François Willermain

Professor François Willermain, the leader of the Ophthalmology Research Group at IRIBHM is also the Head of the Ophthalmology Department of Saint-Pierre Hospital at Brussels. His main tropism in clinic and research is focused on uveitis, a group of disease characterised by an intraocular inflammation.
The Laboratory has been working in the field of experimental autoimmune uveitis (EAU) for more than 10 years. Multiple steps are involved in EAU development, starting with peripheral MHC Class II-mediated Ag presentation to retina-specific T cells, their activation, migration to the eye, extravasation, ocular Ag-specific reactivation and ultimately induction of blood-retinal barrier (BRB) breakdown, allowing aspecific recruitment of immune cells that mediate retinal damage. All those processes represent potential targets for biological therapies.
We have studied the modification of the BRB during uveitis, first focusing on retinal pigment epithelium (RPE), a component of the external BRB and then, turning more recently to the analysis of the expression of adhesion molecules on BRB cells, which play a central role in the infiltration of inflammatory cells into the eye. We showed that VCAM-1 and ICAM-1 are strongly induced in the retina during EAU, with an intensity and extension correlated to disease severity. We further observed a differential expression of those adhesion molecules on the inner (VCAM-1) and outer (ICAM-1) BRB. Those major differences in retinal distribution could represent distinct entry pathways for inflammatory cells to penetrate the eye.
Since autoreactive T cells only induce disease upon local recognition of their cognate antigen, we next focused on the identification of potential antigen-presenting cells (APCs) in the retina during EAU. As expected, we observed strong induction of MHC Class II expression in the retina during intraocular inflammation, correlated to disease severity and associated with upregulation of costimulatory molecules, particularly on MHC IIhi cells. We identified 3 populations of MHC Class II-expressing potential APCs in the retina: non-hematopoietic cells with low MHC Class II expression and hematopoietic cells with higher MHC Class II expression, that could be further separated into 2 subsets depending on the (non)expression of Ly6C. Transcriptome analysis of those 3 sorted populations lead to a clear sample clustering with some enrichment in macrophage markers and microglial cell markers in Ly6C+ and Ly6C- cells, respectively. However, Ly6C expression did not provide a clear-cut segregation of infiltrating macrophages from resident microglia. Functional analysis however revealed that both hematopoietic cell populations were more competent in MHC Class II-associated antigen presentation and T-cell activation than non-hematopoietic cells.
The aim of our actual research is to identify by a similar global approach key genes regulated in retinal cells, especially endothelial cells, during experimental autoimmune uveitis (EAU). Retinal endothelial cells are indeed known to exhibit a massive phenotypic change during EAU development. Transcriptome analysis led us to identify about a hundred genes modulated in retina and/or retinal endothelial cells during EAU. We will next explore in vivo the role of selected key genes in disease development. This approach might lead to a better understanding of the pathophysiology of inner BRB breaching and have an important clinical relevance through the identification of potential targets for the development of future biological therapies.

Prof François Willermain, MD, PhD, Principal Investigator (fwillerm@ulb.ac.be)

phone # +32 (0) 2 555 4104

co-promotors: Catherine Bruyns, PhD, senior scientist and Laure Caspers, MD,

Researchers: Deborah Lipski, MD, PhD, and Vincent Foucart, MD.

Last five years most relevant publications

MHC class II expression and potential antigen-presenting cells in the retina during experimental autoimmune uveitis.
Lipski DA, Dewispelaere R, Foucart V, Caspers LE, Defrance M, Bruyns C, Willermain F.
J Neuroinflammation. 2017 Jul 18;14(1):136.

Single Dexamethasone Intravitreal Implant in the Treatment of Noninfectious Uveitis.
Frère A, Caspers L, Makhoul D, Judice L, Postelmans L, Janssens X, Lefebvre P, Mélot C, Willermain F.  J Ocul Pharmacol Ther. 2017 May;33(4):290-297.

Effect of SOCS1 overexpression on RPE cell activation by proinflammatory cytokines.
Bazewicz M, Draganova D, Makhoul M, Chtarto A, Elmaleh V, Tenenbaum L, Caspers L, Bruyns C, Willermain F. Neurosci Lett. 2016 Sep 6;630:209-15.

ICAM-1 and VCAM-1 are differentially expressed on blood-retinal barrier cells during experimental autoimmune uveitis.
Dewispelaere R, Lipski D, Foucart V, Bruyns C, Frère A, Caspers L, Willermain F.
Exp Eye Res. 2015 Aug;137:94-102.

P2Y2R deficiency attenuates experimental autoimmune uveitis development.
Relvas LJ, Makhoul M, Dewispelaere R, Caspers L, Communi D, Boeynaems JM, Robaye B, Bruyns C, Willermain F. PLoS One. 2015 Feb 18;10(2):e0116518.

Treatment strategies in primary vitreoretinal lymphoma: a 17-center European collaborative study.
Riemens A, Bromberg J, Touitou V, Sobolewska B, Missotten T, Baarsma S, Hoyng C, Cordero-Coma M, Tomkins-Netzer O, Rozalski A, Tugal-Tutkun I, Guex-Crosier Y, Los LI, Bollemeijer JG, Nolan A, Pawade J, Willermain F, Bodaghi B, ten Dam-van Loon N, Dick A, Zierhut M, Lightman S, Mackensen F, Moulin A, Erckens R, Wensing B, le Hoang P, Lokhorst H, Rothova A.
JAMA Ophthalmol. 2015 Feb;133(2):191-7.

Clinical manifestations of patients with intraocular inflammation and positive QuantiFERON-TB gold in-tube test in a country nonendemic for tuberculosis.
Caspers L, Makhoul D, Ebraert H, Michel O, Willermain F.
Am J Ophthalmol. 2014 Sep;158(3):646-7.

Aquaporin expression and function in human pluripotent stem cell-derived retinal pigmented epithelial cells. Juuti-Uusitalo K, Delporte C, Grégoire F, Perret J, Huhtala H, Savolainen V, Nymark S, Hyttinen J, Uusitalo H, Willermain F, Skottman H.
Invest Ophthalmol Vis Sci. 2013 May 1;54(5):3510-9

Interplay between innate and adaptive immunity in the development of non-infectious uveitis.
Willermain F, Rosenbaum JT, Bodaghi B, Rosenzweig HL, Childers S, Behrend T, Wildner G, Dick AD.  Prog Retin Eye Res. 2012 Mar;31(2):182-94.