The MHC-II peptidome of pancreatic islets identifies key features of autoimmune peptides.

Nature Immunology
Xiaoxiao WanEmil R Unanue

Abstract

The nature of autoantigens that trigger autoimmune diseases has been much discussed, but direct biochemical identification is lacking for most. Addressing this question demands unbiased examination of the self-peptides displayed by a defined autoimmune major histocompatibility complex class II (MHC-II) molecule. Here, we examined the immunopeptidome of the pancreatic islets in non-obese diabetic mice, which spontaneously develop autoimmune diabetes based on the I-Ag7 variant of MHC-II. The relevant peptides that induced pathogenic CD4+ T cells at the initiation of diabetes derived from proinsulin. These peptides were also found in the MHC-II peptidome of the pancreatic lymph nodes and spleen. The proinsulin-derived peptides followed a trajectory from their generation and exocytosis in β cells to uptake and presentation in islets and peripheral sites. Such a pathway generated conventional epitopes but also resulted in the presentation of post-translationally modified peptides, including deamidated sequences. These analyses reveal the key features of a restricted component in the self-MHC-II peptidome that caused autoreactivity.

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Citations

Apr 7, 2020·The Journal of Experimental Medicine·Pavel N ZakharovEmil R Unanue
Nov 25, 2020·Proceedings of the National Academy of Sciences of the United States of America·Hao HuEmil R Unanue
Feb 2, 2021·Immunology and Cell Biology·Stuart I Mannering, Pushpak Bhattacharjee
Apr 4, 2021·Biomolecules·Yong Kyung KimHoward W Davidson
Apr 7, 2021·The Journal of Experimental Medicine·Anthony N VomundEmil R Unanue
May 7, 2021·Frontiers in Immunology·Teresa Rodriguez-CalvoJessica L Dunne
Jun 3, 2021·Vaccines·Ramona Clemen, Sander Bekeschus
May 28, 2021·The Journal of Biological Chemistry·Nitin AmdareTeresa P DiLorenzo
May 18, 2021·Frontiers in Immunology·Stuart I ManneringPushpak Bhattacharjee
May 23, 2021·Molecular & Cellular Proteomics : MCP·Arie Admon
Jun 12, 2021·Frontiers in Immunology·Timothy A WilesRocky L Baker
Jun 20, 2021·Molecular & Cellular Proteomics : MCP·Hannah B TaylorJennifer G Abelin
Aug 27, 2021·Nature Communications·Mai T TranHugh H Reid

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Methods Mentioned

BETA
deamidation

Software Mentioned

GraphPad Prism
TLALEVARE
PEAKS PTM
PEAKS
SPIDER
BLAST
ImmunoSpot
PEAKS X

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