Cytoplasmic innate immune sensors

Published on February 3, 2019   58 min

Other Talks in the Series: Cells of the Innate Immune System

0:00
Hi. This is Seth Masters from the Walter and Eliza Hall Institute. Today, I'm going to be discussing "Cytoplasmic Innate Immune Sensors".
0:08
Specifically, we'll start with a discussion of the adaptive and the innate immune systems, comparing and contrasting them with examples of autoinflammatory and autoimmune disease. I'll then proceed to discuss individual cytoplasmic innate immune sensors and use some of these autoinflammatory diseases to explain how each of these cytoplasmic innate immune sensors work in context. Finally, I will finish by discussing some additional concepts, which I hope bring the field together and link some of these different NLRs together in a conceptual framework.
0:41
So to begin, autoinflammatory syndromes or otherwise known as periodic fever syndromes, were initially described as genetically inherited, unprovoked, systemic inflammatory diseases. These stemmed from the fact that they had no predilection towards autoimmunity i.e, no antigen specific T-cells, no high-titer autoantibodies, and in contrast, there was a very strong activation of innate immune cells. So these are things like neutrophils and macrophages, for example. That is what spawned the necessity of distinguishing the autoinflammatory diseases from the autoimmune. And I think that it sets itself up as a very nice dichotomy, where in both cases, you have activation of the immune system, but for autoimmune diseases, you have activation of the adaptive immune system, whereas in autoinflammatory diseases, you have activation of the innate immune system.
1:32
For this reason, many innate immune diseases or mutations that affect innate immune pathways result in autoinflammatory disease, and a lot of these affect cytoplasmic innate immune receptors. There are, of course, many innate immune receptors that exist on your cell surface, of innate immune cells, like macrophages and neutrophils, for example. These are things like toll-like receptors, and they directly recognize a lot of pathogen-associated molecular products, PAMPs, and damage-associated molecular products, DAMPs. It's also possible for a number of these TLRs to be located on endosomes, and TLRs three, seven, and nine are good examples of these, and they're capable of recognizing exogenous RNA and DNA, in some cases, endogenous species of these molecules as well. But things get really interesting when you start to look at the truly cytoplasmic receptors, such as the RNA and DNA receptors encoded by the RLRs, like RIG-I and STING, for example, for recognition of DNA, and for the NLRs , a very large family of NOD-like receptors that are capable of protecting a wide range of potentially pathogenic insults. And all of these cytoplasmic receptors have downstream signaling components that are broadly shared between TLRs, in terms of activating inflammatory pathways, but are somewhat distinct, and particularly for the NLRs, there is the capacity for them to form inflammasome complexes which trigger a formation of a protein platform that can cleave Interleukin-1 and Interleukin-18 into their active forms, whereas, the other signaling pathways involves the activation of transcriptional regulation pathways. So let's begin with a discussion of the inflammasome and some of the NLR proteins.