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Pathophysiology


Naïve T cell


IL-12 Th1 IL-23, TGF-b, IL-6 Th17 IL-4 Th2 IL-6, TNF-a Th22 TGF-b Treg


IFN-γ TNF-a


Autoimmunity, cell mediated immunity against intracellular pathogens


IL-17A/F IL-21 IL-22 IL-26


Autoimmunity, immunity against extracellular pathogens, fungi


IL-5 IL-4 IL-13


Allergy, atopy, immunity against extracellular pathogens


IL-22


IL-10 TGF-b1


Epithelial


differentiation and survival, early host defines


Immunotolerance and homeostasis


Figure 1: Differentiation of naïve T cells toward different effector subtypes. Naïve T cells differentiate into different T cells with peculiar functions and pattern of cytokines depending on antigenic stimulations, cytokines, chemokines and growth factors signalling


pathogens


● Th17 cells, promoted by IL-6, IL-23 and transforming growth factor (TGF)-b, and which secrete IL-17, IL-21, IL-22 and IL-26 and are involved in autoimmune disease and cell-mediated immunity against extracellular pathogens and fungi


● Regulatory T cells (Treg), promoted by TGF-b and which are required for immunotolerance and homeostasis


● Th22 cells, promoted by IL-6 and tumour necrosis factor (TNF)-a, and which mostly produce IL-22 and provide epithelial cellular differentiation, survival and early host defence.12


Psoriatic plaque is characterised by a marked infiltration of activated CD4+ and CD8+ T cells. CD4+ T cells mainly infiltrate the dermis, whereas CD8+ T cells are preferentially present in the epidermis.13


4


The lesional skin of psoriatic patients is also invaded by naïve T cells, which migrate from the periphery in response to tissue-specific, receptor–ligand interactions between T cells and endothelia. Migrated naïve T cells are activated by resident antigen-producing cells and keratinocytes in the dermis and


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epidermis, respectively. Signals delivered by inflammatory cytokines, such as IFN-a, IL-6, and IL-23, would contribute in expanding the local T cell infiltrate, by both regulating T cell growth and apoptosis and enhancing the resistance of effector T cells to the regulatory T cell-mediated immunosuppression.


Cytokines in the development of the psoriatic plaque Immune response requires cross-talk between a variety of different cells, and cytokines play a crucial role, resulting in modulations of gene expression in the target cells. The rapid advancement of molecular technologies and the relative ease of access to the diseased skin tissues has boosted research over the past decades, thereby helping to define the pattern of cytokines produced by T cells in psoriasis. Traditionally psoriasis has been classified as a Th1-associated disease, because T cells infiltrating the lesional skin of psoriatic patients produce high levels of IFN-γ, the signature cytokine of Th1 cell responses. In line with these findings, IL-12, the major Th1-inducing factor in humans, is upregulated in the lesional skin of psoriatic patients.14


More recently, it has


been demonstrated there is also an elevated synthesis of Th17-related cytokines, such as IL-17A, IL-17F, IL-21, and IL-22 in the psoriatic plaque.15 Moreover, a functional role of Th17 cells in psoriasis was suggested by the demonstration that both IL-21 and IL-22 induce keratinocyte hyperplasia, and that Th17 cytokine levels decrease during successful anti-TNF-a treatment.16


This


is corroborated by the effect that highly specific mAbs targeting IL-17A (such as secukinumab and ixekizumab) have on the clinical presentation of psoriasis. IL-21, a γ-chain cytokine, together


with IL-6 and transforming growth factor (TGF) b, is involved in differentiation of naïve CD4+ T cells to Th-17 cells, acting upstream of IL-23.17 IL-21 is highly expressed in the skin and peripheral blood of psoriatic patients and causes epidermal hyperplasia and inflammation when injected intradermally into mice. This cytokine has a different action in the immune system, such as controlling Th17 differentiation, both directly and by a positive autocrine loop in which IL-21 stimulates its own production and the expression of IL-23R.


Moreover, studies with human cells


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