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Foundations of Medicine > Innate Immunity 1 > Flashcards

Innate Immunity 1 Flashcards

1
Q

What does the Immune System do and why is it so important for human health?

A
  1. Protects from pathogens
  2. Elimination of abnormal host cells
  3. Rejection of donor tissues
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2
Q

The immune system must often strike a difficult balance between clearing the pathogen and causing accidental damage to the host.
How does it do this?

A
  1. by distinguishing ‘self’ molecules from ‘non-self’ molecules
  2. by identifying ‘danger’ signals (e.g. from acute inflammation)
  3. or via combinations of the two
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3
Q

What happens when the immune system goes wrong?

A

balance is disrupted therefore optimal effectiveness is also disrupted

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4
Q

what happens when immune system’s balance is disrupted

A

immune over-reaction or under-reaction

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5
Q

what does immune under-reaction lead to?

A

-Cancer (HCV, HIV, EBV)
-Infection (viruses, bacteria, fungi,parasites)

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6
Q

What does immune over-reaction lead to?

A

external threat- allergic reaction (asthma, hayfever, eczema)
internal threat- autoimmune problem (type 1 diabetes, RA, psoriasis, MS, lupus,IDB)

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7
Q

Points of entry for pathogens to infect the body

A
  1. Digestive system
  2. Respiratory system
  3. Urogenital system
  4. Skin damage
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8
Q

Routes of attack for pathogens

A
  1. Lymphatic system
  2. Circulatory system
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9
Q

Constitutive barriers to infection

A
  1. Skin
  2. Mucus
  3. Commensal bacteria
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10
Q

Constitutive barriers to infection: skin

A
  1. Physical barrier
    -composed of tightly packed, highly keratinised, multi-layered cells
    -constantly undergo renewal & replacement
  2. Physiological factors
    -low pH 5.5
    -low oxygen tension
  3. Sebaceous glands
    - secrete hydrophobic oils
    - Lysozyme (enzyme that breaks down bacterial cell walls)
    - Ammonia (antimicrobial)
    -Antimicrobial peptides
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11
Q

Constitutive barriers to infection: mucus

A

mucus membranes line all body cavities that meet the environment: Respiratory, GI & Urogenital tract.
Physical barrier to trap invading pathogens.

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12
Q

How is mucus a protective barrier?

A
  1. Has secretory IgA Ab- prevents bacteria and viruses attaching to and penetrating epithelial cells
  2. Contains Lysozyme, defensins and antimicrobial peptides directly kill invading pathogens
  3. Lactoferrin acts to starve invading bacteria of iron.
  4. Cilia directly trap pathogens and contribute to removal of mucous, assisted by physical manoeuvres such as sneezing and coughing.
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13
Q

Constitutive barriers to infection: commensal bacteria

A

100 trillion (1014) bacteria normally reside at epithelial surfaces.
>500 different microbial species.
Symbiotic relationship with the host

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14
Q

Innate immunity

A

present continuously, it is a defence mechanism that is present from birth.
The same generic response occurs to many different microbial species.

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15
Q

Acquired (adaptive) immunity

A

is (usually) induced by the presence of ‘foreign’ or non-self materials.
A unique response is generated to each individual pathogen

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16
Q

Both (innate & adaptive) are essential for maximal protection, but they work in different ways, How?

A
  1. Innate immune responses attack all pathogens indiscriminately. (no immunological memory)
  2. Acquired immune responses are specifically tailored to each individual pathogen (has immunological memory)
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17
Q

Story of an Infection- Part 1:

A

Early Innate Immune Responses

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18
Q

Early Innate Immune Responses
step 1

A

physical (natural) barriers in place
1. highly keratinised layer
2. commensal non-pathogenic bacteria (staphylococcus epidermis)
3. proliferating cells in basal layer
4. tissue resident macrophages- langerhan cells, mast cells, NK cells, dendritic cells

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19
Q

What happens when physical (natural) barriers are breached?

A

pathogens invade so innate immune response initiated.
Tissue-resident innate immune cells are the first responders to recognise pathogens as ‘non-self’ and dangerous

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20
Q

Examples of tissue-resident innate immune cells

A
  1. Macrophages
  2. Mast cells
  3. NK cells
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21
Q

How do innate immune cells recognise pathogens?

A

Pathogens express ‘signature’ molecules not found on/in human cells: Called Pathogen associated molecular patterns (PAMPS) are recognised by Pattern-recognition receptors (PRRs) on innate immune cells.

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22
Q

Examples of PAMPs

A
  1. Gram-negative bacterial lipopolysaccharide
  2. bacterial-fungal cell wall β-glucans
  3. viral dsRNA
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23
Q

Where are PRRs found?

A

cell surface and cytosol

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24
Q

What’s happening if we have a bacterial or fungal infection in our skin?

A

Initially macrophages ingest extracellular bacteria or fungi (and later on neutrophils).

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25
Q

Macrophages modes of ingestion

A
  1. Pinocytosis
  2. Receptor-mediated endocytosis
  3. Phagocytosis- (major way)
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26
Q

Pinocytosis

A

Ingestion of fluid surrounding cells

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27
Q

Receptor-mediated endocytosis

A

Molecules bound to membrane receptors is internalised

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28
Q

Phagocytosis

A

(Specific form of endocytosis) Intact particles (e.g. bacteria) are internalised whole.
facilitated by Opsonisation

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29
Q

Describe phagocytosis process

A
  1. macrophages & neutrophils express PRRs
  2. Receptor binding to PAMPs signal formation of a phagocytic cup
  3. Cup extends around target & pinches off forming a phagosome
  4. Fusion with a lysosome to form a phagolysosome- killing of pathogens & degradation of contents (acidification, lysosomal hydrolases)
  5. Debris (including antigens) is released into extracellular fluid
  6. pathogen-derived peptides are expressed on special cell surface receptors (MHC-II molecules)
  7. Pro-inflammatory mediators are released (e.g. TNFα)
30
Q

Opsonisation

A

the coating of pathogens by soluble factors (opsonins) to enhance phagocytosis
(so it enhances phagocytosis)

31
Q

What are opsonins?

A

small soluble factors that can bind to pathogens, thereby enhancing phagocytosis

32
Q

Examples of opsonins

A

C3b
C-reactive protein (CRP)
IgG / IgM antibodies

33
Q

What happens in infection by parasites (e.g. big worm)

A

Mast cells step in (As macrophages are too small)

34
Q

Mast cells role

A

prime role is to protect us against large parasitic pathogens

35
Q

Mast cells structure

A
  1. have granules which are pro-inflammatory substances
  2. express PRRs
  3. express receptors for some complement proteins
  4. express receptors for factors that are released by injured & dying host cells
36
Q

How do mast cells protect against danger signals?

A

Mast cells express receptors for dead & dying cells in EC environment.
ATP is example of danger signal that can activate mast cells.
Mast cells can degranulate or activate gene expression

37
Q

Mast cell degranulation

A

granules move to the edge of the cell, fuse with membrane & pro-inflammatory content (histamine) is released into EC environment.

38
Q

Mast cell gene expression

A

Production of new pro-inflammatory substances (e.g. leukotrienes, prostaglandins)

39
Q

Give examples of pro-inflammatory mediators

A

NO
prostaglandins/ leukotrienes
histamines
pro-inflammatory cytokines (TNF alpha)

40
Q

so what does degranulation and gene expression ultimately cause?

A

localised acute inflammation

41
Q

Acute inflammation

A

response to cell injury or infection.
Immediately after infection or injury a number of proteins are released leading to physiological characteristics of inflammation

42
Q

Physiological characteristics of inflammation include..

A

redness
heat
swelling
pain
(pro-inflammatory mediators from mast cells drive these signs)

43
Q

Describe healthy tissue features

A
  1. No inflammatory mediators
  2. Normal vasculature
  3. circulating neutrophils
44
Q

What do Pro-Inflammatory Mediators do to the Local Vasculature?

A

cause inflammation which promotes:
1. vascular changes
2. Recruitment & activation of neutrophils (transendothelial migration)
3. Bacteria and innate immune cells produce chemical signals that attract neutrophils to the site of infection

45
Q

transendothelial migration

A

crossing the endothelial layer

46
Q

transendothelial migration step 1

A
  1. Margination of neutrophils to endothelium near sites of tissue damage/infection
47
Q

transendothelial migration step 2

A
  1. binding of neutrophils to adhesion molecules on the endothelial cells
48
Q

transendothelial migration step 3

A
  1. Migration of neutrophils across endothelium
49
Q

transendothelial migration step 4

A
  1. Movement of neutrophils within tissue via chemotaxis
50
Q

transendothelial migration step 5

A
  1. Activation of neutrophil by PAMPs and TNFα.
51
Q

Why are affected tissues red in inflammation?

A

Due to vasodilation.
More blood flow to affected area
cell accumulation, increased cell metabolism

52
Q

Why is there swelling in inflammation?

A

Due to increased vascular permeability.
(leaking fluid and cells out of the gaps between endothelial cells)
So fluid accumulates in extravascular spaces

53
Q

Why is there pain in inflammation?

A

Stimulation of nerve endings

54
Q

swelling and pain causes

A

loss of function (e.g. you don’t move sore finger or foot much)

55
Q

Why are neutrophils needed?

A

Macrophages can’t cope on their own.
Neutrophils are best type of killing cell in innate immune system.

56
Q

Neutrophils Killing Mechanisms

A
  1. Phagocytosis
  2. Degranulation
  3. NETs
57
Q

Neutrophils Phagocytosis Mechanism 1

A
  1. In infected tissues pathogens release chemical signals that attract neutrophils.
  2. Neutrophils use PRRs to bind and phagocytose these pathogens.
  3. Kill internalised pathogens via 2 distinct mechanisms:
    i) oxygen-dependent killing
    ii) oxygen-independent killing
58
Q

oxygen-dependent killing

A

ROS-mediated killing:
(ROS and RNS are secreted into granules for killing of phagocytosed pathogens)
1. Neutrophil activation
2. Assembly of NADPH oxidase complex
3. Production and release of ROS into granules.

59
Q

Oxygen-independent killing

A

Lysosomal killing:
(granules fuse with phagosome)
1. Bacterium phagocytosed by neutrophil
2. Phagosome fuses with granules
3. pH of phagosome rises, antimicrobial response activated & bacterium is killed
4. pH of phagosome falls, fusion with lysosomes allows acid hydrolases to degrade bacterium completely

60
Q

Neutrophils Degranulation Mechanism 2

A

Release of anti-bacterial proteins from neutrophil granules directly into the extracellular milieu

60
Q

Neutrophils Degranulation Pro and Con

A

Pro: Direct killing of extracellular pathogens bacteria and fungi
Con: Tissue damage and (potentially) systemic inflammation

61
Q

Neutrophil Mechanism 3 NETs (Neutrophil Extracellular Traps) - What is it?

A

EC bacteria can induce NET formation (form of neutrophil suicide) helps trap and kill pathogens

62
Q

What do NETs do?

A
  1. Immboilise pathogens thus preventing them from spreading but also facilitating phagocytosis of trapped microorganisms
63
Q

What are NETs composed of?

A

genomic DNA, histones, granular proteins, enzymes

64
Q

Pus composition

A

Neutrophils
NETs
dead bacteria
cellular debris

65
Q

How does innate immune system respond to viruses?

A

Any cell in the body expresses in the cytosol PRRs that can recognise things such as viral dsRNA

66
Q

Virally infected cells produce…

A

produce and release cytokines called Interferons (IFNalpha/beta)

67
Q

Purpose of IFN’s?

A

Induce antiviral state
(So stop virus production)

68
Q

How do IFNs stop virus production?

A
  1. Signal neighboring uninfected cells to destroy RNA
    & reduce protein synthesis
  2. Signals neighboring infected cells to undergo apoptosis
  3. Activates immune cells e.g. NK cells
69
Q

How do NK cells kill infected cells?

A

Receive signal from IFNs to be activated.
However, 2nd signal is needed as they are normally restrained by an inhibitory receptor.

70
Q

How is 2nd signal activated?

A

Self peptide of a healthy nucleated cell and its MHC class I molecule are ligands for inhibitory receptor.
So when inhibitory receptor is activated, NK cells stop killing. (no attack, no death of healthy cell)

71
Q
A

Foundations of Medicine (5 decks)

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