Is there a viral trigger for vascular manifestations in autoimmune diseases such as systemic sclerosis?

Editorial note

This is a commentary on the article by Hamamdzic et al, which can be found at http://www.biomedcentral.com/1471-2474/2/3 webcite

Systemic sclerosis (SSc) is a chronic fibrotic disease that affects the skin as well as internal organs. The exact aetiology remains unknown. An altered immune system as well as vascular changes are thought to be early factors in the pathogenesis of the disease, and it has been suggested that latent infection with human cytomegalovirus (HCMV) may also play a part [1]. Patients with SSc show a significantly higher prevalence of anti-HCMV antibodies compared with age and sex matched patients with rheumatoid arthritis or osteoarthritis [2]. A recent paper by Lunardi et al[3] found that HCMV was able to generate self-reactive antibodies in patients with SSc. These autoantibodies, which cross-reacted with the CMV late protein UL94, were able to induce endothelial cell apoptosis, probably through interaction with the integrin α3β1- and the α6β1-NAG-2 complex. Apoptosis of endothelial cells in turn is thought to be one of the earliest steps in the vascular pathology of SSc [4].

While these results have provided a potential link between an external trigger (HCMV) and the vascular changes of SSc, important questions remain. For example, why might a ubiquitous virus like HCMV generate vascular pathology in some individuals but not others and are the findings described above a primary event in the pathogenesis of SSc or simply an epiphenomenon due to altered immune responses?

The article by Hamamdzic, Harley, Hazen-Martin and Carwile LeRoy http://www.biomedcentral.com/1471-2474/2/3 webcite adds important experimental evidence to the concept of CMV as a trigger for vascular lesions in autoimmune disease. Hamamdzic et al found that IFN-γR -/- mice that had been infected with murine cytomegalovirus (MCMV) at sublethal doses developed intimal thickening of the ascending aorta. This resembled the vascular lesions found in SSc. When the animals were further immunocompromised by whole body irradiation, both the frequency and the severity of the vascular lesions increased.

Although one must be cautious when extrapolating to humans, these results suggest that immunocompetent status might be the deciding factor for whether vascular lesions occur in patients with SSc. Changes in immune response are another hallmark of the pathogenesis of SSc and can be detected in the earliest stages of the disease, often in coincidence with vascular lesions and usually long before fibrosis of the skin occurs [5]. Therefore, a possible scenario in humans might be that, while a latent infection with HCMV has no obvious effect in healthy individuals, immunological alterations in the early stages of SSc can lead to reactivation of CMV, which then initiates or enhances the vascular changes of the disease.

The second important finding of Hamamdzic et al's study is the morphological similarity between the arterial lesions of IFN-γR -/- mice infected with MCMV and the lesions seen in patients with SSc. In both cases, there is a profound intimal thickening together with focal adventitial inflammation and fibrosis. Tunel positive cells could be found in the intimal layer of affected vessels in the MCMV/IFN-γR -/- animal model as well in patients with the disease. These results suggest an active role of HCMV in the pathogenesis of SSc and indicate that the initial epidemiological reports are unlikely to be a pure epiphenomenon.

However, as Hamamdzic et al emphasise, several issues still need to be addressed in future studies. One study will have to clarify whether the apoptotic cells detected by Tunel technique four months after the infection are also detectable at earlier stages in the MCMV/IFN-γR -/- model, and whether these apoptotic changes can be induced by endothelial cell antibodies as described in humans. In addition, it is unclear how far the high rates of plaque forming units used by Hamamdzic et al for infection with MCMV reflect the situation in patients with SSc. Moreover, while there are some reports of a somewhat higher frequency of macrovascular manifestations, SSc is mainly recognized as a microvascular disease [6]. Hamamdzic et al have focused on changes in the ascending aorta. A crucial question is whether similar changes can also be induced in small vessels of the skin and other organs typically involved in SSc.

Acknowledgements

Supported by a grant from the Leopoldina Foundation (grant BMBF-LPD 9901/8-7)

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