3. Innate immune defences & inflammation 2 Flashcards Preview

BSMS204 Theme I Immunology > 3. Innate immune defences & inflammation 2 > Flashcards

Flashcards in 3. Innate immune defences & inflammation 2 Deck (49)
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1

Innate immune cells

neutrophils, macrophages, dendritic cells, natural killer cells

2

Neutrophils

phagocytosis
reactive oxygen and nitrogen species
antimicrobial peptides
NETs (neutrophil extracellular traps)

3

Macrophages

phagocytosis
inflammatory mediators
antigen presentation
reactive oxygen and nitrogen species
cytokines
complement proteins

4

Dendritic cells

antigen presentation
costimulatory signals
reactive oxygen species
interferon
cytokines

5

phagocyte recruitment steps

Rolling and extravasation
1. rolling
2. activation
3. arrest/adhesion
4. transendothelial migration

6

How does phagocyte recruitment happen?

1. cytokines e.g. TNF-alpha dilate local blood vessels
2. chemokines attract monocytes and neutrophils to the infection
3. cell adhesion molecules (ICAM-1 and ICAM-2) are upregulated on the endothelium which bind to integrins (family of adhesion molecules) on the leukocytes

7

What is phagocytosis?

Phagocytosis is the capture and digestion of foreign particles
Performed by neutrophils and macrophages

Put out processes to feel for foreign objects, but not always recognise them sometimes recognises opsonins on opsonised things

8

What initiates phagocytosis

Active process initiated by binding to pathogen

9

How does phagocytosis occur?

Macrophage receptors recognise components of microbial surfaces
Microorganisms are bound by phagocytic receptors on the macrophage surface
Microorganisms are internalised by receptor-mediated endocytosis
Fusion of the endosome with a lysosome forms a phagolysosome in which microorganisms are degraded

10

Antimicrobial mechanisms of phagocytes

Acidification, toxic oxygen-derived profucts, toxic nitrogen oxides, antimicrobial peptides, enzymes, competitors (e.g. lactoferrin)

11

What are NETs?

When activated some neutrophils undergo a special form of cell death termed ‘NETosis’
During NETosis nuclear chromatin is released from cells trapping microorganisms thus aiding phagocytosis

12

What are pattern recognition receptors (PRRs)

Receptors able to recognise conserved structures

They recognise patterns termed:
pathogen-associated molecular patterns (PAMPs)

13

What are some examples of PRRs?

Toll-like receptors (TLRs)
NOD-like receptors (NLRs)
Rig-I like receptors (RLRs)
Cytosolic DNA sensors (CDS)

14

Pathogen-associated molecular patterns (PAMPs)

PAMPs - Microbes evolve rapidly, so innate immunity must focus on highly conserved and essential components of microbes (cell wall structures; nucleic acids)

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DAMPs

DAMPs – Damage associated molecular patterns, molecules released from necrotic cells

16

Drosophila Toll receptor

Mutagenesis work on Drosophila revealed two members of the Toll family, dToll and 18-wheeler
Important for development
Important for immunity to the fungal and bacterial infections
Mammalian equivalent are the Toll-like receptors

17

Toll-like receptor structure

Extracellular:
LRR domain – site of pathogen binding

Cytosolic side:
TIR-domain - conserved stretch of ~200 amino acids

18

TLRs form functional hetero/homodimers

The convex surfaces of TLR-1 and TLR-2 have binding sites for lipid side chains of triacyl lipopeptides
Binding of each TLR to the same lipopeptide induces dimerization, bringing their cytoplasmic TIR domains into close proximity

19

Different TLRs and their ligands

Extracellular:
TLR1 and 2- triacyl lipopeptides
TLR2 and 6- diacyl lipopeptides
TLR5 - flagellin
TLR4 - LPS

Intracellular:
TLR3, 7, 8 and 9 - DNA and RNA

20

TLR signalling

TLR signalling induces genes that function in host defense
Pro-inflammatory cytokines
Chemokines
MHC & co-stimulatory molecules
antimicrobial peptides & complement components

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What does TLR activate?

IRF3/7, AP1 (thru MAPKs), NFK-beta

22

TLR adaptor proteins

Myd88 (used in all pathways except TLR3)
Mal used by TLR1/2 and TLR4
TRAM just TLR4
TRIF TLR3 and TLR4

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Myd88 gain of function mutation

Waldenström macroglobulinemia is a rare type of non-Hodgkin lymphoma.

B cells make large amounts of IgM that can cause excess bleeding, vision problems and headaches.
Lymphoma cells proliferating in the bone marrow can cause anaemia (low levels of red blood cells), neutropenia (low levels of neutrophils) and thrombocytopenia (low levels of platelets).

24

Myd88 loss of function mutation

Nine MyD88 deficient children suffered from life-threatening, often recurrent pyogenic bacterial infections, but were otherwise healthy, with normal resistance to other microbes.

Their clinical status improved with age, possibly due to a compensatory effect of adaptive immunity or other innate immune mechanisms.

25

TLR-deficiencies

Herpes simplex encephalitis (HSE): Inflammation of the brain due to infection with herpes simplex virus (HSV-1)

HSV-1 is a dsDNA virus, but during viral replication it produces dsRNA

Defects in other signalling molecules involved in the TLR3 signalling pathway have also been associated with HSE

26

TLRs in infection

HIV – TLR8
Sepsis – TLR2 and 4
Tuberculosis – TLR2 and 4

27

TLRs in inflammation

Systemic Lupus Erythamatosus –
TLR7, 8 and 9
Alzheimer's Disease – TLR2 and 4
Atherosclerosis – TLR2 and 4

28

TLR agonists

Infection- genital warts (TLR7)
Cancer - Melanoma (TLR7 ligand)
Allergy – Ragweed pollen (TLR9)
Vaccine adjuvant

29

TLR antagonists

Autoimmunity (TLR7,8,9)
Sepsis (TLR4)
Cancer

30

Nod-like receptors

NLR = Nucleotide-binding Leucine Rich

Cytoplasmic pattern recognition molecules
Two major groups- NLRCs and NLRPs - ‘C’ stands for ‘caspase recruitment domain (CARD)’ and the ‘P’ stands for pyrin domain.