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The Immunologic and Genetic Basis of Psoriasis

Brian J. Nickoloff, MD, PhD
Arch Dermatol. 1999;135(9):1104-1110. doi:10.1001/archderm.135.9.1104.
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In 1991, a comprehensive review was published highlighting the importance of cytokines in the immunopathogenesis of psoriasis.1 Since then, many advances have been made regarding the critical role for pathogenic T cells as causing this common and enigmatic skin disease. While epidermal keratinocytes are clearly involved as participants in establishment of the appropriate cytokine milieu as presented earlier, more recent data point to T lymphocytes as triggering the chain reaction of cellular and molecular networks that culminate in the formation of a psoriatic plaque. In this review, 3 major topics will be addressed.

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Figure 1.

A severe combined immunodeficient mouse with an engrafted human psoriatic plaque. The clinical appearance after transplantation reveals persistent scale and thickened skin.

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Figure 2.

A multistep immunologic model for the development of psoriasis. This pathophysiological pathway bears resemblance to our earlier proposal,1 but highlights sequential interactions of CD4+ T cells with antigen-presenting cells (APCs) in the peripheral lymphoid system (ie, lymph nodes) producing circulating activated skin-seeking CD4+ T cells, which then enter the skin (ie, dermis and epidermis) and provide "help" to generate locally activated APCs that subsequently arouse dormant intraepidermal CD8+ T cells. Once activated, these CD8+ T cells may proliferate and produce cytokines and growth factors that trigger the chain reaction of cellular and molecular events to produce psoriatic plaques. Thus, the sequential 2-cell interactions begin with CD4:APC and are followed by APC:CD8 responses. Such interactions between these 3 different types of immunocytes (ie, CD4+T cells, CD8+T cells, and APCs) are separated by space and time and provide a conceptual basis for some of the complex and occasionally contradictory conclusions made over the past 15 years by skin biologists and clinicians investigating psoriasis. TCR indicates T-cell receptor; CsA, cyclosporin A; CD45RO, memory (rather than naive) T cell; IL, interleukin; and IFN, interferon.

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Figure 3.

Activation of CD8+ T ells with emphasis on costimulatory ligand-receptor interactions between the lymphocyte and antigen-presenting cells (APCs). Note that in addition to antigen recognition as signal 1, there is a critically important requirement for complete activation of a second signal. Signal 2 may involve one or all of the indicated cell surface molecular pairs. MHC indicates major histocompatibility complex; Ag, antigen; TCR, T-cell receptor; ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion molecule; VLA, very late antigen; and LFA, leukocyte function–associated antigen.

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Figure 4.

Activation of natural killer (NK) T cells may involve both engagement of its T-cell receptors (TCRs) by interaction with class I major histocompatibility complex (MHC)–bearing dendritic antigen-presenting cells (APCs), as well as various other receptors (including receptors normally present on NK cells) recognizing their respective ligands on keratinocytes. These 2 pathways are not mutually exclusive. Indeed there may be contributions by both the TCR-mediated pathway (acquired immunity), left side, and the NK regulators (innate immunity), right side, that synergize to generate the initial immunocyte activation critical to trigger psoriasis. Note that some interactions are stimulatory (indicated by plus signs), and others may be inhibitory (designated by minus signs). Ag indicates antigen; MICA is a polymorphic HLA-related antigen.

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