Inflammation control and auto-inflammatory diseases

This lecture began with an overview of the receptors and signalling pathways involved in innate immune responses. It is in this context that the identification of rare hereditary diseases responsible for autoinflammatory pathologies has contributed in recent years to a better understanding of the regulatory pathways (control) of innate immunity. Several genetic anomalies affecting receptors of the NLR (NOD-like receptor) family, involved in the cytoplasm's recognition of microbial molecules, are responsible for the "spontaneous" activation of the inflammatory response inherent in excessive interleukin-1 production. The study of other inflammatory diseases has led to the identification of the ADAR1 molecule as a powerful regulator of the MDA5 signaling pathway, a cytosolic molecule that detects viral double-stranded RNA. A series of hereditary pathologies cause excessive production of type 1 interferon (see seminar 2 below). In this context, the functions of innate immunity overlap with the adaptive immunity responsible for autoimmunity, as a fraction of patients with disseminated lupus with anti-DNA autoantibodies are characterized by excessive production of type 1 interferon, the molecular consequences of which ("interferon signature") can be readily detected. Hypotheses linking excess interferon production, disruption of adaptive immunity and anti-DNA antibody production were discussed during the lecture. The link between innate and adaptive immunity was illustrated by the demonstration of a very rare pathology characterized by the joint occurrence of auto-inflammation and auto-immunity caused by mutations in a gene regulating the NFkB pathway by ubiquitination and degradation of polyubiquitinylated chains of NFkB activator complexes. This "A20" molecule thus controls the level of signaling induced by multiple receptors on immune system cells. Finally, it has been shown how, physiologically, the localization of RNA molecules does or does not cause autoimmune disease: the TLR7 receptor of innate immunity detects single-stranded RNA of viral origin within endosomes. Endogenous RNA is present in the nucleus and cytoplasm, but not in these endosomes. However, a failure to regulate endogenous RNA catabolism (see below) can result in pathological activation of these receptors, leading to autoinflammatory diseases and disseminated lupus.