Immunopathology

Several key cell types participate in the inflammatory and destructive process of PsA, including T cells, macrophages, and dendritic cells in the joints and their analogues in the skin. Numerous pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-a), IL-1, and IL-6 also serve important roles in the disease. TNF- has gained much recent attention, since biologic agents that block its activity are now available (see below). Studies of these agents re-confirm the central role of TNF-a in the inflammation of PsA and psoriasis. TNF-a is produced by macrophages, keratinocy-tes, mast cells, monocytes, dendritic cells, and activated T-cells. It upregulates nuclear transcription factors, including NfkB, resulting in enhanced expression of many molecules central to the inflammatory response, including other cytokines (e.g., IL-1, IL-6) and chemo-kines. In the joints, TNF- mediates other biological processes that can result in cartilage and bone damage, including: expression of metalloproteinases by fibro-blasts and chondrocytes, maturation and activation of osteoclasts from monocytic stem cells, and angiogene-sis. In relation to both the joints and the skin, TNF-induces the expression of endothelial, keratinocyte and dendritic cell surface adhesion molecules such as intercellular adhesion molecule (ICAM)-1 and E-selectin (CD62E). In addition to stimulating pro-inflammatory cells and cytokines in the skin, a key role played by TNF-a is promotion of keratinocyte hyperproliferation and survival, which is important in the psoriatic lesion (Krueger and Bowcock 2005; Mease 2004a, b; Veale et al. 2005).

Several groups have, in the last several years, further elucidated the features which set PsA apart from RA at an immunohistochemical level. These include features such as increased decreased synovial lining cellularity, increased vascularity, increased numbers of polymor-phonuclear leukocytes (PMNs), CD163+ macrophages as well as upregulation of Toll-like receptors 2 and 4, several of which are features consistent with activation of the innate immune system and a possible role for microbial antigens (Baeten et al. 2005; De Rycke et al. 2005; Kruithof et al. 2005; Veale et al. 2005). Comparative synovial sampling of patients with RA and three forms of SpA: AS, PsA, and undifferentiated spondyloarthropathy, demonstrate a high degree of similarity in cellular composition, immunohistochemistry, and vas-cularity amongst the SpA subtypes and clear distinction from RA, further supporting the common patho-physiology amongst the SpA subtypes (Kruithof et al. 2005).

Recently, a Viennese group has developed an animal model for psoriasis and PsA. Inducible epidermal deletion of the gene JunB and its functional companion c-Jun in adult mice led to the histologic and immunohis-tochemical hallmarks of psoriasis and arthritis. In humans, JunB is a component of the activator protein 1 (AP-1) transcription factor, localized in the psoriasis susceptibility region PSORS6, and has diminished expression in human psoriatic skin lesions. They further showed that development of arthritis, but not psoriasis, required the presence of T and B cells and signaling through tumor necrosis factor 1 (TNFR1). Their conclusion was that deletion, or at least diminishment, of JunB/AP-1 in keratinocytes induces chemokine/ cytokine expression, which in turn recruits PMNs and macrophages to the epidermis, leading to both skin and joint lesions (Zenz et al. 2005).

A comprehensive discussion of the pathophysiologic features of PsA can be found in recent reviews (Krueger and Bowcock 2005; Mease 2003, 2004a, b; Mease and Antoni 2005; Ritchlin 2005; Veale et al. 2005).

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