Role of innate immunity in adaptive response of skin

proaches to understand psoriasis are rapidly converging. Psoriasis is a common inherited disease that has been described for 2000 years, and affects 2–3% of the world-wide population. Immunologists, cell biologists, and molecular geneticists are becoming increasingly preoccupied with the cellular and molecular events that produce the commotion in the epidermis that results in a psoriatic plaque. Dermatologists familiar with this enigmatic and chronic disorder recognize that emergence of the distinctive phenotype (widely scattered erythematous plaques; Figure 1) is likely to be multifactorial, related to both environmental and genetic triggering factors (1). Psoriasis currently tops the list, based on population frequencies and familial clustering, of human autoimmune and immunerelated diseases (2). Despite its accessibility, frequency, and persistence since antiquity, many puzzling questions about psoriasis remain unanswered. Perhaps the most obvious unresolved issue, reflecting the lack of an identification of the major genetic susceptibility determinants, is whether this disorder fundamentally reflects an abnormality in the epidermal keratinocyte (KC) or bone-marrow derived immunocyte. This distinction becomes blurred because of cross-talk between activated KCs and immunocytes that begins immediately upon lesion formation and culminates in the mature psoriatic plaque. This uncertainty prompts further questions: Does psoriasis represent a primary defect in the terminal differentiation response to injury by KCs that fail to produce a normal stratum corneum and, therefore, do not create a protective physiological barrier? Alternatively, is the aberrant KC differentiation program in psoriasis a consequence of an influx of pathogenic immunocytes participating in a rogue auto-immune reaction? These possibilities are relevant to our understanding of the hyperresponsiveness of pre-psoriatic skin reported by Travers et al. in this issue of the JCI (3). In this Commentary, I synthesize available data into a multistep model, taking a novel view of psoriasis from the perspective of the innate immune system. This approach may lead to new avenues for investigators confronting this perplexing skin problem that involves dynamic and reversible epidermal remodeling.