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Tytuł:
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Cysteine carboxyethylation generates neoantigens to induce HLA-restricted autoimmunity.
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Autorzy:
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Zhai Y; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Chen L; School of Medicine, Shanghai University, Shanghai 200444, China.
Zhao Q; Clinical Systems Biology Laboratories, Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, China.
Zheng ZH; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Chen ZN; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Bian H; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Yang X; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Lu HY; Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
Lin P; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Chen X; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Chen R; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Sun HY; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Fan LN; State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
Zhang K; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Wang B; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Sun XX; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Feng Z; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Zhu YM; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Zhou JS; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Chen SR; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Zhang T; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Chen SY; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Chen JJ; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Zhang K; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Wang Y; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Chang Y; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Zhang R; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Zhang B; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Wang LJ; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Li XM; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
He Q; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Yang XM; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Nan G; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Xie RH; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Yang L; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
Yang JH; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.; Clinical Systems Biology Laboratories, Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, China.
Zhu P; Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
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Źródło:
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Science (New York, N.Y.) [Science] 2023 Mar 17; Vol. 379 (6637), pp. eabg2482. Date of Electronic Publication: 2023 Mar 17.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Publication: : Washington, DC : American Association for the Advancement of Science
Original Publication: New York, N.Y. : [s.n.] 1880-
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MeSH Terms:
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Autoantibodies*/metabolism
Autoimmune Diseases*/genetics
Autoimmune Diseases*/metabolism
Cysteine*/metabolism
HLA-DRB1 Chains*/genetics
HLA-DRB1 Chains*/metabolism
Protein Processing, Post-Translational*
Integrin alpha2*/metabolism
Spondylitis, Ankylosing*/genetics
Spondylitis, Ankylosing*/metabolism
Animals ; Mice ; Autoimmunity/genetics ; Autoimmunity/immunology ; Mice, Transgenic ; Gastrointestinal Microbiome ; Humans
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Substance Nomenclature:
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0 (Autoantibodies)
K848JZ4886 (Cysteine)
0 (HLA-DRB1 Chains)
0 (Integrin alpha2)
2134-29-4 (3-hydroxypropionaldehyde)
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Entry Date(s):
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Date Created: 20230317 Date Completed: 20230419 Latest Revision: 20230530
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Update Code:
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20240105
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DOI:
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10.1126/science.abg2482
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PMID:
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36927018
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Autoimmune diseases such as ankylosing spondylitis (AS) can be driven by emerging neoantigens that disrupt immune tolerance. Here, we developed a workflow to profile posttranslational modifications involved in neoantigen formation. Using mass spectrometry, we identified a panel of cysteine residues differentially modified by carboxyethylation that required 3-hydroxypropionic acid to generate neoantigens in patients with AS. The lysosomal degradation of integrin αIIb [ITGA2B (CD41)] carboxyethylated at Cys96 (ITGA2B-ceC96) generated carboxyethylated peptides that were presented by HLA-DRB1*04 to stimulate CD4 + T cell responses and induce autoantibody production. Immunization of HLA-DR4 transgenic mice with the ITGA2B-ceC96 peptide promoted colitis and vertebral bone erosion. Thus, metabolite-induced cysteine carboxyethylation can give rise to pathogenic neoantigens that lead to autoreactive CD4 + T cell responses and autoantibody production in autoimmune diseases.
Comment in: Nat Rev Rheumatol. 2023 Jun;19(6):325. (PMID: 37161086)
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