NEJM Volume 361:496-509

Key Cells and Mediators in the Transition from Innate to Adaptive Immunity in Psoriasis.

Innate immune cells produce key cytokines (tumor necrosis factor α [TNF-α], interferon-α, interferon-γ, interleukin-1β, and interleukin-6) that activate myeloid dendritic cells. Activated dendritic cells present antigens and secrete mediators such as interleukin-12 and interleukin-23, leading to the differentiation of type 17 and type 1 helper T cells (Th17 and Th1). T cells, in turn, secrete mediators (e.g., interleukin-17A, interleukin-17F, and interleukin-22) that activate keratinocytes and induce the production of antimicrobial peptides (e.g., LL-37 cathelicidin and β-defensins), proinflammatory cytokines (TNF-α, interleukin-1β, and interleukin-6), chemokines (CXCL8 through CXCL11 and CCL20), and S100 proteins. These soluble mediators feed back into the proinflammatory disease cycle and shape the inflammatory infiltrate.

Proposed Schema of the Evolution of a Psoriatic Lesion from Initiation to Maintenance of Disease.

An interplay between environmental and genetic factors sets the scene for disease-initiating events. Initial triggers such as physical trauma or bacterial products start a cascade of events that include the formation of DNA–LL-37 complexes, activation of plasmacytoid dendritic cells, and secretion of interferon-Proposed Schema of the Evolution of a Psoriatic Lesion from Initiation to Maintenance of Disease.

An interplay between environmental and genetic factors sets the scene for disease-initiating events. Initial triggers such as physical trauma or bacterial products start a cascade of events that include the formation of DNA–LL-37 complexes, activation of plasmacytoid dendritic cells, and secretion of interferon-Proposed Schema of the Evolution of a Psoriatic Lesion from Initiation to Maintenance of Disease.

An interplay between environmental and genetic factors sets the scene for disease-initiating events. Initial triggers such as physical trauma or bacterial products start a cascade of events that include the formation of DNA–LL-37 complexes, activation of plasmacytoid dendritic cells, and secretion of interferon-α. Activated myeloid dendritic cells migrate into draining lymph nodes and induce the differentiation of naive T cells into effector cells such as type 17 helper T cells (Th17) or type 17 cytotoxic T cells (Tc17) and type 1 helper T cells (Th1) or type 1 cytotoxic T cells (Tc1). Effector cells recirculate and slow down in skin capillaries in the presence of selectin-guided and integrin-guided receptor–ligand interactions. Immune cells expressing the chemokine receptors CCR6, CCR4, and CXCR3 emigrate into skin tissue along chemokine gradients. Key processes during disease maintenance are the presentation of putative autoantigens to T cells and the release of interleukin-23 by dermal dendritic cells, the production of proinflammatory mediators such as tumor necrosis factor α (TNF-α) and nitric oxide by TNF-α and inducible nitric oxide synthase–producing (TIP) dendritic cells, and the production of interleukin-17A, interleukin-17F, and interleukin-22 by Th17 and Tc17 cells and interferon-γ and TNF-α by Th1 and Tc1 cells. These mediators act on keratinocytes, leading to the activation, proliferation, and production of antimicrobial peptides (e.g., LL-37 cathelicidin and β-defensins), chemokines (e.g., CXCL1, CXCL9 through CXCL11, and CCL20), and S100 proteins (e.g., S100A7-9) by keratinocytes. Dendritic cells and T cells form perivascular clusters and lymphoidlike structures around blood vessels in the presence of chemokines such as CCL19 produced by macrophages. A key checkpoint is the migration of T cells from the dermis into the epidermis; this migration is controlled through the interaction of α 1β1 integrin (very late antigen 1 [VLA-1]) on T cells and collagen IV at the basement membrane. Unconventional T cells, including natural killer T cells, contribute to the disease process. Feedback loops involving keratinocytes, fibroblasts, and endothelial cells contribute to tissue reorganization with endothelial-cell activation and proliferation and deposition of extracellular matrix. Neutrophils in the epidermis are attracted by chemokines, including interleukin-8 (CXCL8) and CXCL1. CD45RO denotes cluster designation 45RO, EGF epidermal growth factor, KGF-1/2 keratinocyte growth factor types 1 and 2, and TGF-β transforming growth factor β.

. Activated myeloid dendritic cells migrate into draining lymph nodes and induce the differentiation of naive T cells into effector cells such as type 17 helper T cells (Th17) or type 17 cytotoxic T cells (Tc17) and type 1 helper T cells (Th1) or type 1 cytotoxic T cells (Tc1). Effector cells recirculate and slow down in skin capillaries in the presence of selectin-guided and integrin-guided receptor–ligand interactions. Immune cells expressing the chemokine receptors CCR6, CCR4, and CXCR3 emigrate into skin tissue along chemokine gradients. Key processes during disease maintenance are the presentation of putative autoantigens to T cells and the release of interleukin-23 by dermal dendritic cells, the production of proinflammatory mediators such as tumor necrosis factor α (TNF-α) and nitric oxide by TNF-α and inducible nitric oxide synthase–producing (TIP) dendritic cells, and the production of interleukin-17A, interleukin-17F, and interleukin-22 by Th17 and Tc17 cells and interferon-γ and TNF-α by Th1 and Tc1 cells. These mediators act on keratinocytes, leading to the activation, proliferation, and production of antimicrobial peptides (e.g., LL-37 cathelicidin and β-defensins), chemokines (e.g., CXCL1, CXCL9 through CXCL11, and CCL20), and S100 proteins (e.g., S100A7-9) by keratinocytes. Dendritic cells and T cells form perivascular clusters and lymphoidlike structures around blood vessels in the presence of chemokines such as CCL19 produced by macrophages. A key checkpoint is the migration of T cells from the dermis into the epidermis; this migration is controlled through the interaction of α1β1 integrin (very late antigen 1 [VLA-1]) on T cells and collagen IV at the basement membrane. Unconventional T cells, including natural killer T cells, contribute to the disease process. Feedback loops involving keratinocytes, fibroblasts, and endothelial cells contribute to tissue reorganization with endothelial-cell activation and proliferation and deposition of extracellular matrix. Neutrophils in the epidermis are attracted by chemokines, including interleukin-8 (CXCL8) and CXCL1. CD45RO denotes cluster designation 45RO, EGF epidermal growth factor, KGF-1/2 keratinocyte growth factor types 1 and 2, and TGF-β transforming growth factor β.

. Activated myeloid dendritic cells migrate into draining lymph nodes and induce the differentiation of naive T cells into effector cells such as type 17 helper T cells (Th17) or type 17 cytotoxic T cells (Tc17) and type 1 helper T cells (Th1) or type 1 cytotoxic T cells (Tc1). Effector cells recirculate and slow down in skin capillaries in the presence of selectin-guided and integrin-guided receptor–ligand interactions. Immune cells expressing the chemokine receptors CCR6, CCR4, and CXCR3 emigrate into skin tissue along chemokine gradients. Key processes during disease maintenance are the presentation of putative autoantigens to T cells and the release of interleukin-23 by dermal dendritic cells, the production of proinflammatory mediators such as tumor necrosis factor α (TNF-α) and nitric oxide by TNF-α and inducible nitric oxide synthase–producing (TIP) dendritic cells, and the production of interleukin-17A, interleukin-17F, and interleukin-22 by Th17 and Tc17 cells and interferon-γ and TNF-α by Th1 and Tc1 cells. These mediators act on keratinocytes, leading to the activation, proliferation, and production of antimicrobial peptides (e.g., LL-37 cathelicidin and β-defensins), chemokines (e.g., CXCL1, CXCL9 through CXCL11, and CCL20), and S100 proteins (e.g., S100A7-9) by keratinocytes. Dendritic cells and T cells form perivascular clusters and lymphoidlike structures around blood vessels in the presence of chemokines such as CCL19 produced by macrophages. A key checkpoint is the migration of T cells from the dermis into the epidermis; this migration is controlled through the interaction of α1β1 integrin (very late antigen 1 [VLA-1]) on T cells and collagen IV at the basement membrane. Unconventional T cells, including natural killer T cells, contribute to the disease process. Feedback loops involving keratinocytes, fibroblasts, and endothelial cells contribute to tissue reorganization with endothelial-cell activation and proliferation and deposition of extracellular matrix. Neutrophils in the epidermis are attracted by chemokines, including interleukin-8 (CXCL8) and CXCL1. CD45RO denotes cluster designation 45RO, EGF epidermal growth factor, KGF-1/2 keratinocyte growth factor types 1 and 2, and TGF-β transforming growth factor β.

Pathogenesis-Based Targeted Therapy for Psoriasis.

Targeted biologic therapies that have been approved for marketing or for which phase 3 clinical data have been published are shown. The two major therapeutic classes are T-cell–targeted therapies (alefacept and efalizumab) and anticytokine therapies (anti–tumor necrosis factor [TNF] therapies): infliximab, adalimumab, etanercept, and a monoclonal antibody against interleukin-12 and interleukin-23 (ustekinumab). Efalizumab (which has been withdrawn from the market) is a chimeric monoclonal anti-CD11a antibody. It blocks the interaction of CD11a (lymphocyte-function–associated antigen [LFA] 1 [LFA-1]) with intercellular adhesion molecule 1 (ICAM-1), leading to a disruption of the interaction between dendritic cells and T cells at tissue sites and in lymph nodes as well as blocking of immune-cell binding to blood vessels. Alefacept is a human LFA 3 (LFA-3) Fc fusion protein that blocks the interaction between CD2 on T cells and LFA-3 on antigen-presenting cells. It also induces antibody-dependent cytotoxicity in T cells bound to alefacept. Anti-TNF strategies have three variants: a humanized chimeric anti–TNF-α monoclonal antibody, a fully human monocolonal anti–TNF-α antibody, and a human p75 TNF-receptor Fc fusion protein. Finally, blocking of interleukin-12 and interleukin-23 is achieved by means of antibodies targeting the common p40 chain of these cytokines. CD denotes cluster designation, and FcR Fc receptor.

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