Type 1 Diabetes Neo-Epitopes: Autoimmunity Against a Defective Ribosomal Insulin Gene Product
Type 1 diabetes (T1D) is an autoimmune disease where the immune system destroys the insulin-producing pancreatic beta cells. These cells are insulin factories dedicated to the maintenance of glucose homeostasis; insulin, stored in secretory granules, represents 10–15% of the protein content of these cells. Studies of samples from humans with T1D and mouse models of the disease indicate that native insulin and its precursors act as primary autoantigens, and fragments of the preproinsulin peptide have been identified as main targets of cytotoxic islet-autoreactive CD8+ T cells in human T1D. In autoimmune disease, there is increasing evidence that local inflammation or other forms of stress combined with genetic disposition leads to the generation and the accumulation of aberrant or modified proteins (neo-epitopes) to which central tolerance is lacking and thereby triggering autoimmunity. Until now, neo-epitopes have been shown to be generated through transcriptional, post-transcriptional and post-translational processes. However, an important class of neo-epitopes could be generated through non-conventional translational events and this technology is the first evidence of a naturally processed and presented epitope derived from nonconventional islet proteins.
Scientists at Leiden University Medical Center have recently discovered a new neo-epitope generated by defective ribosomal products (DRiPs) from the proinsulin gene. Within the mRNA, the researchers have found an alternative open reading frame encoding a highly immunogenic polypeptide that is targeted by T cells in type 1 diabetes (T1D) patients. They show that cytotoxic T cells directed against the N-terminal peptide of this nonconventional product are present in the circulation of individuals diagnosed with T1D, and provide direct evidence that such CD8+ T cells are capable of killing human beta cells and thereby may be diabetogenic. This is the first evidence of a naturally processed and presented epitope derived from nonconventional islet proteins leading to the destruction of human beta cells by cytotoxic CD8+ T cells. They propose a new pathway of beta cell destruction by the immune system in which the generation of a neoepitope, such as INS-DRiP, plays a central role. Their findings support the emerging concept that beta cells are destroyed in T1D by a mechanism comparable to classical antitumour responses whereby the immune system has been trained to survey for dysfunctional cells in which errors have accumulated. This invention reveals a potential new mechanism underlying the pathology of T1D, and may allow the development of novel T1D diagnostics and therapies (Nat Med. 2017 Apr;23(4):501-507).
Details and State of Development:
Proof of concept.
- Novel T1D diagnostics
- Novel T1D therapies
- Research collaboration to further unravel the mechanism of INS-DriP formation
- Development of novel T1D diagnostics and therapies
- Potential new mechanism underlying the pathology of T1D
- Significant correlation between INS-DRiP formation and immune responses typical of 1D.
Luris reference numberS180605-3480-6387
PCT patent application filed (WO2017/125586).