Skip to main content

Advertisement

Log in

Increased senescent CD8+ T cells in the peripheral blood mononuclear cells of Behçet’s disease patients

  • Original Paper
  • Published:
Archives of Dermatological Research Aims and scope Submit manuscript

Abstract

Behçet’s disease (BD) is a chronic inflammatory disease characterized by recurrent mucocutaneous, ocular, and skin lesions. Immunosenescence is associated with increased susceptibility to infection and chronic low grade inflammation. This study aimed to investigate the differences in the frequencies of immunosenescent cells in the peripheral blood mononuclear cells (PBMCs) of patients with BD. PBMCs were isolated from age-matched patients with active BD (n = 19), inactive BD (n = 20), disease controls (DCs, n = 15) and healthy controls (HCs, n = 15). The frequencies of senescent CD4+ T cells (CD3+ CD4+ CD27− CD28− cells), CD8+ T cells (CD3+ CD8+ CD27− CD28− cells) and B cells (CD19+ CD27− IgD− cells) were analyzed using flow cytometry. Senescence-associated β galactosidase activity was also measured in CD8+ T cells using flow cytometry with 5-dodecanoylaminofluorescein di-β-d-galactopyranoside. Frequencies of senescent CD4+ and CD19+ cells were not significantly different between the groups. The frequency of senescent CD8+ T cells was significantly higher in active BD than in DCs and HCs. C-reactive protein and erythrocyte sedimentation rate levels, which indicate disease activity, did not correlate with increased frequencies of immunosenescent cells. Steroid treatment, specific organ involvement, and HLA-B51 status did not have a significant influence on the frequencies of immunosenescent cells. Frequencies of senescence-associated β galactosidase+ CD8+ T cells were significantly higher in active BD and inactive BD compared to DCs and HCs. There was an increased frequency of senescent CD8+ T cells in the PBMCs of patients with BD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Accardo-Palumbo A, Giardina AR, Ciccia F, Ferrante A, Principato A, Impastato R, Giardina E, Triolo G (2010) Phenotype and functional changes of Vgamma9/Vdelta2 T lymphocytes in Behcet’s disease and the effect of infliximab on Vgamma9/Vdelta2 T cell expansion, activation and cytotoxicity. Arthritis Res Ther 12:R109. https://doi.org/10.1186/ar3043

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ademokun A, Wu YC, Dunn-Walters D (2010) The ageing B cell population: composition and function. Biogerontology 11:125–137. https://doi.org/10.1007/s10522-009-9256-9

    Article  PubMed  Google Scholar 

  3. Ahn JK, Chung H, Lee DS, Yu YS, Yu HG (2005) CD8 bright CD56 + T cells are cytotoxic effectors in patients with active Behcet’s uveitis. J Immunol 175:6133–6142. https://doi.org/10.4049/jimmunol.175.9.6133

    Article  CAS  PubMed  Google Scholar 

  4. Akdeniz N, Esrefoglu M, Keleş MS, Karakuzu A, Atasoy M (2004) Serum interleukin-2, interleukin-6, tumour necrosis factor-alpha and nitric oxide levels in patients with Behcet’s disease. Ann Acad Med Singap 33:596–599

    CAS  PubMed  Google Scholar 

  5. Almanzar G, Schwaiger S, Jenewein B, Keller M, Grubeck-Loebenstein B, Wurzner R, Schonitzer D (2004) IFN-gamma production by CMV-specific CD8+ T cells is high in elderly donors. Exp Gerontol 39:863–865; author reply 867–868. https://doi.org/10.1016/j.exger.2004.01.017.

    Article  CAS  PubMed  Google Scholar 

  6. Ben Ahmed M, Houman H, Miled M, Dellagi K, Louzir H (2004) Involvement of chemokines and Th1 cytokines in the pathogenesis of mucocutaneous lesions of Behcet’s disease. Arthritis Rheum 50:2291–2295. https://doi.org/10.1002/art.20334

    Article  CAS  PubMed  Google Scholar 

  7. Benagiano M, D’Elios MM, Amedei A, Azzurri A, van der Zee R, Ciervo A, Rombola G, Romagnani S, Cassone A, Del Prete G (2005) Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques. J Immunol 174:6509–6517. https://doi.org/10.4049/jimmunol.174.10.6509

    Article  CAS  PubMed  Google Scholar 

  8. Chalan P, van den Berg A, Kroesen BJ, Brouwer L, Boots A (2015) Rheumatoid arthritis, immunosenescence and the hallmarks of aging. Curr Aging Sci 8:131–146. https://doi.org/10.2174/1874609808666150727110744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Debacq-Chainiaux F, Erusalimsky JD, Campisi J, Toussaint O (2009) Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc 4:1798–1806. https://doi.org/10.1038/nprot.2009.191

    Article  CAS  PubMed  Google Scholar 

  10. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, Peacocke M, Campisi J (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92:9363–9367. https://doi.org/10.1073/pnas.92.20.9363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Direskeneli H, Saruhan-Direskeneli G (2003) The role of heat shock proteins in Behcet’s disease. Clin Exp Rheumatol 21(4 Suppl 30):S44-S48

    Google Scholar 

  12. Ekinci NS, Alpsoy E, Karakas AA, Yilmaz SB, Yegin O (2010) IL-17A has an important role in the acute attacks of Behcet’s disease. J Invest Dermatol 130:2136–2138. https://doi.org/10.1038/jid.2010.114

    Article  CAS  PubMed  Google Scholar 

  13. Galeone M, Colucci R, D’Erme AM, Moretti S, Lotti T (2012) Potential infectious etiology of Behcet’s disease. Patholog Res Int 2012:595380. https://doi.org/10.1155/2012/595380

    PubMed  Google Scholar 

  14. Goronzy JJ, Lee WW, Weyand CM (2007) Aging and T-cell diversity. Exp Gerontol 42:400–406. https://doi.org/10.1016/j.exger.2006.11.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gu Z, Cao X, Jiang J, Li L, Da Z, Liu H, Cheng C (2012) Upregulation of p16INK4A promotes cellular senescence of bone marrow-derived mesenchymal stem cells from systemic lupus erythematosus patients. Cell Signal 24:2307–2314. https://doi.org/10.1016/j.cellsig.2012.07.012

    Article  CAS  PubMed  Google Scholar 

  16. Guenane H, Hartani D, Chachoua L, Lahlou-Boukoffa OS, Mazari F, Touil-Boukoffa C (2006) Production of Th1/Th2 cytokines and nitric oxide in Behçet’s uveitis and idiopathic uveitis. J Fr Ophtalmol 29:146–152

    Article  CAS  PubMed  Google Scholar 

  17. Hatemi G, Silman A, Bang D, Bodaghi B, Chamberlain AM, Gul A, Houman MH, Kotter I, Olivieri I, Salvarani C, Sfikakis PP, Siva A, Stanford MR, Stubiger N, Yurdakul S, Yazici H (2008) EULAR recommendations for the management of Behcet disease. Ann Rheum Dis 67:1656–1662. https://doi.org/10.1136/ard.2007.080432

    Article  CAS  PubMed  Google Scholar 

  18. Imirzalioglu N, Dursun A, Tastan B, Soysal Y, Yakicier MC (2005) MEFV gene is a probable susceptibility gene for Behcet’s disease. Scand J Rheumatol 34:56–58. https://doi.org/10.1080/03009740510017931

    Article  CAS  PubMed  Google Scholar 

  19. International Study Group for Behçet’s Disease (1990) Criteria for diagnosis of Behcet’s disease. Lancet 335:1078–1080. https://doi.org/10.1016/0140-6736(90)92643-V

    Google Scholar 

  20. Irschick EU, Philipp S, Shahram F, Schirmer M, Sedigh M, Ziaee N, Gassner C, Schennach H, Meyer M, Larcher C, Herold M, Schoenitzer D, Fuchs D, Schoenbauer M, Maass M, Huemer HP, Davatchi F (2011) Investigation of bacterial and viral agents and immune status in Behcet’s disease patients from Iran. Int J Rheum Dis 14:298–310. https://doi.org/10.1111/j.1756-185X.2011.01601.x

    Article  PubMed  Google Scholar 

  21. Keller M, Spanou Z, Schaerli P, Britschgi M, Yawalkar N, Seitz M, Villiger PM, Pichler WJ (2005) T cell-regulated neutrophilic inflammation in autoinflammatory diseases. J Immunol 175:7678–7686. https://doi.org/10.4049/jimmunol.175.11.7678

    Article  CAS  PubMed  Google Scholar 

  22. Lang A, Brien JD, Nikolich-Zugich J (2009) Inflation and long-term maintenance of CD8 T cells responding to a latent herpesvirus depend upon establishment of latency and presence of viral antigens. J Immunol 183:8077–8087. https://doi.org/10.4049/jimmunol.0801117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lee S, Bang D, Cho YH, Lee ES, Sohn S (1996) Polymerase chain reaction reveals herpes simplex virus DNA in saliva of patients with Behcet’s disease. Arch Dermatol Res 288:179–183. https://doi.org/10.1007/BF02505221

    Article  CAS  PubMed  Google Scholar 

  24. Lehner T, Lavery E, Smith R, van der Zee R, Mizushima Y, Shinnick T (1991) Association between the 65-kilodalton heat shock protein, Streptococcus sanguis, and the corresponding antibodies in Behcet’s syndrome. Infect Immun 59:1434–1441

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Liang L, Tan X, Zhou Q, Zhu Y, Tian Y, Yu H, Kijlstra A, Yang P (2013) IL-1beta triggered by peptidoglycan and lipopolysaccharide through TLR2/4 and ROS-NLRP3 inflammasome-dependent pathways is involved in ocular Behcet’s disease. Invest Ophthalmol Vis Sci 54:402–414. https://doi.org/10.1167/iovs.12-11047

    Article  CAS  PubMed  Google Scholar 

  26. Lu Y, Ye P, Chen SL, Tan EM, Chan EK (2005) Identification of kinectin as a novel Behçet’s disease autoantigen. Arthritis Res Ther 7:R1133–R1139. https://doi.org/10.1186/ar1798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Martin JM, Mateo E, Monteagudo C, Jorda E (2010) Severe flare of Behcet’s disease with intense mucucutaneous manifestations. Reumatol Clin 6:303–305. https://doi.org/10.1016/j.reuma.2010.05.001

    Article  PubMed  Google Scholar 

  28. Mochizuki M, Morita E, Yamamoto S, Yamana S (1997) Characteristics of T cell lines established from skin lesions of Behcet’s disease. J Dermatol Sci 15:9–13. https://doi.org/10.1016/S0923-1811(96)00588-9

    Article  CAS  PubMed  Google Scholar 

  29. Na SY, Park MJ, Park S, Lee ES (2013) Up-regulation of Th17 and related cytokines in Behcet’s disease corresponding to disease activity. Clin Exp Rheumatol 31(3 Suppl 77):S32-S40

    Google Scholar 

  30. Nalbant S, Sahan B, Durna M, Ersanli D, Kaplan M, Karabudak O, Unal M (2008) Cytokine profile in Behçet uveitis. Bratisl Lek Listy 109:551–554

    CAS  PubMed  Google Scholar 

  31. Pawelec G (1999) Immunosenescence: impact in the young as well as the old? Mech Ageing Dev 108:1–7. https://doi.org/10.1016/S0047-6374(99)00010-X

    Article  CAS  PubMed  Google Scholar 

  32. Pawelec G (2014) Immunosenescence: role of cytomegalovirus. Exp Gerontol 54:1–5. https://doi.org/10.1016/j.exger.2013.11.010

    Article  CAS  PubMed  Google Scholar 

  33. Rossol M, Kraus S, Pierer M, Baerwald C, Wagner U (2012) The CD14(bright) CD16+ monocyte subset is expanded in rheumatoid arthritis and promotes expansion of the Th17 cell population. Arthritis Rheum 64:671–677. https://doi.org/10.1002/art.33418

    Article  CAS  PubMed  Google Scholar 

  34. Sakane T, Takeno M, Suzuki N, Inaba G (1999) Behcet’s disease. N Engl J Med 341:1284–1291. https://doi.org/10.1056/nejm199910213411707

    Article  CAS  PubMed  Google Scholar 

  35. Shao L, Fujii H, Colmegna I, Oishi H, Goronzy JJ, Weyand CM (2009) Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis. J Exp Med 206:1435–1449. https://doi.org/10.1084/jem.20082251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shao L, Goronzy JJ, Weyand CM (2010) DNA-dependent protein kinase catalytic subunit mediates T-cell loss in rheumatoid arthritis. EMBO Mol Med 2:415–427. https://doi.org/10.1002/emmm.201000096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Studd M, McCance DJ, Lehner T (1991) Detection of HSV-1 DNA in patients with Behcet’s syndrome and in patients with recurrent oral ulcers by the polymerase chain reaction. J Med Microbiol 34:39–43. https://doi.org/10.1099/00222615-34-1-39

    Article  CAS  PubMed  Google Scholar 

  38. Suzuki Kurokawa M, Suzuki N (2004) Behcet’s disease. Clin Exp Med 4:10–20. https://doi.org/10.1007/s10238-004-0033-4

    Article  CAS  PubMed  Google Scholar 

  39. Šahmatova L, Sügis E, Šunina M, Hermann H, Prans E, Pihlap M, Abram K, Rebane A, Peterson H, Peterson P, Kingo K, Kisand K (2017) Signs of innate immune activation and premature immunosenescence in psoriasis patients. Sci Rep 7:7553. https://doi.org/10.1038/s41598-017-07975-2

    Article  PubMed  PubMed Central  Google Scholar 

  40. Takeuchi M, Kastner DL, Remmers EF (2015) The immunogenetics of Behcet’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 

  41. Targonski PV, Jacobson RM, Poland GA (2007) Immunosenescence: role and measurement in influenza vaccine response among the elderly. Vaccine 25:3066–3069. https://doi.org/10.1016/j.vaccine.2007.01.025

    Article  CAS  PubMed  Google Scholar 

  42. Weiskopf D, Weinberger B, Grubeck-Loebenstein B (2009) The aging of the immune system. Transpl Int 22:1041–1050. https://doi.org/10.1111/j.1432-2277.2009.00927.x

    Article  CAS  PubMed  Google Scholar 

  43. Yuksel S, Eren E, Hatemi G, Sahillioglu AC, Gultekin Y, Demiroz D, Akdis C, Fresko I, Ozoren N (2014) Novel NLRP3/cryopyrin mutations and pro-inflammatory cytokine profiles in Behcet’s syndrome patients. Int Immunol 26:71–81. https://doi.org/10.1093/intimm/dxt046

    Article  PubMed  Google Scholar 

  44. Zhang X, Meng X, Chen Y, Leng SX, Zhang H (2017) The biology of aging and cancer: frailty, inflammation, and immunity. Cancer J 23:201–205. https://doi.org/10.1097/PPO.0000000000000270

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea government (MSIP) (NRF-2016R1A2B1008803).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Eun-So Lee.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study protocol was approved by the Ajou Institutional Review Board (IRB No.: AJIRB-BMR-GEN-14-462) prior to study commencement and was in accordance with the Declaration of Helsinki.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, J.Y., Park, M.J., Park, S. et al. Increased senescent CD8+ T cells in the peripheral blood mononuclear cells of Behçet’s disease patients. Arch Dermatol Res 310, 127–138 (2018). https://doi.org/10.1007/s00403-017-1802-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00403-017-1802-8

Keywords

Navigation