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. 2012 Mar;8(3):429-30.
doi: 10.4161/auto.19261. Epub 2012 Feb 24.

Processing of Proteins in Autophagy Vesicles of Antigen-Presenting Cells Generates Citrullinated Peptides Recognized by the Immune System

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Free PMC article

Processing of Proteins in Autophagy Vesicles of Antigen-Presenting Cells Generates Citrullinated Peptides Recognized by the Immune System

Jamie M Ireland et al. Autophagy. .
Free PMC article

Abstract

Our laboratory has been investigating for some time the nature of the response of T lymphocytes in autoimmunity in the reactions against self-proteins that result in a number of diseases, such as type 1 diabetes, multiple sclerosis, rheumatoid arthritis (RA) and others. T cells recognize peptides generated from proteins that are processed by antigen-presenting cells (APC). The peptides may derive from exogenous proteins or from the normal catabolism of self-proteins. The peptides complexed to major histocompatibility complex (MHC) molecules constitute the chemical entity that is engaged by the antigen-receptor of T cells. An important hypothesis postulates that self-peptides that suffer post-translational modifications in the APC may form neo-antigens that are recognized by the immune system and form the target of autoimmunity. Our interest in citrullination in the context of antigen processing and presentation stemmed from studies suggesting that an immune response to citrullinated self-peptides may be involved in autoimmunity. In a first publication, we found T cells that specifically recognized citrullinated peptides after immunization of inbred mice with standard foreign proteins. We used the small protein hen-egg white lysozyme. These T cells only recognized the citrullinated peptide and not the unmodified one, thus proving that a neo-epitope had been created by this modification. But how this modification took place was not known. Our recent report describes a central role for autophagy in citrullination of peptides by APC.

Figures

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Figure 1. Model of citrullination by (A) DC and macrophages, or (B) B cells. (A and B) represent the possible scenarios taking place in APC that result in citrullination of peptide-MHC complexes (pMHC). (A) represents the pathways in DC or macrophages. These cells undergo constitutive autophagy and present the citrullinated peptides after the protein antigen comes into contact with the autophagy vesicles (AV). In (A), the protein antigen lysozyme (HEL) binds to the plasma membrane, and traffics to early endosomal vesicles (EV). From the EV it follows two pathways. In one it is taken to late vesicles (LV), processed to peptides and presented at the cell surface as a pMHC complex. In the second pathway, the protein is taken to an autophagic vesicle (AV) where it is processed to peptides, some of which are citrullinated and presented at the cell surface (cit-pMHC). (B) represents the pathways in B cells. Citrullination in B cells occurs only after autophagy is induced by engagement by antigen of the B cell receptor, shown as an immunoglobulin (Ig) molecule on the cell membrane. Receptor engagement leads to striking subcellular changes that lead to colocalization of AV and antigen-processing compartments, and presentation of citrullinated peptides. (B) shows that the antigen HEL can enter the B cell directly after interaction with plasma membrane, and is taken to EV and LV, to generate unmodified pMHC complexes. However, when HEL is bound to the surface Ig molecules, autophagy is induced, and some of the HEL-Ig complex then traffics to the AV to be processed, and generates the cit-pMHC complex.

Comment on

  • Ireland JM, Unanue ER. Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells. J Exp Med. 2011;208:2625–32. doi: 10.1084/jem.20110640.

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