Review of the innate Immune system

Question 1

Why do we need the innate system when we have the adaptive immune response for an infection?

Answer 1

• Adaptive Immune Response (antibodies + T cells) are too slow to protect us from some new pathogens
• Especially for infections which have a high replication rate
• So innate provides first line of defence to keep infection under control until antibodies and T cells kick in
• Resolution of infection requires both adaptive and innate immune responses

Question 2

State the key difference between adaptive and innate immunity?

Answer 2

• Adaptive immunity - involves very specific recognition of a particular infectious agent (usually sees a protein = antigen)
• Innate immunity - no specific antigen recognition + involves recognition of broadly conserved features of different classes of pathogens (PAMPS)

Question 3

Pattern recognition of pathogens
What molecules does pattern recognition of pathogens occur by and describe it?

Answer 3

• Pattern recognition is through Pathogen-associated Molecular Patterns (PAMPs)
• Molecules present only on pathogens and not on host cells
• Essential for survival of pathogens
• Invariant structures shared by entire class of pathogens

Question 4

State examples of PAMPs for G -ve, G+ve, bacteria, and viruses?

Answer 4

• Gram-negative bacteria; lipopolysaccharides (LPSs) found in outer membrane
• Gram-positive bacteria; teichoic acid, lipoteichoic acid, peptidoglycan found in outer membrane
• Bacterial flagellin
• Abnormal protein glycosylation
• Abnormal nucleic acids - viruses

Question 5

What are pattern recognition receptors (PRs)?

Answer 5

• Host factors that specifically recognise a particular type of PAMP
• They are germ-line encoded: These receptors evolved to recognize conserved products of microbial metabolism produced by microbial pathogens,

Question 6

State the 3 functional classes of PR’s

Answer 6

• Extracellular: They recognise PAMPs outside of a cell and coordinate a response to the pathogen •
• Intracellular (cytoplasmic): They recognise PAMPs inside a cell and act to co-ordinate a response to the pathogen
• Secreted: They act to tag circulating pathogens for elimination

Question 7

Components of the innate system
State the 5 key components of innate immunity?

Answer 7

• The inflammatory response
• Phagocytes: Monocytes/granulocytes/neutrophils
• Complement
• Cytokines, chemokines and anti-microbial peptides (AMPs)
• Natural Killer cells
• They’re all related as they all trigger each other

Question 8

Describe the inflammatory response and it’s effects

Answer 8

• A generic defence mechanism whose purpose is to localize and eliminate injurious agents and to remove damaged tissue components
• Effects:
• Enhanced permeability and extravasation: Permeability, so cells can get to site of infection. Extravasation = cells from blood to tissue
• Neutrophil recruitment
• Enhanced cell adhesion
• Enhance clotting

Question 9

How is the inflammatory response triggered?

Answer 9

Triggered by the release of pro-inflammatory cytokines and chemokines at the site of infection

Question 10

How do phagocytes distingiush between recognising what to target and how to know when they are infected?

Answer 10

• Phagocytes have to be able to recognise what to eat, but they need to know as well when they are infected in order to produce cytokines and chemokines
• The molecular recognition events are distinct: i.e. they use different pattern recognition receptors (PRRs)

Question 11

State the type of phagocytes that can carry out phagocytosis in multicellular animals?

Answer 11

• Dendritic cells, macrophages and neutrophils
• Considered as professional phagocytes

Question 12

State the 3 distinct roles of macrophages and dendritic cells in immunity

Answer 12

• Phagocytosis; material is destroyed in lysosomes •
• Infections can trigger macrophage activation - activated macrophages produce cytokines and chemokines to stimulate both innate and adaptive immune responses - this triggers the inflammatory response and can promote a local anti-microbial state
• Peptides from broken down pathogens can be presented through MHC and promote the development or recall of an adaptive T cell response (more for D cell)
• The major histocompatibility complex (MHC) is a series of genes that code for cell surface proteins which control the adaptive immune response

Question 13

State 5 ways pathogens use recognition for phagocytes to eat?

Answer 13

1. By detecting phosphatidylserine on exterior membrane surface (cells undergoing apoptosis
2. By detecting “atypical sugars” (e.g. mannose, fucose, beta-glucan) on cell surfaces
3. By Scavenger receptors -> receptors that are non-self
4. By “passive sampling”
5. By detecting complement proteins bound to the pathogen surface

Question 14

Describe what the complement system is used for

Answer 14

• Originally described as a heat-sensitive component of serum that could augment the ability of antibodies to inactivate antigen.
• Originally thought to be a biochemical complex antibody-dependent effector mechanism leading to:
• Opsonisation
• Recruitment of phagocytic cells, vasoactive function
• Punches holes in target membranes (MAC)
• there are all an effector mechanism used as a vital part of innate system

Question 15

Describe the role of complement proteins?

Answer 15

Complement proteins act as secreted Pattern recognition receptors (PRRs) and can be activated by a range of PAMPs, and can also be activated by “altered self”

Question 16

Draw the complement system outlining the pathways, PRs and PAMPs?

Answer 16

VD

Question 17

State the 3 types of PRRs describing the PAMPs recognised and the outcome of the receptor?

Answer 17

• Receptor: Toll like receptors (surface and endosomal) - Ligand: LPS, lipoproteins, Flagellin - Outcome: Inflammation: Cytokine release, enhanced killing like reactive oxygen species
• Receptor: NOD like receptors - Ligand: Peptidoglycan from G+ and G- bacteria, some viral DNA/RNA - Outcome: Inflammation cytokine release
• Receptor: RIG like receptors - Ligand: Viral dsRNA and 5’ triphospho RNA - Outcome: Type 1 interferon production

Question 18

Describe the difference between cytokines and chemokines?

Answer 18

• Glycoprotein hormones that affect the immune response
• Cytokines: Act to modify the behaviour of cells in the immune response. Most of these are called interleukins (eg. IL-1) - upregulate IF response
• Chemokines: Act as chemotactic factors - i.e. they create concentration gradients which attract (or occasionally repel) specific cell types to a site of infection

Question 19

Interferons
Describe interferons and state its features?

Answer 19

• Interferons; the main anti-viral cytokines
• Secreted factors (type I and type III): Type Il is for lungs
• Induced by viral infection
• Offer cross-protection
• Widely distributed in evolution, from fish upwards, but species-specific

Question 20

Describe the interferon system?

Answer 20

VD

Question 21

What enzyme can lead to transcriptional arrest from interferons?

Answer 21

viral dsRNA -> PKRa -> transcriptional arrest

Question 22

What are anti-microbial peptides and how they do work?

Answer 22

• Anti-microbial peptides (AMPs) (e.g. Defensins)
• Secreted short peptides (18-45 amino acids)
• Usually work by disrupting cell wall leading to lysis
• Some are induced by bacterial infection
• Offer broad protection

Question 23

Describe what natural killer cells are and their function?

Answer 23

• Natural Killer (NK) cells (Large granular lymphocytes)
• 4% white blood cells
• Lymphocyte-like but larger with granular cytoplasm
• Kill certain tumour & virally infected cells
• Target cell destruction is caused by cytotoxic molecules called granzymes & perforins

Question 24

Describe the activation of NK cells?

Answer 24

• NK cells possess the ability to recognise and lyse virally infected cells and certain tumour cells.
• Selectivity is conferred by LOSS of “self” MHC molecules on target cell surfaces, AND up-regulation of activating ligands.

Question 25

Explain the activation of natural killer cells

Answer 25

- All Uninfected cells have MHC class I on their surface -> These present peptides which trigger cytoxic T cell attack - NK cells have MH receptors which if they detect MHC class I on cell, won't attack as its 'self' - So infected cells remove MHC class to prevent Tc attack - But NK cells detect no MHC class and therefore induce cell death via: Perforin + cytotoxic granules or Engagement of death receptors

Question 26

State inherited defects and the diseases that arise from the complement, macrophage, cytokines and interferons? (PART 1)

Answer 26

- Complement: Core defects (e.g. C3) linked to development of autoimmune diseases such as lupus. Non-core defects linked to suseptibility to specific types of pathogens such as Neisseria - Macrophage deficiencies: Chronic granulomatous disease (CGD); No oxidative burst for bacterial killing. IRF8 mutations linked to susceptibility to TB

Question 27

State inherited defects and the diseases that arise from the complement, macrophage, cytokines and interferons? (PART 2)

Answer 27

- Aicardi-Goutières syndrome associated with constitutive production of inflammatory cytokines - Lack of interferon-responsiveness - sensitivity to viral infection (e.g. measles)

Question 28

Compare the innate immunity with adaptive immunity in terms of cell types, speed, memory, specificity, receptors

Answer 28

- Innate immunity: - Cell types: Macrophages, Neutrophils, DCs - Speed: Fast - Memory: No - Specificity: Low - Receptors: Pattern recognition - Strategy of recognition: Small number of microbial ligands that are highly conserved between pathogens; germ-line encoded receptors evolved by natural selection

Question 29

Compare the innate immunity with adaptive immunity in terms of cell types, speed, memory, specificity, receptors

Answer 29

- Adaptive immunity: - Cell types: Lymphocytes - Speed: Slow - Memory: Yes - Specificity: High - Receptors: Ig, TCR - Strategy of recognition: Billions of possible antigens. Receptors generated randomly within individual; can’t be inherited