A synthetic human antibody antagonizes IL-18Rβ signaling through an allosteric mechanism

Publication date: Available online 15 January 2020Source: Journal of Molecular BiologyAuthor(s): Shusu Liu, Shane Miersch, Ping Li, Bingxin Bai, Chunchun Liu, Wenming Qin, Jie Su, Haiming Huang, James Pan, Sachdev S. Sidhu, Donghui WuAbstractThe interleukin-18 subfamily belongs to the interleukin-1 family and plays important roles in modulating innate and adaptive immune responses. Dysregulation of IL-18 has been implicated in or correlated with numerous diseases including inflammatory diseases, autoimmune disorders and cancer. Thus, blockade of IL-18 signaling may offer therapeutic benefits in many pathological settings. Here, we report the development of synthetic human antibodies that target human IL-18Rβ and block IL-18-mediated IFN-γ secretion by inhibiting NF-κB and MAPK dependent pathways. The crystal structure of a potent antagonist antibody in complex with IL-18Rβ revealed inhibition through an unexpected allosteric mechanism. Our findings offer a novel means for therapeutic intervention in the IL-18 pathway and may provide a new strategy for targeting cytokine receptors.Graphical abstractBinding of scFv 3131 to IL-18Rβ blocks formation of the IL-18/IL-18Rα/IL-18Rβ ternary complex. Superposition of IL-18Rβ in complex with scFv 3131 (PDB code: 6KN9) on to the ternary complex (PDB code: 3WO4) was performed using the D3 domains of the two IL-18Rβ molecules as reference. In the IL-18Rβ/scFv 3131 complex, IL-18Rβ i...
Source: Journal of Molecular Biology - Category: Molecular Biology Source Type: research

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In conclusion, taller body height at the entry to adulthood, supposed to be a marker of early-life environment, is associated with lower risk of dementia diagnosis later in life. The association persisted when adjusted for educational level and intelligence test scores in young adulthood, suggesting that height is not just acting as an indicator of cognitive reserve. A Comparison of Biological Age Measurement Approaches https://www.fightaging.org/archives/2020/02/a-comparison-of-biological-age-measurement-approaches/ Researchers here assess the performance of a range of approaches to measuring biological...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
The field of Alzheimer's disease research is in the midst of a slow-moving and consequential debate over the role of infection in the development of the condition. The fundamental question is this: in the absence of genetic variants that raise risk, why do only some people progress to full blown Alzheimer's disease? The presence - in only some people - of sufficient degrees of persistent infection is one possible answer to that question. Candidates include herpesviruses, oral bacteria such as P. gingivalis, lyme disease spirochetes, and others. Alzheimer's is a condition characterized by amyloid-β aggregation i...
Source: Fight Aging! - Category: Research Authors: Tags: Medicine, Biotech, Research Source Type: blogs
Abstract TNF is a key proinflammatory and immunoregulatory cytokine whose deregulation is associated with the development of autoimmune diseases and other pathologies. Recent studies suggest that distinct functions of TNF may be associated with differential engagement of its two receptors: TNFR1 or TNFR2. In this review, we discuss the relative contributions of these receptors to pathogenesis of several diseases, with the focus on autoimmunity and neuroinflammation. In particular, we discuss the role of TNFRs in the development of regulatory T cells during neuroinflammation and recent findings concerning targeting...
Source: Journal of Leukocyte Biology - Category: Hematology Authors: Tags: J Leukoc Biol Source Type: research
We report the case of a 28-year-old man diagnosed with a mediastinal germ cell tumor 9 years after presenting with anti-Hu-positive limbic encephalitis.
Source: Neurology Neuroimmunology and Neuroinflammation - Category: Neurology Authors: Tags: Autoimmune diseases, Paraneoplastic syndrome Clinical/Scientific Notes Source Type: research
CONCLUSIONS: The topics here discussed prove the undisputed role of mAbs as innovative biopharmaceuticals molecules and as vital components of targeted pharmacological therapies. PMID: 32072887 [PubMed - as supplied by publisher]
Source: Current Medicinal Chemistry - Category: Chemistry Authors: Tags: Curr Med Chem Source Type: research
by Robin A. Welsh, Nianbin Song, Catherine A. Foss, Tatiana Boronina, Robert N. Cole, Scheherazade Sadegh-Nasseri DO (HLA-DO, in human; murine H2-O) is a highly conserved nonclassical major histocompatibility complex class II (MHC II) accessory molecule mainly expressed in the thymic medulla and B cells. Previous reports have suggested possible links between DO and autoimmunity, Hepatitis C (HCV) infection, a nd cancer, but the mechanism of how DO contributes to these diseases remains unclear. Here, using a combination of various in vivo approaches, including peptide elution, mixed lymphocyte reaction, T-cell receptor (TC...
Source: PLoS Biology: Archived Table of Contents - Category: Biology Authors: Source Type: research
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Source: Fight Aging! - Category: Research Authors: Tags: Investment Source Type: blogs
Authors: Chelvanambi M, Weinstein AM, Storkus WJ Abstract The ability of the immune system to prevent or control the growth of tumor cells is critically dependent on inflammatory processes that lead to the activation, expansion, and recruitment of antitumor effector cells into the tumor microenvironment (TME). These processes are orchestrated by soluble cytokines produced in tissues that alarm local immune surveillance cells (such as dendritic cells, DCs) to mobilize protective antitumor immune populations (B cells, T cells). The interleukin (IL)-36 family of pro-inflammatory cytokines plays an important role ...
Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
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Source: Sensors - Category: Biotechnology Authors: Tags: Review Source Type: research
Authors: Maria ATJ, Bourgier C, Martinaud C, Borie R, Rozier P, Rivière S, Crestani B, Guilpain P Abstract Fibrogenesis is a universal and ubiquitous process associated with tissue healing. The impairment of tissue homeostasis resulting from the deregulation of numerous cellular actors, under the effect of specific cytokine and pro-oxidative environments can lead to extensive tissue fibrosis, organ dysfunction and significant morbidity and mortality. This situation is frequent in internal medicine, since fibrosis is associated with most organ insufficiencies (i.e. cardiac, renal, or hepatic chronic failures)...
Source: Revue de Medecine Interne - Category: Internal Medicine Tags: Rev Med Interne Source Type: research
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