Aglycosylated extracellular loop of inwardly rectifying potassium channel 4.1 (KCNJ10) provides a target for autoimmune neuroinflammation - Inserm - Institut national de la santé et de la recherche médicale Accéder directement au contenu
Article Dans Une Revue Brain Communications Année : 2023

Aglycosylated extracellular loop of inwardly rectifying potassium channel 4.1 (KCNJ10) provides a target for autoimmune neuroinflammation

Résumé

Abstract Multiple sclerosis is an autoimmune disease of the central nervous system. Yet, the autoimmune targets are still undefined. The extracellular e1 sequence of KCNJ10, the inwardly rectifying potassium channel 4.1, has been subject to fierce debate for its role as a candidate autoantigen in multiple sclerosis. Inwardly rectifying potassium channel 4.1 is expressed in the central nervous system but also in peripheral tissues, raising concerns about the central nervous system-specificity of such autoreactivity. Immunization of C57Bl6/J female mice with the e1 peptide (amino acids 83–120 of Kir4.1) induced anti-e1 immunoglobulin G- and T-cell responses and promoted demyelinating encephalomyelitis with B cell central nervous system enrichment in leptomeninges and T cells/macrophages in central nervous system parenchyma from forebrain to spinal cord, mostly in the white matter. Within our cohort of multiple sclerosis patients (n = 252), 6% exhibited high anti-e1 immunoglobulin G levels in serum as compared to 0.7% in the control cohort (n = 127; P = 0.015). Immunolabelling of inwardly rectifying potassium channel 4.1-expressing white matter glia with the anti-e1 serum from immunized mice increased during murine autoimmune neuroinflammation and in multiple sclerosis white matter as compared with controls. Strikingly, the mouse and human anti-e1 sera labelled astrocytoma cells when N-glycosylation was blocked with tunicamycin. Western blot confirmed that neuroinflammation induces Kir4.1 expression, including its shorter aglycosylated form in murine experimental autoencephalomyelitis and multiple sclerosis. In addition, recognition of inwardly rectifying potassium channel 4.1 using mouse anti-e1 serum in Western blot experiments under unreduced conditions or in cells transfected with the N-glycosylation defective N104Q mutant as compared to the wild type further suggests that autoantibodies target an e1 conformational epitope in its aglycosylated form. These data highlight the e1 sequence of inwardly rectifying potassium channel 4.1 as a valid central nervous system autoantigen with a disease/tissue-specific post-translational antigen modification as potential contributor to autoimmunity in some multiple sclerosis patients.
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Origine : Publication financée par une institution
Licence : CC BY - Paternité
Origine : Publication financée par une institution
Licence : CC BY - Paternité

Dates et versions

inserm-04131283 , version 1 (16-06-2023)

Identifiants

Citer

Arnaud Nicot, Jean Harb, Alexandra Garcia, Flora Guillot, Hoa-Le Mai, et al.. Aglycosylated extracellular loop of inwardly rectifying potassium channel 4.1 (KCNJ10) provides a target for autoimmune neuroinflammation. Brain Communications, 2023, 5 (2), pp.fcad044. ⟨10.1093/braincomms/fcad044⟩. ⟨inserm-04131283⟩
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