Insights into the role of latent virus in the vasculitis in sheep-associated malignant catarrhal fever

Malignant catarrhal fever (MCF) is a generally fatal γ-herpesvirus-associated sporadic disease in ruminants. Systemic vasculitis, mainly in the form of a mononuclear arteritis, is a key pathological process, and cytotoxic T cells play a major role in it. So far, the pathogenesis of MCF vasculitis is not clear. We hypothesized that it develops due to interactions between virus infected cells and immune cells and undertook a retrospective in situ study on rete mirabile arteries of ovine herpesvirus-2 associated MCF cases. The results indicate that the arteritis develops from an adventitial infiltration, with superimposed luminal recruitment of leukocytes. Infiltration of the wall can then lead to chronic proliferative changes. Besides T cells, macrophages are the dominant infiltrating cells, both proliferate locally. RNA- in situ hybridisation and immunohistology served to show that the process is associated with widespread latent viral infection, not only in infiltrating leukocytes, but also in endothelial cells, medial smooth muscle cells and adventitial fibroblasts. This suggests that latently infected, locally proliferating T cells and macrophages are equally important for the vasculitis in MCF. The initial trigger/insult is not yet known, but there is evidence that, among others, latently infected, acvitated endothelial cells play a role in this. Releasing pro-inflammatory mediators, activated monocytes/macrophages could then induce the characteristic vascular changes. für die BKF-Vaskulitis zu sein. Deren Auslöser ist noch nicht bekannt, jedoch scheinen u.a. aktivierte Endothelzellen eine Rolle zu spielen. Aktivierte, pro-inflammatorische Mediatoren freisetzende Monozyten/Makrophagen könnten dann die characteristischen Gefässveränderungen bewirken. Abstract Malignant catarrhal fever (MCF) is a generally fatal γ-herpesvirus-associated sporadic disease in susceptible dead-end hosts in which a systemic vasculitis is a key pathological process. The vasculitis generally presents as a mononuclear arteritis in which cytotoxic T cells which have recently been shown to carry productive viral infection, play a major role. Nonetheless, the pathogenesis of MCF vasculitis is not yet clear. We hypothesized that it develops due to an interaction between virus infected cells and immune cells and undertook a retrospective in situ study on the rete mirabile arteries of confirmed ovine herpesvirus-2 associated MCF cases. Our results indicate that the arteritis develops from an adventitial infiltration upon which luminal recruitment of leukocytes is often superimposed; infiltration of the wall can then lead to chronic changes including neointimal proliferation. Macrophages are the dominant infiltrating cells besides T cells, and proliferate locally. Using RNA- in situ hybridization and immunohistology, we could show that the process is accompanied by widespread latent viral infection, not only in infiltrating leukocytes, but also in vascular endothelial cells, medial smooth muscle cells and adventitial fibroblasts. Our results suggest that latently infected T cells, monocytes and locally proliferating macrophages are equally important for the vasculitis in MCF. The initial trigger/insult that leads to leukocyte recruitment and activation is not yet known, but there is at least evidence that latently infected, acvitated endothelial cells play a role in this. Activated monocytes/macrophages would then release the necessary proinflammatory mediators and, eventually, induce the characteristic vascular changes.