更新于：2024-11-01

IL-27 x IL6RB

更新于：2024-11-01

基本信息

关联

项与 IL-27 x IL6RB 相关的药物

Anti gp130/IL27 bispecific antibody(Pfizer)

靶向gp130/IL27双特异性抗体(辉瑞)

靶点

IL-27 x IL6RB

作用机制

IL-27抑制剂 [+1]

在研机构

Pfizer Inc.

原研机构

Pfizer Inc.

在研适应症

炎症性肠病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 IL-27 x IL6RB 相关的临床结果

登录后查看更多信息

100 项与 IL-27 x IL6RB 相关的转化医学

登录后查看更多信息

0 项与 IL-27 x IL6RB 相关的专利（医药）

登录后查看更多信息

项与 IL-27 x IL6RB 相关的文献（医药）

2022-08-01·Psychiatric Genetics4区 · 医学

Variants of Th17 pathway-related genes influence brain morphometric changes and the risk of schizophrenia through epistatic interactions

4区 · 医学

Article

作者: Subbanna, Manjula ; Varambally, Shivarama ; Debnath, Monojit ; Shivakumar, Venkataram ; Venkatasubramanian, Ganesan ; Bhalerao, Gaurav

ObjectiveT helper 17 (Th17) pathway has been reported to be abnormal in schizophrenia; however, it is not known whether variation within genes of this pathway has any impact on schizophrenia. Herein, the impact of genetic variations and gene–gene interactions of Th17 pathway-related genes on the risk, psychopathology, and brain volume was examined in schizophrenia patients.MethodsFunctional polymorphisms within interleukin 6 (IL6)(rs1800795 and rs1800797), IL10 (rs1800872 and rs1800896), IL17A (rs2275913 and rs8193036), IL22 (rs2227484 and rs2227485), IL23R (rs1884444), and IL27 (rs153109 and rs181206) genes were studied in 224 schizophrenia patients and 226 healthy controls. These variants were correlated with the brain morphometry, analyzed using MRI in a subset of patients (n = 117) and controls (n = 137).ResultsPatients carrying CC genotype of rs2227484 of IL22 gene had significantly higher apathy total score [F (1,183) = 5.60; P = 0.019; partial ɳ2 = 0.030]. Significant epistatic interactions between IL6 (rs1800797) and IL17A (rs2275913) genes were observed in schizophrenia patients. GG genotype of rs2275913 of IL17A gene was associated with reduced right middle occipital gyrus volume in schizophrenia patients (T = 4.56; P < 0.001).ConclusionInteractions between genes of Th17 pathway impact the risk for schizophrenia. The variants of Th17 pathway-related genes seem to have a determining effect on psychopathology and brain morphometric changes in schizophrenia.

2021-08-01·Journal of Allergy and Clinical Immunology1区 · 医学

Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome

1区 · 医学

Article

作者: Michael D.W. Griffin ; Tracy L. Putoczki ; Shruti Marwaha ; Chunli Zhao ; Christine M. Eng ; Jonathan A. Bernstein ; Veerabahu Shanmugasundaram ; Arian Laurence ; Colleen McCormack ; Lisa Gartner ; Riley D. Metcalfe ; Freia Krause ; Dirk Schmidt-Arras ; Laure Fresard ; Craig J. Morton ; Matthew T. Wheeler ; Stephen B. Montgomery ; Yong Huang ; Yin-Huai Chen ; Elizabeth A. Worthey ; Paul G. Fisher ; David Bick ; Holm H. Uhlig ; Diane B. Zastrow ; Euan A. Ashley ; Jessica Gold ; Michael W. Parker

BACKGROUNDBiallelic variants in IL6ST, encoding GP130, cause a recessive form of hyper-IgE syndrome (HIES) characterized by high IgE level, eosinophilia, defective acute phase response, susceptibility to bacterial infections, and skeletal abnormalities due to cytokine-selective loss of function in GP130, with defective IL-6 and IL-11 and variable oncostatin M (OSM) and IL-27 levels but sparing leukemia inhibitory factor (LIF) signaling.OBJECTIVEOur aim was to understand the functional and structural impact of recessive HIES-associated IL6ST variants.METHODSWe investigated a patient with HIES by using exome, genome, and RNA sequencing. Functional assays assessed IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF signaling. Molecular dynamics simulations and structural modeling of GP130 cytokine receptor complexes were performed.RESULTSWe identified a patient with compound heterozygous novel missense variants in IL6ST (p.Ala517Pro and the exon-skipping null variant p.Gly484_Pro518delinsArg). The p.Ala517Pro variant resulted in a more profound IL-6- and IL-11-dominated signaling defect than did the previously identified recessive HIES IL6ST variants p.Asn404Tyr and p.Pro498Leu. Molecular dynamics simulations suggested that the p.Ala517Pro and p.Asn404Tyr variants result in increased flexibility of the extracellular membrane-proximal domains of GP130. We propose a structural model that explains the cytokine selectivity of pathogenic IL6ST variants that result in recessive HIES. The variants destabilized the conformation of the hexameric cytokine receptor complexes, whereas the trimeric LIF-GP130-LIFR complex remained stable through an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site in GP130 consequently caused additional defective LIF signaling and Stüve-Wiedemann syndrome.CONCLUSIONOur data provide a structural basis to understand clinical phenotypes in patients with IL6ST variants.

2020-03-02·Journal of Experimental Medicine1区 · 医学

Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome

1区 · 医学

Article

作者: Batkovskyte, Dominyka ; Grigelioniene, Giedre ; Abdulwahab, Firdous ; Jedrycha, Katarina ; Alkuraya, Fowzan S. ; Huber, Celine ; Chen, Yin-Huai ; Aschenbrenner, Dominik ; Kurdi, Wesam I.Y. ; Hamel, Ben ; Hammarsjö, Anna ; Cormier-Daire, Valérie ; Nishimura, Gen ; Devey, Luke ; Gisselsson, David ; Shanmugasundaram, Veerabahu ; Bacrot, Séverine ; Gullander, Jacob ; Newton, Phillip T. ; Brodszki, Jana ; Uhlig, Holm H. ; Elfving, Maria ; Laurence, Arian ; Chagin, Andrei S. ; Alsaif, Hessa S. ; Papadogiannakis, Nikos ; Gürtl-Lackner, Barbara

The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann–like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development.