The role of IL-23 and the IL-23/TH17 immune axis in the pathogenesis and treatment of psoriasis
01 Oct 2017-Journal of The European Academy of Dermatology and Venereology (J Eur Acad Dermatol Venereol)-Vol. 31, Iss: 10, pp 1616-1626
TL;DR: A better understanding of the IL‐23/TH17 immune axis is vital and will promote the development of additional targets for psoriasis and other inflammatory diseases that share similar genetic aetiology and pathogenetic pathways.
Abstract: Psoriasis is a chronic, immune-mediated disease affecting more than 100 million people worldwide and up to 2.2% of the UK population. The aetiology of psoriasis is thought to originate from an interplay of genetic, environmental, infectious and lifestyle factors. The manner in which genetic and environmental factors interact to contribute to the molecular disease mechanisms has remained elusive. However, the interleukin 23 (IL-23)/T-helper 17 (TH 17) immune axis has been identified as a major immune pathway in psoriasis disease pathogenesis. Central to this pathway is the cytokine IL-23, a heterodimer composed of a p40 subunit also found in IL-12 and a p19 subunit exclusive to IL-23. IL-23 is important for maintaining TH 17 responses, and levels of IL-23 are elevated in psoriatic skin compared with non-lesional skin. A number of agents that specifically inhibit IL-23p19 are currently in development for the treatment of moderate-to-severe plaque psoriasis, with recent clinical trials demonstrating efficacy with a good safety and tolerability profile. These data support the role of this cytokine in the pathogenesis of psoriasis. A better understanding of the IL-23/TH 17 immune axis is vital and will promote the development of additional targets for psoriasis and other inflammatory diseases that share similar genetic aetiology and pathogenetic pathways.
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TL;DR: The immunologic role of interleukin (IL)-17, the major effector cytokine in the pathogenesis of psoriatic disease, is reviewed, along with the rationale for targeting the IL-17 cytokine family (IL-17A, Il-17F, and IL- 17 receptor A) in the treatment of psoriasis and psoratic arthritis.
Abstract: Psoriasis is a chronic, immune-mediated, inflammatory disease that is pathogenically driven by proinflammatory cytokines. This article reviews the immunologic role of interleukin (IL)-17, the major effector cytokine in the pathogenesis of psoriatic disease, along with the rationale for targeting the IL-17 cytokine family (IL-17A, IL-17F, and IL-17 receptor A) in the treatment of psoriasis and psoriatic arthritis. Emerging evidence indicates that major sources of IL-17A in patients with psoriatic disease are mast cells, γδ T cells, αβ T cells, and innate lymphoid cells in lesional skin and synovial fluid. Within the skin and joints, IL-17A acts on cellular targets, including keratinocytes, neutrophils, endothelial cells, fibroblasts, osteoclasts, chondrocytes, and osteoblasts, to stimulate production of various antimicrobial peptides, chemokines, and proinflammatory and proliferative cytokines, which, in turn, promote tissue inflammation and bone remodeling. The critical importance of the IL-23/IL-17A axis to the pathogenesis of psoriatic disease has resulted in many new biologic treatments targeting these cytokines. These biologics dramatically improve skin and joint symptoms in patients with moderate-to-severe psoriasis and psoriatic arthritis.
372 citations
TL;DR: The current review emphasizes the aberrant interplay of immune cells and skin-resident keratinocytes in establishing and sustaining inflammatory and immune responses in psoriasis.
Abstract: Psoriasis is a chronic inflammatory skin disease resulting from genetic, epigenetic, environmental, and lifestyle factors. To date, several immunopathogenic mechanisms of psoriasis have been elucidated, and, in the current model, the cross talk between autoreactive T cells and resident keratinocytes generates inflammatory and immune circuits responsible for the initiation, progression, and persistence of the disease. Several autoantigens derived from keratinocytes (i.e., LL37 cathelecidin/nucleic acid complexes, newly generated lipid antigens) have been identified, which may trigger initial activation of T cells, particularly IL-17-producing T cells, T helper (Th)1 and Th22 cells. Hence, lymphokines released in skin lesions are pivotal for keratinocyte activation and production of inflammatory molecules, which in turn lead to amplification of the local immune responses. Intrinsic genetic alterations of keratinocytes in the activation of signal transduction pathways dependent on T-cell-derived cytokines are also fundamental. The current review emphasizes the aberrant interplay of immune cells and skin-resident keratinocytes in establishing and sustaining inflammatory and immune responses in psoriasis.
240 citations
Cites background from "The role of IL-23 and the IL-23/TH1..."
...T-cell infiltrate present in active psoriatic skin establishes a cytokine milieu that dictates specific gene signatures in keratinocytes, which, thus, overexpress several inflammatory mediators amplifying local immune reactions (12, 13)....
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...J Invest Dermatol (2011) 131(12):2428–37....
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TL;DR: This review comments on epidemiologic, genetic, and mechanistic studies that analyzed the relation between psoriasis and cardiovascular comorbidity, and the hypothesis of Psoriasis potentially being an independent cardiovascular risk factor, driving atherosclerosis via inflammation-induced endothelial dysfunction will be discussed.
Abstract: Psoriasis is a common inflammatory skin disease characterized by the appearance of red scaly plaques that can affect any part of the body. High prevalence, chronicity, disfiguration, disability, and associated comorbidity make it a challenge for clinicians of multiple specialties. Likewise, its complex pathogenesis, comprising inflammation, hyperproliferation, and angioneogenesis, intrigues numerous scientific disciplines, namely, immunology. From a clinical perspective, the severity of psoriasis is highlighted by its increased mortality, with cardiovascular diseases contributing the highest excess risk. From a scientific point of view, psoriasis has to be considered a systemic inflammatory condition, as blood biomarkers of inflammation are elevated and imaging techniques document sites of inflammation beyond the skin. While the association of psoriasis with cardiovascular diseases is now widely accepted, causes and consequences of this association are controversially discussed. This review comments on epidemiologic, genetic, and mechanistic studies that analyzed the relation between psoriasis and cardiovascular comorbidity. The hypothesis of psoriasis potentially being an independent cardiovascular risk factor, driving atherosclerosis via inflammation-induced endothelial dysfunction, will be discussed. Finally, consequences for the management of psoriasis with the objective to reduce the patients' excess cardiovascular risk will be pointed out.
169 citations
Cites background from "The role of IL-23 and the IL-23/TH1..."
...Then, the role of TH17 lymphocytes was stressed in the light of clinical studies documenting the high clinical efficacy of therapies targeting the IL-17 pathway (76)....
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TL;DR: Guselkumab demonstrated a favourable benefit-risk profile and might be an effective treatment option for patients with active psoriatic arthritis.
166 citations
TL;DR: This review sets into context the current knowledge about innate and adaptive immunological processes in psoriasis and other autoimmune or autoinflammatory diseases.
Abstract: Over the past three decades, a considerable body of evidence has highlighted T cells as pivotal culprits in the pathogenesis of psoriasis This includes the association of psoriasis with certain MHC (HLA) alleles, oligoclonal expansion of T cells in some cases, therapeutic response to T cell-directed immunomodulation, the onset of psoriasis following bone marrow transplantation, or induction of psoriasis-like inflammation by T cells in experimental animals There is accumulating clinical and experimental evidence suggesting that both autoimmune and autoinflammatory mechanisms lie at the core of the disease Indeed, some studies suggested antigenic functions of structural proteins, and complexes of self-DNA with cathelicidin (LL37) or melanocytic ADAMTSL5 have been proposed more recently as actual auto-antigens in some cases of psoriasis These findings are accompanied by various immunoregulatory mechanisms, which we increasingly understand and which connect innate and adaptive immunity Specific adaptive autoimmune responses, together with our current view of psoriasis as a systemic inflammatory disorder, raise the question of whether psoriasis may have connections to autoimmune or autoinflammatory disorders elsewhere in the body While such associations have been suspected for many years, compelling mechanistic evidence in support of this notion is still scant This review sets into context the current knowledge about innate and adaptive immunological processes in psoriasis and other autoimmune or autoinflammatory diseases
110 citations
References
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