Journal of Clinical and Aesthetic Dermatology

Plaque-type Psoriasis Supplement 2016

An evidence-based, peer-reviewed journal for practicing clinicians in the field of dermatology

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S4 SUPPLEMENT TO THE JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY [JUNE 2016 • VOLUME 9 • NUMBER 6 • SUPPLEMENT 1] high numbers to lymphoid tissue. In the case of psoriasis, both plasmacytoid dendritic cells and cluster of differentiation (CD)11c+ dermal dendritic cells have been identified in high levels in psoriatic plaques. Activated d endritic cells produce the pro-inflammatory cytokines IL-12 and IL-23. IL-12 in turn promotes differentiation of Th1 T- cells, while IL-23 is the driving factor behind the survival, proliferation, and activation of Th17 T-cells. 12 Th17 cells. Th17 cells are a distinct class of helper T- cells separate from Th1 and Th2 cells. These CD4+ effector T-cells mature in response to IL-23 produced by dendritic cells in the skin. Th17 cells are the primary cells responsible for immune defense against extracellular pathogens, e.g., Candida albicans and Staphylococcus aureus, in the skin and mucous membranes, and they influence both innate and adaptive responses. When activated, Th17 cells have the capability of producing large amounts of pro-inflammatory cytokines, namely IL-17A, as well as IL-17F, IL-22, and TNFα. 1 3 Other cytokines produced by Th17 cells include IL- 21, granulocyte macrophage colony stimulating factor (GM- CSF), and C-C motif chemokine ligand (CCL) 20. Collectively, the cytokines produced by Th17 cells have effects on cell differentiation, recruitment and activation of immune cells, and release of antimicrobial peptides. 1 4,15 Both over-activity and under-activity of Th17 T-cell responses are associated with disease in the skin. Hyperactivity is involved in the pathogenesis of psoriasis. Low activity of Th17 cell function is associated with the development of Candida infections of the skin and mucous membranes. 16 Job syndrome (aka, hyperimmunoglobulin E syndrome) is characterized by eczematous skin lesions, recurrent staphylococcal skin infections, and mucocutaneous candidiasis. There are gene defects in signal transducer and activator of transcription (STAT) 3 in this condition, which leads to loss of IL-17A production. 17 Th1 cells. Th1 cells are subtypes of T-cells that produce cytokines, including IFNγ, IL-2, and TNFα, and which are involved in immune defense against intracellular pathogens (e.g., M. tuberculosis). Differentiation of Th1 cells from naïve T-cells is stimulated by IL-12 produced by dendritic cells. 18,19 Regulatory T cells. Regulatory T cells (T-reg) are a subset of CD4+ T-cells which function to suppress the activation of effector and memory T-cells. In regulating T- cells, T-reg cells maintain peripheral tolerance and prevent self-reactivity. T-reg cells activity is supported by TGF-β and IL-10. It has been demonstrated that the numbers of T-reg cells as well as their suppressive functioning is reduced in psoriasis patients. 18 Mast cells. Mast cells are blood cells particularly important in allergy and itch. They contain vasoactive mediators, including histamine, leukotrienes, prostaglandins, and kinins. They also play a key role in inflammation and produce pro-inflammatory cytokines, such as TNFα. Messengers, such as IL-23, stimulate mast cells to produce IL-17, which, along with IL-17 produced by Th17 cells and neutrophils, contributes to inflammation seen in psoriasis. Mast cells are abundant in the dermis of psoriatic plaques and are thought to play a role in stress-related psoriasis exacerbations. 20,21 Macrophages. Macrophages are white blood cells primarily involved in the phagocytosis of foreign and cellular d ebris. Additionally, they secrete pro-inflammatory cytokines. In particular, macrophages are known to produce TNFα, which activate dendritic cells and T-cells to promote inflammatory processes. Of note, large numbers of macrophages are observed in psoriatic plaques. 22 Structural and Immunologic Defects in Psoriasis Psoriatic skin demonstrates many differences from healthy skin on both the macroscopic and microscopic level. While the stratum corneum of healthy skin has a basket- weave appearance histologically, keratinocytes in psoriasis cells are retained and become densely stacked, clinically giving the appearance of white, micaceous scale. 23 Moreover, stratum corneum function is compromised, shown by increases in TEWL levels. 24 Psoriatic keratinocytes are characterized by hyperproliferation, rapid mitoses with abnormal differentiation, and retained nuclei. There is reduction in the size of the granular layer with epidermal acanthosis and elongated dermal papillae and enlargement of dermal vasculature. 25 These histologic changes correlate with the thick, erythematous plaques that are clinically observed. In additional to structural changes, there are complex immunologic abnormalities seen in psoriatic patients. Th17 T- cells have been identified as the key abnormal cell involved in psoriatic immune dysregulation, and circulating Th17 cell levels have been found to be statistically higher (P<0.001) in psoriasis patients compared to non-psoriasis comparator patients. 26 Over-activity of Th17 cells lead to defects in antigen presentation, innate and adaptive immune cell function, and imbalanced cytokine production, which all contribute to the pathologic inflammation observed in psoriasis. 7,14 Current theories on the pathogenesis of psoriasis suggest that exogenous triggers interact with the patient's immune system leading to dysregulated inflammation in genetically susceptible individuals. There is little data on triggering factors, but generally accepted ones include emotional stress, medications, cigarette smoking, and certain infections. 27,28 A single external factor is not enough to cause psoriasis. After an initial trigger, the inflammatory response must be propagated by continued immune dysregulation in the affected patient. It is currently thought that immature plasmacytoid dendritic cells in the skin are activated to produce IFN-alpha. Myeloid dendritic cells then become activated and begin to produce pro-inflammatory cytokines, including IL-23. 29,30 High levels of IL-23 in turn promote maturation of naïve T-cells into Th17 type cells. 31 These Th17 cells then produce IL-17A, the key cytokine involved in the development of psoriasis. Other pro-inflammatory cytokines, such as IL-17F, IL-22, and TNFα are also released by the Th17 cells. Elevated IL-17 levels promote keratinocyte hyperproliferation and stimulate them to produce pro-

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