Gaël Ménasché et Fernando Sepulveda

Molecular basis of altered immune homeostasis

Our work is at the interface between immunology, cell biology and genetics. We aim to determine the pathophysiological mechanisms underlying severe alterations of immune homeostasis using rare monogenic disorders as paradigm. This approach offers unique opportunities for describing key physiological processes, as well as complex disease-causing mechanisms, allowing us to develop new diagnostic and therapeutic tools.

In this context, we are developing two main research axes:

Decoding the cellular, molecular and genetic basis of haemophagocytic lymphohistiocytosis (HLH).

HLH is a unique immunopathological phenotype characterized by uncontrolled expansion and activation of polyclonal T lymphocytes and hyperinflammation. Over the years, we have greatly contributed to establish the relationship between genetic defects affecting cytotoxic activity of lymphocytes and HLH development. However, several inherited cases of HLH present without impairment in lymphocytes’ cytotoxicity, indicating that defects in other regulatory mechanism(s) could contribute to HLH development. The goal of our research intends to unveil new immunoregulatory mechanism(s) critical to maintain immune homeostasis, by identifying new genetic defects responsible of HLH cases presenting with normal cytotoxic activity of lymphocytes.

A M2 student position is currently available. For more information contact fernando.sepulveda@inserm.fr

Cellular and molecular dissection of inherited cases of severe allergies.

Allergies result from an inappropriate immune response against otherwise harmless antigens. Although we now have a better understanding of allergic disease development, it has become clear that associated complex phenotypes involve many different inflammatory circuits and signalling pathways in effector cells calling for novel research to delineate the underlying mechanisms. The goal of our research is designed to (i) discover new molecular effectors of allergic reactions (i.e. drug targets), and (ii) understand severe allergic diseases at the genomic and transcriptomic levels.