Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities - PubMed (original) (raw)

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Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities

Brian J Nickoloff et al. J Clin Invest. 2004 Jun.

Abstract

Chronic and excessive inflammation in skin and joints causes significant morbidity in psoriasis patients. As a prevalent T lymphocyte-mediated disorder, psoriasis, as well as the side effects associated with its treatment, affects patients globally. In this review, recent progress is discussed in the areas of genetics, the immunological synapse, the untangling of the cytokine web and signaling pathways, xenotransplantation models, and the growing use of selectively targeted therapies. Since psoriasis is currently incurable, new management strategies are proposed to replace previous serendipitous approaches. Such strategic transition from serendipity to the use of novel selective agents aimed at defined targets in psoriatic lesions is moving rapidly from research benches to the bedsides of patients with this chronic and debilitating disease.

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Figures

Figure 1

Figure 1

Clinical and histological appearance of stable chronic psoriatic plaques. Note the well-demarcated erythematous plaques covered by white-silvery scale (arrows), widely distributed on the lower back and extremities. Prepsoriatic symptomless skin is clearly demarcated from lesional skin. Psoriasis often develops at skin sites where minor trauma may occur, such as elbows and buttocks. Induction of psoriatic lesions by trauma is referred to as the K_bner phenomenon. Insets: Histological appearance of prepsoriatic (symptomless) skin (upper left panel), with unremarkable epidermis and dermis, and rare mononuclear cells present predominantly in the dermis. By contrast, a chronic psoriatic plaque (lower left panel) reveals markedly thickened skin due primarily to accumulation of scale and elongation of rete ridges. In addition, there is loss of the granular cell layer, increased layers of epidermal keratinocytes, and an influx of lymphocytes, DCs, and macrophages into the dermis, accompanied by the presence of dilated and tortuous blood vessels.

Figure 2

Figure 2

Translational arcs of discovery in psoriasis. In the past, therapeutic agents used by dermatologists were generally discovered serendipitously. Current therapeutic agents are characterized by more specific targeting of defined molecules in the pathological pathways, including, most recently, the use of biologics, which target T cells (alefacept, efalizumab, and etanercept; approved by the US Food and Drug Administration [FDA] for the treatment of psoriasis), and TNF inhibitors (etanercept, infliximab, and adalimumab; approved by the FDA for the treatment of RA). Several agents listed (Past column), including corticosteroids and UV-B light, are still currently used by some dermatologists to treat psoriasis patients. Future drug development should provide additional smart drugs that target specific molecular mediators implicated in the immunopathogenesis of psoriasis. Note: Biologics are defined as therapeutic agents produced by organisms through the use of recombinant biotechnology. CsA, cyclosporin A; PUVA, psoralen and UV-A light therapy; Vit, vitamin.

Figure 3

Figure 3

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.

Figure 4

Figure 4

Immune synapse_related signaling pathway and autoimmune diseases. A possible role for genetic mutations involved in several autoimmune diseases is highlighted, including ZAP-70 (RA); SLC9A3R1 and NAT9 (psoriasis); PDCD1 (systemic lupus erythematosus [SLE]); and SLC22A4 (RA and Crohn disease). T lymphocytes contain both surface receptors and intracellular signaling components that become activated when the TCR is engaged by interactions with an appropriate APC in which antigen is presented in the context of MHC molecules. The APC is displayed in the upper portion of this schematic view. The TCR mediates signaling in conjunction with molecules located in the plasma membrane, including CD3 and ζ-chains, which contribute to the formation of an immunological synapse and a lipid raft, leading to activation of proximal, intermediate, and distal signaling components. Several but not all components are portrayed in this figure. Ultimately, transcription factors become activated and bind to respective promoter regions to either enhance or suppress target gene expression. Potential mechanisms linking the genetic findings to functional components of the immunological synapse are shown by solid bold lines.

Figure 5

Figure 5

(A) T cell_targeted therapies in psoriasis. Two FDA-approved biologics (alefacept and efalizumab) are portrayed; the molecular target is identified on the T cell surface (upper panels). Note that the site of action of these agents is depicted in the skin, but the therapeutic efficacy may include other anatomical sites such as lymph nodes or other secondary lymphoid tissues. Alefacept targets the CD2:LFA-3 ligand/receptor interactions, whereas efalizumab targets the LFA-1:ICAM-1 ligand/receptor pair of surface molecules expressed by T cells and APCs, respectively. (B) The clinical response of a patient with severe psoriasis (left) to efalizumab administered for 2 months. Note the almost complete clearing of lesions on the lower extremities and hand (right).

Figure 6

Figure 6

Innovations in psoriasis therapy. Future potential targets in the treatment of psoriasis are depicted. These therapeutic opportunities can be considered in the context of four broad areas: (I) T cell trafficking, (II) T cell activation, (III) cytokine inhibitors, and (IV) counteroffensive strategies. To enhance patient compliance and safety, anti-inflammatory and next-generation immunosuppressants ideally would be able to be ingested rather than injected.

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