Working model for immunopathogenesis of psoriasis. Multiple stages are proposed for trafficking patterns of immunocytes, involving signals in which symptomless skin is converted into a psoriatic plaque. Symptomless skin is endowed with a confederacy of bone marrow_derived cells, and continuous leukocyte migration between skin and lymph nodes provides immunological vigilance to monitor invading pathogenic organisms. Known mediators of homeostatic trafficking for Langerhans cells (LCs), resident DCs, and T cells are portrayed (left panel). Ideal therapeutic agents for psoriasis should not perturb this physiological process. Following a stimulus, an acute psoriatic lesion forms in which DCs and T cells become activated with formation of an immunological synapse. No consistent antigen has been identified (middle panel). Stimuli may include a danger signal, either an extrinsic, pathogen-associated signal (e.g., pathogen-associated molecules that bind to pattern-recognition Toll-like receptors) or an intrinsic signal derived from within the body (e.g., heat shock proteins that bind to receptors, HIV-1, and ingested medications such as lithium or β-blockers). Once dendritic APCs and T cells become activated, they release cytokines, chemokines, and growth factors that trigger keratinocyte proliferation, altered differentiation, and an angiogenic tissue response. A vicious cycle of continuous T cell and DC activation can be envisioned within the chronic psoriatic plaque (right panel). A list of relevant cytokines, chemokines, and growth factors that likely conspire with resident and recruited cells to create and sustain psoriatic plaques is provided (lower right panel). Key inflammatory events include intraepidermal trafficking by CD8+ T cells and neutrophils.