Increased understanding of the pathophysiology of psoriasis has been one of the driving forces in the development of new therapies. An understanding of the processes involved is important in the optimal management of the disease. The last 30 years of research and clinical practice have revolutionized our understanding of the pathogenesis of psoriasis as the dysregulation of immunity triggered by environmental and genetic stimuli. Psoriasis was originally regarded as a primary disorder of epidermal hyperproliferation. However, experimental models and clinical results from immunomodulating therapies have refined this perspective in conceptualizing psoriasis as a genetically programmed pathologic interaction among resident skin cells; infiltrating immunocytes; and a host of proinflammatory cytokines, chemokines, and growth factors produced by these immunocytes. Two populations of immunocytes and their respective signaling molecules collaborate in the pathogenesis: (1) innate immunocytes, mediated by antigen-presenting cells (APCs)(including natural killer [NK] T lymphocytes, Langerhans cells, and neutrophils), and (2) acquired or adaptive immunocytes, mediated by mature CD4+ and CD8+ T lymphocytes in the skin. Such dysregulation of immunity and subsequent inflammation is responsible for the development and perpetuation of the clinical plaques and histological inflammatory infiltrate characteristic of psoriasis.
Although psoriasis is considered to be an immune-mediated disease in which intralesional T lymphocytes and their proinflammatory signals trigger primed basal layer keratinocytes to rapidly proliferate, debate and research focus on the stimulus that incites this inflammatory process. Our current understanding considers psoriasis to be triggered by exogenous or endogenous environmental stimuli in genetically susceptible individuals. Such stimuli include group A streptococcal pharyngitis, viremia, allergic drug reactions, antimalarial drugs, lithium, beta-blockers, IFN-α, withdrawal of systemic corticosteroids, local trauma (Köbner phenomenon), and emotional stress. These stimuli correlate with the onset or flares of psoriatic lesions. Psoriasis genetics centers on susceptibility loci and corresponding candidate genes, particularly the psoriasis susceptibility (PSORS) 1 locus on the major histocompatibility complex (MHC) class I region. Current research on the pathogenesis of psoriasis examines the complex interactions among immunologic mechanisms, environmental stimuli, and genetic susceptibility. After discussing the clinical presentation and histopathologic features of psoriasis, we will review the pathophysiology of psoriasis through noteworthy developments, including serendipitous observations, reactions to therapies, clinical trials, and animal model systems that have shaped our view of the disease process. In addition to the classic skin lesions, approximately 23% of psoriasis patients develop psoriatic arthritis, with a 10-year latency after diagnosis of psoriasis.1
Principles of Immunity
The immune system, intended to protect its host from foreign invaders and unregulated cell growth, employs 2 main effector pathways—the innate and the acquired (or adaptive) immune responses—both of which contribute to the pathophysiology of psoriasis.2 Innate immunity responses occur within minutes to hours of antigen exposure but fail to develop memory for when the antigen is encountered again. However, adaptive immunity responses take days to weeks to respond after challenged with an antigen. The adaptive immune cells have the capacity to respond to a greater range of antigens and develop immunologic memory via rearrangement of antigen receptors on B and T cells. These specialized B and T cells can then be promptly mobilized and differentiated into mature effector cells that protect the host from a foreign pathogen.
Innate and adaptive immune responses are highly intertwined; they can initiate, perpetuate, and terminate the immune mechanisms responsible for inflammation. They can modify the nature of the immune response by altering the relative proportions of type 1 (TH1), type 2 (TH2), and the more recently discovered type 17 (TH17) subset of helper T cells and their respective signaling molecules. A TH1 response is essential for a cellular immunologic reaction to intracellular bacteria and viruses or cellular immunity. A TH2 response promotes IgE synthesis, eosinophilia, and mast cell maturation for extracellular parasites and helminthes as well as humoral immunity, while a TH17 response is important for cell-mediated immunity to extracellular bacteria and plays a role in autoimmunity.3 The innate and adaptive immune responses employ common effector molecules such as chemokines and cytokines, which are essential in mediating an immune response.