Pathogenesis

The biochemical basis for the pathogenesis of psoriasis, which is as equally varied as the genetic basis, can be attributed to both overexpression and underexpression of certain proteins in psoriatic lesions (Duvic et al. 1998). The anomalies in protein expression can be divided into three areas: abnormal keratinocyte differentiation, hyperproliferation of the keratinocyte, and infiltration of inflammatory elements (Duvic et al. 1998).


Keratinocyte Differentiation

At least six markers of abnormal keratinocyte differentiation have been found, and all have implications in the pathogenesis of the disease. These include aberrations of keratinocyte transglutaminase type I (TGase K), skin-derived antileukoproteinase (SKALP), migration inhibitory factor-related protein-8 (MRP-8), Involucrin, Filaggrin and keratin expression.

TGase K, which catalyzes a critical step of CE formation, is precociously expressed in psoriasis (Shroeder et al. 1992). The overexpression of this enzyme causes the excessive cornification seen in psoriatic lesions, which directly contributes to the hard lesions manifested on the skin in psoriatic patients.

Another marker of psoriasis is SKALP, which is only found in psoriatic skin (Schalkwijk et al. 1993). This polypeptide is a major elastase inhibitor, which is secreted by epidermal keratinocytes (Molhuizen et al. 1993). Elastase is a lysosomal serine proteinase that is specific for the degredation of elastin, a protein found in tissues requiring elasticity. In addition to its inhibitory effects, SKALP was shown to act as a substrate for transglutamase, indicating its role in psoriasis (Molhuizen et al. 1993).

An additional marker of abnormal keratinocyte differentiation is MRP-8, a Ca^­2+-binding protein. Although its biochemical function is not completely understood, it has been found in psoriasis and other inflammatory diseases, but not in normal skin (Nagpal et al. 1996). A functional role of MRP-8 in the reorganization of the cytoskeleton during psoriasis has been implicated, because it is specifically expressed during terminal differentiation and associated with intermediate filaments (Goebeler et al. 1995).

Involucrin, a precursor protein that helps to stabilize the CE, is also upregulated in psoriasis vulgaris (Isha-Yamamoto et al. 1995). In normal skin, this protein is a major constituent of the CE only during its early stages of assembly. However, in psoriatic skin, CE formation seems to be initiated prematurely, and involucrin remains the major constituent of the CE during maturation (Isha-Yamamoto et al. 1995). This problem with keratinocyte terminal differentiation in the form of excessive CE formation is yet a further explanation for the hardened psoriatic lesion.

Keratin expression is also disrupted in psoriasis (Thewes et al. 1988). K6 and K16, markers of abnormal hyperproliferative conditions, are upregulated in psoriatic epidermis, whereas K1 and K10, markers of terminal differentiation, are downregulated (Thewes et al. 1988). This buildup of cells then accumulates on the skin surface in the form of the psoriatic plaque.

Filaggrin, which is normally found in the granular layer of the skin, is absent in psoriatic lesions (Bernard et al. 1986). The loss of the granular layer of skin through scaling in psoriasis most likely accounts for filaggrin's absence.


Hyperproliferation

Hyperproliferating keratinocytes is the second category of anomalies that contributes to the symptoms of psoriasis vulgaris. Several possible biochemical causes for the overproduction of the keratinocytes have been found in psoriatic skin: epidermal growth factor (EGF), bone morphogenetic protein-6 (BMP-6), transforming growth factor-alpha (TGF-a), ornithine decarboxylase, activating protein (AP1) and mitogen-activated protein kinase (MAPK).

EGF, which stimulates growth and differentiation of human epidermis, mediates cellular responses by binding to specific receptors (Nanney et al. 1993). EFG binding capacity is doubled in the upper layers of the epidermis of psoriatic skin and concurrently [125I]EFG binding is increased (Nanney et al. 1993). This increase in binding over-stimulates the growth of the keratinoctyes, causing hyperproliferation.

BMP-6, another growth factor, is present in newborns, but normally disappears by adulthood, except in psoriatic patients (Blessing et al. 1996). Blessing et al. (1996) were able to induce psoriasis in mice using epidermal BMP-6, which makes it a prime candidate for a growth factor sponsoring the formation of psoriatic lesions in humans.

Elder et al. (1989) first discovered that TGF-a expression was upregulated in psoriatic skin. Then, Nickoloff et al. found TGF-a in the epidermal roof of psoriatic lesions, but not in normal skin (Nickoloff et al. 1991). Vasoactive intestinal polypeptide (VIP), a major neuropeptide, causes the production of TGF-a in vivo, so VIP is now presumed to stimulate keratinocyte growth through TGF-a (Sung et al. 1999). Before this study, it had been suggested that the hyperproliferative effects of VIP were mediated by increased levels of cyclic adenosine monophosphate (cAMP) caused by activated adenylate cyclase activity, because this intracellular second messenger mediates many of VIP's effects. However, Sung et al. (1999) clearly showed that VIP stimulated the growth of keratinocytes via TGF-a rather than via cAMP.

Activity of ornithine decarboxylase, an essential enzyme in polyamine biosynthesis, is higher in lesional and nonlesional psoriatic skin (Kagramanova et al. 1991). Thus, this enzyme contributes to the pathogenesis of psoriasis by indirectly causing hyperproliferation of the keratinocytes by stimulating mitosis.

AP1, a complex of the oncoproteins Jun and Fos, stimulates the expression of many genes that are important in cell proliferation and inflammation (Nagpal et al. 1995). These factors were shown to have an altered expression pattern in plaque psoriasis, and so they have also been implicated in the pathogenesis of psoriasis (Basset-Seguin et al. 1991; Duvic et al. 1998).

The last indicator, MAPK, helps to regulate cellular proliferation (Dimon-Gadal et al. 1998). Numerous growth factors and cytokines modulate MAPK's activity, which is higher in psoriatic fibroblasts (Dimon-Gadal et al. 1998). Determination of the exact mechanism by which elevated MAPK causes hyperproliferation of the keratinocyte could add another valuable piece to the puzzle of the pathogenesis of psoriasis.


Inflammatory Elements

The inflammatory aspect of psoriasis is physically evident by the redness of psoriatic plaques. The biochemical basis for this inflammation stems from several immune modulators including various cytokines released from keratinocytes and other proteins involved in the inflammatory response, which are increased in psoriasis at both local and systemic level (Bonifati et al. 1997). These inflammatory mediators most likely play a crucial role in the pathogenesis of psoriasis.

Among the interleukins (ILs), IL-1, IL-6, IL-7 and IL-8 are upregulated in psoriatic skin (Grossman et al. 1989; Kulke et al. 1992; Konstanitinova et al. 1996; Lundqvist et al. 1997; Bonifati et al. 1997; Hammerberg et al. 1998). In addition, IL-15, which reduces keratinocyte cell apoptosis, is elevated in psoriatic lesions (Ruckert et al. 2000). Proteinase-activated receptor-2 has also been implicated in the pathogenesis of psoriasis by mediating the proinflammatory effects of proteases such as tryptase (Steinhoff et al. 1999a). Other factors, which cause the inflammation seen in psoriatic skin, include neutrophil activating peptide-1/Il-8, intercellular adhesion molecule-1, HLA-DR, tumor necrosis factor-a, interferon-g, macrophage migration inhibitory factor, and GRO-a (Griffiths et al. 1991; Kulke et al. 1992; Sticherling et al. 1996; Bonifati et al. 1997; Bachelez et al. 1998; Steinhoff et al. 1999b).

Likewise, pituitary adenylate cyclase activating polypeptide (PACAP) is an inflammatory mediator that is upregulated in psoriatic lesions (Steinhoff et al. 1999c). Immune cells synthesize PACAP, a regulatory neuropeptide of the VIP family. Its involvement in psoriasis also accounts for the tendency of psoriasis to worsen with stress, because neuropeptides are known for their involvement in skin-nervous system interactions (Steinhoff et al. 1999c).

All of these inflammatory factors exert specific effects on T cells, endothelial cells, macrophages and neutrophils, which in turn spawn the immunogenic inflammatory response seen in psoriasis (Steinhoff et al. 1999a). As a result, psoriasis is now considered an example of an autoimmune disease mediated by a T-helper type 1 cell (TH1-type immune) response to an as-of-yet unidentified antigen (Uyemura et al. 1989; Cooper 1999).

Summary

Understanding the biochemical mechanisms behind the pathogenesis of psoriasis vulgaris has provided the basis for the development of treatments that more adequately control this physically and psychologically debilitating disease. Many of today's medications seek to reduce the inflammation of psoriatic skin and further understanding its cause will continue to help in developing new, more specific treatments. The up- and down-regulation of many differentiation-related factors can serve not only as a means to identify psoriasis, but also as other possible areas to research for psoriasis treatment development. As this knowledge increases, we may closer to a developing a permanent cure for psoriasis.