T lymphocyte activation in systemic auto immune diseases

T lymphocytes in auto-immune diseases…

  • 1.1 Platelets are an active player in autoimmunity

    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.

  • 1.2 TFH are acting as CD8+ T cell helper through IL21 secretion in SLE

  • 1.3. OX40L impacts TFHreg and Treg functions

  • 1.4 Contribution of endothelial cells and TSLP/OX40L axis in immune modulation and skin fibrosis in human SSc

People involved: Patrick Blanco, Cécile Bordes, …

People involved: Agnès Bru, Mélanie Nguyen Ky, Nathalie Schmitt (ATIP-Avenir)

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.

“Pause-café au violon”, by dominik Lobera

PUBLICATIONS

Main Publications

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.

COLLABORATIONS

Pascale Jeannin (Université d’Angers)
Eric Vivier (CIML, Marseille)

Hideki Ueno (NYC, USA)

FUNDING