, Cosan F, Kirino Y, Ombrello MJ, Abaci N, Satorius C, Le JM, Yang B, Korman BD, Cakiris A, Aglar O, Emrence Z, Azakli H, Ustek D, Tugal-Tutkun I, Akman-Demir G, Chen W, Amos CI, Dizon MB, Kose AA, Azizlerli G, Erer B, Brand OJ, Kaklamani VG, Kaklamanis P, Ben-Chetrit E, Stanford M, Fortune F, Ghabra M, Ollier WE, Cho YH, Bang D, O’Shea J, Wallace GR, Gadina M, Kastner DL, Gül A (2010) Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet’s disease. Nat Genet 42(8):698–702. https://doi.org/10.1038/ng.625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kirino Y, Bertsias G, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E, Ozyazgan Y, Sacli FS, Erer B, Inoko H, Emrence Z, Cakar A, Abaci N, Ustek D, Satorius C, Ueda A, Takeno M, Kim Y, Wood GM, Ombrello MJ, Meguro A, Gül A, Remmers EF, Kastner DL (2013) Genome-wide association analysis identifies new susceptibility loci for Behçet’s disease and epistasis between HLA-B*51 and ERAP1. Nat Genet 45(2):202–207. https://doi.org/10.1038/ng.2520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Xavier JM, Shahram F, Sousa I, Davatchi F, Matos M, Abdollahi BS, Sobral J, Nadji A, Oliveira M, Ghaderibarim F, Shafiee NM, Oliveira SA (2015) FUT2: filling the gap between genes and environment in Behcet’s disease? Ann Rheum Dis 74(3):618–624. https://doi.org/10.1136/annrheumdis-2013-204475

    Article  CAS  PubMed  Google Scholar 

  9. Masatlioglu S, Seyahi E, Tahir Turanli E, Fresko I, Gogus F, Senates E, Oguz Savran F, Yazici H (2010) A twin study in Behçet’s syndrome. Clin Exp Rheumatol 28(4 Suppl 60):S62–S66

    PubMed  Google Scholar 

  10. Gül A, Inanç M, Öcal L, Aral O, Çarin M, Koniçe M (1997) HLA-B51 negative monozygotic twins discordant for Behçet’s disease. Br J Rheumatol 36:922–923

    Article  Google Scholar 

  11. Takeuchi M, Kastner DL, Remmers EF (2015) The immunogenetics of Behçet’s disease: a comprehensive review. J Autoimmun 64:137–148. https://doi.org/10.1016/j.jaut.2015.08.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yoshioka T, Kurokawa MS, Sato T, Nagai K, Iizuka N, Arito M, Takakuwa Y, Nakano H, Ooka S, Suematsu N, Okamoto K, Yudoh K, Nakamura H, Suzuki N, Ozaki S, Kato T (2014) Protein profiles of peripheral blood mononuclear cells as a candidate biomarker for Behçet’s disease. Clin Exp Rheumatol 32(4 Suppl 84):S9–19

    PubMed  Google Scholar 

  13. International Study Group for Behçet’s Disease (1990) Criteria for diagnosis of Behçet’s disease. International Study Group for Behçet’s Disease. Lancet 335(8697):1078–1080

    Google Scholar 

  14. Yamashita S, Suzuki A, Yanagita T, Hirohata S, Kamada M, Toyoshima S (2000) Analysis of neutrophil proteins of patients with Behçet’s disease by two-dimensional gel electrophoresis. Biol Pharm Bull 23(5):519–522

    Article  CAS  Google Scholar 

  15. Lee KH, Chung HS, Kim HS, Oh SH, Ha MK, Baik JH, Lee S, Bang D (2003) Human alpha-enolase from endothelial cells as a target antigen of anti-endothelial cell antibody in Behçet’s disease. Arthritis Rheum 48(7):2025–2035. https://doi.org/10.1002/art.11074

    Article  CAS  PubMed  Google Scholar 

  16. Mao L, Dong H, Yang P, Zhou H, Huang X, Lin X, Kijlstra A (2008) MALDITOF/TOF-MS reveals elevated serum haptoglobin and amyloid A in Behçet’s disease. J Proteome Res 7:4500–4507. https://doi.org/10.1021/pr800279m

    Article  CAS  PubMed  Google Scholar 

  17. Okunuki Y, Usui Y, Takeuchi M, Kezuka T, Hattori T, Masuko K, Nakamura H, Yudoh K, Usui M, Nishioka K, Kato T (2007) Proteomic surveillance of autoimmunity in Behcet’s disease with uveitis: selenium binding protein is a novel autoantigen in Behcet’s disease. Exp Eye Res 84(5):823–831. https://doi.org/10.1016/j.exer.2007.01.003

    Article  CAS  PubMed  Google Scholar 

  18. Hu CJ, Pan JB, Song G, Wen XT, Wu ZY, Chen S, Mo WX, Zhang FC, Qian J, Zhu H, Li YZ (2017) Identification of novel biomarkers for Behçet disease diagnosis using human proteome microarray approach. Mol Cell Proteomics 16(2):147–156. https://doi.org/10.1074/mcp.M116.061002

    Article  CAS  PubMed  Google Scholar 

  19. Petrak J, Ivanek R, Toman O, Cmejla R, Cmejlova J, Vyoral D, Zivny J, Vulpe CD (2008) Déjà vu in proteomics. A hit parade of repeatedly identified differentially expressed proteins. Proteomics 8(9):1744–1749. https://doi.org/10.1002/pmic.200700919

    Article  CAS  PubMed  Google Scholar 

  20. Ooka S, Nakano H, Matsuda T, Okamoto K, Suematsu N, Kurokawa MS, Ohtani-Kaneko R, Masuko K, Ozaki S, Kato T (2010) Proteomic surveillance of autoantigens in patients with Behcet’s disease by a proteomic approach. Microbiol Immunol 54(6):354–361. https://doi.org/10.1111/j.1348-0421.2010.00215.x

    Article  CAS  PubMed  Google Scholar 

  21. Shin SJ, Kim BC, Kim TI, Lee SK, Lee KH, Kim WH (2011) Anti-alpha-enolase antibody as a serologic marker and its correlation with disease severity in intestinal Behçet’s disease. Dig Dis Sci 56(3):812–818. https://doi.org/10.1007/s10620-010-1326-y

    Article  CAS  PubMed  Google Scholar 

  22. Kile BT, Panopoulos AD, Stirzaker RA, Hacking DF, Tahtamouni LH, Willson TA, Mielke LA, Henley KJ, Zhang JG, Wicks IP, Stevenson WS, Nurden P, Watowich SS, Justice MJ (2007) Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia. Blood 110(7):2371–2380. https://doi.org/10.1182/blood-2006-10-055087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kim ML, Chae JJ, Park YH, De Nardo D, Stirzaker RA, Ko HJ, Tye H, Cengia L, DiRago L, Metcalf D, Roberts AW, Kastner DL, Lew AM, Lyras D, Kile BT, Croker BA, Masters SL (2015) Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β. J Exp Med 212(6):927–938. https://doi.org/10.1084/jem.20142384

    Article  PubMed  PubMed Central  Google Scholar 

  24. Standing AS, Malinova D, Hong Y, Record J, Moulding D, Blundell MP, Nowak K, Jones H, Omoyinmi E, Gilmour KC, Medlar A, Stanescu H, Kleta R, Anderson G, Nanthapisal S, Gomes SM, Klein N, Eleftheriou D, Thrasher AJ, Brogan PA (2017) Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1. J Exp Med 214(1):59–71. https://doi.org/10.1084/jem.20161228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Papadopoulou C, Omoyinmi E, Standing A, Pain CE, Booth C, D’Arco F, Gilmour K, Buckland M, Eleftheriou D, Brogan PA (2019) Monogenic mimics of Behçet’s disease in the young. Rheumatology (Oxford). https://doi.org/10.1093/rheumatology/key445

    Article  PubMed  Google Scholar 

  26. Biaoxue R, Hua L, Wenlong G, Shuanying Y (2016) Overexpression of stathmin promotes metastasis and growth of malignant solid tumors: a systemic review and meta-analysis. Oncotarget 7(48):78994–79007. https://doi.org/10.18632/oncotarget.12982

    Article  PubMed  PubMed Central  Google Scholar 

  27. Patel PC, Fisher KH, Yang EC, Deane CM, Harrison RE (2009) Proteomic analysis of microtubule-associated proteins during macrophage activation. Mol Cell Proteomics 8(11):2500–2514. https://doi.org/10.1074/mcp.M900190-MCP200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Xu K, Harrison RE (2015) Down-regulation of Stathmin Is Required for the Phenotypic Changes and Classical Activation of Macrophages. J Biol Chem 290(31):19245–19260. https://doi.org/10.1074/jbc.M115.639625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhao Y, Yan X, Li X, Zheng Y, Li S, Chang X (2016) PGK1, a glucose metabolism enzyme, may play an important role in rheumatoid arthritis. Inflamm Res 65(10):815–825. https://doi.org/10.1007/s00011-016-0965-7

    Article  CAS  PubMed  Google Scholar 

  30. Fan P, Ma J, Jin X (2018) Far upstream element-binding protein 1 is up-regulated in pancreatic cancer and modulates immune response by increasing programmed death ligand 1. Biochem Biophys Res Commun 505(3):830–836. https://doi.org/10.1016/j.bbrc.2018.10.009

    Article  CAS  PubMed  Google Scholar 

  31. Yang WH, Ding MJ, Cui GZ, Yang M, Dai DL (2018) Heterogeneous nuclear ribonucleoprotein M promotes the progression of breast cancer by regulating the axin/β-catenin signaling pathway. Biomed Pharmacother 105:848–855. https://doi.org/10.1016/j.biopha.2018.05.014

    Article  CAS  PubMed  Google Scholar 

  32. Fujita T, Matsushita M, Endo Y (2004) The lectin-complement pathway - its role in innate immunity and evolution. Immunol Rev 198:185–202

    Article  CAS  Google Scholar 

  33. Ma YJ, Lee BL, Garred P (2017) An overview of the synergy and crosstalk between pentraxins and collectins/ficolins: their functional relevance in complement activation. Exp Mol Med 49(4):e320. https://doi.org/10.1038/emm.2017.51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Morito D, Nagata K (2012) ER Stress Proteins in Autoimmune and Inflammatory Diseases. Front Immunol 3:48. https://doi.org/10.3389/fimmu.2012.00048

    Article  PubMed  PubMed Central  Google Scholar 

  35. Rock KL, Reits E, Neefjes J (2016) Present Yourself! By MHC Class I and MHC Class II Molecules. Trends Immunol 37(11):724–737. https://doi.org/10.1016/j.it.2016.08.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hasnain SZ, Lourie R, Das I, Chen AC, McGuckin MA (2012) The interplay between endoplasmic reticulum stress and inflammation. Immunol Cell Biol 90(3):260–270. https://doi.org/10.1038/icb.2011.112

    Article  CAS  PubMed  Google Scholar 

  37. McGonagle D, Aydin SZ, Gül A, Mahr A, Direskeneli H (2015) ‘MHC-I-opathy’-unified concept for spondyloarthritis and Behçet disease. Nat Rev Rheumatol 11(12):731–740. https://doi.org/10.1038/nrrheum.2015.147

    Article  CAS  PubMed  Google Scholar 

  38. Ackerman AL, Cresswell P (2004) Cellular mechanisms governing cross-presentation of exogenous antigens. Nat Immunol 5(7):678–684. https://doi.org/10.1038/ni1082

    Article  CAS  PubMed  Google Scholar 

  39. López de Castro JA (2018) How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins. Front Immunol 9:2463. https://doi.org/10.3389/fimmu.2018.02463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Holoshitz J, De Almeida DE, Ling S (2010) A role for calreticulin in the pathogenesis of rheumatoid arthritis. Ann N Y Acad Sci 1209:91–98. https://doi.org/10.1111/j.1749-6632.2010.05745.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ohkuro M, Kim JD, Kuboi Y, Hayashi Y, Mizukami H, Kobayashi-Kuramochi H, Muramoto K, Shirato M, Michikawa-Tanaka F, Moriya J, Kozaki T, Takase K, Chiba K, Agarwala KL, Kimura T, Kotake M, Kawahara T, Yoneda N, Hirota S, Azuma H, Ozasa-Komura N, Ohashi Y, Muratani M, Kimura K, Hishinuma I, Fukamizu A (2018) Calreticulin and integrin alpha dissociation induces anti-inflammatory programming in animal models of inflammatory bowel disease. Nat Commun 9(1):1982. https://doi.org/10.1038/s41467-018-04420-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ni M, Wei W, Wang Y, Zhang N, Ding H, Shen C, Zheng F (2013) Serum levels of calreticulin in correlation with disease activity in patients with rheumatoid arthritis. J Clin Immunol 33(5):947–953. https://doi.org/10.1007/s10875-013-9885-2

    Article  CAS  PubMed  Google Scholar 

  43. Watanabe K, Ohira H, Orikasa H, Saito K, Kanno K, Shioya Y, Obara K, Sato Y (2006) Anti-calreticulin antibodies in patients with inflammatory bowel disease. Fukushima J Med Sci 52(1):1–11

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to express our gratitude to Prof Dr Hasan Yazıcı for his valuable comments on research design and critical reviewing of the manuscript. We also would like to thank all patients who participated in this study, as well as the members of Division of Rheumatology, Cerrahpaşa Medical Faculty, especially Dilşen Çevirgen, for their help on collecting patients’ samples.

Funding

This work was supported by the Technological and Scientific Research Council of Turkey (Grant No: 113S904) and Istanbul Technical University, Scientific Research Fund (Grant No: 37800).

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Authors and Affiliations

  1. Department of Molecular Biology-Genetics and Biotechnology, Graduate School of Science, Engineering and Technology, İstanbul Technical University, İstanbul, Turkey

    Asli Kirectepe Aydin

  2. Division of Rheumatology, Department of Internal Medicine, Cerrahpaşa Medical Faculty, İstanbul University—Cerrahpaşa, Istanbul, Turkey

    Yeşim Özgüler & Emire Seyahi

  3. Division of Ophthalmology, Department of Surgical Medicine, Cerrahpaşa Medical Faculty, İstanbul University—Cerrahpaşa, Istanbul, Turkey

    Didar Uçar

  4. Department of Medical Biology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey

    Murat Kasap & Gürler Akpınar

  5. Department of Molecular Biology and Genetics, Dr. Orhan Öcalgiray, Molecular Biology-Biotechnology and Genetics Research Centre (MOBGAM), Graduate School of Science, Engineering and Technology, Istanbul Technical University, Ayazağa Campus, 34469, Istanbul, Maslak, Turkey

    Eda Tahir Turanli

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  1. Asli Kirectepe Aydin
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Contributions

ETT contributed to the conception and design of the study, analysis of the data, supervise the study, and critically revise the manuscript, providing financial grants for the study. AKA performed experiments, analyzed data and wrote the manuscript. YÖ and DU contributed to patient follow-up and collection of relevant biological materials. MK and GA performed experiments and did the analysis of mass spectrometer. ES contributed to the conception and design of the study and patient follow-up, and critically revise the manuscript.

Corresponding author

Correspondence to Eda Tahir Turanli.

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The authors declare that they have no conflict of interests.

Ethical approval

This study was approved by the Ethical Committee of Istanbul University, Cerrahpaşa Medical Faculty (approval number and dates: 83045809/5584, 5 March 2013).

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Kirectepe Aydin, A., Özgüler, Y., Uçar, D. et al. Peripheral blood mononuclear cell proteome profile in Behçet’s syndrome. Rheumatol Int 40, 65–74 (2020). https://doi.org/10.1007/s00296-019-04417-2

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