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Il-23 and psoriasis

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https://www.readbyqxmd.com/read/27905482/pharmacologic-modulation-of-ror%C3%AE-t-translates-to-efficacy-in-preclinical-and-translational-models-of-psoriasis-and-inflammatory-arthritis
#1
Xiaohua Xue, Pejman Soroosh, Aimee De Leon-Tabaldo, Rosa Luna-Roman, Marciano Sablad, Natasha Rozenkrants, Jingxue Yu, Glenda Castro, Homayon Banie, Wai-Ping Fung-Leung, Luis Santamaria-Babi, Thomas Schlueter, Michael Albers, Kristi Leonard, Alison L Budelsky, Anne M Fourie
The IL-23/IL-17 pathway is implicated in autoimmune diseases, particularly psoriasis, where biologics targeting IL-23 and IL-17 have shown significant clinical efficacy. Retinoid-related orphan nuclear receptor gamma t (RORγt) is required for Th17 differentiation and IL-17 production in adaptive and innate immune cells. We identified JNJ-54271074, a potent and highly-selective RORγt inverse agonist, which dose-dependently inhibited RORγt-driven transcription, decreased co-activator binding and promoted interaction with co-repressor protein...
December 1, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27892456/il-12-protects-from-psoriasiform-skin-inflammation
#2
Paulina Kulig, Stephanie Musiol, Sandra Nicole Freiberger, Bettina Schreiner, Gabor Gyülveszi, Giancarlo Russo, Stanislav Pantelyushin, Kenji Kishihara, Francesca Alessandrini, Thomas Kündig, Federica Sallusto, Günther F L Hofbauer, Stefan Haak, Burkhard Becher
Neutralization of the common p40-subunit of IL-12/23 in psoriasis patients has led to a breakthrough in the management of moderate to severe disease. Aside from neutralizing IL-23, which is thought to be responsible for the curative effect, anti-p40 therapy also interferes with IL-12 signalling and type 1 immunity. Here we dissect the individual contribution of these two cytokines to the formation of psoriatic lesions and understand the effect of therapeutic co-targeting of IL-12 and IL-23 in psoriasis. Using a preclinical model for psoriatic plaque formation we show that IL-12, in contrast to IL-23, has a regulatory function by restraining the invasion of an IL-17-committed γδT (γδT17) cell subset...
November 28, 2016: Nature Communications
https://www.readbyqxmd.com/read/27883001/psoriasis
#3
Jacqueline E Greb, Ari M Goldminz, James T Elder, Mark G Lebwohl, Dafna D Gladman, Jashin J Wu, Nehal N Mehta, Andrew Y Finlay, Alice B Gottlieb
Psoriasis is a chronic, immune-mediated disorder with cutaneous and systemic manifestations and substantial negative effects on patient quality of life. Psoriasis has a strong, albeit polygenic, genetic basis. Whereas approximately half of the accountable genetic effect of psoriasis maps to the major histocompatibility complex, >70 other loci have been identified, many of which implicate nuclear factor-κB, interferon signalling and the IL-23-IL-23 receptor axis. Psoriasis pathophysiology is characterized by abnormal keratinocyte proliferation and immune cell infiltration in the dermis and epidermis involving the innate and adaptive immune systems, with important roles for dendritic cells and T cells, among other cells...
November 24, 2016: Nature Reviews. Disease Primers
https://www.readbyqxmd.com/read/27868150/clinical-efficiency-of-topical-calcipotriol-betamethasone-treatment-in-psoriasis-relies-on-suppression-of-the-inflammatory-tnf%C3%AE-il-23-il-17-axis
#4
Minna E Kubin, Nina Kokkonen, Riitta Palatsi, Päivi M Hägg, Juha P Väyrynen, Virpi Glumoff, Kirsi-Maria Haapasaari, Tiina Hurskainen, Kaisa Tasanen
The effects of topical calcipotriol/betamethasone combination therapy and betamethasone monotherapy on inflammatory T cell numbers and molecular markers were compared in patients with psoriasis. Combination therapy down-regulated the expression of tumour necrosis factor (TNF)-α, interleukin (IL)-23A, IL-17A, S100A7, CCL-20 and interferon (IFN)-γ in skin and TNF-α, IL-6, IL-23A, T-bet and IFN-γ in peripheral blood mononuclear cells (PBMCs). Betamethasone monotherapy had less effect. Expression of FoxP3 in both skin and PBMCs was down-regulated by calcipotriol/betamethasone, but not by betamethasone...
November 21, 2016: Acta Dermato-venereologica
https://www.readbyqxmd.com/read/27836567/management-of-psoriatic-arthritis-early-diagnosis-monitoring-of-disease-severity-and-cutting-edge-therapies
#5
REVIEW
Siba P Raychaudhuri, Reason Wilken, Andrea C Sukhov, Smriti K Raychaudhuri, Emanual Maverakis
Psoriatic arthritis (PsA) is a heterogeneous disease that can involve a variety of distinct anatomical sites including a patient's peripheral and axial joints, entheses, skin and nails. Appropriate management of PsA requires early diagnosis, monitoring of disease activity, and utilization of cutting edge therapies. To accomplish the former there are a variety of PsA-specific tools available to screen, diagnose, and assess patients. This review will outline the recently developed PsA screening tools, including the Toronto Psoriatic Arthritis Screening Questionnaire (TOPAS), the Psoriasis Epidemiology Screening Tool (PEST), the Psoriatic Arthritis Screening and Evaluation (PASE), and the Psoriasis and Arthritis Screening Questionnaire (PASQ)...
November 8, 2016: Journal of Autoimmunity
https://www.readbyqxmd.com/read/27824222/association-between-endocrinological-immunological-and-psychosocial-variables-in-psoriasis-patients
#6
Özlem Bilgiç, Ayhan Bilgiç, Abdullah Sivrikaya, Yavuz Selvi, Ali Ünlü, Hilmi C Altinyazar
BACKGROUND: There is limited data concerning the relationship between psychosocial problems of psoriasis patients and the function of their hypothalamic-pituitary-adrenal (HPA) axis and immunologic markers. This study aimed to determine serum levels of basal cortisol and adrenocorticotropic hormone (ACTH) and circulating levels of various cytokines and chemokines and their association with psychological measures in psoriasis patients. METHODS: Serum concentrations of endocrinological and immunological variables were quantified, and psychiatric questionnaires were completed...
December 2016: Giornale Italiano di Dermatologia e Venereologia: Organo Ufficiale, Società Italiana di Dermatologia e Sifilografia
https://www.readbyqxmd.com/read/27810232/potential-role-of-il-17-producing-cd4-cd8-double-negative-%C3%AE-%C3%AE-t-cells-in-psoriatic-skin-inflammation-in-a-tpa-induced-stat3c-transgenic-mouse-model
#7
Azumi Ueyama, Chihiro Imura, Yasuyuki Fusamae, Kenichiro Tsujii, Yoko Furue, Miwa Aoki, Minoru Suzuki, Tomohiko Okuda, Itsuki Oshima, Kiyoshi Yasui, Michitaka Shichijo, Mina Yamamoto
BACKGROUND: Psoriasis is one of the most common immune-mediated chronic inflammatory skin disorders and is accompanied by erythematous scaly plaques. There is growing evidence that the IL-23/Th17 axis plays a critical role in development of the disease. It was recently shown that in addition to CD4(+) Th17 cells, various IL-17-producing cell subsets such as CD8(+) Tc17 cells, dermal γδ T cells, and innate lymphoid cells are also involved in the development of psoriatic inflammation in humans...
October 19, 2016: Journal of Dermatological Science
https://www.readbyqxmd.com/read/27765025/staphylococcus-aureus-bacteremia-with-iliac-artery-endarteritis-in-a-patient-receiving-ustekinumab
#8
Insa Joost, Johannes Steinfurt, Philipp T Meyer, Winfried V Kern, Siegbert Rieg
BACKGROUND: Ustekinumab (Stelara®), a human monoclonal antibody targeting the p40-subunit of interleukin (IL)-12 and IL-23, is indicated for moderate to severe plaque psoriasis and psoriatic arthritis. In large multicenter, prospective trials assessing efficacy and safety of ustekinumab increased rates of severe infections have not been observed so far. CASE PRESENTATION: Here, we report the case of a 64-year old woman presenting with chills, pain and swelling of her right foot with dark maculae at the sole, and elevated inflammatory markers...
October 20, 2016: BMC Infectious Diseases
https://www.readbyqxmd.com/read/27743912/palmoplantar-pustular-psoriasis-pppp-is-characterized-by-activation-of-the-il-17a-pathway
#9
Robert Bissonnette, Judilyn Fuentes-Duculan, Shunya Mashiko, Xuan Li, Kathleen M Bonifacio, Inna Cueto, Mayte Suárez-Fariñas, Catherine Maari, Chantal Bolduc, Simon Nigen, Marika Sarfati, James G Krueger
BACKGROUND: Palmoplantar pustular psoriasis (PPPP) is a variant of psoriasis, which has significant negative impact on quality of life. The cellular and molecular inflammatory pathways involved in PPPP have not been well studied. OBJECTIVE: Study the expression of cytokines and chemokines involved in the IL-17/IL-23 axis in palmoplantar pustular psoriasis and other difficult to treat psoriasis areas (palms, scalp, elbows and lower legs). METHODS: Skin biopsies were performed on a total of 80 patients with PPPP, non-pustular palmoplantar psoriasis (NPPPP), or psoriasis located on elbows, knees and scalp as well as 10 healthy subjects...
September 29, 2016: Journal of Dermatological Science
https://www.readbyqxmd.com/read/27734413/regulation-of-interleukin-23-expression-in-health-and-disease
#10
Iain Welsby, Stanislas Goriely
Interleukin (IL)-23 plays a central role in the orchestration of inflammatory responses. Produced by dendritic cells and macrophages, this cytokine promotes the protection of the host against mucosal pathogens through the induction of IL-17 and related cytokines by lymphoid cells. Preclinical disease models and association studies in humans have also clearly demonstrated the implication of IL-23 signalling pathway in inflammatory diseases. Indeed, this cytokine is now considered as a major therapeutic target in immune-based pathologies such as psoriasis, ankylosing spondylitis or Crohn's disease...
2016: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27730667/a-successful-treatment-with-ustekinumab-in-a-case-of-relapsing-bullous-pemphigoid-associated-with-psoriasis
#11
J Loget, J Plee, F Antonicelli, P Bernard
Predisposing factors for bullous pemphigoid (BP), the most common autoimmune blistering disease, include neurological disorders, chronic use of certain drugs (spironolactone, loop diuretics, psycholeptics).(1) The coexistence of psoriasis with classical BP is occasionally observed, whereas half of the patient population with anti-laminin γ1 pemphigoid of Japanese origin have coexisting psoriasis.(2-3) We report for the first time a case of relapsing BP associated with psoriasis, in which both dermatoses completely disappeared after treatment with ustekinumab, a monoclonal antibody that targets the p40 subunit of IL-12/23...
October 12, 2016: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/27726924/oral-administration-of-a-novel-ror%C3%AE-t-antagonist-attenuates-psoriasis-like-skin-lesion-of-two-independent-mouse-models-through-neutralization-of-il-17
#12
Mikiro Takaishi, Masayuki Ishizaki, Keisuke Suzuki, Takashi Isobe, Takaichi Shimozato, Shigetoshi Sano
BACKGROUND: Targeting the IL-17 pathway represents a highly effective strategy for the treatment of psoriasis, using antibodies against IL-17A and IL-17 receptor, suggesting that Th17 cells essentially contribute to development of psoriasis. Th17 differentiation depends on the key transcription factor, RORγt. OBJECTIVE: To develop a novel RORγt antagonist which is effective on psoriasis via oral administration. METHODS: A chemical library was screened using cell-based high-throughput methods, luciferase reporter assay, competitive binding assay, and T cell differentiation assay...
October 3, 2016: Journal of Dermatological Science
https://www.readbyqxmd.com/read/27718760/brodalumab-for-the-treatment-of-psoriasis
#13
M Galluzzo, S D'Adamio, L Bianchi, M Talamonti
Psoriasis is a complex disease in which the alteration of the IL-23/Th17 axis appears to be crucial for its pathogenic mechanisms, and anti-IL17 agents are rapidly becoming important therapeutic tools. Brodalumab, a fully human Chinese hamster ovary cell-derived immunoglobulin G2 (IgG2) anti-IL-17RA monoclonal antibody, is currently the most-developed treatment that binds to the IL-17RA. The authors review and provide updates of efficacy and safety by several studies on brodalumab. Areas covered: A PubMed search was performed for relevant literature...
October 10, 2016: Expert Review of Clinical Immunology
https://www.readbyqxmd.com/read/27702671/major-differences-between-human-atopic-dermatitis-and-murine-models-as-determined-by-global-transcriptomic-profiling
#14
David A Ewald, Shinji Noda, Margeaux Oliva, Thomas Litman, Saeko Nakajima, Xuan Li, Hui Xu, Peter Scheipers, Naila Svitacheva, Tord Labuda, James G Krueger, Mayte Suárez-Fariñas, Kenji Kabashima, Emma Guttman-Yassky
BACKGROUND: Atopic dermatitis (AD) is caused by a complex interplay between immune and barrier abnormalities. Murine models of AD are essential for preclinical assessments of new treatments. While many models have been used to simulate AD, their transcriptomic profiles are not fully understood, and a comparison of these models with the human AD transcriptomic fingerprint is lacking. OBJECTIVE: We sought to evaluate the transcriptomic profiles of six common murine models and determine how they relate to human AD skin...
October 1, 2016: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/27697724/suppressive-effect-of-%C3%AE-%C3%AE-dimethylacryloyl-alkannin-on-activated-dendritic-cells-in-psoriasis-by-the-tlr7-8-pathway
#15
Yan Wang, Jingxia Zhao, Tingting Di, Mingxing Wang, Zhitong Ruan, Lu Zhang, Xiangjiang Xie, Yujiao Meng, Yan Lin, Xin Liu, Ning Wang, Ping Li
β,β-dimethylacryloyl alkannin (DMA) is a key component of Lithospermum and possesses good efficacy for treating psoriasis. DMA inhibits activated dendritic cells (DCs), but the mechanism is unknown. Therefore, this study aimed to explore the modulation of the TLR7/8 pathway by DMA in psoriasis-activated DCs. Models of psoriasis-like skin lesions were established using BALB/c mice; 8 mice were treated with DMA (2.5mg/kg). Bone marrow cells were isolated and induced into DCs using R848, a TLR7/8 agonist. Splenic CD11c+ cells were detected by flow cytometry...
September 30, 2016: International Immunopharmacology
https://www.readbyqxmd.com/read/27690678/targeted-therapies-what-they-teach-us-about-the-pathogenesis-of-psoriasis-and-psoriatic-arthritis
#16
Wang Sin Gina Tan, Stephen Kelly, Constantino Pitzalis
Biologic therapy has revolutionized treatment pathways in psoriatic joint and skin disease. It has also provided a useful tool with which pathological pathways of this condition may be explored. Areas Covered: This review presents data on the clinical and biological effects of targeted therapy in psoriatic arthritis and psoriasis. Therapeutic agents covered include inhibitors of TNFα, inhibitors of the IL-23/IL-17 axis and inhibitors of intracellular small molecules involved in the transduction of the inflammatory signal...
October 3, 2016: Expert Review of Clinical Immunology
https://www.readbyqxmd.com/read/27686018/highly-effective-new-treatments-for-psoriasis-target-the-il-23-type-17-t-cell-autoimmune-axis
#17
Jaehwan Kim, James G Krueger
Psoriasis vulgaris, affecting the skin, is one of the most common organspecific autoimmune diseases in humans. Until recently, psoriasis was treated by agents or approaches discovered largely through serendipity. Many of the available drugs were inherently quite toxic when used as continuous treatment for many years in this chronic disease. However, an increasing understanding of disease-specific immune pathways has spurred development of pathway-targeted therapeutics during the past decade. Psoriasis is now the most effectively treated human autoimmune disease, with high-level clinical improvements possible in ∼90% of patients using a new generation of drugs that selectively target the IL-23/Type 17 T cell axis...
September 23, 2016: Annual Review of Medicine
https://www.readbyqxmd.com/read/27671649/keratinocytes-contribute-intrinsically-to-psoriasis-upon-loss-of-tnip1-function
#18
Sirish K Ippagunta, Ruchika Gangwar, David Finkelstein, Peter Vogel, Stephane Pelletier, Sebastien Gingras, Vanessa Redecke, Hans Häcker
Psoriasis is a chronic inflammatory skin disease with a clear genetic contribution, characterized by keratinocyte proliferation and immune cell infiltration. Various closely interacting cell types, including innate immune cells, T cells, and keratinocytes, are known to contribute to inflammation. Innate immune cells most likely initiate the inflammatory process by secretion of IL-23. IL-23 mediates expansion of T helper 17 (Th17) cells, whose effector functions, including IL-17A, activate keratinocytes. Keratinocyte activation in turn results in cell proliferation and chemokine expression, the latter of which fuels the inflammatory process through further immune cell recruitment...
October 11, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27666819/are-psoriasis-and-psoriatic-arthritis-the-same-disease-the-il-23-il-17-axis-data
#19
Lazaros I Sakkas, Dimitrios P Bogdanos
Psoriatic arthritis (PsA) is a psoriasis (Ps)-associated inflammatory joint disease that affects peripheral joints, entheses, spine, and eyes. PsA and Ps are likely to be the same disease. PsA develops in nearly 70% of patients with Ps, and the hallmark of the disease is bone erosions and bone formation. Both innate and adaptive immunity appear to contribute to pathogenesis of PsA and Ps. Trauma may be a trigger factor for both PsA and Ps. The same T cell clones were reported to be present in both synovial tissues and skin lesions suggesting that a common antigen drives T cell immune response in the joints and skin lesions of patients with PsA...
September 22, 2016: Autoimmunity Reviews
https://www.readbyqxmd.com/read/27641916/functional-genomics-and-its-bench-to-bedside-translation-pertaining-to-the-identified-susceptibility-alleles-and-loci-in-ankylosing-spondylitis
#20
REVIEW
Tony J Kenna, Aimee Hanson, Mary-Ellen Costello, Matthew A Brown
Ankylosing spondylitis (AS) is a highly heritable disease for which there is a great unmet need for improved therapies. Genetics research has identified several major pathways involved in the disease, from which treatments have either now entered clinical practice or are in development. In particular, therapies targeting the IL-23 pathway were repositioned for use in AS following the discovery of multiple genes in the pathway as determinants of AS risk. Discovery of the association of aminopeptidase genes with AS, and subsequently with psoriasis, inflammatory bowel disease and other conditions, has triggered research into therapies targeting this pathway...
October 2016: Current Rheumatology Reports
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