Skip to main content

Advertisement

SpringerLink
Log in

Neue Aspekte zur Pathogenese der Gicht

Danger-Signale, Autoinflammation und darüber hinaus

New aspects of the pathogenesis of gout

Danger signals, autoinflammation and beyond

  • Aktuelles aus der Immunologie
  • Published:
Zeitschrift für Rheumatologie Aims and scope Submit manuscript

Zusammenfassung

Die Gicht wird durch eine Entzündungsreaktion auf kristalline Natriumuratausfällungen im Gelenk und im periartikulären Gewebe hervorgerufen. Natriumuratkristalle aktivieren den NOD-like-Rezeptor (NLR) NALP3, der zur Gruppe der Mustererkennungsrezeptoren („pattern recognition receptors“/PRR) gezählt wird. Folge der NALP3-Aktivierung ist die Überführung der Pro-Form des Interleukin- (IL-)1b in aktives IL-1b, eine damit verbundene Aktivierung weiterer Zellen und ein IL-8-vermittelter Neutrophileneinstrom ins Gelenk. Diese neuen Erkenntnisse zur Pathophysiologie der Gicht bildeten den Ausgangspunkt für eine offene Pilotstudie, in der kürzlich 10 Gichtpatienten mit dem löslichen IL-1R-Antagonisten Anakinra erfolgreich behandelt wurden. Die physiologische Rolle von Natriumuratkristallen liegt möglicherweise in einer Funktion als „Danger-Signal“ im Gewebe, wo sie dendritische Zellen zur Reifung stimulieren. Die Bedeutung von NLR und anderen PRR für die Pathogenese (auto-)inflammatorischer Erkrankungen wird durch die Identifizierung von krankheitsassoziierten Polymorphismen unterstrichen (z. B. NALP3: verschiedene hereditäre, autoinflammatorischer Syndrome, „nucleotide-binding oligomerization domain containing protein 2“/NOD2: M. Crohn, Blausyndrom). Neben der Erkennung von „Danger-assoziierten“ Molekülen wie Natriumuratkristallen kommt PRR bei der Erkennung von Autoantigen und Aktivierung des angeborenen und adaptiven Immunsystems bei Autoimmunerkrankungen eine Bedeutung zu. So wurden jüngst die durch Erkennung DNS- und RNS-haltiger Immunkomplexe über „Toll-like-Rezeptoren“ (TLR) induzierte Aktivierung von B-Zellen beim systemischen Lupus erythematodes und die zur Reifung dendritischer Zellen führende Erkennung der Proteinase 3 über den „Protease-activated receptor-2“ (PAR-2) bei der Wegener-Granulomatose berichtet.

Abstract

Gout is caused by monosodium urate (MSU) crystal-induced inflammation of the joints and periarticular tissues. MSU crystals activate the NOD-like receptor (NLR) NALP3, which functions as a pattern recognition receptor (PRR). Activated NALP3 mediates interleukin-1b (IL-1b) generation from its inactive pro-form, resulting in the activation of further cells and an IL-8-mediated neutrophil influx into the joint. Based on these new findings on the pathophysiology of gout, an open pilot study has recently demonstrated successful treatment of gout with the soluble IL-1R antagonist anakinra in 10 patients. The physiological role of MSU crystals might be that of a danger signal in peripheral tissues, where they stimulate dendritic cell maturation. The role of PRRs such as the NLR is underlined by NALP3 mutations causing hereditary autoinflammatory syndromes and NOD2 polymorphisms as genetic risk factors for Crohn’s disease. In addition to the recognition of danger-associated molecular patterns (e.g. MSU), PRRs confer autoantigen recognition and activation of the innate and adaptive immune system in autoimmune diseases. Detection of RNA and DNA-containing immune complexes by toll-like receptors inducing B-cell activation in systemic lupus erythematosus and of proteinase 3 by the protease-activated receptor-2 inducing dendritic cell maturation in Wegener’s granulomatosis have recently been reported.

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
Abb. 3

Abbreviations

ASC:

„Apoptosis-associated speck-like protein“

CARD:

„Caspase recruitment domain“

CINCA:

„Chronic infantile neurological cutaneous and articular syndrome“

DAMP:

“(Host) danger-associated molecular pattern“

FCAS:

„Familial cold autoinflammatory syndrome“

FCU:

„Familial cold urticaria“

FIIND:

„Domain with function to find“

IL:

Interleukin

LRR:

„Leucin-rich repeat“

MWS:

„Muckle-Wells syndrome“

NACHT:

NAIP („neuronal apoptosis inhibitory protein“), CIITA („MHC class II transcription activator“), HET-E („incompatibility locus protein from Podospora anserine“) and TP1 („telomerase-associated protein“)

NAD:

„NACHT-associated domain“

NALP3:

„NACHT, LRR, and pyrine domain containing protein 3“

NLR:

„NOD-like receptor“

NOD2:

„Nucleotide-binding oligomerization domain containing protein 2“

NOMID:

„Neonatal-onset multisystem inflammatory disease“

PAMP:

„Pathogen associated molecular pattern“

PAR-2:

„Protease-activated receptor-2“

PRR:

„Pattern-recognition receptor“

PYD:

„Pyrin domain“

RIG:

„Retinoic acid-like gene“

RLH:

„RIG-like helicase“

SLE:

„Systemischer Lupus erythematodes“

TGF-β:

„Transforming growth factor beta“

TLR:

„Toll-like receptor“

TNF-α:

Tumornekrosefaktor alpha

Literatur

  1. Chapman PT, Yarwood H, Harrison AA et al. (1997) Endothelial activation in monosodium urate monohydrate crystal-induced inflammation: In vitro and in vivo studies on the roles of tumor necrosis factor alpha and interleukin-1. Arthritis Rheum 40: 955–965

    Article  PubMed  CAS  Google Scholar 

  2. Chen CJ, Shi Y, Hearn A et al. (2006) MyD88-dependent IL-1 receptor signalling is essential for gouty inflammation stimulated by monosodium urate crystals. J Clin Invest 116: 2262–2271

    Article  PubMed  CAS  Google Scholar 

  3. Csernok E, Ai M, Gross WL et al. (2006) Wegener’s autoantigen induces maturation of dendritic cells and licences them for Th1 priming via the protease-activated receptor-2 pathway. Blood 107: 4440–4448

    Article  PubMed  CAS  Google Scholar 

  4. Duerr RH, Taylor KD, Brant SR et al. (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314: 1461–1463

    Article  PubMed  CAS  Google Scholar 

  5. Faires JS, McCarty DJ (1962) Acute arthritis in man and dog after intrasynovial infection of sodium urate crystals. Lancet 280: 682–685

    Article  Google Scholar 

  6. Goldbach-Mansky R, Dailey N, Canna S et al. (2006) Neonatal-onset multisystem inflammatory disease responsive to interleukin-1b inhibition. N Engl J Med 355: 581–592

    Article  PubMed  CAS  Google Scholar 

  7. Hachicha M, Naccache PH, McColl SR (1995) Inflammatory microcrystalls differentially regulate the secretion of macrophage inflammatory protein 1 and interleukin-8 by human neutrophils: a possible mechanism of neutrophil recruitment to sites of inflammation in synovitis. J Exp Med 182: 2019–2025

    Article  PubMed  CAS  Google Scholar 

  8. Hampe J, Franke A, Rosenstiel P et al. (2007) A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 39: 207–211

    Article  PubMed  CAS  Google Scholar 

  9. Jin Y, Mailloux CM, Gowan K et al. (2007) NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med 356: 1216–1225

    Article  PubMed  CAS  Google Scholar 

  10. Lamprecht P (2006) Vom Gen zur Therapie: Hereditäre Fiebersyndrome, Gicht und Entzündung. Z Rheumatol 65: 610–612

    Article  PubMed  CAS  Google Scholar 

  11. Landis RC, Yagnik DR, Florey O et al. (2002) Safe disposal of inflammatory monosodium urate monohydrate crystals by differentiated macrophages. Arthritis Rheum 46: 3026–3033

    Article  PubMed  CAS  Google Scholar 

  12. Liu-Bryan R, Pritzker K, Firestein GS, Terkeltaub R (2005) TLR2 signaling in chondrocytes drives calcium pyrophosphate dihydrate and monosodium urate crystal-induced nitric oxide generation. J Immunol 174: 5016–5023

    PubMed  CAS  Google Scholar 

  13. Liu-Bryan R, Scott P, Sydlaske A et al. (2005) Innate immunity conferred by Toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum 52: 2936–2946

    Article  PubMed  CAS  Google Scholar 

  14. Marshak-Rothstein A (2006) Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol 6: 823–835

    Article  PubMed  CAS  Google Scholar 

  15. Martinon F, Petrilli V, Mayor A et al. (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440: 237–241

    Article  PubMed  CAS  Google Scholar 

  16. Martinon F, Glimcher LH (2006) Gout: New insights into an old disease. J Clin Invest 116: 2073–2075

    Article  PubMed  CAS  Google Scholar 

  17. Matzinger P (2007) Friendly and dangerous signals: Is the tissue in control? Nat Immunol 8: 11–13

    Article  PubMed  CAS  Google Scholar 

  18. Meylan E, Tschopp J, Karin M (2006) Intracellular pattern recognition receptors in the host response. Nature 442: 39–44

    Article  PubMed  CAS  Google Scholar 

  19. Nishimura A, Akahoshi T, Takahashi M et al. (1997) Attenuation of monosodium urate crystal-induced arthritis in rabbits by a neutralizing antibody against interleukin-8. J Leukoc Biol 62: 444–449

    PubMed  CAS  Google Scholar 

  20. Pascual E, Jovani V (1995) A quantative study of the phagocytosis of urate crystals in the synovial joints of patients with gout. Br J Rheumatol 34: 724–726

    Article  PubMed  CAS  Google Scholar 

  21. Rosenstiel P, Till A, Schreiber S (2007) NOD-like receptors and human diseases. Microbes Infect 9: 648–657

    Article  PubMed  CAS  Google Scholar 

  22. Rothschild BM, Tanke D, Carpenter K (1997) Tyrannosaurs suffered from gout. Nature 387: 357

    Article  PubMed  CAS  Google Scholar 

  23. Samuels J, Ozen S (2006) Familial Mediterranean fever and the other autoinflammatory syndromes: Evaluation of the patient with recurrent fever. Curr Opin Rheumatol 18: 108–117

    Article  PubMed  Google Scholar 

  24. Shi Y, Evans JE, Rock KL. (2003) Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425: 516–525

    Article  PubMed  CAS  Google Scholar 

  25. So A, De Smedt T, Revaz S, Tschopp J (2007) A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther 9: R28–R33

    Article  PubMed  Google Scholar 

  26. Shirahama T, Cohen AS (1974) Ultrastructural evidence for leakage of lysosomal contents after phagocytosis of monosodium urate crystals. Am J Pathol 76: 501–520

    PubMed  CAS  Google Scholar 

  27. Tausche AK, Richter K, Grässler A et al. (2004) Severe gouty arthritis refractory to anti-inflammatory drugs: Treatment with anti-tumour necrosis factor-a as a new option. Ann Rheum Dis 63: 1351–1352

    Article  PubMed  CAS  Google Scholar 

  28. Tausche AK, Unger S, Richter K et al. (2006) Hyperurikämie und Gicht: Diagnostik und Therapie. Internist 47: 509–520

    Article  PubMed  CAS  Google Scholar 

  29. Yagnik DR, Evans BJ, Florey O et al. (2004) Macrophage release of transforming growth factor b1 during resolution of monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum 50: 2273–2280

    Article  PubMed  CAS  Google Scholar 

  30. Zurier RB, Hoffstein S, Weismann G (1978) Mechanisms of lysosomal enzyme release from human leukocytes. J Cell Biol 58: 27–41

    Article  Google Scholar 

Download references

Danksagung

Unterstützt durch die Deutsche Forschungsgemeinschaft (DFG: KFO170), das Land Schleswig-Holstein (Innovationsfonds) und den Verein zur Förderung der Erforschung und Bekämpfung rheumatischer Erkrankungen Bad Bramstedt e. V.

Interessenkonflikt

Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht.

Author information

Authors and Affiliations

  1. Poliklinik für Rheumatologie - Universität zu Lübeck, Vaskulitiszentrum - Universitätsklinikum Schleswig-Holstein (UKSH) und Rheumaklinik Bad Bramstedt, Ratzeburger Allee 160, 23538, Lübeck, Deutschland

    P. Lamprecht

  2. Institut für Klinische Molekularbiologie, Universitätsklinikum Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Deutschland

    A. Till

  3. Institut für Immunologie, Universitätsklinikum Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Deutschland

    D. Kabelitz

Authors
  1. P. Lamprecht
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Till
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Kabelitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. Lamprecht.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lamprecht, P., Till, A. & Kabelitz, D. Neue Aspekte zur Pathogenese der Gicht. Z. Rheumatol. 67, 151–156 (2008). https://doi.org/10.1007/s00393-007-0254-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00393-007-0254-5

Schlüsselwörter

Keywords

Search

Navigation