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ICB > Innate Immunity > Flashcards

Innate Immunity Flashcards

1
Q

Innate Immunity

A
  • ability of the organism to detect and defend against invading microbes or other foreign life-forms to which it hasn’t been exposed
  • found in all domains of life and conserved
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2
Q

Detection and effectors

A
  • the immune system needs to be able to detect an infection and its general type as well as trigger effector mechanisms killing that class of infecting organism
  • inappropriate effectors do not clear the infection and can damage the host
  • adaptive immunity relies on innate detection and effectors: innate immunity instructs adaptive responses and effectors
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3
Q

Responses to Infection

A
  1. barriers can prevent infection
  2. recognition by preformed nonspecific and broadly specific effectors (complement)
  3. recruitment of effector cells : recognition of PAMPs for effector activation/inflammation (early induced response)
  4. adaptive response: lymphocytes like B and T cells recognise antigen transported into lymphoid organs.
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4
Q

Microbe Detection

A
  • innate immune response is dependent on the ability to recognise microbes
  • detection can be direct (via recognition of molecule moieties of pathogens) or indirect (via detection of pathology generated by infection)
  • pathology detected by changes in physiology
  • PAMPs detected by PRRs
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5
Q

Fundamentals of Innate Detection

A
  1. direct detect of molecules present on foreign organisms and absent from host (PAMP)
  2. detection of modifications made to host molecules
  3. detection of host derived danger signals / signs of aberrant processes
  4. detection of missing self molecules (ie. antigen production shut down)
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6
Q

PAMP

A
  • pathogen associated molecular moiety
    Want moieties that are:
  • conserved across many microbial species (limited number of innate receptors)
  • not found in host cells
  • fairly abundant so immune response can be efficiently activated
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7
Q

Types of Bacterial PAMPs

A

Gram Positive: lipoteichoic acid, lipoprotein, peptidoglycan
Gram Negative: LPS, porin, peptidoglycan
Mycobacteria: glycolipid, LAM, mycolic acid, peptidoglycan, galactan

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8
Q

Fungal PAMPs

A
  • mannan (poly-saccharide)
  • B-glucan (poly-saccharide)
  • Chitin (N-acetylglu)
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9
Q

Innate Immune Receptors

A
  1. phagocytic receptors: expressed by phagocytes and mdediate internalization of detected nonself organisms
  2. signalling receptors: detect invaders and alter gene expression in the detecting cell often driving signalling to other cells (activate cytokine expression instructing further cellular activity)
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10
Q

Phagocytic Receptors

A
  • bind to PAMPs or antibodies bound to the microbe
  • internalised cells put into the lysosome with proteases and hydrolytic enzymes for destruction
  • these receptors are a specific kind of pattern recognition receptor : bind to PAMPs to allow recognition of invasive particles by phagocytes allowing the invader to be phagocytosed and killed
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11
Q

Signalling Receptors

A
  • activated by microbial moieties to drive the activation of signal transduction pathways resulting in gene expression changes
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12
Q

Types of Signalling PRRs

A
  1. lectins: recognise carbohydrate moieties
  2. peptidoglycan recognition proteins
  3. toll-like receptors: wide microbial recognition
    - expression of these systems is found in the surveillance cells of the innate system
    - eg. dendritic cells, neutrophils, macrophages
    - important for the type of infection to be distinguished for B/T cell activation
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13
Q

Toll Like Receptors

A
  • type 1 integral membrane glycoproteins with extracellular domains containing varying numbers of Leucine Rich Repeat motifs and cytoplasmic domains homologous to that of IL-1 receptor (signalling domain)
  • homologous structure within the family
  • recognises induces conformational changes of TIR domain constitutes the signal to initiate a cascade of cytoplasmic protein interaction
  • leads to transcriptional activation of cytokine and chemokine genes
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14
Q

Types of TLRs

A

Cell surface: recognise microbes and cellular invaders

Phagosome/endosome: recognise nucleic acids from viruses

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15
Q

Cell Surface TLR Recognition

A
  • specific cytosolic components involved for scaffolding
  • intracellular signalling domain recruits transduction proteins like Mal and MyD88, signalling to IRAK1/4 and therefore NF-kB
  • promotes transcription of inflammatory cytokines
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16
Q

NFkb/Rel

A
  • key transcriptional activator downstream of TLR’s
  • conserved family of TF activated by innate immune response
  • TLF activation triggers a signalling pathway resulting in cleavage of an inhibitory domain of NFkB
  • permits DNA binding domain access to the nucleus where it drives transcription of its target genes
  • targets are proinflammatory cytokines (TNFa, IL1)
17
Q

Virus Detection

A
  • viruses produced in host cells from host components and the only non host molecules are specific proteins
  • adaptive responses detect viral proteins by binding to antibodies or T cell receptors
  • innate responses detect viral proteins by detecting cell damage and unusual nucleic acid signatures (wrong place and shape)
18
Q

Endosomal TLR Recognition

A
  • NFkB pathway to produce inflammatory cytokines
  • IRF3 (TF) pathway to produce type 1 interferons
  • this is activated mainly by nucleotide ligands
  • endosomal detection is tuned for viruses as viral RNA/DNA is exposed in the endosome due to low pH levels
19
Q

IRF3

A
  • second transcription factor of endosomal pathways
  • key in engaging the antiviral response in mammals
  • endosomal activation triggers signalling pathway resulting in phosphorylation of IRF3
  • dimerisation + nuclear localisation to drive target gene transcription
  • key target is type 1 interferons
20
Q

TLR-NFkB

A
  • induces proinflammatory cytokines and chemokines
  • IL-1 and 6 enhances the immune response and induces protein secretion
  • IL-8 is a chemoattractant for neutrophils
  • TNF-a enables a systemic endothelial response by inducing vascular changes for cell recruitment
21
Q

TLR-IL-1 Amplificaiton

A
  • TLRs and IL-1R share common signal pathways using IRAK1/4 and TRAF6 signal proteins
  • thus a persistent and chronic infection can cause chromic inflammator
  • the inflammasome is a signal mechanism that can facilitate or prevent this
22
Q

Inflammasome

A
  • detects intracellular/cytosolic bacterial infection
  • animal cells have no cytosolic TLR’s
  • cytosolic bacteria are recognised by NLR (NOD and leucine rich repeat) proteins
  • NOD: nucleotide binding and oligomerization domain)
  • LRR: binds microbial moieties
  • NLR’s triggers activation of IL-1B via inflammasome
23
Q

Inflammasome Formation

A
  • primary step of TLR/TNFR/IL-1R receptor activation causing de novo transcription of pro-IL-1B and NLRP3
  • activation step forms the assembled NLRP3 inflammasome complex that activates pro-IL-1B
  • IL-1B has caspase activity activating pore formation in the cell membrane
  • IL-1B can activate IL-1R to permit further amplification
24
Q

Viral Nucleic Acid Detection

A
  • numerous sensors
  • for RNA viruses
    1. RIG-I like
    2. DExD helicases: similar to RIG like lacking some domains
    3. others
  • signalling pathways then lead to IRF and NFkB TF production of IFN-a/B
25
Q

RIG-I like receptors

A
  • 3 domains: signal, binding of viral RNA, and CTD shutting the system down when not detecting RNA
  • CTD binds the CARD N terminal (signal) domain when not active
  • activation leads to similar signal path as TLR
  • IRF3/NF-kB activation
26
Q

Identifying foreign RNA structures

A
  • foreign RNA recognition depends on presence of long dsRNA structure
  • respond to absence of 5’ RNA modification
  • RIG-1 recognises mRNA with naked 5’ triphosphate or bad cap as foreign
27
Q

TNF

A
  • causes endothelial permeability
  • allows immune cell entry
  • leads ultimately to circulation loss
  • can be dangerous as permeability throughout the body causes a loss of vasculature integrity
  • organ failure
28
Q

Type 1 Interferon

A
  • antiviral cytokines
  • transcription targets of IRF3
  • activated by mainly nucleotide ligands
  • IFNa comes from immune cells and IFNB from virus infected non-immune cells
  • IFNy activity focused on epithlial layers
  • IFNB induces IFNa production (signals to plasmid dendritic cells for antiviral amplification)
29
Q

IFNa/B

A
  • inhibit proliferation/translation
  • promot apoptosis
  • stimulate cytotoxic activity of NK and T cells + other immune cells
  • stimulate expressed of other surface molecules
  • repression of anti-apoptotic genes

ICB (15 decks)

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