Skip to main content
SpringerLink
Log in

Pathogenese des systemischen Lupus erythematodes

Pathogenesis of systemic lupus erythematosus

  • Leitthema
  • Published:
Zeitschrift für Rheumatologie Aims and scope Submit manuscript

Zusammenfassung

Der systemische Lupus erythematodes (SLE) ist eine Autoimmunerkrankung mit einer äußerst komplexen Pathogenese. Basierend auf einer genetischen Disposition, kann die Erkrankung durch multiple Stressfaktoren unter Einbeziehung epigenetischer Mechanismen und unter dem Einfluss des innaten Immunsystems induziert werden. Insbesondere Clearance-Defekte von Immunkomplexen und apoptotischem Material, eine gesteigerte NETose sowie eine Hochregulation von Typ-I-Interferon treiben das adaptive Immunsystem zum Toleranzbruch gegen Selbst. Folge ist eine B-Zell-Hyperaktivität, die zur Generation einer Vielzahl von unterschiedlichen Autoantikörpern, die nicht nur gegen nukleäre Antigene gerichtet sind, führt. Autoantikörper sind der Initiator für viele Organbeteiligungen, die sich durch Beteiligung von Effektor-T-Zellen, weiteren Entzündungszellen und Zytokinen verstärken. Die Entwicklung eines autoreaktiven immunologischen Plasmazellgedächtnisses trägt entscheidend zur Chronifizierung bei und erklärt therapierefraktäre Krankheitsverläufe. Die Auslöschung des adaptiven Immunsystems einschließlich des therapierefraktären autoimmunen Gedächtnisses mittels Immunablation kann zur Entwicklung eines gesunden adaptiven Immunsystems, das wieder tolerant gegen Selbst ist, führen.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with an extremely complex pathogenesis. Due to a genetic predisposition the disease can be induced by multiple stress factors involving epigenetic mechanisms and under the influence of the innate immune system. Defective clearance of immune complexes and apoptotic material together with enhanced neutrophil extracellular trap formation (NETosis) as well as up-regulation of type 1 interferon in particular, drive the adaptive immune system to a breakdown of self-tolerance. The result is a B cell hyperactivity, which leads to the generation of a multitude of different autoantibodies that are not only directed against nuclear antigens. Autoantibodies are the initiators for the involvement of many organs, which enhances further inflammatory cells and cytokines by participation of effector T-cells. Finally, an autoreactive immunological (plasma cell) memory is formed, which contributes to chronification and is associated with therapy-refractive courses of the disease. The depletion of the autoreactive immunological memory by immunoablation can lead to induction of self-tolerance and long-term remission.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2

Literatur

  1. Alexander T, Sarfert R, Klotsche J et al (2015) The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann Rheum Dis. doi:10.1136/annrheumdis-2014-206016

  2. Alexander T, Sattler A, Templin L et al (2013) Foxp3 + Helios + regulatory T cells are expanded in active systemic lupus erythematosus. Ann Rheum Dis 72:1549–1558

    Article  CAS  PubMed  Google Scholar 

  3. Alexander T, Thiel A, Rosen O et al (2009) Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system. Blood 113:214–223

    Article  CAS  PubMed  Google Scholar 

  4. Altorok N, Sawalha AH (2013) Epigenetics in the pathogenesis of systemic lupus erythematosus. Curr Opin Rheumatol 25:569–576

    Article  CAS  PubMed  Google Scholar 

  5. Ambrosi A, Sonesson SE, Wahren-Herlenius M (2014) Molecular mechanisms of congenital heart block. Exp Cell Res 325:2–9

    Article  CAS  PubMed  Google Scholar 

  6. Baechler EC, Batliwalla FM, Karypis G et al (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A 100:2610–2615

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Belot A, Cimaz R (2012) Monogenic forms of systemic lupus erythematosus: new insights into SLE pathogenesis. Pediatr Rheumatol Online J 10:21

    Article  PubMed Central  PubMed  Google Scholar 

  8. Blanco P, Palucka AK, Gill M et al (2001) Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science 294:1540–1543

    Article  CAS  PubMed  Google Scholar 

  9. Blanco P, Pitard V, Viallard JF et al (2005) Increase in activated CD8 + T lymphocytes expressing perforin and granzyme B correlates with disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 52:201–211

    Article  CAS  PubMed  Google Scholar 

  10. Bravo-Zehnder M, Toledo EM, Segovia-Miranda F et al (2015) Anti-ribosomal p protein autoantibodies from patients with neuropsychiatric lupus impair memory in mice. Arthritis Rheum 67:204–214

    Article  CAS  Google Scholar 

  11. Brinkmann V, Reichard U, Goosmann C et al (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535

    Article  CAS  PubMed  Google Scholar 

  12. Cheng Q, Mumtaz IM, Khodadadi L et al (2013) Autoantibodies from long-lived „memory“ plasma cells of NZB/W mice drive immune complex nephritis. Ann Rheum Dis 72:2011–2017

    Article  CAS  PubMed  Google Scholar 

  13. Crispin JC, Oukka M, Bayliss G et al (2008) Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J Immunol 181:8761–8766

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Crow MK (2014) Type I interferon in the pathogenesis of lupus. J Immunol 192:5459–5468

    Article  CAS  PubMed  Google Scholar 

  15. Dai C, Deng Y, Quinlan A et al (2014) Genetics of systemic lupus erythematosus: immune responses and end organ resistance to damage. Curr Opin Immunol 31C:87–96

    Article  Google Scholar 

  16. Doria A, Cutolo M, Ghirardello A et al (2002) Steroid hormones and disease activity during pregnancy in systemic lupus erythematosus. Arthritis Rheum 47:202–209

    Article  CAS  PubMed  Google Scholar 

  17. Gall A, Treuting P, Elkon KB et al (2012) Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity 36:120–131

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Giannakopoulos B, Krilis SA (2013) The pathogenesis of the antiphospholipid syndrome. N Engl J Med 368:1033–1044

    Article  CAS  PubMed  Google Scholar 

  19. Hakkim A, Furnrohr BG, Amann K et al (2010) Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci U S A 107:9813–9818

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Hiepe F, Alexander T, Voll RE (2015) Plasmazellen. Z Rheumatol 74:20–25

    Article  CAS  PubMed  Google Scholar 

  21. Hughes T, Sawalha AH (2011) The role of epigenetic variation in the pathogenesis of systemic lupus erythematosus. Arthritis Res Ther 13:245

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Humrich JY, Morbach H, Undeutsch R et al (2010) Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus. Proc Natl Acad Sci U S A 107:204–209

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Humrich JY, Spee-Mayer C von, Siegert E et al (2015) Rapid induction of clinical remission by low-dose interleukin-2 in a patient with refractory SLE. Ann Rheum Dis. doi:10.1136/annrheumdis-2014-206506

  24. Knight JS, Kaplan MJ (2012) Lupus neutrophils: „NET“ gain in understanding lupus pathogenesis. Curr Opin Rheumatol 24:441–450

    Article  CAS  PubMed  Google Scholar 

  25. Kowal C, Degiorgio LA, Lee JY et al (2006) Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. Proc Natl Acad Sci U S A 103:19854–19859

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Kyogoku C, Smiljanovic B, Grün JR et al (2013) Cell-specific type I IFN signatures in autoimmunity and viral infection: what makes the difference? PLoS One 8:e83776

    Article  PubMed Central  PubMed  Google Scholar 

  27. Lech M, Anders HJ (2013) The pathogenesis of lupus nephritis. J Am Soc Nephrol 24:1357–1366

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Lu-Fritts PY, Kottyan LC, James JA et al (2014) Association of systemic lupus erythematosus with uranium exposure in a community living near a uranium-processing plant: a nested case-control study. Arthritis Rheum 66:3105–3112

    Article  Google Scholar 

  29. Munoz LE, Lauber K, Schiller M et al (2010) The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat Rev Rheumatol 6:280–289

    Article  PubMed  Google Scholar 

  30. Scofield RH, Bruner GR, Namjou B et al (2008) Klinefelter’s syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome. Arthritis Rheum 58:2511–2517

    Article  PubMed Central  PubMed  Google Scholar 

  31. Smith-Bouvier DL, Divekar AA, Sasidhar M et al (2008) A role for sex chromosome complement in the female bias in autoimmune disease. J Exp Med 205:1099–1108

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Stohl W, Hiepe F, Latinis KM et al (2012) Belimumab reduces autoantibodies, normalizes low complement, and reduces select B-cell populations in patients with systemic lupus erythematosus. Arthritis Rheum 64:2328–2337

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Stojan G, Baer AN (2012) Flares of systemic lupus erythematosus during pregnancy and the puerperium: prevention, diagnosis and management. Expert Rev Clin Immunol 8:439–453

    Article  CAS  PubMed  Google Scholar 

  34. Tsokos GC (2011) Systemic lupus erythematosus. N Engl J Med 365:2110–2121

    Article  CAS  PubMed  Google Scholar 

  35. Wahren-Herlenius M, Dörner T (2013) Immunopathogenic mechanisms of systemic autoimmune disease. Lancet 382:819–831

    Article  CAS  PubMed  Google Scholar 

  36. Wang X, Huang W, Mihara M et al (2002) Mechanism of action of combined short-term CTLA4Ig and anti-CD40 ligand in murine systemic lupus erythematosus. J Immunol 168:2046–2053

    Article  CAS  PubMed  Google Scholar 

Download references

Einhaltung ethischer Richtlinien

Interessenkonflikt. T. Alexander, A. Radbruch und F. Hiepe: unterstützt durch die Deutsche Forschungsgemeinschaft: SFB 650 TP12 (FH, TA) und TP17 (FH, AR); TRR130 TP15 (FH). Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

Author information

Authors and Affiliations

  1. Medizinische Klinik m. S. Rheumatologie und Klinische Immunologie, Charité - Universitätsmedizin Berlin; Deutsches RheumaForschungszentrum Berlin – ein Institut der Leibniz-Gemeinschaft, Charitéplatz 1, 10117, Berlin, Deutschland

    T. Alexander, A. Radbruch &  F. Hiepe

Authors
  1. T. Alexander
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Radbruch
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. Hiepe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F. Hiepe.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alexander, T., Radbruch, A. & Hiepe, F. Pathogenese des systemischen Lupus erythematodes. Z. Rheumatol. 74, 183–190 (2015). https://doi.org/10.1007/s00393-014-1456-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00393-014-1456-2

Schlüsselwörter

Keywords

Search

Navigation