Foreignness as a matter of degree: the relative immunogenicity of peptide/MHC ligands |
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Authors: | van den Berg Hugo A Rand David A |
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Institution: | Interdisciplinary Programme for Cellular Regulation, Mathematics Institute, University of Warwick, Coventry CV4 7AL, UK |
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Abstract: | The ability of T lymphocytes (T cells) to recognize and attack foreign invaders while leaving healthy cells unharmed is often analysed as a discrete self/non-self dichotomy, with each peptide/MHC ligand classified as either self or non-self. We argue that the ligand immunogenicity is more naturally treated as a continuous quantity, and show how to define and quantitate relative ligand immunogenicity. In our theory, self-tolerance is acquired through reduction of the relative immunogenicity of autoantigens, whereas xenoantigens, typically not presented during induction of deletional tolerance, retain a high degree of relative immunogenicity. Autoantigens that are not prominently presented in deletional tolerance likewise retain a high relative immunogenicity and remain essentially foreign. According to our analysis, any given autoantigen can attain a high level of relative immunogenicity, provided it is presented at sufficiently high levels. Our theory provides a quantitative tool to analyse the immunogenicity of tumour-associated neoantigens and the ætiology of autoimmune disease. |
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Keywords: | T cell tolerance T cell ignorance Negative selection Immunogenicity Autoimmunity Large deviations theory |
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