Geneviève de Saint Basile

Normal and pathological homeostasis of the immune system

Geneviève de Saint Basile
  • Fernando Sepulveda
  • Gaël Ménasché
  • Sophia Maschalidi
  • Marie-Thérèse El-Daher
  • Claire Leveau
  • Isabelle Munoz
  • Meriem Belabed
  • Alexandrine Garrigue
  • Mathieu Kurowska

Meilleures publications

Sepulveda, F.E. Polygenic mutations in the cytotoxicity pathway increase susceptibility to develop HLH immunopathology in mice. Blood 2016.127:2113-2121.


Maschalidi S. Therapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice. Blood 2016. 128:60-71.


DE SAINT BASILE, G. A novel immunoregulatory role for NK-cell cytotoxicity in protection from HLH-like immunopathology in mice Blood 125:1427-1434


Isabelle Munoz. Kinesin-1 controls mast cell degranulation and anaphylaxis through PI3K- dependent recruitment to the granular Slp3/Rab27b complex. Journal of cell Biology 2016 Oct 24;215(2):203-216.


BIGORGNE AE TTC7A mutations disrupt intestinal epithelial apicobasal polarity J Clin Invest 2014 124 :328-337


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Normal and pathological homeostasis of the immune system

The mechanisms controlling immune homeostasis and inflammation are many and complex. Rare inherited conditions offer unique opportunities for describing complex mechanisms and gaining insight into key physiological processes. In addition, understanding the pathophysiology of primary immune diseases allows developing new diagnostic and therapeutic tools.

We have undertaken a research program aiming at the characterization of the molecular and functional bases responsible for two inherited conditions associated with severe disturbance of immune homeostasis..

One of these conditions, the Haemophagocytic lymphohistiocytosis (HLH), is a unique immunopathological phenotype characterized by uncontrolled expansion and activation of polyclonal T lymphocytes and hyperinflammation. The condition may develop in a variety of disease contexts. Through the study of human natural mutants causing this condition, we have evidenced the involvement of the lymphocyte’s cytotoxic function in this process and have identified critical effectors of the granule-dependent cytotoxic activity. Several murine models that recapitulate the human disorder have been generated.

The goal of our research is now to further dissect the precise molecular mechanisms tightly regulating the cytotoxic function of lymphocytes as well as the cellular bases of the development of the primary and “acquired” forms of HLH.

Three major objectives will be pursued:

  • An analysis of the interplay between the components of the cytotoxic machinery that control granule transport, docking and fusion at the secretion site, as well as their function in other hematopoietic cells.
  • An analysis of the cellular dynamics and molecular events leading to the development of HLH in cytotoxic-deficient host, by using appropriate cellular and murine models.
  • A search for factors that account for the development of “acquired” forms of HLH, via a survey of pathological conditions in humans and the development of in vivo murine models.

 

 

These approaches should provide detailed molecular and functional information on how cytotoxic cells regulate immune homeostasis and are expected to discover the existence of additional immune regulatory pathways.

A second condition results in a dysfunction of the immune system and changes in the epithelial architecture along the entire gastrointestinal tract. Severity of the disease varies from multiple intestinal atresia (MIA) to inflammatory bowel disease (IBD). Recently, we showed that the tetratricopeptide-repeat-domain-7A (TTC7A) responsible of these phenotypes leads to constitutive activation of Rho Kinase activity and impairs cell polarity. Although the function of TTC7A has yet to be defined, it is likely a key factor that bridges the process of both immune system and digestive tract homeostasis.

The goal of our research is to shed light on the molecular pathway and cellular function involving TTC7A in health and disease.

Two major objectives will be pursued:

 

  • As a tetratricopeptide repeat-containing protein, TTC7A might act in a plurality of function through multiple protein complexes interactions that will be determined by a quantitative proteomic analysis followed by functional approaches.

 

  • The natural murine Ttc7 mutant, the flaky skin (fsn) mouse, will be used to better analyse in vivo the precise underlying mechanisms leading to the complex phenotype observed and to test innovative therapeutic approaches of this condition and potentially of other IBD-like disorders.