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1.8*

* p < 0.05 vs IL-17+/--IL-1Ra-/- mice by Mann-Whitney U test

* p < 0.05 vs IL-17+/--IL-1Ra-/- mice by Mann-Whitney U test inflammatory cytokines and chemokines, resulting in the development of inflammation (Kollias and Kontoyiannis 2002). It is also known that TNFa induces the expression of vascular cell adhesion molecule-1 in en-dothelial cells; this promotes the early adhesion of mononuclear leukocytes to the arterial endothelium at sites of inflammation (Feldmann 2002).

Consistent with our observations, it was recently reported that In-fliximab, an anti-TNFa antibody, improved endothelial dysfunction in antineutrophil cytoplasmic antibody-associated systemic vasculitis in humans (Booth et al. 2004). Although the etiopathogenesis of this vas-culitis has not been completely elucidated, it is thought that both aortitis in IL-1Ra-/- mice and antineutrophil cytoplasmic antibody-associated systemic vasculitis in humans share a similar pathogenic process involving TNFa. These observations provide new insight into the pathogenesis of vasculitis, and the IL-1Ra-/- mice should be a useful model for the study of the pathogenic mechanisms of vasculitis (Fig. 5).

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Vascular system

Fig. 5. Pathogenesis of aortitis: TNFa plays an important role in the development of aortitis in IL-1Ra-//- mice

Vascular system

Fig. 5. Pathogenesis of aortitis: TNFa plays an important role in the development of aortitis in IL-1Ra-//- mice

8.4 The Role of TNFa in the Development of Dermatitis 8.4.1 Development of Psoriasis-Like Dermatitis in IL-1Ra-/- Mice

Psoriasis-like skin disease, first reported by Shepherd et al. (2004), was evident in IL-1Ra-/- mice on the BALB/c background. However, we could not identify disease in animals on the C57BL/6 background, indicating that strain-specific background genes are also involved in the development of this disease. The mice on the BALB/c background develop redness and scaling of their ears and tail (Fig. 6), a pathology characterized by extensive thickening of the epidermis associated with hyperkeratosis of the skin. The majority of keratinocytes retained their nucleus in the cornified cellular layer. We also observed massive neutrophil infiltration into the epidermis and dermis. With increasing disease progression, the epidermal layer gradually penetrated into the dermal layer, forming ridges. Aseptic microabscesses formed under the skin. CD4+ T cells were occasionally observed within the dermis.

Interestingly, however, significant disease developed in scid/scid-IL-1Ra-/- mice. Furthermore, IL-1Ra-/- T cell transfer could not induce dermatitis in nu/nu mice, in contrast to cases of arthritis or aortitis in

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