Molekulare Pathogenese primär systemischer Vaskulitiden

Zusammenfassung

Die molekulare Pathogenese verschiedener primär systemischer Vaskulitiden weist bedeutende Unterschiede auf. Bei der Riesenzellarteriitis scheint die Aktivierung ortsständiger dendritischer Zellen in der Adventitia ein frühes Ereignis zu sein. Nachfolgend werden CD4⁺-Th1-Typ-Zellen über Vasa vasorum rekrutiert, die durch ihre Zytokinproduktion Makrophagen aktivieren und zur Riesenzellentwicklung beitragen. Bei der Takayasu-Arteriitis werden im zellulären Infiltrat in der Arterienwand Perforin exprimierende, oligoklonale γδ-T-Zellen, CD8⁺-T-Zellen und NK-Zellen sowie einzelne CD4⁺-T-zellen und Makrophagen nachgewiesen. Inwieweit infektiöse Erreger für die Aktivierung dendritischer Zellen und die T-Zellaktivierung und -rekrutierung verantwortlich sind, ist Gegenstand von Diskussionen. Bei Immunkomplex-Vaskulitiden trägt die durch Immunkomplexe und C1q-Komplement verlangsamte P-Selektin-vermittelte Rollgeschwindigkeit in den Kapillaren zu einer verstärkten Extravasation von Neutrophilen und anderen Leukozyten bei. Dies begünstigt die Fc-gamma-Rezeptor-vermittelte Erkennung von abgelagerten Immunkomplexen und die nachfolgende endothelnahe Neutrophilenaktivierung und -degranulation mit Endothelschädigung. Bei den antineutrophile zytoplasmatische Autoantikörper (ANCA-) assoziierten Vaskulitiden kommt es durch die Interaktion von ANCA mit Neutrophilen zur Endothelschädigung. Neuere Untersuchungen weisen darauf hin, dass die Expansion von CD28^--Th1-Typ-Zellen sowie erste Hinweise auf eine mögliche Ausbildung ektoper lymphatischer Strukturen im Granulom bei der Wegenerschen Granulomatose im Zusammenhang mit der Persistenz der Autoimmunreaktion gegen das „Wegenersche Autoantigen” Proteinase 3 stehen könnten.

Abstract

The molecular pathogenesis of primary systemic vasculitides is characterized by substantial differences in the underlying pathophysiological mechanisms. Activation of dendritic cells in the adventitia seems to be an early event in giant cell arteritis. Subsequently, CD4⁺ Th1-type cells are recruited via the vasa vasorum. Cytokine release of CD4⁺ Th1-type cells contributes to macrophage activation and giant cell formation. The cellular infiltrate in the arterial wall in Takayasu arteritis consists of perforin producing, oligoclonal γδ T-cells, CD8⁺ T-cells, NK-cells, CD4⁺ T-cells, and macrophages. Whether infectious agents activate dendritic cells and stimulate T-cell activation and recruitment, remains to be discussed. Slowing-down of P-selectin mediated rolling by immune-complexes and C1 q complement induces enhanced extravasation of neutrophils and other leukocytes in immune-complex vasculitides. This process facilitates Fc-gamma mediated recognition of deposited immune-complexes and subsequent neutrophil activation, degranulation, and endothelial damage. The interaction of anti-neutrophil cytoplasmic autoantibodies (ANCA) with neutrophils and subsequent endothelial damage are important steps in the initiation of ANCA-associated vasculitides. Recent studies indicate that both the expansion of CD28^- Th1-type cells and the possible formation of ectopic lymphatic structures in granulomatous lesions, might be correlated with the sustained autoimmune reaction to “Wegener’s autoantigen” proteinase 3 in Wegener’s granulomatosis.

Vaskulitis - Riesenzellarthritis - ANCA - Wegenersche Granulomatose

Vasculitis - giant cell arthritis - ANCA - Wegenersche granulomatosis

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