Immune recognition of non-self or self proteins may be either favored or hampered by antigen posttranslational modifications such as citrullination, phosphorylation or N-glycosylation. This may contribute to autoimmunity such as in multiple sclerosis (MS), a demyelinating CNS disorder. Strikingly, the glial potassium channel KCNJ10 (Kir4.1) can exhibit low to high glycosylated forms and initial works from different laboratories identified variable proportions of MS patients harboring high levels of anti-Kir4.1 IgGs. Using a well-controlled ELISA, six percent of MS patients exhibit high seric levels of IgGs directed against the extracellular e1 domain (aa83-120) of Kir4.1 (Nicot et al 2023). Immunization of C57Bl6/J mice with the e1 peptide induces immune responses, and could promote demyelinating encephalomyelitis with B cell enrichment in the CNS and T cells/macrophages in the CNS white matter. Immunolabeling of KCNJ10-expressing white matter glia with the anti-e1 serum from immunized mice increased during murine autoimmune neuroinflammation (EAE) and in MS as compared with controls. Western blot of denatured protein samples using a commercial C-ter antibody confirmed that neuroinflammation induces Kir4.1 expression, including its shorter form, in inflamed CNS as compared to controls. Anti-e1 IgGs from e1-immunized mice or MS patients labeled Kir4.1-expressing astrocytoma when N-glycosylation was blocked with tunicamycin and labeled CHO cells transfected with the N104-glycosylation defective Kir4.1 mutant, indicating that autoantibodies target the conformational aglycosylated e1 domain. Our data confort Kir4.1 as a valid autoantigen for a subset of MS patients and highlight the importance of tissue-specific post-translational modifications that can contribute to the autoimmunity processes.