Zeitschrift für Rheumatologie

, Volume 67, Issue 2, pp 151–156 | Cite as

Neue Aspekte zur Pathogenese der Gicht

Danger-Signale, Autoinflammation und darüber hinaus
Aktuelles aus der Immunologie

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.

Schlüsselwörter

NALP3 NOD-like-Rezeptor Natriumurat Autoinflammation Autoimmunität 

Abkürzungsliste

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

New aspects of the pathogenesis of gout

Danger signals, autoinflammation and beyond

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.

Keywords

NALP3 NOD-like receptor Monosodium urate Autoinflammation Autoimmunity 

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Copyright information

© Springer Medizin Verlag 2008

Authors and Affiliations

  1. 1.Poliklinik für Rheumatologie - Universität zu Lübeck, Vaskulitiszentrum - Universitätsklinikum Schleswig-Holstein (UKSH) und Rheumaklinik Bad BramstedtLübeckDeutschland
  2. 2.Institut für Klinische MolekularbiologieUniversitätsklinikum Schleswig-Holstein (UKSH), Campus KielKielDeutschland
  3. 3.Institut für ImmunologieUniversitätsklinikum Schleswig-Holstein (UKSH), Campus KielKielDeutschland

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