“Pause-café au violon”, by dominik Lobera
LUPUS, SYSTEMIC SCLEROSIS, RHUMATOID ARTHRITIS
Innate immunity and modulation of T cell activation in lupus, systemic sclerosis, rhumatoid arthritis
Head : Patrick Blanco
Microparticles (MPs) are vesicular structures derived from multiple cellular sources, involved in the regulation of inflammation, coagulation and healing processes. Their involvement in the pathophysiology of autoimmune diseases is beginning to be recognized. Lupus and systemic sclerosis are autoimmune diseases sharing common pathophysiological traits: genetic susceptibility factors, platelet activation, interferon-alpha transcriptomic signature, and endothelial cell dysfunction. Moreover, MPs have just been involved in the pathophysiology of both diseases. The purpose of this project is to characterize the utility of MPs as biomarkers as well as their phenotypic and functional specificities in each disease, through a translational project involving patient’s cohorts in vitro experiences and murine models.
Systemic sclerosis (SSc) is an autoimmune disease characterized by the fibrosis of different organs including the skin, lungs and gut. Vasculopathy is another primary feature of this rare but severe disease. Both may be linked from a pathogenesis point of view; however, neither the precise nature of the mechanism nor the ensuing therapeutic targets are known. Recent studies have identified interleukin (IL)13 as a key downstream mediator in the development of fibrosis. At the genetic level, genes involved in wound healing and fibrosis are linked to the Th2-associated cytokines IL4, IL5 and IL13. Accordingly, IL13 promotes the differentiation of fibroblasts into myofibroblasts and the production of extracellular matrix components such as collagen. Finally, IL13 expression increases in SSc mouse models and in SSc patients.
Abnormalities of endothelial cells are thought to occur very early in the course of the disease. The fact that Raynaud phenomenon often precedes the other symptoms is one of the arguments for this hypothesis. Early intervention on vasculopathy could prevent fibrosis and irreversible damages to happen.
One of our major axis is to find the link between autoimmunity, vascular damages and fibrosis in scleroderma.
CD4 T cells in Multiple Sclerosis (ATIP-Avenir)
Head: Nathalie SCHMITT
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system. Our current research aims at understanding how CD4 T cells are promoting multiple sclerosis in human.
The clinical course of MS is highly diverse, yet most MS patients eventually present severe physical and cognitive disabilities. Several therapeutic options are available but no treatment completely stops the progression of the disease. Notably there is also no treatment effective for the patients with the most aggressive forms of MS. A deeper understanding of the mechanism of the disease progression is therefore essential to develop more efficient treatment strategies. Previous studies suggest that both genetic and environmental factors confer susceptibility to MS. While it is widely accepted that CD4 T cells play a key role in the formation of the lesions in the central nervous system, the nature and functions of the pathogenic CD4 T cells in MS remains largely uncharacterized.
We hypothesize that differences in the type and the functions of CD4 T cells might be associated to differences in the clinical course of MS. The main objective of our research is to define CD4 T cell pathogenicity in MS patients at different clinical stages.
We expect that our study will uncover new therapeutic approaches to treat MS patients, particularly those with the most aggressive forms of the disease.
Truchetet ME, Demoures B, Eduardo Guimaraes J, Bertrand A, Laurent P, Jolivel V, Douchet I, Jacquemin C, Khoryati L, Duffau P, Lazaro E, Richez C, Seneschal J, Doutre MS, Pellegrin JL, Constans J, Schaeverbeke T, Blanco P, Contin-Bordes C; Fédération Hospitalo-Universitaire ACRONIM. Platelets Induce Thymic Stromal Lymphopoietin Production by Endothelial Cells: Contribution to Fibrosis in Human Systemic Sclerosis. Arthritis Rheumatol. 2016, Nov;68(11):2784-2794.
Khoryati L, Augusto JF, Shipley E, Contin-Bordes C, Douchet I, Mitrovic S, Truchetet ME, Lazaro E, Duffau P, Couzi L, Jacquemin C, Barnetche T, Vacher P, Schaeverbeke T, Blanco P, Richez C; FHU ACRONIM. IgE inhibits TLR-7 and -9 mediated expression of interferon-alpha by plasmacytoid dendritic cells in systemic lupus patients. Arthritis Rheumatol. 2016, Sep;68(9):2221-31.
Blanco P, Ueno H, Schmitt N. T follicular helper (Tfh) cells in lupus: activation and involvement in SLE pathogenesis. Eur J of Immunology 2016, Feb;46(2):281-90.
Berge J, Blanco P, Rooryck C, Boursier R, Marnat G, Gariel F, Wavasseur T, Desal H, Dousset V. Understanding flow patterns and inflammatory status in intracranial aneurysms: Towards a personalized medicine. J Neuroradiol. 2016, Mar;43(2):141-7
Turpin D, Truchetet ME, Faustin B, Augusto JF, Contin-Bordes C, Brisson A, Blanco P, Duffau P. Role of extracellular vesicles in autoimmune diseases. Autoimmun Rev. 2016, Feb;15(2):174-83
M Leroux, C Desveaux, M Parcevaux, B Julliac, J-B Gouyon, D Dallay, J-L Pellegrin, M Boukerrou, P Blanco and E Lazaro. Impact of hydroxychloroquine on preterm delivery and intrauterine growth restriction in pregnant women with systemic lupus erythematosus: a descriptive cohort study. Lupus. 2015, Nov;24(13):1384-91.
Jacquemin C, Schmitt N, Contin-Bordes C, Liu Y, Narayanan P, Seneschal J, Maurouard T, Dougall D, Spence Davizon E, Dumortier H, Douchet I, Raffray L, Richez C, Lazaro E, Duffau P, Truchetet ME, Khoryati L, Mercié P, Couzi L, Merville P, Schaeverbeke T, Viallard JF, Pellegrin JL, Moreau JF, Muller S, Zurawski S, Coffman RL, Pascual V, Ueno H and Blanco P. OX40 Ligand Contributes to the Pathogenesis of Autoimmunity by Promoting T follicular Helper Response. Immunity. 2015 Jun 16;42(6):1159-70.
Raffray L, Douchet I, Augusto JF, Youssef J, Contin-Bordes C, Richez C, Duffau P, Truchetet ME, Moreau JF, Cazanave C, Leroux L, Mourrissoux G, Camou F, Gruson D, Jeannin P, Delneste Y, Gabinski C, Guisset O, Lazaro E and Blanco P. Septic shock sera containing circulating histones induce dendritic cell regulated necrosis in fatal septic shock patients. Critical Care Medicine. 2015 Apr;43(4):e107-16.
Richez C, Barnetche T, Khoryati L, Duffau P, Kostine M, Contin-Bordes C, Blanco P, Schaeverbeke T. Tocilizumab treatment decreases circulating myeloid dendritic cells and monocytes, 2 components of the myeloid lineage. J Rheumatol. 2012; 1192-7.
Truchetet ME, Beven L, Renaudin H, Douchet I, Férandon C, Charron A, Blanco P, Schaeverbeke T, Contin-Bordes C*, Bébéar C*. Potential role of Mycoplasma hominis in interleukin (IL)-17-producing CD4+ T-cell generation via induction of IL-23 secretion by human dendritic cells. *Equal contribution. J Infect Dis. 2011; 1796-805.
Couzi L, Merville P, Deminière C, Moreau JF, Combe C, Pellegrin JL, Viallard JF, Blanco P (2007) . Predominance of CD8+ T lymphocytes among periglomerular infiltrating cells and link to the prognosis of class III and class IV lupus nephritis. Arthritis Rheum. 2007; 56:2362-70.
Patrick Blanco, A. Karolina Palucka, Virginia Pascual and Jacques Banchereau (2008). Dendritic Cells and Cytokines in Human Inflammatory and Autoimmune Diseases. Cytokine Growth Factor Rev. 2008;19:41-52.
Blanco P, Viallard JF, Pellegrin JL, Moreau JF (2005) . Cytotoxic T-lymphocytes and autoimmunity. Curr Opin Rheumatol. 2005(6):731-734.
P Blanco, V Pitard, JF Viallard, JL Taupin, JL Pellegrin, JF Moreau (2005) . Increase in activated T-lymphocytes expressing perforin and granzyme B correlates to disease activity in systemic lupus erythematosus patients. Arthritis Rheum 2005;52:201-11.
Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J (2001) . Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science 2001;294:1540-3.