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Immune pathways in autoimmune disorders

Peter van Endert
Team description

Our team is dedicated to investigating cellular and metabolic control of TLR activation, MHC class I cross-presentation, and the regulation of beta cell-directed autoimmunity by antimicrobial peptides and intrinsic beta cell responses.

Protective anti-pathogen as well as unwanted anti-self immunity implicates sequential activation of innate and adaptive responses. The discovery of intracellular antigen processing machineries starting in the early 90s revealed how ligands recognized in adaptive T cell reponses are produced, although the underlying cell biology, notably concerning (cross-)presentation of exogenous ligands, remains incompletely understood.

In recent years, the focus has shifted to the innate response, which precedes and regulates adaptive immunity. Innate response intricately links with intracellular receptor trafficking. Understanding the cell biology of antigen-presenting cells is crucial. For instance, Toll-like receptors (TLRs) in endocytic compartments influence cross-presentation, highlighting the intimate connection between innate and adaptive responses. Recent findings, including our research, suggest that innate signaling is influenced by cellular metabolism, including lipid composition modifications affecting TLR activation.

While specific innate and antigen processing pathways are involved in autoimmune type 1 diabetes (T1D), recent discoveries, including those from our team, suggest a role for beta cell intrinsic mechanisms that shape the course of autoimmune aggression. Additionally, there appears to be a cross-talk between beta cells and the intestinal microbiota. However, the underlying mechanisms of both pathways remain largely unexplored.

A breakdown of our research objectives :

  1. Understand the role of endocytic pathway trafficking in regulating TLR activation and cross-presentation.
  2. Elucidate endocytic trafficking pathways that enable efficient cross-presentation by splenic CD169 macrophages and their contribution to T cell immunity.
  3. Unravel the cell biological alterations, especially in the endolysosomal system, resulting from gene mutations in patients with severe metabolic diseases, and comprehend how they trigger innate inflammatory pathways.
  4. Investigate a novel pathway that comes into prominence in the absence of insulin-degrading enzyme (IDE) and mediates beta cell regeneration and protection from autoimmunity.
  5. Explore the role of the innate immune system in autoimmune diseases, with a specific focus on the immunoregulatory potential of antimicrobial peptides and the gut microbiota in type 1 diabetes - Julien Diana
Key publications
Liang W, Enée E, Andre-Vallee C, Falcone M, Sun J, Diana J. Intestinal Cathelicidin Antimicrobial Peptide Shapes a Protective Neonatal Gut Microbiota Against Pancreatic Autoimmunity. Gastroenterology. 2022; Apr;162(4):1288-1302.e16. doi: 10.1053/j.gastro.2021.12.272. PMID: 34973295 .
Hamel Y, Mauvais FX, Madrange M, Renard P, Lebreton C, Nemazanyy I, Pellé O, Goudin N, Tang X, Rodero MP, Tuchmann-Durand C, Nusbaum P, Brindley DN, van Endert P, de Lonlay P. Compromised mitochondrial quality control triggers lipin1-related rhabdomyolysis.. Cell Rep Med. 2021; Aug 17;2(8):100370. doi: 10.1016/j.xcrm.2021.100370. PMID: 34467247 ; PMCID: PMC8385327.
Dubreil C, Sainte Catherine O, Lalatonne Y, Journé C, Ou P, van Endert P, Motte L. Tolerogenic Iron Oxide Nanoparticles in Type 1 Diabetes: Biodistribution and Pharmacokinetics Studies in Nonobese Diabetic Mice. Small. 2018; Oct;14(40):e1802053. doi: 10.1002/smll.201802053. PMID: 30184337 .
Weimershaus M, Mauvais FX, Saveanu L, Adiko C, Babdor J, Abramova A, Montealegre S, Lawand M, Evnouchidou I, Huber KJ, Chadt A, Zwick M, Vargas P, Dussiot M, Lennon-Dumenil AM, Brocker T, Al-Hasani H, van Endert P. Innate Immune Signals Induce Anterograde Endosome Transport Promoting MHC Class I Cross-Presentation. Cell Rep. 2018; Sep 25;24(13):3568-3581. doi: 10.1016/j.celrep.2018.08.041. PMID: 30257216 .
Miani M, Le Naour J, Waeckel-Enée E, Verma SC, Straube M, Emond P, Ryffel B, van Endert P, Sokol H, Diana J. Gut Microbiota-Stimulated Innate Lymphoid Cells Support β-Defensin 14 Expression in Pancreatic Endocrine Cells, Preventing Autoimmune Diabetes. Cell Metab. 2018; Oct 2;28(4):557-572.e6. doi: 10.1016/j.cmet.2018.06.012. PMID: 30017352 .
Funding and grants