Immunoregulation And Immunointervention in Transplantation and Autoimmunity
Laureline Berthelot
Research Scientist

Research Associate INSERM

The research project mainly focuses on immunopathology involving Immunoglobulin A (IgA), IgA receptors and an associated enzyme : the Transglutaminase 2 (TG2). These molecular partners play a crucial role in IgA nephropathy, a primary glomerulonephritis characterized by anormally glycosylated IgA1 forming complexes with their Fc receptor (CD89 or FcαRI) and which are deposited in the kidney. TG2 also participates to the kidney deposition mechanisms. This enzyme plays an important role in multiple sclerosis. So, the research projects are aimed to understand the pathological mechanisms involving these proteins in kidney diseases, transplantation and multiple sclerosis.

Description

Dysfunction of the immune system lead to multifactorial complex inflammatory diseases such as IgA nephropathy and multiple sclerosis. The origins of these diseases are unknown. However, their etiology indicates the influence of environmental and genetic factors.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, characterized by a demyelination. In France, over 90000 patients suffer with this disease, leading to motor and cognitive disabilities. No curative treatment is available. Only therapies targeting the immune system have shown benefits.

Iga nephropathy (IgAN) is characterized by mesangial IgA deposits and is the most frequent glomerulonephritis worldwide. 30% of patients undergo kidney failure and it represents 10% of organ transplantation in France. To understand the pathophysiology of IgAN could bring new therapeutic strategies and avoid the dialyse and transplantation.

For this objective, the research project will assess the role of IgA, IgA receptors and TG2 in these pathologies and develop new therapies targeting these molecules.

IgA is the most secreted immunoglobulin at the mucosal surface to exclude pathogens, stopping their entrance in the body and leading to their neutralization. IgA regulate the microbiota. In the circulation, blood IgA exhibit anti-inflammatory functions in a physiological context. IgA deposits in kidney are associated to the Fc receptor CD89 or FcαRI, inducing the overexpression of TG2, an enzyme increasing the stability of deposits (Berthelot et al. J Exp Med 2012). This multifunctional enzyme is associated to several pathologies such as cancer, Alzheimer, MS, asthma, fibrosis… Using TG2 KO mice and developing a floxed transgenic mouse, the role of this enzyme will be explored in disease mouse model (EAE for MS and α1KI-CD89Tg for IgAN). Its expression will be induced in different subset of cells to study their function.