Purpose of review: Description on post-translational modification of islet-autoantigens in type 1 diabetes (T1D).
Recent findings: T1D is an autoimmune disease characterized by progressive destruction of the insulin-producing beta-cells. It is a complex disease process that results from the loss of tolerance to beta-cell autoantigens. This loss of tolerance can be caused by modification of beta-cell autoantigens, generating 'neo-autoantigens', and inducing T-cell responses. Post-translational modifications (PTMs) within the endoplasmic reticulum of stressed beta-cells might impact on the autoantigen T-cell epitope repertoire and on T1D pathogenesis progression. This review summarizes the processes involved in beta-cell stress and PTM of beta-cell autoantigens in T1D.
Summary: PTMs of beta-cell autoantigens provide a novel hypothesis to understand how autoreactive T-cells can escape immune tolerance and cause destruction of beta-cells ('beta-cell homicide'). Additionally, aberrant proteins produced by stressed beta-cells can cause their own destruction ('beta-cell suicide'). Upon endoplasmic reticulum-stress, proteins are misfolded or modified changing the protein structure. In T1D, this may generate new beta-cell (neo)autoantigens. PTM of islet-autoantigens provides a mechanism by which pathogenic T-cells can escape thymic deletion. This amplifies the immune response when encountering a modified beta-cell neo-autoantigen bound to T1D predisposing human leucocyte antigen molecules in the periphery.