ARC - CYTAID
Exploring the roles of cytokines to identify new therapeutic targets for systemic autoimmune diseases SLE and SSc
Internal Reference Number : 19/24-098
Start date: 01/10/2019
End date: 30/09/2024
Partners
- Prof. Sophie LUCAS (spokesperson)
Université catholique de Louvain (UCLouvain) / de Duve Institute (DDUV) / Cell Genetics (GECE) - Laure DUMOUTIER
Université catholique de Louvain (UCLouvain) / de Duve Institute (DDUV) / Experimental medecine (MEXP) - François HUAUX
Université catholique de Louvain (UCLouvain) / Institute of Experimental and Clinical Research (IREC) / Louvain Centre for Toxicology and Applied Pharmacology (LTAP) - Patrick DUREZ
Université catholique de Louvain (UCLouvain) / Institute of Experimental and Clinical Research (IREC) /Rheumatic Pathologies Centre (RUMA) - Nisha LIMAYE
Université catholique de Louvain (UCLouvain) / de Duve Institute (DDUV) / Genetics of Autoimmune Diseases and Cancer (GEDI) - Thomas MICHIELS
Université catholique de Louvain (UCLouvain) / de Duve Institute (DDUV) / Virology (VIRO)
Aims of the coordinated research project
The collaborations between our laboratories, initiated by strong preliminary data, provided the impetus for the formation of this consortium and the crystallization of the following Specific Aims:
- Identify genetic “drivers” of SLE and SSc in the type I IFN, TGF-b and IL-17/22 pathways, using genome-wide sequencing on rare, familial SLE and SSc, and targeted deep-sequencing on sporadic patient materials. Our aim is to identify germline or somatic variants for which we can demonstrate a disease-relevant functional effect in vitro and in vivo in mouse models of disease.
- Identify triggers and effector mechanisms of type I IFN signalling in SLE and SSc. The “interferon signature” consistently identified in SLE includes PKR, a molecule that acts as both an effector and a regulator of IFN activity. We will study the activation mechanisms and effects of PKR in PBMCs from patients and in lupus-prone mice. Mouse models of SLE and SSc will serve to study particle-induced IFN activation in autoimmunity and fibrosis.
- Explore TGF-b activation in SLE and SSc. The TGF-b activator GARP was recently suggested to prevent SLE-like symptoms in mice. We will study mice deficient for GARP in specific blood cell types to dissect its effects on autoimmunity. We will also test the effects of a TGF-b2 variant that we identified in familial SSc, in endothelial cells and fibroblasts. Accordingly, bleomycin-induced SSc will be assessed in mice engineered to express the mutation.
- Determine the role of IL-17/IL-22 cytokines in the development of SLE and SSc. Data on the roles of IL-17 and IL-22 in autoimmunity are compelling yet conflicting, at least partially due to their complex inter-regulation and differing actions on different cell-types. We will modulate IL-22 in lupus-prone mice and the bleomycin-induced SSc model, to study chemokine modulation and autoimmunity in these conditions. In addition, the effects of an IL17RA (splice) mutation that we identified in familial SSc will be studied in fibroblasts in vitro and on bleomycin-induced fibrosis in vivo.
The research team
Sophie Lucas (PI - spokesperson)
An expert on the multi-faceted functions of TGF-b cytokines and their regulator GARP. Her lab has developed a host of specialized tools for the precise dissection of the complex regulation of these cytokines in diverse cell-types.
Research Group
People working on the project under other sources of funding:
- PhD students: 2
- Post-docs: 2
- Technician: 1
People to be funded by the project:
- Technician: 1
Nisha Limaye (PI)
Studies the genetic bases of rare diseases, combining genome wide and targeted Next Generation Sequencing with functional studies to identify molecular drivers of disease, particularly phenotypes driven by combined immunological and vascular dysregulation.
Research Group
People working on the project under other sources of funding:
- PhD student: 1
People to be funded by the project:
- Technician : 1 (time share between N. Limaye and P. Durez)
Laure Dumoutier (PI)
Discovered IL-22 and its soluble receptor IL-22BP. Has developed unique animal models, antibodies and other reagents to understand the role of this cytokine and its close relative IL-17, in inflammatory and autoimmune conditions.
Research Group
People working on the project under other sources of funding:
- PhD student: 1
- Post-doc: 1
- Technician: 1
People to be funded by the project:
- Post-doc: 1
Patrick Durez (PI)
Was trained in rheumatology and rehabilitation, and has spent 1 year in immunology, molecular biology research and studying animal models of inflammation. Is involved in the clinical research program at UCLouvain - Cliniques Universitaires Saint-Luc and is responsible for the arthritis clinic at this site.
Research Group
People working on the project under other sources of funding:
- Post-docs: 2
People to be funded by the project:
- Technician : 1 (time share between N. Limaye and P. Durez)
François Huaux (PI)
An immuno-toxicologist with extensive experience studying the impact of nano- and micro-particles on human health, particularly inflammation and fibrosis. Has developed several mouse models to study particle-induced inflammation and IFN response.
Research Group
People working on the project under other sources of funding:
- PhD student: 1
- Technicians: 2
People to be funded by the project:
- PhD student: 1
Thomas Michiels (PI)
Studies the interplay between viruses and host innate immune responses. Has long-standing expertise in the role, regulation, and effector mechanisms of type I and type III IFNs, key players in autoimmunity.
Research Group
People working on the project under other sources of funding:
- PhD students: 2
- Technician: 1
People to be funded by the project:
- Technician: 1
- PhD student: 1
Theses defended within the framework of the CYTAID project
The C-Terminal region of IL-22Ra: a novel potential therapeutic target for psoriasis
- PhD Student : Camille Michiels
- Date of defense : 15/10/2020
- Supervisor at UCLouvain : Laure Dumoutier
Role of GARP in regulating autoimmunity and immune responses to infection or protein immunisation
- PhD Student : Xuhao Zhang
- Date of defense : 25/01/2021
- Supervisor at UCLouvain : Laure Dumoutier
PKR regulation by phosphorylation and antiviral activity of the PKR-ADAR1 axis
- PhD Student : Camille Michiels
- Date of defense : 17/07/2021
- Supervisor at UCLouvain : Thomas Michiels
Activities & materials organized/produced within the framework of the CYTAID Research Project
Annual International Meeting
- Annual international meeting « Lateral Root Workshop »
2019, September 12-13 at Louvain-la-Neuve, Belgium
This workshop, organised by Xavier Draye, gathered 40 participants interested in the last developments of lateral root formation. It included a visit of the UCLouvain phenotyping facilities to which the ARC project contributes.
- Plant Science for Climate Emergency, international meeting
2021, June 7-9 at VIB Conference, Ghent, Belgium. Virtual edition.
François Chaumont was a member of the organising committee
Summer School
- Summer School on Modeling water fluxes in the soil-plant system
2021, August 21-26 at Louvain-la-Neuve, Belgium.
This summer school was organised by M. Javaux. Amongst more than 100 applicants, 25 PhD students were selected for attending this one-week course in which M. Javaux, X. Draye, but also Ali Mehmandoost Kotlar and international colleagues gave lectures.
More info : https://soil-modeling.org/activities/summer-school/summer-school-advanced-soil-physics
Publications in connection with the CYTAID project
Articles published in peer-reviewed journals (Co-PIs of the coordinated research project are in bold, all other contributing members are underlined)
- Lecomte S, Devreux J, de Streel G, van Baren N, Havelange V, Schröder D, Vaherto N, Vanhaver C, Vanderaa C, Dupuis N, Pecquet C, Coulie PG, Constantinescu S, Lucas S. Therapeutic activity of GARP:TGF-β1 blockade in murine primary myelofibrosis. Blood 2022, DOI: 10.1182/blood.2022017097.
- Choteau M, Scohy A, Messe S, Luyckx M, Dechamps M, Montiel V, Yombi JC, Gruson D, Limaye N, Michiels T, Dumoutier L. Development of SARS-CoV2 humoral response including neutralizing antibodies is not sufficient toprotectpatients against fatal infection. Sci Rep. 2022, 12(1):2077.
- Gaignage M, Zhang X, Stockis J, Dedobbeleer O, Michiels C, Cochez P, Dumoutier L, Coulie PG, Lucas S. Blocking GARP-mediated activation of TGF-β1 did not alter innate or adaptive immune responses to bacterial infection or protein immunization in mice. Cancer Immunol. Immunoth. 2022, Aug;71(8):1851-1862.
- Georgery H, Devresse A, Saad Albichr I, Lucas S, Yombi J-C, Belkhir L, De Greef J, Scohy A, Kabamba B,Goffin E, Kanaan N. Delayed Humoral Response after Two Doses of the BNT162b2 Vaccine in a Belgian Kidney TransplantCohort. Transplantation. 2022, 106(3): e192-e193.
- Puigdevall L, Michiels C, Stewardson C, Dumoutier L. JAK/STAT: Why choose a classical or an alternative pathway when you can have both ? J Cell Mol Med. 2022. Review.
- Ronsmans S, Sørig Hougaard K, Nawrot TS, Plusquin M, Huaux F, Jesús Cruz M, Moldovan H, VerpaeleS, Jayapala M, Tunney M, Humblet-Baron S, Dirven H, Cecilie Nygaard U, Lindeman B, Duale N, Liston A,Meulengracht Flachs E, Kastaniegaard K, Ketzel M, Goetz J, Vanoirbeek J, Ghosh M, Hoet PHM. The EXIMIOUS project-Mapping exposure-induced immune effects: connecting the exposome and theimmunome. Environ Epidemiol. 2022, 6(1):e193.
- Hiéronimus L, Demazy R, Christiaens L, Uwambayinema F, Geuens JF, Yacoub Y, Huaux F. Mouse innate-like B-1 lymphocytes promote inhaled particle-induced in vitro granuloma formation and inflammation in conjunction with macrophages. Arch Toxicol. 2022, 96(2):585-599.
- Sorgeloos F, Peeters M, Hayashi Y, Borghese F, Capelli N, Drappier M, Cesaro T, Colau D, Stroobant V,Vertommen D, de Bodt G, Messe S, Forné I, Mueller-Planitz F, Collet JF, Michiels T. A case of convergent evolution: Several viral and bacterial pathogens hijack RSK kinases through a common linear motif. Proc Natl Acad Sci U S A. 2022, 119: e2114647119.
- Michiels C, Puigdevall L, Cochez P, Achouri Y, Cheou P, Hendrickx E, Dauguet N, Blanchetot C, Dumoutier L. A Targetable, Noncanonical Signal Transducer and Activator of Transcription 3 Activation Induced by the Y-Less Region of IL-22 Receptor Orchestrates Imiquimod-Induced Psoriasis-Like Dermatitis in Mice. J InvestDermatol. 2021, 141(11):2668-2678.e6.
- Ferté L, Marino A, Battault S, Bultot L, Van Steenbergen A, Bol A, Cumps J, Ginion A, Koepsell H, Dumoutier L, Hue L, Horman S, Bertrand L, Beauloye C. New insight in understanding the contribution of SGLT1 in cardiac glucose uptake: evidence for atruncated form in mice and humans. Am J Physiol Heart Circ Physiol. 2021, 320(2), H838-H853.
- Schnepf DC, Pedro H, Tanel M, Crotta S, Sullender M, Peterson ST, Ohnemus A, Michiels C, Gentle I, Dumoutier L, Reis CA, Diefenbach A, Wack A, Baldridge MT, Staeheli P. Rotavirus susceptibility of antibiotic-treated mice ascribed to diminished expression of interleukin-22. PloSOne 2021, 16, e0247738.
- Huaux F. Interpreting Immunoregulation in Lung Fibrosis: A New Branch of the Immune Model. Front Immunol. 2021, 12:690375. Boulanger C, Chatzis O, Nolf D, Brichard B, Lauwerys B*, Nassogne MC, Limaye N. Atypical phenotype? The answer's in the genotype: AGS caused by a novel RNASEH2C variant combined with XLA caused by a BTK deficiency. Rheumatology (Oxford). 2021, 60(7):e240-e242. *Co-PI on ARC until departure from UCLouvain in April 2020.
- Triaille C, Durez P, Sokolova T, Tilman G, Méric de Bellefon L, Galant C, Coulie P, Lauwerys B*, Limaye N. Common Transcriptomic Effects of Abatacept and Other DMARDs on Rheumatoid Arthritis Synovial Tissue. Front Immunol. 2021, 12:724895. *Co-PI on ARC until departure from UCLouvain in April 2020.
- Tilman G, Bouzin C, Aydin S, Tamirou F, Galant C, Coulie PG, Houssiau F, Lauwerys B*, Limaye N. Highp16INK4a, a marker of cellular senescence, is associated with renal injury, impairment and outcome in lupusnephritis. RMD Open. 2021, 7(3):e001844. *Co-PI on ARC until departure from UCLouvain in April 2020.
- Bertrand C, Van Meerbeeck P, de Streel G, Vaherto-Bleeckx N, Benhaddi F, Rouaud L, Noel A, Coulie PG,van Baren N, Lucas S. Combined Blockade of GARP:TGF-beta1 and PD-1 Increases Infiltration of T Cells and Density of Pericyte-Covered GARP(+) Blood Vessels in Mouse MC38 Tumors. Front Immunol. 2021, 12:704050.
- Noël G, Langouo Fontsa M, Garaud S, De Silva P, de Wind A, Van den Eynden GG, Salgado R, Boisson A,Locy H, Thomas N, Solinas C, Migliori E, Naveaux C, Duvillier H, Lucas S, Craciun L, Thielemans K,Larsimont D, Willard-Gallo K. Functional Th1-oriented T follicular helper cells that infiltrate human breast cancer promote effectiveadaptive immunity. J Clin Invest. 2021, pii: e139905.
- de Streel G, Lucas S. Targeting immunosuppression by TGF-beta1 for cancer immunotherapy. Biochem Pharmacol. 2021, 192:114697. Review.
- Slattery K, Woods E, Zaiatz-Bittencourt V, Marks S, Chew S, Conroy M, Goggin C, MacEochagain C,Kennedy J, Lucas S, Finlay DK, Gardiner CM. TGFbeta drives NK cell metabolic dysfunction in human metastatic breast cancer. J ImmunoTher Cancer. 2021, 9(2): e002044.
- Lafont V, Lucas S, Bonnefoy N. Novel Strategies for Cancer Immunotherapy: Targeting Immune-Mediated Suppressive Mechanisms. Front Immunol. 2021, 12:691899. Editorial.
- Cesaro T and Michiels T. Inhibition of PKR by Viruses. Front Microbiol. 2021, 12: 757238. Review
- Cesaro T, Hayashi Y, Borghese F, Vertommen D, Wavreil F, Michiels T. PKR activity modulation by phosphomimetic mutations of serine residues located three aminoacids upstream of double- stranded RNAbinding motifs. Sci Rep. 2021, 11(1): 9188.
- de Montjoye L, Darrigade A-S, Giménez-Arnau A, Herman A, Dumoutier L, Baeck M. Correlations between disease activity, autoimmunity and biological parameters in patients with chronic spontaneous urticaria. Eur Ann Allergy Clin Immunol, 2021, 53 : 55-66.
- Boulanger C, Chatzis O, Nolf D, Brichard B, Lauwerys B*, Nassogne MC, Limaye N. Atypical phenotype? The answer's in the genotype: AGS caused by a novel RNASEH2C variant combined with XLA caused by a BTK deficiency. Rheumatology (Oxford). 2021, 60 : e240-e242. *Co-PI on ARC until departure from UCLouvain in April 2020.
- La Sala G, Michiels C, Kukenshöner T, Brandstoetter T, Maurer B, Koide A, Lau K, Pojer F, Koide S, Sexl V, Dumoutier L, & Hantschel O. Selective inhibition of STAT3 signaling using monobodies targeting the coiled-coil and N-terminal domains. Nature Communications 2020, 11, 4115.
- de Heusch M, Steenwinckel V, Cochez P, Louahed J, Warnier G, Lemaire M M, Renauld J-C, Dumoutier L. IL-9 exerts biological function on antigen-experienced murine T cells and exacerbates colitis induced by adoptive transfer. Eur J Immunol. 2020, 50, 1034-1043.
- Cochez P, Choteau M, Limaye N, Baeck M, Dumoutier L. Implication of T Helper Cytokines in Contact Dermatitis and Atopic Dermatitis. In: Curr Treat Options Allergy. 2020, 7, 258-273.
- Van Belle A, Cochez P, De Heusch M, Pointner L, Ospomer R, Raynaud P, Achouri Y, Hendrickx E, Cheou P, Renauld J-C, Baeck M, Dumoutier L. IL-24 contributes to skin inflammation in Para-Phenylenediamine-induced contact hypersensitivity. Sci Rep. 2019, 9, 1852 [1-11].
- de Montjoye L, Choteau M, Herman A, Hendrickx E, Cheou P, Baeck M, Dumoutier, L. IL-6 and IL-1βexpression is increased in autologous serum skin test of patients with chronic spontaneous urticaria. Allergy 2019, 74(12), 2522-2524.