Research Summary

IBRI DIABETES CENTER (IDC) - EIZIRIK LAB

Focus: Mechanisms of beta-cell dysfunction and death in type 1 diabetes (T1D) the dialog between beta-cells and the immune system

Type 1 diabetes (T1D) is one of the most common chronic diseases in children, shortening lifespan by >10 years. Its incidence is growing at an alarming rate, making T1D a major health challenge. T1D results from the interaction between predisposing genes and environmental factors, such as viral infections, triggering an autoimmune attack against pancreatic beta-cells that provokes islet inflammation and progressive beta-cell loss due to apoptosis. Islet inflammation takes place in the context of a dialogue between invading immune cells and the targeted beta-cells. This dialog is modulated by T1D candidate genes acting on both immune and pancreatic beta-cells, and by inflammatory mediators (cytokines and chemokines).

Recent studies from the Eizirik team suggest that stress pathways triggered within beta cells early in T1D may initiate and/or accelerate autoimmune beta-cell destruction. These studies also show that T1D candidate genes regulate beta-cell responses to “danger signals”, innate immunity and activation of apoptosis, affecting the beta-cell phenotype. The molecular mechanisms linking genetic variation, environmental factors and the signaling events promoting beta-cell dysfunction and loss remain poorly understood, and this is the main research focus of the Eizirik laboratory.

Specific scientific areas of focus in the lab include:

Understanding the dialogue between the beta cells and the immune system in early T1D.

Dr. Eizirik research interest focuses on the molecular pathways leading to beta-cell dysfunction and death in type 1 diabetes (T1D). His work has led to fundamental concepts such as the dialogue between the immune system and beta-cells that triggers and amplifies insulitis and beta-cell damage. He pioneered studies on global gene expression in pancreatic beta-cells, clarifying the cytokine-, virus- and metabolically-regulated gene networks that define beta-cell dysfunction and death in diabetes. This led to the discovery: a. that key “beta-cell gene modules” define the beta-cell outcomes following injury; b. that >80% of the candidate genes for T1D are expressed in human islets, and expression of at least half of them is modified by cytokines or viral infections. He studied the function of several of these candidate genes, observing that most of them regulate local innate immune responses, particularly type I IFN signaling.

Two other research lines from his group focus on the role of the endoplasmic reticulum (ER) stress and alternative splicing (AS) in beta-cell dysfunction and death and on multi-omics analysis of stress human beta-cells. These multi-omics databases generated are also used to mine for specific-beta cell surface proteins, that can be used for beta-cell imaging and for the targeting of potentially protective agents. Recent findings from his group identified the key role for the type 1 interferon (IFN) IFNa in the induction of three hallmarks of early human beta-cell dysfunction in T1D, namely HLA class I overexpression, ER stress and apoptosis. Interestingly, type 1 IFNs also induce beta-cell “defense” mechanisms against the immune system, such as PDL1 expression. His group is now focusing on characterizing the signal transduction behind these deleterious or beneficial effects of IFNa with the aim to discover novel therapies that may prevent its pro-inflammatory signals while preserving the protective ones.

Use of human iPSC-derived beta cells to characterize the function of candidate genes for T1D acting at the beta cell level.

iPSCs from T1D donors and normoglycemic individuals with relevant risk variants – mostly related to type 1 IFN signal transduction - are differentiated into human pre-beta cells using a well-established 7-step procedure. Isogenic controls for these cells are developed using CRISPR/Cas9. These cells, once differentiated, provide a unique model to understand the role of these candidate genes in beta-cells and in the dialog between beta-cells and the immune system. Furthermore, they provide a unique model to screen for novel drugs that may arrest this dialog and protect beta-cells against cytokine-induced apoptosis.

Lab Team


Highlights and Publications

  • Eizirik DL, Sammeth M, Bouckenooghe T, Bottu G, Sisino G, Igoillo-Esteve M, Ortis F, Santin I, Colli ML, Barthson J, Bouwens L, Hughes L, Gregory L, Lunter G, Marselli L, Marchetti P, McCarthy MI, Cnop M. The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines. PLoS Genetics 8: e1002552, 2012 
  • Nogueira TC, Paula FV, Villate O, Colli ML, Moura RF, Cunha DA, Marselli L, Marchetti P, Cnop M, Julier C, Eizirik DL. GLIS3, a susceptibility gene for type 1 and 2 diabetes mellitus, modulates pancreatic beta cell apoptosis via regulation of a splice variant of the BH3-only protein Bim. PLoS Genet 9: e1003532, 2013 
  • Marroqui L, Lopes M, Santos RSD, Roivainen M, Richardson S, Morgan N, Op de Beeck A, Eizirik DL. Differential cell autonomous immune responses determine the outcome of coxsackievirus infections in pancreatic β and α cells. eLIFE 4: e06990, 2015 
  • Gonzalez-Duque S, Azoury ME, Colli ML, Afonso G, Turatsinze J-V, Nigi L, Lalanne AI, Sebastiani G, Carre A, Pinto S, Culina S, Corcos N, Bugliani M, Marchetti P, Armanet M, Diedisheim M, Kyewski B, Steinmetz LM, Buus S, You S, Dubois-Laforgue D, Larger E, Beressi JP, Bruno G, Dotta F, Scharfmann R, Eizirik DL*, Verdier Y*, Vinh J*, Mallone R. Conventional and neo-antigenic peptides presented by ? cells are targeted by circulating naïve CD8+ T cells in type 1 diabetic and healthy donors. Cell Metab, 28: 946-960, 2018 (*equal contribution).
  • Ramos-Rodriguez M, Raurell-Vila H, Colli ML, Alvelos MI, Subirana M, Juan-Mateu J, Norris R, Turatsinze JV, Nakayasu ES, Webb-Robertson BJ, Marchetti P, Piemonti L, Esteller M, Todd JA, Metz TO, Eizirik DL, Pasquali L The impact of pro-inflammatory cytokines on the ?-cell regulatory landscape provides new insights into the genetics of type 1 diabetes. Nature Genet, “in press”, 2019

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