16- Innate Immune System

Question 1

LO: importance of innate immunity as the first line of defence when encountering new pathogens

Answer 1

first line of defence as initial immune response to invading pathogens, provides non-specific clearance in the time it takes for the adaptive response to prepare

barriers - physical, chemical and microbiological

immediate response, activates quickly upon encountering a pathogen

effector mechanisms - inflammation, phagocytosis, production of antimicrobial peptides, and activation of the complement system

Question 2

LO: general principles of pathogen recognition & PRRs in the innate immune system

Answer 2

PRRs = germ-line encoded receptors that recognize conserved PAMPs

type of PRRs:
- TLRs =
detect extracellular and endosomal PAMPs
- NLRs = intracellular bacterial peptidoglycans
- RIG-1-like receptors = viral RNA in the cytoplasm
- C-type lectin receptors = bind to carbohydrate structures on fungi and bacteria

PAMPs:
- LPS for gram-negative bacteria, LOS for certain species
- peptidoglycans from gram-pos
- flagellin
- viral RNA/ DNA
- fungal beta-glycans
- unmethylated CpG DNA

Question 3

LO: importance of innate immunity in triggering an appropriate adaptive immune response

Answer 3

how innate immunity helps bridge towards adaptive immunity:

cytokine production & chemokines form activated innate immune cells - neutrophils, macrophages = influence adaptive immunity

APCs & antigen presentation = provide signals for T cell activation

co-stimulatory molecules from innate APCs (e.g. CD80/86) for full T cell activation

creates inflammatory environment of cytokines, recruits and activates adaptive immune cells

Question 4

LO: compare and contrast innate and adaptive immune system

Answer 4

innate immunity
- immediate response
- non specific, recognises common PAMPs
- no immunological memory, same response every time
- consists of: physical barriers, phagocytes (macrophages, neutrophils), NK cells, complement system, cytokines, and chemokines
- germline encoded PRRs as receptors

adaptive immunity:
- slower response (days/ weeks)
- high specificity, recognises unique antigens
- long-lasting memory with specific memory B/ T cytotoxic cells = stronger and faster response upon re-encounter with the same pathogen
- consists of: B cells (produce antibodies), T cells (helper and cytotoxic), APCs (e.g., dendritic cells)
- TCRs and BCRs as receptors = generated through somatic recombination for diverse and specific antigen recognition

Question 5

PAMPs for gram negative bacteria

Answer 5

lipopolysaccharides mainly - on outer membrane

flagellin - protein used to build flagella

peptidoglycans - structural component of bacterial cell walls

Question 6

PAMPs for gram positive bacteria

Answer 6

peptidoglycans
flagellin
lipotechoic acid

Question 7

what are PRRs?

Answer 7

pattern recognition receptors

germ-line encoded host factors that specifically recognise specific types of PAMPs

Question 8

three different types of PRRS?

Answer 8

secreted - tag circulating pathogens for killing = e.g. complements

extracellular - recognise PAMPs outside cells = e.g. TLRs (2 & 4)

intracellular - recognise intrac. PAMPs = e.g. Nod-like receptors/NLRs and TLR9

Question 9

other PAMPs for bacteria/ fungi/ viruses?

Answer 9

viral DNA or RNA
fungal beta-glycans
unmethylated CpG DNA (in bacterial/viral genomes)

Question 10

components of the innate immune system

Answer 10

inflammatory response

phagocytes

monocytes/granulocytes/neutrophils

complement

cytokines, chemokines and anti-microbial peptides (AMPs)

natural killer cells

Question 11

(overview) mechanism of the inflammatory response

Answer 11

triggered by pro-inflammatory cytokines and chemokines

leads to increased permeability, neutrophil recruitment, and enhanced cell adhesion and clotting

Question 12

purpose of the inflammatory response?

Answer 12

localize and eliminate injurious agents

remove damaged tissue components

Question 13

how do phagocytes know what to ‘eat’? - list methods

Answer 13

• detect phosphatidylserine on outer cell membranes = indicates cells undergoing apoptosis
• detect ‘atypical sugars’ - e.g. mannose
• scavenger receptors
• complements bound to pathogen surface = detected by phagocyte CRs
• through passive sampling

Question 14

types of professional phagocytes?

Answer 14

dendritic cells
macrophages
neutrophils

Question 15

functions of phagocytes

Answer 15

phagocytose debris and infected cells
recognize pathogens via PRRs
produce cytokines and chemokines
present antigens via MHC

Question 16

three main roles of macrophages & dendrites

Answer 16

1. phagocytosis, ensures microbes are destroyed in lysosomes
2. producing chemokines and cytokines to stimulate innate & adaptive responses, inflammation
3. antigen presentation via MHC 2 to stimulate an adaptive T cell response

Question 17

what is the complement system?

Answer 17

heat-sensitive component of serum enhancing antibodies’ ability to inactivate antigens

Question 18

functions of the complement system

Answer 18

opsonisation - marks pathogens for phagocytosis

recruitment of phagocytic cells, inducing vasoactive responses

membrane attack complex formation - punch holes, form pores in pathogen cell membranes = leads to cell lysis

Question 19

how is the complement system activated - triggers?

Answer 19

antigens binding to antibodies - C1q binds to immune complex = activates classical pathway

detection of PAMPs - LPS, abnormal phospholipids, atypical sugars, lack of control host factors = detected by complements which act as secreted PRRs and activate the complement cascade through different pathways

e.g. mannose-binding lectin receptors detecting atypical sugars like mannose - activates lectin pathway

e.g. lack of control host factors detected by complements activates alternative pathway

Question 20

what do TLRs recognise? what cytokines do they induce the release of?

Answer 20

recognise LPS, flagellin, unmethylated CpG DNA

induce release of:
- inflammatory cytokines IL-1 & 12
- ROS and NO for oxidative killing

Question 21

what do NLRs recognise? what cytokines do they induce the release of?

Answer 21

recognise peptidoglycan of gram neg and pos bacteria, viral DNA/ RNA

induce release of IL-1 & 8 as inflammatory cytokines

Question 21

what do RIG-like-1 receptors recognise? what cytokines do they induce the release of?

Answer 21

recognise viral dsRNA

induce release of type 1 interferons - good at stimulating viral detection pathways, upregulating MHC and T & B cells

Question 22

what are cytokines?

Answer 22

glycoprotein hormones which modify the behaviour of cells in the immune response - often interleukins

Question 23

what are chemokines?

Answer 23

chemotactic factors which attract a specific cell type to the site of production/ infection via a concentration gradient

Question 24

what are antimicrobial peptides/ AMPs?

Answer 24

short 18-45 amino acid length peptides - e.g. defensins - which disrupt cell walls and induce cell lysis

have a broad-spectrum of protection during bacterial infections

Question 25

what are interferons?

Answer 25

release induced by viral infection - induce an antiviral state in other cells, provide antiviral protection

types 1 and 2 - provide cross-protection to other cells

Question 26

describe the antiviral protection mechanism of the interferon system

Answer 26

virally infected cell produces interferons before it dies which act on neighbouring cells

interferons bind to receptors on neighbouring cells, trigger JAK-STAT pathway = induces the transcription of over 400 genes - e.g.

1. protein kinase R upregulated transcriptionally
   - PKR made as an inactive enzyme
   - activated by the viral co-factor dsRNA (virus trying to replicate inside cell)
   - PKR becomes active, causes mass translational arrest
   - cell stops all protein synthesis = virus can’t replicate or spread
2. OSAi enzyme is triggered and causes global mRNA degradation
3. procaspase is upregulated by interferon - dsRNA presence activates it to caspase = destroys cell through apoptosis

neighbouring cells reach an antiviral state by the time viral progeny is released - helps prevent the spread of viral infection, though it isn’t good for cell growth

Question 27

what are NK cells?

Answer 27

large granular lymphocytes

kill certain tumour and virally infected cells

Question 28

mechanism of action of NK cells?

Answer 28

cytotoxic granules contain granzymes and perforins - destroy target cells, induce apoptosis or cell lysis

NK cells are activated when there is a loss of “self” MHC molecules on the surface of target cells
- recognise and lyse cells lacking ‘self’ MHC and have upregulated activating ligands

Question 29

diseases associated with the complement system

Answer 29

core detects - e.g. C3 - linked to autoimmune diseases like lupus

non-core defects linked to specific pathogen susceptibility - e.g. Neisseria

Question 30

diseases associated with macrophage deficiencies

Answer 30

CGD/ chronic granulomatous disease - defects in phagocyte oxidases/ NAPDH impair oxidative killing

IRF8 mutations linked to TB susceptibility

Question 31

Aicardi-Goutières Syndrome - what is it as an innate immune defect?

Answer 31

associated with constant production of inflammatory cytokines