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Immunology > L3. Elements of Innate Immunity > Flashcards

L3. Elements of Innate Immunity Flashcards

1
Q

What are the 4 roles of innate immune cells?

A
  1. Recgonise and activated by pathogen
  2. Eliminate pathogen
  3. Communicate with other cells
  4. Activate and steer adaptive immune responses.
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2
Q

What are all immune cells derived from?

A

Haematopoietic stem cells (pluripotent stem cells)

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3
Q

What are the 2 main lineages derived from haematopoietic stem cells and what cells do these produce?

A
  1. Myeloid cells (all innate)
    >Monoblast derived: Monocytes, Dendritic cells, and Macrophages
    >Polymorphonuclear leukocytes (PMNs (Neutrophils, eosinophils, basophils)
    >Mast cells
  2. Lymphoid cells (all adaptive other than NK cells)
    >B cells
    >T cells
    >Natural killer cells
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4
Q

What cells are derived from myeloblast precursors?

A

Polymorphonuclear leukocytes (PMNs): Neutrophil, Eosinophil, and Basophil

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5
Q

What gave basophils, eosinophils, and neutrophils their names?

A

Scientists tried to classify them, stained them with different dyes, blue basic dye stained basophils (basic dye loving), red acidic dye stained eosinophils (loved acidic eosin dye), most cells didn’t stain with either called neutrophils (for neutral)

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6
Q

What % of leukocytes in blood are a) Neutrophils b) Eosinophils c) Basophils?

A

a) Neutrophils: (60-70%) leukocytes in blood

b) Eosinophils: ~6% (normally), but also beneath mucous surfaces

c) Basophils: ~1% of white blood cells.

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7
Q

Describe the life cycle of a Neutrophil?

A

> Released in large numbers from bone marrow, make millions per day.

> Live for < 24hr in blood then die (short live)

> Life extended on entering tissues in response to chemoattractants (C5a, C3a) towards infection

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8
Q

What receptors do neutrophils have?

A

Receptors for C3b, IgG, IgA (to recognise antigen coated in antibodies) as well as receptors for chemoattractants C5a and C3a

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9
Q

What are the functions of neutrophils?

A

Main function is phagocytosis, but also “NETosis”

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10
Q

What is NETosis?

A

NETosis= dying neutrophils throw out DNA and histones as well as antimicrobials like defensins to make a NET (neutrophil extracellular trap) to catch and kill bacteria

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11
Q

What receptors do Eosinophils have?

A

Receptors for C3b (for phagocytosis), IgG, IgA, (IgE in certain circumstances)

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12
Q

What are the 3 functions of Eosinophils?

A
  1. Can do phagocytosis but not good at it, instead Release toxic proteins, free radicals (e.g. ROS binds to components of pathogens to cause damage)
  2. Defence against multicellular parasites
    >Too big to phagocytose so need extracellular toxins and free radicals to damage and kill parasite.
  3. Role in allergy (especially asthma)
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13
Q

What receptors do Basophils have?

A

Receptors for C3a, C5a (chemoattractants), IgE

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14
Q

What are the 3 roles of Basophils?

A
  1. Release heparin
    >Heparin increases blood flow
  2. Release histamine
    >Histamine is inflammatory mediator.
  3. Defence against parasites, and role in allergy
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15
Q

How is concentration of Basophils different in people with allergies?

A

Normal individuals have low conc of these cells, people with allergies have increased numbers.

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16
Q

What are Mast cells?

A

Cells similar to basophils but found under mucous surfaces and skin

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17
Q

Where are mast cells found?

A

Restricted to tissues - protect mucosal surfaces (e.g. nose, lungs) and under the skin.

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18
Q

What receptors do mast cells have?

A

Receptors for C3a, C5a, IgE

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19
Q

What are mast cells often referred to as and why?

A

Sometimes referred to as “Sentinel” cells as they alert the body of infection

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20
Q

What is the function of mast cells?

A

> Defence against parasites, and role in allergy

> Release histamine etc. from granules as inflammatory mediators.

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21
Q

What are the differences between a) Monocytes b) Macrophages?

A

a) Monocytes:
>Found in blood
>Short-lived, fast moving

b) Macrophages:
>Found in tissue
>Long-lived (months/years)

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22
Q

What are the 3 roles of macrophages?

A
  1. Act as “sentinel” cells – often the first to detect infections as are found in tissues surrounding mucous surfaces.
  2. Efficient phagocytosis (can phagocytose 100 cells)
  3. Can present antigen to T lymphocytes, linking innate to adaptive immune system.
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23
Q

What receptors do macrophages have?

A

Receptors for C3b (opsonin), IgG, IgA (Fc eeceptors for them)

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24
Q

How are macrophages produced?

A

> Macrophages can be derived from monocytes during infection

> Not all macrophages are derived from blood monocytes, some enter tissues early in development and self-renew in the tissues.

25
Q

What are the names of resident macrophages in a) lungs b) brain?

A

a) alveolar macrophages

b) microglia

26
Q

Where are dendritic cells found?

A

Found in skin and lymphoid tissues

27
Q

What are the long finger-like processes called on dendritic cells?

A

Dendrites

28
Q

What is the role of dendritic cells?

A

> Take up foreign material by phagocytosis/micropinocytosis (for soluble proteins, means cell drinking)

> Digest foreign material and display fragments on their cell surface

29
Q

How are dendritic cells specialised for their function?

A

> Specialised for presenting antigen to T cells

> Specialised because they constitutively express high levels of Major Histocompatibility Type II (MHCII) proteins

30
Q

What type of cells can carry out phagocytosis?

A

> “professional phagocytes” (neutrophils, monocytes, macrophages, dendritic cells)

> Many cells can do phagocytosis even epithelial cells, but professional phagocytes are specialised to be efficient.

31
Q

Why are healthy cells aren’t phagocytosed?

A

Healthy “self” cells express a protein (CD47) which is recognised by phagocytes and prevents phagocytosis (inhibitory signal)

32
Q

What are the 6 steps of phagocytosis?

A
  1. Bacterium adheres to phagocyte (recognised)
  2. Phagocyte puts out pseudopod processes, gradually engulfing bacterium
  3. Pseudopods fuse to invaginate and encapsulate bacterium in phagosome
  4. Phagosome fuses with specialised lysosomes containing toxic compounds and can generate free radicals to destroy bacterium.
  5. Phagolysosome forms where bacterium will be destroyed

6.The contents are released by exocytosis.

33
Q

What are the 6 phagocyte bactericidal agents and which is the most important?

A
  1. Acidification
    >Lysosome is acidic (pH 3.5-4), stops bacteria growing and can kill.
  2. Toxic oxygen-derived products (most important)
    >Free radicals produced very reactive binding to bacterial proteins and DNA denaturing it and killing the organism.
    >Toxic oxygen-derived products and Toxic nitrogen oxides
  3. Toxic nitrogen oxides (most important)
    >Nitrogen radicals particularly nitric oxide
  4. Antimicrobial peptides
    >Defensins
  5. Enzymes
    >Lysozymes
    >Acid hydrolases
  6. Competitors
    >Lactoferrin binds to Fe
    >Vitamin B12 binding protein (Bacteria need Fe and B12 to divide, so lysosomes having competitors means bacteria can’t divide)
34
Q

What is the process where the free radicals produced which are used during phagocytosis?

A

Produced following “oxidative burst, a rapid increase in O2 consumption in phagocytes when they phagocytose foreign material.

35
Q

How do the free radicals used in phagocytosis not damage the body’s own tissue?

A

Short-lived, and contained in phagosome

36
Q

Describe the process of oxygen-dependent killing during phagocytosis?

A
  1. NADPH oxidase normally inactive, following phagocytosis becomes active, converting oxygen into superoxide ion (O2-) can bind to bacterial components and damage them (very reactive)
    >NADPH + 2O2 -> NADP+ + H+ + 2O2-
  2. A second enzyme, superoxide dismutase (SOD) too, converting superoxide to hydrogen peroxide (bleach for hair)
    >2O2- (superoxide) + H+ -> H2O2 (hydrogen peroxide) + Cl-
  3. In neutrophils another enzyme, myeloperoxidase, which converts hydrogen peroxide into hypo-chloride (bleach poured into toilet) and hydroxyl radicals
    >H2O2 + Cl- -> OH- + HOCl (hypo-chloride)
  4. The increase in oxygen also helps activate nitric oxide synthetase in the phagolysosome membrane can also lead to the production of nitric oxide and other toxic reactive nitrogen species (causes damage in same way)
    >arginine + 2O2 → citrulline + NO

> All of these free radicals are very reactive and bind to and denature bacterial DNA and proteins.

37
Q

What is an oxidative burst during phagocytosis?

A

“Oxidative burst” - transient increase in oxygen consumption following phagocytosis due to activation of a membrane-bound NADPH oxidase (on membrane of phagosome)

38
Q

What are phagocytes most important for defending against?

A

Phagocytes most important for bacterial and fungal infections, macrophages do play role against viruses though

39
Q

What are the main roles of NK cells?

A
  1. Kill infected host cells, especially until adaptive immunity is triggered
  2. Recognise “altered self”
    >Cancer cells
    >Viral infection and intracellular bacteria.
40
Q

How do NK cells recgonise non-self cells?

A

All nucleated cells in body express MHCI proteins, act as “self” labels, when infected with virus, it interferes with levels of expression of MHCI on surface, NK cells detect this decrease in MHCI and kill infected cell.

41
Q

How do NK cells recgonise some cancer cells?

A

As cancer cells try evade adaptive immune response by downregulated MHCI receptors on surface, NK cells notice this and kill cancer cells.

42
Q

Describe the process of how NK cells induce infected host cells to undergo apoptosis?

A
  1. Activated NK cells produce a pore-forming protein, perforin (similar to membrane attack complex structure), which inserts into the membrane of the infected host cell.
  2. When NK cells contact target cell, the evenly distributed granules move to side in contact with target cell (polarisation of NK cell granules)
  3. Allows granule contents to enter cell
  4. Granule contents (“granzymes”) are released into the target cell, activate apoptosis pathway (one way by direcxtly activating caspases initiating caspase cascade).
  5. Target cells undergo apoptosis.
    >Recently discovered that a some granzyme can enter intracellular bacteria, killing them directly inside the target cell.
43
Q

What is advantageous about NK cells triggering apoptosis for infected cells?

A

Not directly toxic to cells but trigger apoptosis in cells for clean death so virus doesn’t spread.

44
Q

What are the 4 simple steps of the innate immune response?

A

Threat -> Recognition -> Communication -> Elimination

45
Q

What do pattern recognition receptors (PRR) on innate cells recognise?

A

MAMPs and DAMPs.

46
Q

What are the 4 properties of Microbe-associated molecular patterns (MAMPs)?

A
  1. Shared by many microbes
  2. Distinct from “self” molecules
  3. Critical for survival/function of pathogens (microbe)
  4. Tend to be conserved amongst pathogens
47
Q

What are Damage-associated molecular patterns (DAMPs) and when are these released?

A

> Host components released during injury and cell damage

> Released by heart attack, cancer or injury/ stress showing this damage has to be prepared

48
Q

What are examples of MAMPs for 1) Bacteria 2) Fungi 3) Viruses 4) Protozoa (eukaryotic)

A

1) Bacteria
>Gram -ve: LPS (Lipopolysaccharides)
>Gram +ve (thick peptidoglycan): Flagellins, N-formylated proteins (on N terminal of their proteins) , unmethylated CpG in DNA

2) Fungi
>Chitin
>Beta-glucose

3) Viruses
>dsRNA

4) Protozoa (eukaryotic)
>GPI-linked proteins, (we have these but we have less)
>mannose-rich glycans

49
Q

What are 5 examples of DAMPs?

A
  1. Fragments of extracellular matrix proteins (holds our cells together, in long extended molecule but when in fragments is signal body is damaged)
    >e.g. fibronectin
  2. Exposed phosphatidylserine
    >Usually found on inside of bilayer but when cell is damaged will be present to outside showing cell is damaged.
  3. Mitochondrial components
    >Should be intracellular, if extra shows cell is damaged
  4. Uric acid
    >Build up when excess of purines *during stress e.g.)
    >Leads to gout.
  5. DNA
    >Expected to be inside cells, if detected outside is signal for damage.
50
Q

How to PRRs cope with ever evolving pathogens?

A

PRR is inherited from DNA, can’t evolve rapidly, but can recognise more than 1000 PAMPs or DAMPs in humans.

51
Q

What are the 3 classes of PRRs and examples for each?

A
  1. Soluble receptors
    >e.g. Mannose-binding lectin (involved in activating complement)
  2. Membrane receptors
    >Lectin receptors (Lectin binds carbohydrates (In this case on bacteria))
    >Chemotactic receptors
    >Toll-like receptors
  3. Cytoplasmic receptors (in cytosol/ inside cell)
    >NOD-like receptors (NLR)
    >As bacterial components and viruses can get inside the cell.
52
Q

What cells express PPRs?

A

> Membrane receptors and Cytoplasmic receptors are expressed by immune and non-immune cells

> E.g. fibroblasts and epithelial cells (first cells that a pathogen encounters).

53
Q

Describe how the 3 membrane PPRs work 1. Lectin receptors 2. Chemotactic receptors 3. Toll-like receptors

A
  1. MAMP binding may initiate phagocytosis, chemotaxis or signalling.
    >e.g. macrophage mannose receptor (recognises mannose residues on surface of bacteria) triggers phagocytosis, CD14 expressed on macrophages recognises LPS (phagocytosis triggered)
  2. CHEMOTACTIC RECEPTORS recognise CHEMOATTRACTANTS on bacteria
    >e.g. f-met-leu-phe receptor recognises N-formylated polypeptides, produced by bacteria (bacteria often add formyl residue on N terminus of their proteins) acting as chemoattracting for white blood cells to follow concentration gradient.
  3. Toll-like receptors or TLRs: sensors that signal the presence of microbial components.
    >Don’t trigger phagocytosis or chemotaxis, instead signal to body that infection is present and signals for change in gene expression.
54
Q

How man Toll-like receptors are found in humans?

A

10

55
Q

Why are Toll-like receptors called this?

A

Originally found in drosophila and our receptors are like these, so are called Toll-like to the original Toll receptors.

56
Q

Where are Toll-like receptors found?

A

Can be on the cell-surface or endosomal (especially TRL3 recognising viral DNA.

57
Q

How does ligand binding to extracellular domain cause signalling of Toll-like receptors?

A

Ligand induced dimerization triggers signalling (two receptors with antigen bound move close together causing cytoplasmic domains to be close together causing signalling initiation).

58
Q

What is the stereotypical shape of the extracellular ligand binding domain of a Toll-like receptor?

A

Horse shoe shape (especially TLR3).

Immunology (20 decks)

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