Homeostasis of the host-commensal interface : stealth and/or active tolerogenesis ?

The fifth lecture, entitled "Homeostasis of the host-commensal interface: stealth and/or active tolerogenesis?" aimed to establish a truly integrated and dynamic vision of the mechanisms enabling tolerance of the commensal microbiota despite recognition of its bacterial components by the innate and adaptive immune system. "Fighting ignorance to learn tolerance" was the ultimately highly societal theme of this presentation, which described in an integrated way the bacterial, epithelial and immune factors combining to establish tolerance of these flora. Any breakdown in these homeostatic mechanisms of tolerogenesis can lead to pathologies, particularly inflammatory ones. This is the case of inflammatory bowel diseases (IBD). The seminar given by Jean-Pierre Hugot illustrated this last point. The presenter was one of the first to demonstrate that a high percentage of familial Crohn's disease, an IBD of increasing incidence in our populations, was linked to a mutation in nod2/card 15, a gene coding for a cytosolic protein which our group has concurrently shown to be a sensor of muramyldipeptide (MDP), a component of the bacterial wall or peptidoglycan. We collaboratively showed that these mutations led to a loss of function of Nod2, unable, even in the presence of its MDP agonist, to activate the innate pro-inflammatory NF-κB and MAPKinase signalling pathways. This and subsequent work in human genetics thus confirmed that the loss of a bacterial flora recognition mechanism can lead to a sometimes dramatic breakdown in homeostasis and tolerance.