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Kabashima - Pathogenesis with US VVMC code_disclaimer10May2021

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WHICH ARE THE IMMUNE PATHWAYS ASSOCIATED WITH AD PATHOGENESIS? Atopic dermatitis is an extremely heterogenous disease, with a complex pathophysiology involving both immune dysregulation and epidermal barrier dysfunction. It is thought to be triggered by environmental factors in genetically susceptible individuals. AD is a T-cell-driven disease. It was previously believed that the Th2 pathway was the main disease driver in the acute phase of AD, with a switch to Th1 in the chronic phase; however, recent research has shown that several Th-cell subsets are involved in both acute and chronic AD, including the Th1, Th2, Th17, and Th22 axes, with a progressive increase in activation across Th cell subsets as the chronicity of the disease progresses. WHICH CYTOKINES PLAY A KEY ROLE? There is a strong Th2 component in AD, associated with IL-4 and IL-13 overproduction. These cytokines play a key role in dysregulation of the skin barrier, downregulating numerous genes involved in epidermal barrier function, decreasing keratinocyte differentiation, and inhibiting Th1 (interferon-gamma) and Th17 (IL-17) skin defense mechanisms, therefore promoting skin microbiota dysbiosis, particularly Staphylococcus aureus colonization. IL-4 and IL-13 also promote B-cell immunoglobin E (IgE) class switching and production of antigen-specific IgE molecules, likely contributing to the allergic reactivity and disease flares seen in many AD patients. In addition, these cytokines are pruritogens which can act on cutaneous sensory neurons directly to stimulate itch. These Th2 cytokines are known to be produced by both Th2 cells and group 2 innate lymphoid cells. IL-31 is released by several type 2 immunity cells, such as Th2 cells, in skin lesions and can promote itch by directly stimulating cutaneous sensory neurons expressing the IL-31Rα subunit. Type 2 immune responses mediated by Th2 cytokines, such as IL-4, 5, and IL-13, are initiated at epithelial interfaces, where alarmins, such as IL-33, IL-25 and TSLP, activate innate lymphoid cells, Th2 cells and B-cells. The Th22 cytokine, IL-22, has been identified as a key mediator of epidermal hyperplasia in AD. Like IL-4 and IL-13, IL-22 reduces keratinocyte differentiation. Th17 T cells have particularly been implicated in the pathogenesis of AD in pediatric patients and Asian adults. The Asian phenotype of AD regularly includes more ‘psoriasiform’ disease characteristics than seen in European and American patients, with increased expression of IL-17 and interferon-gamma, but hallmark AD features, such as Th2-driven immunoglobin E allergic responses also remain common in these patients. WHY IS THE JAK-STAT PATHWAY IMPORTANT IN AD PATHOGENESIS? The pathogenesis of AD involves multiple inflammatory pathways, which consistently include the Th2 and Th22 cytokines, such as IL-4, IL-13, IL-31, and IL-22, and varying involvement of Th1 and Th17 cytokines, such as IFN-gamma and IL-17. The JAK-STAT pathway is one of a few pathways that is involved in modulating the immune pathways across these Th subsets. The JAK family comprises four types of cytoplasmic tyrosine kinase, JAK1, JAK2, JAK3, and TYK2, and these activate in pairs to phosphorylate STAT proteins; activated STATs translocate to the nucleus to activate gene transcription. These pairings differ depending on the activating cytokine. JAK1 pairs with JAK2 to mediate the signaling of IL-31 and TSLP, and pairs with JAK2 or TYK2 to mediate the signaling of IL-13, while IL-4 requires the pairing of JAK1 and JAK3. Modulating the signaling of these key cytokines involved in AD through targeting the JAK-STAT pathway therefore represents a viable therapeutic target for AD.

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Duration: 6 minutes and 11 seconds
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Language: English
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Posted by: gabriella61 on Dec 15, 2021

Kabashima - Pathogenesis with US VVMC code_disclaimer10May2021

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