Interferon-α (IFN-α) – an innate immune mediator in early type 1 diabetes

Type 1 diabetes (T1D) develops from a complex “dialogue” that is established between invading immune cells, which release a variety of chemokines and cytokines and putative immunogenic signals released by injured or dying β cells, leading to local inflammation. This dialogue is shaped by the host genetic architecture, key clinical/demographic features, and environmental factors such as a precipitating viral infection or endogenous “danger signals”. Accumulating evidence suggests that the nature and tempo of this inflammatory response varies by disease stage, with cytokine signatures predominating during the initiation of T1D (when there is probably a major contribution by the innate immune response) that are distinct from than those present during more advanced stages of autoimmunity and β cell decline.

Interferon-alpha (IFN-α) is a Type 1 interferon that signals through the IFN-α receptor (IFNAR1) and the downstream tyrosine kinase effectors Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2) via interactions with STAT proteins. Children with high genetic risk of T1D present a type I IFN-inducible transcriptional signature that precedes the development of autoantibodies, while islets from living donors with very recent onset T1D display a prominent type I IFN signature. Data from our own group has shown that IFNα activates downstream signaling pathways within the β cell that create a feed-forward cycle of inflammation and self-antigen presentation. On the other hand, IFNa also triggers “defense” signals in beta cells, such as PDL1 overexpression, that may protect – at least temporarily – these cells against the immune assault. These findings are of interest, because drugs that target the IFNα-receptor have shown efficacy in mouse models of T1D, whereas JAK and TYK2 inhibitors are currently being tested in Phase 2 and 3 clinical trials for other autoimmune diseases. Given this background, we hypothesize that IFNα-mediated signalling orchestrates early β cell and immune interactions during T1D initiation and is a pathway that can be targeted therapeutically to prevent the progression of T1D.These and other related findings will be discussed at the lecture.

Background literature for the lecture

Eizirik DL et al Nature Rev Endocrinol, 5: 219-226, 2009 Marroqui L et al. Diabetes, 64: 3808-3817, 2015 Op de Beeck A, Eizirik DL Nature Rev Endocrinol, 12:263-273, 2016 Marroqui L et al. Diabetologia, 60:656-667, 2017 Coomans de Brachene A et al. Diabetologia, 61:636–640, 2018 Colli M et al. EBiomedicine “in press”, 2018