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Autoantibody and T cell responses to oxidative post-translationally modified insulin neoantigenic peptides in type 1 diabetes
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- Strollo, Rocky (författare)
- Univ Campus Biomed Roma, Italy
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- Vinci, Chiara (författare)
- Queen Mary Univ London, England
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- Man, Y. K. Stella (författare)
- Queen Mary Univ London, England
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- Bruzzaniti, Sara (författare)
- CNR, Italy; Univ Napoli Federico II, Italy
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- Piemonte, Erica (författare)
- Univ Napoli Federico II, Italy
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- Alhamar, Ghadeer (författare)
- Univ Campus Biomed Roma, Italy
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- Briganti, Silvia Irina (författare)
- Univ Campus Biomed Roma, Italy
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- Malandrucco, Ilaria (författare)
- Azienda Sanit Locale ASL Frosinone, Italy
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- Tramontana, Flavia (författare)
- Univ Campus Biomed Roma, Italy
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- Fanali, Chiara (författare)
- Univ Campus Biomed Roma, Italy
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- Garnett, James (författare)
- Kings Coll London, England; Queen Mary Univ London, England
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- Buccafusca, Roberto (författare)
- Queen Mary Univ London, England
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- Guyer, Perrin (författare)
- Benaroya Res Inst, WA USA
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- Mamula, Mark (författare)
- Yale Univ, CT 06510 USA
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- James, Eddie A. (författare)
- Benaroya Res Inst, WA USA
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- Pozzilli, Paolo (författare)
- Univ Campus Biomed Roma, Italy
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- Ludvigsson, Johnny (författare)
- Linköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten,Region Östergötland, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus
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- Winyard, Paul G. (författare)
- Univ Exeter, England
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- Galgani, Mario (författare)
- CNR, Italy; Univ Napoli Federico II, Italy
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- Nissim, Ahuva (författare)
- Queen Mary Univ London, England
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(creator_code:org_t)
- 2022-10-07
- 2023
- Engelska.
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 66:1, s. 132-146
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https://liu.diva-por... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Aims/hypothesis Antibodies specific to oxidative post-translational modifications (oxPTM) of insulin (oxPTM-INS) are present in most individuals with type 1 diabetes, even before the clinical onset. However, the antigenic determinants of such response are still unknown. In this study, we investigated the antibody response to oxPTM-INS neoepitope peptides (oxPTM-INSPs) and evaluated their ability to stimulate humoral and T cell responses in type 1 diabetes. We also assessed the concordance between antibody and T cell responses to the oxPTM-INS neoantigenic peptides. Methods oxPTM-INS was generated by exposing insulin to various reactive oxidants. The insulin fragments resulting from oxPTM were fractionated by size-exclusion chromatography further to ELISA and LC-MS/MS analysis to identify the oxidised peptide neoepitopes. Immunogenic peptide candidates were produced and then modified in house or designed to incorporate in silico-oxidised amino acids during synthesis. Autoantibodies to the oxPTM-INSPs were tested by ELISA using sera from 63 participants with new-onset type 1 diabetes and 30 control participants. An additional 18 fresh blood samples from participants with recently diagnosed type 1 diabetes, five with established disease, and from 11 control participants were used to evaluate, in parallel, CD4(+) and CD8(+) T cell activation by oxPTM-INSPs. Results We observed antibody and T cell responses to three out of six LC-MS/MS-identified insulin peptide candidates: A:12-21 (SLYQLENYCN, native insulin peptide 3 [Nt-INSP-3]), B:11-30 (LVEALYLVCGERGFFYTPKT, Nt-INSP-4) and B:21-30 (ERGFFYTPKT, Nt-INSP-6). For Nt-INSP-4 and Nt-INSP-6, serum antibody binding was stronger in type 1 diabetes compared with healthy control participants (p <= 0.02), with oxidised forms of ERGFFYTPKT, oxPTM-INSP-6 conferring the highest antibody binding (83% binders to peptide modified in house by hydroxyl radical [(OH)-O-?] and >88% to in silico-oxidised peptide; p <= 0.001 vs control participants). Nt-INSP-4 induced the strongest T cell stimulation in type 1 diabetes compared with control participants for both CD4(+) (p<0.001) and CD8(+) (p=0.049). CD4(+) response to oxPTM-INSP-6 was also commoner in type 1 diabetes than in control participants (66.7% vs 27.3%; p=0.039). Among individuals with type 1 diabetes, the CD4(+) response to oxPTM-INSP-6 was more frequent than to Nt-INSP-6 (66.7% vs 27.8%; p=0.045). Overall, 44.4% of patients showed a concordant autoimmune response to oxPTM-INSP involving simultaneously CD4(+) and CD8(+) T cells and autoantibodies. Conclusions/interpretation Our findings support the concept that oxidative stress, and neoantigenic epitopes of insulin, may be involved in the immunopathogenesis of type 1 diabetes.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Nyckelord
- Autoimmunity; Immune response; Insulin; Insulin autoantibodies; Insulin neoepitope peptide; Neoantigen; Neoepitope; Oxidative post-translational modifications; Post-translational modifications
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Strollo, Rocky
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Vinci, Chiara
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Man, Y. K. Stell ...
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Bruzzaniti, Sara
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Piemonte, Erica
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Alhamar, Ghadeer
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visa fler...
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Briganti, Silvia ...
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Malandrucco, Ila ...
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Tramontana, Flav ...
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Fanali, Chiara
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Garnett, James
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Buccafusca, Robe ...
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Guyer, Perrin
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Mamula, Mark
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James, Eddie A.
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Pozzilli, Paolo
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Ludvigsson, John ...
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Winyard, Paul G.
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Galgani, Mario
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Nissim, Ahuva
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Endokrinologi oc ...
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Diabetologia
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Linköpings universitet