![]() ![]() The identification of these numerous molecular mechanisms represents the outcome of several key technological advances in genetics, genomics, statistics, computational biology, peptide–HLA tetramer use for T cell repertoire interrogation and epitope mapping, structural biology and transgenics. The molecular mechanisms identified to date that influence HLA–peptide–TCR interactions and that have been implicated in autoimmune disease development include alternate TCR docking, low-affinity-mediated thymic escape, TCR stabilization of weak peptide–HLA complexes, altered binding registers, 'hotspot' molecular mimicry, post-translational modification of antigenic peptides, hybrid peptides and differential HLA expression and stability. Understanding the molecular principles that govern these interactions - so as to distil them into mechanistic insight regarding the role of HLA in driving and protecting against immunopathology - presents an ongoing biomedical research challenge but also holds much therapeutic promise. The specificity of HLA–peptide–T cell receptor (TCR) tripartite interactions is fundamental in enabling the adaptive immune system to mount an efficient and appropriate response to counteract infection and malignancy while maintaining self tolerance and preventing autoimmune disease. Five decades since the first description of an HLA association with disease, the HLA molecule has been demonstrated to be central to physiology, protective immunity and deleterious immune reactivity. ![]()
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