Level 2 Immune System Sensing Danger 2024 PDF
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Uploaded by CongratulatoryJudgment6552
University of Glasgow
Kevin Maloy
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Summary
This document presents a lecture on how the immune system detects and responds to danger. It covers various aspects of pathogen recognition, including PAMPs and DAMPs, various cell types involved, and mechanisms of immune response.
Full Transcript
How does the immune system sense danger? Prof. Kevin Maloy [email protected] Key learning objective Describe how microbes can be sensed by immune cells, and mechanisms microbes use to evade detection The immune system has to make decisions How can I discriminate between substanc...
How does the immune system sense danger? Prof. Kevin Maloy [email protected] Key learning objective Describe how microbes can be sensed by immune cells, and mechanisms microbes use to evade detection The immune system has to make decisions How can I discriminate between substances that are? Foreign + dangerous Innocuous or self Self epithelial cell Bacteria Pollen Virus Questions for this lecture What microbial substances activate the immune system? How does the immune system recognise the damage pathogens cause? Which cells and receptors respond to microbial products? What are the consequences of microbial sensing for the host? How do microbes evade detection? Overview of initial response to infection Dendritic cell Blood vessel Activation of local innate immune cells Increased permeability of Bacteria local blood vessel Neutrophils Migration into tissues of more Macrophage immune cells and plasma proteins Monocytes (acute inflammation) Mast cell Charles Janeway: predicted the the presence of host receptors that recognised conserved patterns on pathogenic molecules Nobel Prize Physiology and Medicine, 2011 1943-2003 Approaching the Asymptote? Cold Spring Harbor 1989 PAMPs: what makes microbes look different from host cells PAMPs: Pathogen Associated Molecular Patterns Viruses Bacteria Fungus Protozoa Viral nucleic acids Bacterial DNA Polysaccharides Glycolipids Glycoproteins Cell wall components Polly Matzinger: argued that the immune system senses danger rather than non-self Described the ”Danger Model” of the immune system Immune responses triggered by damage or danger rather than “non-self” antigens DAMPs: evidence of damage resulting from infection DAMPS: Damage Associated Molecular Patterns Nuclear and Nucleic acids Metabolites cytoplasmic proteins Released from dying cells Pathogens are sensed by innate cells and information about them is passed down to adaptive immune cells Pathogens DCs and other innate cells Adaptive immune cells CD4+ Co-ordinate DC T cell immune response CD8+ Kill infected cells T cell Make antibody to B cell clear up pathogen Information Transfer Leukocytes and tissue cells detect and control pathogens at infection sites Immune cells Tissue cells Dendritic cells Macrophages and monocytes Epithelial cells Engulf and destroy pathogens Engulf pathogens to activate Release inflammatory molecules adaptive immune cells Neutrophils Mast cells Eosinophils Fibroblasts Release toxic molecules or Release toxic molecules engulf and destroy pathogens to kill pathogens Numerous host soluble and cell surface molecules help sense pathogens Pathogens that can evade these molecules are better at causing disease Complement acts in multiple ways to control pathogens Complement: series of plasma proteins that act in an enzymatic cascade Effect Complement mediators Consequence Enhance acute Soluble C3a and C5a Increased influx of immune inflammation released at infection site cells to control pathogen Complement receptor Opsonisation of Improved phagocytosis pathogens leads to faster clearance and killing of pathogen MAC: made up of complement C5-C9 Formation of membrane attack complex Kill pathogens Serna et al Nature Comms, 2016 Host cells and some pathogens can evade complement Smallpox virus protein: CD46: inactivates C3b SPICE inactivates C3b CD59: stops MAC from forming Influenza virus and HIV pick up host complement inhibitors E.coli recruits C1 inhibitor C1 inhibitor –cleaves early complement components to stop Schistsoma and Trypanosoma: amplification of immune response express CRIT: blocks early steps in complement activation PAMPs: what makes microbes look different from host cells PAMPs: Pathogen Associated Molecular Patterns Viruses Bacteria Fungus Protozoa Viral nucleic acids Bacterial DNA Polysaccharides Glycolipids Glycoproteins Cell wall components PAMPs are recognised by Pattern Recognition Receptors (PRR) Bacterial essential cell wall molecules are PAMPs Pattern Recognition Receptors – danger sensors Toll Like Receptors: Nucleotide-binding C-type lectin-Like Receptors: Mostly recognise PAMPs oligomerization domain-Like Pathogen and host Receptors: range of PAMPs carbohydrates and DAMPs NLRs CLRs TLRs Absent in melanoma 2-Like Receptors: Retinoic acid-inducible gene-I-Like Receptors: Bacterial or viral cytoplasmic DNA Pathogen or host ss or ds RNA ALRs RLRs Why do you think there are so many different types of pattern recognition receptors? PRR are found in different parts of the cell Bacteria and fungal sensing PRRs on the cell membrane TLRs CLRs Viral and bacterial TLRs in endosomes NLRs DAMP and PAMP sensing PRR in cytoplasm ALRs nucleus RLRs DNA and RNA sensing PRRs in the cytoplasm Pathogens can hide from PRR recognition The flagellin of Helicobacter pylori has evolved to reduce TLRs recognition by TLR5 Polio virus steals RNA NLRs host 5’ caps from host mRNA to hide from NLRs Listeria monocytogenes has altered cell wall to reduce nucleus recognition by NLRs PRR are found on leukocytes and tissue cells Leukocytes Tissue cells Dendritic cells Macrophages and monocytes Epithelial cells Fibroblasts Mast cells Neutrophils All of these cells can sense pathogens and danger – and do something about it! Consequences of PRR activation PRR senses microbe Tell neighbouring cells Limit microbe replication about the threat Tell the adaptive immune system Control pathogen Make inflammatory cytokines Phagocytose the microbe and take it to the draining lymph node What links pathogen activation of PRR to altered immune responses? Bacteria alter gene transcription via NF-κB activation TLR MyD88 TLR activation drives an intracellular pathway that activates NF-κB NF-κB NF-κB translocates into the nucleus and drives altered gene transcription nucleus This allows the cell to warn the immune system about the infection Some pathogens can limit NF-κB activation MyD88 E.coli virulence factors NF-κB degrade NF-κB nucleus Shigella enzyme cause degradation of an activator of NF-κB The warning signal to the immune system is reduced Some NLR form ‘inflammasomes’: cytosolic platforms for Caspase-1 activation NLR ASC Pro-Caspase1 Caspase1 Inflammation Pro-IL-1 IL-1 Pro-IL-18 IL-18 Influenza virus infection leads to inflammatory cytokine release and potentially cell death Influenza virus infects epithelial cells in the respiratory tract TLR RIG-I MyD88 NF-κB nucleus Apoptosis Inflammatory cytokines Type I IFN Activate immune response Reduce viral spread by warning neighbouring cells Influenza virus inhibits intracellular activation of PRRs and reduces anti-viral immune response TLR NS1 binds and blocks RIG-I RIG-I MyD88 NF-κB NS1 inhibits NF-κB activation nucleus Apoptosis Interleukin 1 Type I Interferon Immune system not warned Virus can keep spreading to new cells Pathogens are sensed by innate cells and information about them is passed down to adaptive immune cells Pathogens DCs and other innate cells Adaptive immune cells CD4+ Co-ordinate DC immune response PAMPS Migration to T cell and secondary DAMPS lymphoid organs CD8+ Kill infected cells T cell Complement Inflammatory and PRR cytokines Make antibody to B cell clear up pathogen Information Transfer Summary and related lectures Pathogens and the damage they cause trigger innate immune responses via various different host molecules This sometimes leads to adaptive immune responses: Outsmarting the bugs: adaptive immunity Vaccination: design and mechanisms Pathogens can evade recognition/activation of the innate immune response And sometimes the immune response is activated at the wrong time: Gut Feeling: examining microbiomes and their impact Self harming: allergy and autoimmunity