Frédéric Rieux-Laucat

Immunogenetics of pediatric autoimmune diseases

Frédéric Rieux-Laucat
  • Aude Magérus-Chatinet
  • Fabienne Mazerolles
  • Aniko Hancz
  • Marie-Claude Stolzenberg
  • Mathieu Moncan
  • Laura Barnabéi
  • Caroline Besnard
  • Aurélien Adoue
  • Sidonie Jacques
  • Bénédicte Neven
  • Brigitte Bader-Meunier
  • Pierre Quartier

Immunogenetics of pediatric autoimmune diseases

Our project focuses on the mechanisms involved in the control of self-tolerance in primary human immunodeficiencies and in hyper immune syndromes. The autoimmune lymphoproliferative syndrome (ALPS), characterized by a benign tumoral syndrome along with autoimmune cytopenia, is associated with heterozygous dominant mutations of the FAS gene and apoptosis deficiencies. This condition thus represents a key model to study some aspects predisposing to autoimmune diseases in the context of apoptosis deficiency. Moreover, we discovered that the apparent non-penetrance of the germline FAS mutations is explained by additional somatic events affecting the second allele of FAS in patients. We believe that such somatic events may account for the onset of other pediatric autoimmune diseases.

Based on our preliminary findings we are now studying three groups of patients presenting with:

1- ALPS and related diseases: the recent identification of KRAS mutations in this group of patients extent the group of apoptosis-related diseases and is prolonged by the study of Juvenile Myelo-Monocytic Leukemia. We are searching for modifiers by combining apoptosis functional assays and a genetic screen.

2- Evan’s syndrome: This disease is defined by an early-onset severe cytopenia. It can be variably accompanied with other autoimmune manifestations such as autoimmune enteropathy or endocrinopathy. Following a whole-exome-sequencing (WES) approach we are currently validating gene mutations affecting the immune regulation.

3- Pediatric lupus (pSLE): a WES approach performed on a cohort of pSLE patients allowed us to identify an activating mutations of TMEM173/STING, encoding an adaptor of the cytosolic DNA sensing, in a familial case of autoinflammation and lupus features. The study of additional mutations of genes related to nucleotide sensing is currently under progress and should decipher the genetic as well as the pathophysiological bases of the pSLE.

This project is based on the availability of the patients’ blood samples, as well as on the development of animal or cellular models. This work should provide a better understanding of the molecular and cellular bases of the mechanisms involved in T cells homeostasis and self-tolerance, and should allow the identification of susceptibility factors to human auto-immune diseases.