Cutaneous Lupus Erythematosus (CLE) is a rare variant of Systemic Lupus Erythematosus, a disease predominately known to affect skin and kidneys. CLE is an autoimmune disorder that arises due to immune cells aberrantly recognizing “self” molecules as “non-self” and as a result mounting an immune response. Increasing evidence suggests that auto-reactive peripheral T lymphocytes play an important role in the pathogenesis of CLE. CLE can affect people of all age groups; in severe cases, it can cause disfigurement of the affected individual and give rise to cancer. Currently there is no specific cure for CLE.
Our recent work has delineated a role for the protein coronin 1 in peripheral T cell activation, and several lines of evidence suggest that coronin 1 is crucial for the generation of T cell responses against autoantigens, while being largely dispensable for immunity against infectious organisms. The goal of this project is to further characterize coronin 1-dependent T cell activation and in particular to develop and characterize therapeutic strategies based on coronin 1 inhibition that may be useful for the treatment of CLE.
Quelles sont les particularités de ce projet?
As mentioned, there is currently no cure for Cutaneous Lupus Erythematosus (CLE) and once diagnosed, the treatment is aimed at controlling symptoms through general immunosuppression, causing severe side effects such as susceptibility to opportunistic infections and the development of malignancies. CLE is an autoimmune disease, and the research proposed here aims to block a novel target, coronin 1, whose activity is crucial for inducing autoimmune symptoms in animal models. Importantly, preliminary work suggests that blocking coronin 1 does not cause susceptibility to infections and has no adverse effect on any physiological parameter analyzed, which is in sharp contrast to the currently used general immunosuppressive treatments.
The precise cellular pathways involved in coronin 1-dependent immune cell activation remain largely unclear. First, we have characterized the coronin 1-dependent signal transduction cascade that is important for these processes. Second, we explored a number of different strategies to interfere with this coronin 1-dependent immune activation pathway as a mean to curb the development of cutaneous lupus erythematosus. Our results suggest that interference of the coronin 1-dependent immune cell activation pathway is a viable strategy to attenuate the immune responses in vitro as well as the development of cutaneous lupus erythematosus in a mouse model.
Lang MJ, Mori M, Ruer-Laventie J, and Pieters J. (2017). A Coronin 1-Dependent Decision Switch in Juvenile Mice Determines the Population of the Peripheral Naive T Cell Compartment. J Immunol. 199(7):2421-31;
Tchang VS, Stiess M, Siegmund K, Karrer U, and Pieters J. (2017). Role for coronin 1 in mouse NK cell function. Immunobiology. 222(2):291-300;
Liu, X., BoseDasgupta, S., Jayachandran, R., Studer, V., Ruhl, S., Stiess, M., Pieters, J. Activation of the cAMP/protein kinase A signalling pathway by coronin 1 is regulated by cyclin-dependent kinase 5 activity. (2016). FEBS Letters 590:279-287;
Jayachandran, R., Pieters, J. Regulation of immune cell homeostasis and function by coronin 1. (2015). Int. Immunopharmacol. 28:825-828;
Pieters, J., Muller, P., and Jayachandran, R. (2013). On guard: coronin proteins in innate and adaptive immunity. Nat Rev Immunol 13, 510-518
Personnes participant au projet
Dernière mise à jour de cette présentation du projet 04.09.2019