Innate Immunity 1 Flashcards
What does the Immune System do and why is it so important for human health?
- Protects from pathogens
- Elimination of abnormal host cells
- Rejection of donor tissues
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?
- by distinguishing ‘self’ molecules from ‘non-self’ molecules
- by identifying ‘danger’ signals (e.g. from acute inflammation)
- or via combinations of the two
What happens when the immune system goes wrong?
balance is disrupted therefore optimal effectiveness is also disrupted
what happens when immune system’s balance is disrupted
immune over-reaction or under-reaction
what does immune under-reaction lead to?
-Cancer (HCV, HIV, EBV)
-Infection (viruses, bacteria, fungi,parasites)
What does immune over-reaction lead to?
external threat- allergic reaction (asthma, hayfever, eczema)
internal threat- autoimmune problem (type 1 diabetes, RA, psoriasis, MS, lupus,IDB)
Points of entry for pathogens to infect the body
- Digestive system
- Respiratory system
- Urogenital system
- Skin damage
Routes of attack for pathogens
- Lymphatic system
- Circulatory system
Constitutive barriers to infection
- Skin
- Mucus
- Commensal bacteria
Constitutive barriers to infection: skin
- Physical barrier
-composed of tightly packed, highly keratinised, multi-layered cells
-constantly undergo renewal & replacement - Physiological factors
-low pH 5.5
-low oxygen tension - Sebaceous glands
- secrete hydrophobic oils
- Lysozyme (enzyme that breaks down bacterial cell walls)
- Ammonia (antimicrobial)
-Antimicrobial peptides
Constitutive barriers to infection: mucus
mucus membranes line all body cavities that meet the environment: Respiratory, GI & Urogenital tract.
Physical barrier to trap invading pathogens.
How is mucus a protective barrier?
- Has secretory IgA Ab- prevents bacteria and viruses attaching to and penetrating epithelial cells
- Contains Lysozyme, defensins and antimicrobial peptides directly kill invading pathogens
- Lactoferrin acts to starve invading bacteria of iron.
- Cilia directly trap pathogens and contribute to removal of mucous, assisted by physical manoeuvres such as sneezing and coughing.
Constitutive barriers to infection: commensal bacteria
100 trillion (1014) bacteria normally reside at epithelial surfaces.
>500 different microbial species.
Symbiotic relationship with the host
Innate immunity
present continuously, it is a defence mechanism that is present from birth.
The same generic response occurs to many different microbial species.
Acquired (adaptive) immunity
is (usually) induced by the presence of ‘foreign’ or non-self materials.
A unique response is generated to each individual pathogen
Both (innate & adaptive) are essential for maximal protection, but they work in different ways, How?
- Innate immune responses attack all pathogens indiscriminately. (no immunological memory)
- Acquired immune responses are specifically tailored to each individual pathogen (has immunological memory)
Story of an Infection- Part 1:
Early Innate Immune Responses
Early Innate Immune Responses
step 1
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
What happens when physical (natural) barriers are breached?
pathogens invade so innate immune response initiated.
Tissue-resident innate immune cells are the first responders to recognise pathogens as ‘non-self’ and dangerous
Examples of tissue-resident innate immune cells
- Macrophages
- Mast cells
- NK cells
How do innate immune cells recognise pathogens?
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.
Examples of PAMPs
- Gram-negative bacterial lipopolysaccharide
- bacterial-fungal cell wall β-glucans
- viral dsRNA
Where are PRRs found?
cell surface and cytosol
What’s happening if we have a bacterial or fungal infection in our skin?
Initially macrophages ingest extracellular bacteria or fungi (and later on neutrophils).
Macrophages modes of ingestion
- Pinocytosis
- Receptor-mediated endocytosis
- Phagocytosis- (major way)
Pinocytosis
Ingestion of fluid surrounding cells
Receptor-mediated endocytosis
Molecules bound to membrane receptors is internalised
Phagocytosis
(Specific form of endocytosis) Intact particles (e.g. bacteria) are internalised whole.
facilitated by Opsonisation
Describe phagocytosis process
- macrophages & neutrophils express PRRs
- Receptor binding to PAMPs signal formation of a phagocytic cup
- Cup extends around target & pinches off forming a phagosome
- Fusion with a lysosome to form a phagolysosome- killing of pathogens & degradation of contents (acidification, lysosomal hydrolases)
- Debris (including antigens) is released into extracellular fluid
- pathogen-derived peptides are expressed on special cell surface receptors (MHC-II molecules)
- Pro-inflammatory mediators are released (e.g. TNFα)
Opsonisation
the coating of pathogens by soluble factors (opsonins) to enhance phagocytosis
(so it enhances phagocytosis)
What are opsonins?
small soluble factors that can bind to pathogens, thereby enhancing phagocytosis
Examples of opsonins
C3b
C-reactive protein (CRP)
IgG / IgM antibodies
What happens in infection by parasites (e.g. big worm)
Mast cells step in (As macrophages are too small)
Mast cells role
prime role is to protect us against large parasitic pathogens
Mast cells structure
- have granules which are pro-inflammatory substances
- express PRRs
- express receptors for some complement proteins
- express receptors for factors that are released by injured & dying host cells
How do mast cells protect against danger signals?
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
Mast cell degranulation
granules move to the edge of the cell, fuse with membrane & pro-inflammatory content (histamine) is released into EC environment.
Mast cell gene expression
Production of new pro-inflammatory substances (e.g. leukotrienes, prostaglandins)
Give examples of pro-inflammatory mediators
NO
prostaglandins/ leukotrienes
histamines
pro-inflammatory cytokines (TNF alpha)
so what does degranulation and gene expression ultimately cause?
localised acute inflammation
Acute inflammation
response to cell injury or infection.
Immediately after infection or injury a number of proteins are released leading to physiological characteristics of inflammation
Physiological characteristics of inflammation include..
redness
heat
swelling
pain
(pro-inflammatory mediators from mast cells drive these signs)
Describe healthy tissue features
- No inflammatory mediators
- Normal vasculature
- circulating neutrophils
What do Pro-Inflammatory Mediators do to the Local Vasculature?
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
transendothelial migration
crossing the endothelial layer
transendothelial migration step 1
- Margination of neutrophils to endothelium near sites of tissue damage/infection
transendothelial migration step 2
- binding of neutrophils to adhesion molecules on the endothelial cells
transendothelial migration step 3
- Migration of neutrophils across endothelium
transendothelial migration step 4
- Movement of neutrophils within tissue via chemotaxis
transendothelial migration step 5
- Activation of neutrophil by PAMPs and TNFα.
Why are affected tissues red in inflammation?
Due to vasodilation.
More blood flow to affected area
cell accumulation, increased cell metabolism
Why is there swelling in inflammation?
Due to increased vascular permeability.
(leaking fluid and cells out of the gaps between endothelial cells)
So fluid accumulates in extravascular spaces
Why is there pain in inflammation?
Stimulation of nerve endings
swelling and pain causes
loss of function (e.g. you don’t move sore finger or foot much)
Why are neutrophils needed?
Macrophages can’t cope on their own.
Neutrophils are best type of killing cell in innate immune system.
Neutrophils Killing Mechanisms
- Phagocytosis
- Degranulation
- NETs
Neutrophils Phagocytosis Mechanism 1
- In infected tissues pathogens release chemical signals that attract neutrophils.
- Neutrophils use PRRs to bind and phagocytose these pathogens.
- Kill internalised pathogens via 2 distinct mechanisms:
i) oxygen-dependent killing
ii) oxygen-independent killing
oxygen-dependent killing
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.
Oxygen-independent killing
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
Neutrophils Degranulation Mechanism 2
Release of anti-bacterial proteins from neutrophil granules directly into the extracellular milieu
Neutrophils Degranulation Pro and Con
Pro: Direct killing of extracellular pathogens bacteria and fungi
Con: Tissue damage and (potentially) systemic inflammation
Neutrophil Mechanism 3 NETs (Neutrophil Extracellular Traps) - What is it?
EC bacteria can induce NET formation (form of neutrophil suicide) helps trap and kill pathogens
What do NETs do?
- Immboilise pathogens thus preventing them from spreading but also facilitating phagocytosis of trapped microorganisms
What are NETs composed of?
genomic DNA, histones, granular proteins, enzymes
Pus composition
Neutrophils
NETs
dead bacteria
cellular debris
How does innate immune system respond to viruses?
Any cell in the body expresses in the cytosol PRRs that can recognise things such as viral dsRNA
Virally infected cells produce…
produce and release cytokines called Interferons (IFNalpha/beta)
Purpose of IFN’s?
Induce antiviral state
(So stop virus production)
How do IFNs stop virus production?
- Signal neighboring uninfected cells to destroy RNA
& reduce protein synthesis - Signals neighboring infected cells to undergo apoptosis
- Activates immune cells e.g. NK cells
How do NK cells kill infected cells?
Receive signal from IFNs to be activated.
However, 2nd signal is needed as they are normally restrained by an inhibitory receptor.
How is 2nd signal activated?
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)
