Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease

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dc.contributor.authorOzen, Ahmet
dc.contributor.authorKasap, Nurhan
dc.contributor.authorVujkovic-Cvijin, Ivan
dc.contributor.authorApps, Richard
dc.contributor.authorCheung, Foo
dc.contributor.authorKarakoc-Aydiner, Elif
dc.contributor.authorAkkelle, Bilge
dc.date.accessioned2024-02-23T14:16:44Z
dc.date.available2024-02-23T14:16:44Z
dc.date.issued2021
dc.departmentNEÜen_US
dc.description.abstractCHAPLE disease is a lethal syndrome caused by genetic loss of the complement regulatory protein CD55. Lenardo, Ozen and their colleagues report that blockade of C5 complement activation in a small cohort of pediatric patients with CHAPLE disease reduced gastrointestinal pathology and restored their immunity and growth. Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.en_US
dc.description.sponsorshipDivision of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, BCBB Support Services [HHSN316201300006W/HHSN27200002]; Marmara University, Scientific Research Projects Committee (BAPKO) [SAG-C-TUP-230119-0018]; NIAID Microbiome Program, NIAID, NIH; NIH [R01-GM129325]en_US
dc.description.sponsorshipThis work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, BCBB Support Services Contract HHSN316201300006W/HHSN27200002, and The Marmara University, Scientific Research Projects Committee (BAPKO, grant no. SAG-C-TUP-230119-0018). We thank the Turkish National Society of Allergy and Clinical Immunology (TNSACI) for supporting travel expenses for the screening studies. We thank C. Kemper of the National Heart, Lung and Blood Institute for thoughtful editing of the final manuscript. We thank M. Quinones, the Center for Human Immunology and the NIAID Microbiome Program, NIAID, NIH, for research support. We also thank A. Kiykim for patient care, A. Dalga and I. Tatli for technical assistance and H. Su and X. He for advice and assistance; D. Comrie, S. Kubo and J. Ravell for critical reading of the manuscript; and R. Kissinger for artwork. We thank important colleagues at Regeneron: A. N. Thomas for sample processing; C. Huang for biomarker analysis; H. Qiu, and E. Sook Yen for eculizumab analysis; and C. H. Lai, L. DeStefano and K. Donohue for total C5 analysis. Molecular graphics and analyses were performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization and Informatics at the University of California, San Francisco, with support from NIH R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, NIAID.en_US
dc.identifier.doi10.1038/s41590-020-00830-z
dc.identifier.endpageU24en_US
dc.identifier.issn1529-2908
dc.identifier.issn1529-2916
dc.identifier.issue2en_US
dc.identifier.pmid33398182en_US
dc.identifier.scopus2-s2.0-85098779482en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage128en_US
dc.identifier.urihttps://doi.org/10.1038/s41590-020-00830-z
dc.identifier.urihttps://hdl.handle.net/20.500.12452/12763
dc.identifier.volume22en_US
dc.identifier.wosWOS:000604865800004en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherNature Portfolioen_US
dc.relation.ispartofNature Immunologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject[Keyword Not Available]en_US
dc.titleBroadly effective metabolic and immune recovery with C5 inhibition in CHAPLE diseaseen_US
dc.typeArticleen_US

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