Discrete class I molecules on brain endothelium differentially regulate neuropathology in experimental cerebral malaria.

التفاصيل البيبلوغرافية
العنوان:	Discrete class I molecules on brain endothelium differentially regulate neuropathology in experimental cerebral malaria.
المؤلفون:	Fain CE; Department of Immunology, Mayo Clinic, Rochester, MN 55905USA.; Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905USA., Zheng J; Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905USA.; Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905USA., Jin F; Department of Immunology, Mayo Clinic, Rochester, MN 55905USA., Ayasoufi K; Department of Immunology, Mayo Clinic, Rochester, MN 55905USA., Wu Y; Department of Immunology, Mayo Clinic, Rochester, MN 55905USA.; Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905USA., Lilley MT; Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905USA., Dropik AR; Department of Immunology, Mayo Clinic, Rochester, MN 55905USA.; Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905USA., Wolf DM; Department of Immunology, Mayo Clinic, Rochester, MN 55905USA., Rodriguez RC; Department of Immunology, Mayo Clinic, Rochester, MN 55905USA., Aibaidula A; Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905USA.; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905USA., Tritz ZP; Department of Immunology, Mayo Clinic, Rochester, MN 55905USA.; Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905USA., Bouchal SM; Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905USA., Pewe LL; Department of Pathology, University of Iowa, Iowa City, IA 52242USA., Urban SL; Department of Pathology, University of Iowa, Iowa City, IA 52242USA., Chen Y; Department of Immunology, Mayo Clinic, Rochester, MN 55905USA.; Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905USA., Chang SY; Department of Neurosurgery, Mayo Clinic, Rochester, MN 55905USA., Hansen MJ; Department of Immunology, Mayo Clinic, Rochester, MN 55905USA., Kachergus JM; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224USA., Shi J; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224USA., Thompson EA; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224USA., Jensen HE; Department of Immunology, Mayo Clinic, Rochester, MN 55905USA., Harty JT; Department of Pathology, University of Iowa, Iowa City, IA 52242USA., Parney IF; Department of Neurosurgery, Mayo Clinic, Rochester, MN 55905USA., Sun J; Department of Medicine, University of Virginia, Charlottesville, VA 22903USA., Wu LJ; Department of Immunology, Mayo Clinic, Rochester, MN 55905USA.; Department of Neurology, Mayo Clinic, Rochester, MN 55905USA., Johnson AJ; Department of Immunology, Mayo Clinic, Rochester, MN 55905USA.; Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905USA.; Department of Neurology, Mayo Clinic, Rochester, MN 55905USA.
المصدر:	Brain : a journal of neurology [Brain] 2024 Feb 01; Vol. 147 (2), pp. 566-589.
نوع المنشور:	Journal Article; Research Support, N.I.H., Extramural
اللغة:	English
بيانات الدورية:	Publisher: Oxford University Press Country of Publication: England NLM ID: 0372537 Publication Model: Print Cited Medium: Internet ISSN: 1460-2156 (Electronic) Linking ISSN: 00068950 NLM ISO Abbreviation: Brain Subsets: MEDLINE
أسماء مطبوعة:	Publication: Oxford : Oxford University Press Original Publication: London.
مواضيع طبية MeSH:	Malaria, Cerebral/pathology , Malaria, Cerebral/prevention & control, Mice ; Humans ; Animals ; Endothelial Cells/pathology ; Brain/pathology ; Blood-Brain Barrier/pathology ; CD8-Positive T-Lymphocytes ; Endothelium/pathology ; Mice, Inbred C57BL ; Disease Models, Animal
مستخلص:	Cerebral malaria is the deadliest complication that can arise from Plasmodium infection. CD8 T-cell engagement of brain vasculature is a putative mechanism of neuropathology in cerebral malaria. To define contributions of brain endothelial cell major histocompatibility complex (MHC) class I antigen-presentation to CD8 T cells in establishing cerebral malaria pathology, we developed novel H-2Kb LoxP and H-2Db LoxP mice crossed with Cdh5-Cre mice to achieve targeted deletion of discrete class I molecules, specifically from brain endothelium. This strategy allowed us to avoid off-target effects on iron homeostasis and class I-like molecules, which are known to perturb Plasmodium infection. This is the first endothelial-specific ablation of individual class-I molecules enabling us to interrogate these molecular interactions. In these studies, we interrogated human and mouse transcriptomics data to compare antigen presentation capacity during cerebral malaria. Using the Plasmodium berghei ANKA model of experimental cerebral malaria (ECM), we observed that H-2Kb and H-2Db class I molecules regulate distinct patterns of disease onset, CD8 T-cell infiltration, targeted cell death and regional blood-brain barrier disruption. Strikingly, ablation of either molecule from brain endothelial cells resulted in reduced CD8 T-cell activation, attenuated T-cell interaction with brain vasculature, lessened targeted cell death, preserved blood-brain barrier integrity and prevention of ECM and the death of the animal. We were able to show that these events were brain-specific through the use of parabiosis and created the novel technique of dual small animal MRI to simultaneously scan conjoined parabionts during infection. These data demonstrate that interactions of CD8 T cells with discrete MHC class I molecules on brain endothelium differentially regulate development of ECM neuropathology. Therefore, targeting MHC class I interactions therapeutically may hold potential for treatment of cases of severe malaria. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
معلومات مُعتمدة:	F31 NS116924 United States NS NINDS NIH HHS; R01 NS103212 United States NS NINDS NIH HHS; RF1 NS122174 United States NS NINDS NIH HHS; R01 AI167847 United States AI NIAID NIH HHS; T32 AI007425 United States AI NIAID NIH HHS
فهرسة مساهمة:	Keywords: CD8 T cells; MHC Class I; brain microvascular endothelial cells; cerebral malaria; neuroimmunology
تواريخ الأحداث:	Date Created: 20230930 Date Completed: 20240205 Latest Revision: 20240306
رمز التحديث:	20240307
DOI:	10.1093/brain/awad319
PMID:	37776513
قاعدة البيانات:	MEDLINE

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تدمد:	1460-2156
DOI:	10.1093/brain/awad319