Pathogenesis of psoriasis.

The information summarized in this article supports the "framework hypothesis." The details of cells of the immune system in the pathogenesis are covered elsewhere in this issue. We believe the observations reported herein allow the following conclusions. The entire epidermis of any individual with the psoriatic phenotype has the capacity to express overt clinical disease. Control of expression is linked to a complex interaction of cells of the epidermis, cells of the dermis, cells of the immune system, and possibly other noncellular humoral elements. The keratinocytes of psoriatic patients are unique in that the inherent phenotype has a capacity for hyperproliferation and altered differentiation. Proliferation and differentiation are controlled at the level of the gene. Thus, it is important to consider not only cytokines and growth factors released by the various cell types, but also the role of regulators of transcription, translation, and the modification of the cytokines and growth factors. The large number of alterations of cytokine and growth factor profiles within psoriasis cause us to postulate that the genetic aberration in psoriasis is quite basic, that is, it is proximal to the common element in the cascade of inflammatory events that lead to a lesion of psoriasis. We speculate that such a defect may be in transcription regulatory elements associated with one or more cytokines (or growth factors). This mutation could occur (1) in the regulatory element itself; (2) in the receptor, which binds both ligand and regulatory element; (3) in the ligand (cytokine or growth factor); or (4) in a gene responsible for the control of proliferation that is under the influence of the sites mentioned in 1, 2, and 3. A mutation within a key regulatory element for a gene controlling proliferation could produce the following scenario of lesional expression. Such a mutation will probably result in less affinity for a receptor/ligand complex. Because this regulatory element in interaction with the receptor/ligand complex normally suppresses gene expression of a promoter of proliferation, the result is a phenotype that tends to be more proliferative and less differentiative. Conversely, if such a mutation produced a regulatory element that has increased affinity for a promoter receptor/ligand complex, then the same phenotype can evolve. Because a wide variety of receptor/ligand complexes can modulate each regulatory element, such a genetic defect could have wide-ranging effects on phenotypic expression. Moreover, as this change in affinity for binding the receptor/ligand complexes only represents a change in sensitivity, not total unresponsiveness, one can expand on the scenario to conclude that the clinical phenotype is only expressed once the system is overwhelmed. This scenario fits the information presented. Both keratinocytes and fibroblasts from psoriatic subjects are hyperproliferative, but only under specific culture conditions. Furthermore, psoriatic keratinocytes appear to be relatively resistant to the antiproliferative and prodifferentiative effects of retinoids or the vitamin D analogues that have antipsoriatic activity. If a genetic defect decreases the affinity of a suppressive receptor/ligand complex for the regulatory element of IL-6 or TGF-alpha, for example, then these cells could be relatively resistant to homeostatic regulation by indigenous corticosteroids, vitamin D, and retinoids. This would result in a situation in which any trigger phenomenon that releases a cytokine, whose receptor/ligand complex upregulates this regulatory element, would overwhelm the defective counterregulatory signal. Subsequently, cells in the skin generate additional cytokines that invoke an inflammatory cascade that eventuates in the egress of immune cells into the skin and the evolution of a lesion of psoriasis. Similar scenarios could be derived from mutations in the other pathways described in this article.