Skip to main content

Advertisement

Log in

Peripheral blood lymphocyte apoptosis and circulating dendritic cells in patients with systemic lupus erythematosus: correlation with immunological status and disease-related symptoms

  • Original Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

We investigated in vivo the relationship between the degree of peripheral blood lymphocyte apoptosis and circulating dendritic cells (DC) as well as the immunological status in 45 patients with systemic lupus erythematous (SLE). Apoptosis was detected by phosphatidylserine externalization and assays to detect caspase activation. The total DC count (tDC) and their myeloid, mDCl (BDCA1+) and mDC2 (BDCA3+), and plasmacytoid, pDC (BDCA3+), subtypes were assessed. Moreover, several immunological parameters, such as complement proteins, interferons (IFN), tumor necrosis factor (TNF)-α, interleukin (IL)-4, and IL-6 levels were assessed. There were no significant differences in both the intensity of apoptosis and DC counts between active and inactive SLE as well as between untreated patients and those treated with steroids. The incidence of lymphocyte apoptosis correlated positively with T-cell count, both T-helper (p=0.004) and cytotoxic T cells (p=0.001), but not with B or natural killer (NK) cells. The intensity of apoptosis enhanced along with the increase in complement C3 (p=0.016) and decrease in IFN-γ (p=0.040) levels. The apoptotic cell count correlated with tDC (p=0.031), mDCl (p=0.007), and pDC (p=0.039) counts. Both tDC and mDCl counts correlated positively with antinuclear antibody (ANA) titers (p=0.017 and 0.032, respectively). Moreover, tDC correlated with C4 (p=0.039) and pDC with both C3 (p=0.032) and C4 (p=0.007) levels. The DC counts correlated inversely with IFN-γ (tDC, p=0.038; mDCl, p=0.009), IL-6 (mDC2, p=0.031), or serum IgG levels (tDC, p=0.006; mDCl, p < 0.001; mDC2, p=0.001). We found a positive correlation between lymphocyte apoptosis and peripheral blood DC count as well as the level of complement proteins in patients with SLE. The enhanced lymphocyte apoptosis was accompanied by the decrease in concentration of some cytokines, such as IFN-γ or IL-6, as well as serum IgG level. This finding may reflect pathogenetic events during development of the disease, which include a persistent signal derived from circulating apoptotic lymphocytes, mobilizing the complement system, and attracting peripheral blood DC.

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.

Institutional subscriptions

Similar content being viewed by others

References

  1. Stollar BD, Stephenson F (2002) Apoptosis and nucleosomes. Lupus 11:78778–78779

    Article  Google Scholar 

  2. Licht R, Dieker JW, Jacobs CW, Tax WJ, Berden JH (2004) Decreased phagocytosis of apoptotic cells in diseased SLE mice. J Autoimmun 22:139–145

    Article  PubMed  CAS  Google Scholar 

  3. Herrmann M, Voll RE, Zoller OM, Hagenhofer M, Ponner BB, Kalden JR (1998) Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum 41:1241–1250

    Article  PubMed  CAS  Google Scholar 

  4. Aringer M, Wintersberger W, Steiner CW, Kiener H, Presterl E, Jaeger U, Smolen JS, Graninger WB (1994) High levels of bcl-2 protein in circulating T lymphocytes, but not B lymphocytes, of patients with systemic lupus erythematosus. Arthritis Rheum 37:1423–1430

    Article  PubMed  CAS  Google Scholar 

  5. Bijl M, Horst G, Limburg PC, Kallenberg CG (2001) Fas expression on peripheral blood lymphocytes in systemic lupus erythematosus (SLE): relation to lymphocyte activation and disease activity. Lupus 10:866–872

    Article  PubMed  CAS  Google Scholar 

  6. Lorenz HM, Grunke M, Hieronymus T, Herrmann M, Kuhnel A, Manger B, Kalden JR (1997) In vitro apoptosis and expression of apoptosis-related molecules in lymphocytes from patients with systemic lupus erythematosus and other autoimmune diseases. Arthritis Rheum 40:306–317

    Article  PubMed  CAS  Google Scholar 

  7. Miret C, Font J, Molina R, Garcia-Carrasco M, Filella X, Ramos M, Cervera R, Ballesta A, Ingelmo M (2001) Relationship of oncogenes (sFas, Bcl-2) and cytokines (IL-10, alfa-TNF) with the activity of systemic lupus erythematosus. Anticancer Res 21:3053–3059

    PubMed  CAS  Google Scholar 

  8. Sakata K, Sakata A, Vela-Roch N, Espinosa R, Escalante A, Kong L, Nakabayashi T, Cheng J, Talal N, Dang H (1998) Fas (CD95)-transduced signal preferentially stimulates lupus peripheral T lymphocytes. Eur J Immunol 2:2648–2660

    Article  Google Scholar 

  9. Shortman K, Liu YJ (2002) Mouse and human dendritic cell subtypes. Nature Rev Immunol 2:153–163

    Google Scholar 

  10. Siegal FP, Kadowaki N, Shodell M, Fitzgerald-Bocarsly PA, Shah K, Ho S, Antonenko S, Liu YJ (1999) The nature of the principal type 1 interferon producing cells in human blood. Science 284:1835–1837

    Article  PubMed  CAS  Google Scholar 

  11. Pascual V, Bancheveau J, Palucka AK (2003) The central role of dendritic cells and interferon-alpha in SLE. Curr Opin Rheumatol 15:548–556

    Article  PubMed  CAS  Google Scholar 

  12. Cella M, Jarrossay D, Facchetti F, Alebardi O, Nakajima H, Lanzavecchia A, Colonna M (1999) Plasmacytoid monocytes migrate to inflamed lymph node and produce large amounts of type I interferon. Nature Med 5:919–923

    Article  PubMed  CAS  Google Scholar 

  13. Scheinecker C, Zwölfer B, Koller M, Manner G, Smolen JS (2001) Alterations of dendritic cells in systemic lupus erythematosus: phenotypic and functional deficiencies. Arthritis Rheum 44:856–865

    Article  PubMed  CAS  Google Scholar 

  14. Baumann I, Kolowos W, Voll RE, Manger B, Gaipl U, Neuhuber WL, Kirchner T, Kalden JR, Herrmann M (2002) Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus. Arthritis Rheum 46:191–201

    Article  PubMed  Google Scholar 

  15. Taylor PR, Carugati A, Fadok VA, Cook HT, Andrews M, Carroll MC, Savill JS, Henson PM, Botto M, Walport MJ (2000) A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J Exp Med 192:359–366

    Article  PubMed  CAS  Google Scholar 

  16. Botto M (2001) Links between complement deficiency and apoptosis. Arthritis Res 3:207–210

    Article  PubMed  CAS  Google Scholar 

  17. Shoshan Y, Shapira I, Toubi E, Frolkis I, Yaron M, Mevorach D (2001) Accelerated fas-mediated apoptosis of monocytes and maturing macrophages from patients with systemic lupus erythematosus: relevance to in vitro impairment of interaction with iC3b-opsonized apoptotic cells. J Immunol 167:5963–5969

    PubMed  CAS  Google Scholar 

  18. Gaipl US, Beyer TD, Baumann I, Voll RE, Stach CM, Heyder P, Kalden JR, Manfredi A, Herrmann M (2003) Exposure of anionic phospholipids serves as anti-inflammatory and immunosuppressive signal—implications for antiphospholipid syndrome and systemic lupus erythematosus. Immunobiology 207:73–81

    Article  PubMed  CAS  Google Scholar 

  19. Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725

    Article  PubMed  CAS  Google Scholar 

  20. Liang MM, Socher SA, Larson MG, Schur PH (1989) Reliability and validity of six systems for the clinical assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum 32:1107–1118

    Article  PubMed  CAS  Google Scholar 

  21. Robak E, Wozniacka A, Sysa-Jedrzejowska A, Stepieh H, Robak T (2002) Circulating angiogenesis inhibitor endostatin and positive growth regulators in patients with systemic lupus erythematosus. Lupus 11:348–355

    Article  PubMed  CAS  Google Scholar 

  22. Albrecht J, Berlin JA, Braverman IM, Callen JP, Costner MI, Dutz J, Fivenson D, Franks AG, Jorizzo JL, Lee LA, McCauliffe DP, Sontheimer RD, Werth VP (2004) Dermatology position paper on the revision of the 1982 ACR criteria for systemic lupus erythematosus. Lupus 13:839–849

    Article  PubMed  CAS  Google Scholar 

  23. Koopman G, Reutelingsperger CPM, Kuijten GAM, Keehnen RMJ, Pals ST, Oers MHJ (1994) Annexin V for flow cytometric detection of phosphatidylserine expression of B cells undergoing apoptosis. Blood 84:1415–1420

    PubMed  CAS  Google Scholar 

  24. Smolewski P, Bedner E, Du L, Hsieh TC, Wu JM, Phelps DJ, Darzynkiewicz Z (2001) Detection of caspases activation by fluorochrome-labeled inhibitors: multiparameter analysis by laser scanning cytometry. Cytometry 44:73–82

    Article  PubMed  CAS  Google Scholar 

  25. Robak E, Smolewski E, Woźniacka A, Sysa-Jçdrzejowska A, Robak T (2004) Clinical significance of circulating dendritic cells in patients with systemic lupus erythematosus. Med In-flamm 13:171–180

    CAS  Google Scholar 

  26. Emlen W, Niebur J, Kadera R (1994) Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus. J Immunol 152:3685–3692

    PubMed  CAS  Google Scholar 

  27. Perniok A, Wedekind F, Herrmann M, Specker C, Schneider M (1998) High levels of circulating early apoptotic peripheral blood mononuclear cells in systemic lupus erythematosus. Lupus 7:113–118

    Article  PubMed  CAS  Google Scholar 

  28. Lorenz HM, Grunke M, Hieronymus T, Winkler S, Blank N, Rascu A, Wendler J, Geiler T, Kalden JR (2002) Hypore-sponsiveness to gammac-chain cytokines in activated lymphocytes from patients with systemic lupus erythematosus leads to accelerated apoptosis. Eur J Immunol 32:1253–1263

    Article  PubMed  CAS  Google Scholar 

  29. Funauchi M, Sugiyama M, SukYoo B, Ikoma S, Ohno M, Kinoshita K, Kanamaru A (2001) A possible role of apoptosis for regulating autoreactive responses in systemic lupus erythematosus. Lupus 10:284–288

    Article  PubMed  CAS  Google Scholar 

  30. Dzionek A, Fuchs A, Schmidt P, Cremer S, Zysk M, Miltenyi S, Buck DW, Schmitz J (2000) BDCA-2, BDCA-3 and BDCA-4 three markers for distinct subsets of dendritic cells in human peripheral blood. J Immunol 165:6037–6046

    PubMed  CAS  Google Scholar 

  31. Blomberg S, Eloranta ML, Magnusson M, Alm GV, Ronnb-lom L (2003) Expression of the markers BDCA-2 and BDCA-4 and production of interferon alpha by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Rheum 48:2524–2532

    Article  PubMed  CAS  Google Scholar 

  32. Farkas L, Beiske K, Lund-Johansen F, Brandtzaeg P, Jahuseu FL (2001) Plasmacytoid dendritic cells natural interferon-α/β-producing cells accumulate in cutaneous lupus erythematosus lesions. Am J Pathol 109:237–243

    Google Scholar 

  33. Manfredi AA, Rovere P, Galati G, Heltai S, Bozzolo E, Soldini L, Davoust J, Balestrieri G, Tincani A, Sabbadini MG (1998) Apoptotic cell clearance in systemic lupus erythematosus. I. Opsonization by antiphospholipid antibodies. Arthritis Rheum 41:205–214

    Article  PubMed  CAS  Google Scholar 

  34. Vallin H, Perers A, Aim GV, Ronnblom L (1999) Anti-doublestranded DNA antibodies and immunostimulatory plasmid DNA in combination mimic the endogenous IFN-alpha inducer in systemic lupus erythematosus. J Immunol 163:6306–6313

    PubMed  CAS  Google Scholar 

  35. Bave U, Vallin H, Aim GV, Ronnblom L (2001) Activation of natural interferon-alpha producing cells by apoptotic U937 cells combined with lupus IgG and its regulation by cytokines. J Autoimmun 17:71–80

    Article  PubMed  CAS  Google Scholar 

  36. Bave U, Magnusson M, Eloranta ML, Perers A, Aim GV, Ronnblom L (2003) Fc gamma RIIa is expressed on natural IFN-alpha-producing cells (plasmacytoid dendritic cells) and is required for the IFN-alpha production induced by apoptotic cells combined with lupus IgG. J Immunol 171:3296–3302

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Piotr Smolewski.

Additional information

Published online: 24 January 2006

Rights and permissions

Reprints and permissions

About this article

Cite this article

Robak, E., Sysa-Jędrzejowska, A., Robak, T. et al. Peripheral blood lymphocyte apoptosis and circulating dendritic cells in patients with systemic lupus erythematosus: correlation with immunological status and disease-related symptoms. Clin Rheumatol 25, 225–233 (2006). https://doi.org/10.1007/s10067-005-1163-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-005-1163-0

Keywords

Navigation