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Use knowledge on antigen processing to understand and treat autoimmune diabetes

from basic science:
  • antigen processing
  • dendritic cells
to the translational research:
  • autoimmune diabetes
  • diagnostics and therapy
Peter Van Endert
Antigen presentation by MHC molecules: mechanisms and impact of Toll-like receptors
Peter van Endert, M.D. initiated his training in immunology in 1986 at the German Cancer Research Centre, working on anti-idiotype therapy for Non-Hodgkin lymphoma. A post-doctoral stint at Stanford University then introduced him to MHC class I antigen processing. In 1993, he moved to the Necker campus in Paris, continuing to study antigen processing but also interested in cellular responses in type 1 diabetes. Appointed as INSERM staff scientist in 1998, he became director of INSERM U580 and then INSERM U1013 starting in 2006, and joined INEM as the director of the immunology/infectiology/hematology department in 2014. He was appointed professor of immunology at University Paris Descartes in 2007, heads the HLA typing laboratory of the Necker hospital and coordinates teaching of immunology to 2nd year medical students. 141 Pub-Med listed publications, h factor 50.

Focus

  • Cell biological and metabolic control of TLR activation and MHC class I cross-presentation
  • Regulation of beta cell-directed autoimmunity by antimicrobial peptides and the intrinsic beta cell reponse

Introduction

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. More recently the focus has shifted to the innate response, preceding and controling the adaptive response. Because activation of the innate response is tightly linked to intracellular receptor trafficking, studying the cell biology of antigen presenting cells is primordial for its understanding. A prime example is the activation of Toll-like receptors (TLRs) in endocytic compartments which in turn modulates cross-presentation, illustrating the intimate connection between innate and adaptive responses. Exciting very recent results including data obtained by us suggest that innate signaling is also affected by the cellular and notably energetic metabolism, which for example by modifying the lipid composition of endocytic membranes controls TLR activation.

While in part specific innate and antigen processing pathways are involved in autoimmune type 1 diabetes (T1D), recent results, including some obtained by our team, indicate a role for beta cell intrinsic mechanisms modulating the course of the autoimmune aggression, as well as for cross-talk between beta cells and the intestinal microbiota. However, the mechanisms underlying both pathways remain largely unexplored.

Research objectives

  • To understand how trafficking in the endocytic pathway regulates TLR activation as well as cross-presentation
  • To elucidate endocytic trafficking pathways underlying efficient cross-presentation by splenic CD169 macrophages and study the contrbution of these cells to generation of T cell immunity
  • To decipher the cell biological alterations, especially in the endolysosomal system, resulting from gene mutations in patients with severe metabolic diseases and to understand how they trigger innate inflammatory pathways
  • To study a novel pathway boosted in the absence of insulin-degrading enzyme (IDE) mediating beta cell regeneration and protection from autoimmunity
  • To study the role of the innate immune system in autoimmune diseases, with a focus on the immunoregulatory potential of anti-microbial peptides and the gut microbiota in type 1 diabetes and in multiple sclerosis

5 main publications

  • Enée E et al. ZnT8 is a major CD8+ T cell-recognized autoantigen in pediatric type 1 diabetes. Diabetes 61 (2012): 1779-84
  • Maschalidi S et al. Asparagine endopeptidase controls anti-influenza virus immune responses through TLR7 activation. PLoS Pathogens e1002841 (2012).
  • Diana J et al.. Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes. Nat. Med. 19 (2013): 65-73
  • Sun J et al. Pancreatic beta cells express a cathelicidin-related antimicrobial peptide regulating autoimmune diabetes. Immunity 43 (2015): 304-17
  • Van Endert P. Intracellular recycling and cross-presentation by MHC class I molecules. Immunol. Rev. 272 (2016): 80-96
Last 30 publications

2017

  • Chen K, Chen H, Faas MM, de Haan BJ, Li J, Xiao P, Zhang H, Diana J, de Vos P, Sun J. Specific inulin-type fructan fibers protect against autoimmune diabetes by modulating gut immunity, barrier function and microbiota homeostasis. Mol Nutr Food Res. 2017 Feb 20. doi: 10.1002/mnfr.201601006. [Epub ahead of print]
  • Smith N, Pietrancosta N, Davidson S, Dutrieux J, Chauveau L, Cutolo P, Dy M, Scott-Algara D, Manoury B, Zirafi O, McCort-Tranchepain I, Durroux T, Bachelerie F, Schwartz O, Münch J, Wack A, Nisole S, Herbeuval JP. Natural amines inhibit activation of human plasmacytoid dendritic cells through CXCR4 engagement. Nat Commun. 2017 Feb 9;8:14253. doi: 10.1038/ncomms14253.
  • 2016

  • Lawand M, Abramova A, Manceau V, Springer S, van Endert P. TAP-Dependent and -Independent Peptide Import into Dendritic Cell Phagosomes. J Immunol. 2016 Nov 1;197(9):3454-3463.
  • Kokkala P, Mpakali A, Mauvais FX, Papakyriakou A, Daskalaki I, Petropoulou I, Kavvalou S, Papathanasopoulou M, Agrotis S, Fonsou TM, van Endert P, Stratikos E, Georgiadis D. Optimization and Structure-Activity Relationships of Phosphinic Pseudotripeptide Inhibitors of Aminopeptidases That Generate Antigenic Peptides. J Med Chem. 2016 Oct 13;59(19):9107-9123.
  • Chen H, Li L, Weimershaus M, Evnouchidou I, van Endert P, Bouvier M. ERAP1-ERAP2 dimers trim MHC I-bound precursor peptides; implications for understanding peptide editing. Sci Rep. 2016 Aug 12;6:28902. doi: 10.1038/srep28902.
  • Stamogiannos A, Papakyriakou A, Mauvais FX, van Endert P, Stratikos E. Screening Identifies Thimerosal as a Selective Inhibitor of Endoplasmic Reticulum Aminopeptidase 1. ACS Med Chem Lett. 2016 May 31;7(7):681-5.
  • van Endert P. Intracellular recycling and cross-presentation by MHC class I molecules. Immunol Rev. 2016 Jul;272(1):80-96. doi: 10.1111/imr.12424.
  • Hamel Y, Mauvais FX, Pham HP, Kratzer R, Marchi C, Barilleau É, Waeckel-Enée E, Arnoux JB, Hartemann A, Cordier C, Mégret J, Rocha B, de Lonlay P, Beltrand J, Six A, Robert JJ, van Endert P. A unique CD8(+) T lymphocyte signature in pediatric type 1 diabetes. J Autoimmun. 2016 Sep;73:54-63.
  • Lipecka J, Chhuon C, Bourderioux M, Bessard MA, van Endert P, Edelman A, Guerrera IC. Sensitivity of mass spectrometry analysis depends on the shape of the filtration unit used for filter aided sample preparation (FASP). Proteomics. 2016 Jul;16(13):1852-7. doi: 10.1002/pmic.201600103.
  • Duvallet E, Boulpicante M, Yamazaki T, Daskalogianni C, Prado Martins R, Baconnais S, Manoury B, Fahraeus R, Apcher S. Exosome-driven transfer of tumor-associated Pioneer Translation Products (TA-PTPs) for the MHC class I cross-presentation pathway. Oncoimmunology. 2016 Jun 21;5(9):e1198865.
  • Rasid O, Mériaux V, Khan EM, Borde C, Ciulean IS, Fitting C, Manoury B, Cavaillon JM, Doyen N. Cathepsin B-Deficient Mice Resolve Leishmania major Inflammation Faster in a T Cell-Dependent Manner. PLoS Negl Trop Dis. 2016 May 16;10(5):e0004716. doi: 10.1371/journal.pntd.0004716.
  • Antigny F, Hautefort A, Meloche J, Belacel-Ouari M, Manoury B, Rucker-Martin C, Péchoux C, Potus F, Nadeau V, Tremblay E, Ruffenach G, Bourgeois A, Dorfmüller P, Breuils-Bonnet S, Fadel E, Ranchoux B, Jourdon P, Girerd B, Montani D, Provencher S, Bonnet S, Simonneau G, Humbert M, Perros F. Potassium Channel Subfamily K Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension. Circulation. 2016 Apr 5;133(14):1371-85.
  • Mauvais FX, Diana J, van Endert P. Beta cell antigens in type 1 diabetes: triggers in pathogenesis and therapeutic targets. F1000Res. 2016 Apr 22;5. pii: F1000 Faculty Rev-728. doi: 10.12688/f1000research.7411.1.
  • Cluzeau T, Lambert J, Raus N, Dessaux K, Absi L, Delbos F, Devys A, De Matteis M, Dubois V, Filloux M, Fort M, Hau F, Jollet I, Labalette M, Masson D, Mercier B, Pedron B, Perrier P, Picard C, Quainon F, Ramounau-Pigot A, Renac V, Van Endert P, Charron D, Peffault de la Tour R, Taupin JL, Loiseau P. Risk factors and outcome of graft failure after HLA matched and mismatched unrelated donor hematopoietic stem cell transplantation: a study on behalf of SFGM-TC and SFHI. Bone Marrow Transplant. 2016 May;51(5):687-91. doi: 10.1038/bmt.2015.351.
  • Cluzeau T, Lambert J, Raus N, Dessaux K, Absi L, Delbos F, Devys A, De Matteis M, Dubois V, Filloux M, Fort M, Hau F, Jollet I, Labalette M, Masson D, Mercier B, Pedron B, Perrier P, Picard C, Quainon F, Ramounau-Pigot A, Renac V, Van Endert P, Charron D, Peffault de la Tour R, Taupin JL, Loiseau P. Risk factors and outcome of graft failure after HLA matched and mismatched unrelated donor hematopoietic stem cell transplantation: a study on behalf of SFGM-TC and SFHI. Bone Marrow Transplant. 2016 Feb 8. doi: 10.1038/bmt.2015.351.
  • 2015

  • Tohmé M, Manoury B. Invariant chain is a new chaperone for TLR7 in B cells. Mol Immunol. 2015 Jul 18. pii: S0161-5890(15)00436-8. doi: 10.1016/j.molimm.2015.06.012. [Epub ahead of print] Review.
  • Sun J, Furio L, Mecheri R, van der Does AM, Lundeberg E, Saveanu L, Chen Y, van Endert P, Agerberth B, Diana J. Pancreatic β-Cells Limit Autoimmune Diabetes via an Immunoregulatory Antimicrobial Peptide Expressed under the Influence of the Gut Microbiota. Immunity. 2015 Aug 18;43(2):304-17.
  • Costantino F, Talpin A, Evnouchidou I, Kadi A, Leboime A, Said-Nahal R, Bonilla N, Letourneur F, Leturcq T, Ka Z, van Endert P, Garchon HJ, Chiocchia G, Breban M. ERAP1 Gene Expression Is Influenced by Nonsynonymous Polymorphisms Associated With Predisposition to Spondyloarthritis. Arthritis Rheumatol. 2015 Jun;67(6):1525-34.
  • Papakyriakou A, Zervoudi E, Tsoukalidou S, Mauvais FX, Sfyroera G, Mastellos DC, van Endert P, Theodorakis EA, Vourloumis D, Stratikos E. 3,4-diaminobenzoic acid derivatives as inhibitors of the oxytocinase subfamily of M1 aminopeptidases with immune-regulating properties. J Med Chem. 2015 Feb 12;58(3):1524-43.
  • Brahimi-Horn MC, Lacas-Gervais S, Adaixo R, Ilc K, Rouleau M, Notte A, Dieu M, Michiels C, Voeltzel T, Maguer-Satta V, Pelletier J, Ilie M, Hofman P, Manoury B, Schmidt A, Hiller S, Pouysségur J, Mazure NM. Local mitochondrial-endolysosomal microfusion cleaves voltage-dependent anion channel 1 to promote survival in hypoxia. Mol Cell Biol. 2015 May;35(9):1491-505. doi: 10.1128/MCB.01402-14. Epub 2015 Feb 17. PubMed PMID: 25691661; PubMed Central PMCID: PMC4387213.
  • 2014

  • Evnouchidou I, Weimershaus M, Saveanu L, van Endert P. ERAP1-ERAP2 dimerization increases peptide-trimming efficiency. J Immunol. 2014 Jul 15;193(2):901-8.
  • Hsu HT, Janßen L, Lawand M, Kim J, Perez-Arroyo A, Culina S, Gdoura A, Burgevin A, Cumenal D, Fourneau Y, Moser A, Kratzer R, Wong FS, Springer S, van Endert P. Endoplasmic reticulum targeting alters regulation of expression and antigen presentation of proinsulin. J Immunol. 2014 Jun 1;192(11):4957-66.
  • Tenzer S, Crawford H, Pymm P, Gifford R, Sreenu VB, Weimershaus M, de Oliveira T, Burgevin A, Gerstoft J, Akkad N, Lunn D, Fugger L, Bell J, Schild H, van Endert P, Iversen AK. HIV-1 adaptation to antigen processing results in population-level immune evasion and affects subtype diversification. Cell Rep. 2014 Apr 24;7(2):448-63.
  • Culina S, Mauvais FX, Hsu HT, Burgevin A, Guénette S, Moser A, van Endert P. No major role for insulin-degrading enzyme in antigen presentation by MHC molecules. PLoS One. 2014 Feb 7;9(2):e88365. doi: 10.1371/journal.pone.0088365. eCollection 2014. PubMed PMID: 24516642; PubMed Central PMCID: PMC3917890.
  • Khan ME, Borde C, Rocha EP, Mériaux V, Maréchal V, Escoll P, Goyard S, Cavaillon JM, Manoury B, Doyen N. TLR9 activation is triggered by the excess of stimulatory versus inhibitory motifs present in Trypanosomatidae DNA. PLoS Negl Trop Dis. 2014 Nov 13;8(11):e3308. doi: 10.1371/journal.pntd.0003308. eCollection 2014 Nov. PubMed PMID: 25392997; PubMed Central PMCID: PMC4230925.
  • Diana J, Lehuen A. Macrophages and β-cells are responsible for CXCR2-mediated neutrophil infiltration of the pancreas during autoimmune diabetes. EMBO Mol Med. 2014 Jun 26;6(8):1090-104.
  • 2013

  • Beuzelin C, Evnouchidou I, Rigolet P, Cauvet-Burgevin A, Girard PM, Dardalhon D, Culina S, Gdoura A, van Endert P, Francesconi S. Deletion of the fission yeast homologue of human insulinase reveals a TORC1-dependent pathway mediating resistance to proteotoxic stress. PLoS One. 2013 Jun 24;8(6):e67705. doi: 10.1371/journal.pone.0067705. Print 2013. PubMed PMID: 23826334; PubMed Central PMCID: PMC3691139.
  • Ma Y, Adjemian S, Mattarollo SR, Yamazaki T, Aymeric L, Yang H, Portela Catani JP, Hannani D, Duret H, Steegh K, Martins I, Schlemmer F, Michaud M, Kepp O, Sukkurwala AQ, Menger L, Vacchelli E, Droin N, Galluzzi L, Krzysiek R, Gordon S, Taylor PR, Van Endert P, Solary E, Smyth MJ, Zitvogel L, Kroemer G. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity. 2013 Apr 18;38(4):729-41.
  • Saveanu L, Babdor J, Lawand M, van Endert P. Insulin-regulated aminopeptidase and its compartment in dendritic cells. Mol Immunol. 2013 Sep;55(2):153-5.
  • Permanent researcher
    Barbara Bertocci
    Researcher
    +33 (0)1 72 60 64 45
    Marie Courbebaisse
    Professor Researcher
    +33 (0)1 72 60 64 71
    Pascale De Lonlay
    -
    Julien Diana
    Researcher
    +33 (0)1 44 49 50 69
    Benedicte Manoury
    Researcher
    +33 (0)1 44 49 53 75
    Peter Van Endert
    Professor Researcher
    +33 (0)1 44 49 25 63
    Non permanent researcher
    François-Xavier Mauvais
    Clinician
    +33 (0)1 44 49 41 38
    Permanent engineer
    Emmanuelle Waeckel-Enee
    Engineer
    +33 (0)1 44 49 41 38
    Non permanent engineer
    Jacqueline Leib
    -
    Marine Madrange
    -
    Post-doctoral degree
    Maria Miacela Lopez Alarcon
    Post-Doctoral Researcher
    Sebastian Montealegre
    Post-Doctoral Researcher
    Clarissa Nascimento
    Post-Doctoral Researcher
    PhD
    Wenjie Liang
    PhD Student
    Student
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    Graduate student
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    -
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    Graduate student
    Perrine Renard
    Graduate student
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    Ayse Yilmaz
    Graduate student
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    HRH Princess Caroline of Hanover, who through the Princess Grace Foundation, already supports medical research and anything that helps to relieve the sick children in France and around the world, has agreed to commit to our side so that our Center of Molecular medicine continues to meet the current challenges and fight diseases, and in particular the ones affecting children.

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