Overview of innate immune system Flashcards
What are the 2 types of immune response?
innate
adaptive
What are the roles of the immune system?
protection from infectious agents
protection from harmful substances (toxin)
protection for aberrant cells (cancer)
What are pathological consequences of an (over)functioning immune system?
autoimmunity
allergy/hypersensitivity
transplant rejection
What are the main characteristics of the innate immune system?
non-specific
rapid
born with it, so present before infection
developed by evolution
responds in the same manner every time, even to repeated infections (by same pathogen)
What are the functions of the innate immune system?
reacts to microbes and injured cells
first line of defence
rapid (maximal response is within hours)
prevents, controls and sometimes eliminates infection
What is the main drawback with the innate immune system?
most pathogens have evolved to escape or evade innate immune system mechanisms
AND IIS holds no memory for future infections
How are most pathogens eliminated?
by activation of the adaptive immune system
What are the main components of the IIS?
barriers
soluble molecules
cells
What are the physical barriers in the IIS?
epithelial surface - prevents entry
tight junctions between cells so no gap for pathogens to squeeze between
mucus - coats microbes and prevents attachment to epithelia
cilia waft pathogens in mucus out of body
What are the chemical barriers present in IIS?
antibacterial enzymes (e.g. lysosymes) antimicrobial peptides (defensives, cathelicidins)
Which cells produce antimicrobial peptides? How do these peptides work?
produced by epithelia, polymorphonuclear neutrophils (PMNs), NK cells and cytotoxic T cells
kill bacterial by damaging bacterial PM
What are the microbiological barriers in IIS?
commensal flora
acts by competing with pathogens for nutrients and niches
What is the main side effect of Antibiotics for commensal bacteria?
Antibiotics may also wipe out commensal populations living in the body and so side effects may include GI symptoms for e.g.
What are the main defects in IIS which may predispose an individual to infection?
loss of integrity: e.g. wounds or burns genetic defects: cystic fibrosis - defective mucus production - inhibition of ciliary movements - frequent respiratory infections
What cell-mediated mechanism is key for pathogens that evade or overcome IIS barriers?
phagocytosis
by APCs
What are the main immune effectors of IIS?
Phagocytes: neutrophils, macrophages, dendritic cells
Other cells: mast cells, eosinophils, basophils, NK cells,
What is the function of phagocytes? What is their origin?
identify, ingest and destroy pathogens
origin: myeloid lineage
What is the origin of non-phagocytic IIS cells?
mast cells, macrophages, dendritic cells (myeloid) NK cells (lymphoid)
Which cells are known as granulocytes?
= granular leukocytes
- neutrophils
- basophils
- eosinophils
- mast cell
What are basophils?
H&E stain: blue granules present
few present in circulation/blood (0.2-1% of WBCs)
Main role: type 1 hypersensitivity (allergy)
Degranulation leads to inflammation
Granule contents (histamine, peroxidase, heparin, kallkrein)
What are mast cells?
located in tissues, close to blood vessels
main role: type 1 hypersensitivity (allergy), parasites
Degranulation leads to inflammation
Granule contents (histamine, serotonin/5-HT)
What are eosinophils?
H&E stain: pink granules
Present in circulation (4% of WBCs)
Main role: parasites and type 1 hypersensitivity (allergy)
Degranulation to kill bigger pathogenic targets
Granule contents (eosinophilic cationic protein), MBP, peroxidase)
What cells types are phagocytes?
neutrophils
macrophages
dendritic cells
What are neutrophils?
most abundance cell type in circulation/blood (70% of WBCs) early IIS response present in acute inflammation killing of microbes by phagocytosis enzymes: lysozyme, collagenase, elastase
What are monocytes and macrophages? What is their nucleus shaped like?
kidney-shaped nucleus
monocytes are present in the blood
Once activated they differentiate into macrophages (tissue)
professional APCs
efficient at phagocytosis
microbe killing
secrete inflammatory cytokines (TNFa, IL-6)
What are dendritic cells?
tissue-resident
present in the barrier tissues
- skin (Langerhans), mucosa and tissues
capture microbes by in their dendrite like mesh
and then vacuum up by phagocytosis
phagocytosed and digested microbial peptides are then presented to T cells via MHC and co-stimulation
LINK between IIS and adaptive IS
What are the main ligand-receptor complex interactions needed for DC-T cell activation and Ag presentation?
Signal 1: Ag RECOGNITION
MHC-antimicrobial peptide (dendritic cell) and T cell receptor, TCR (T cell)
Signal 2: CO-STIMULATION
CD80/CD86 (dendritic cell) and CD28 (T cell)
Signal 3: CYTOKINES (bidirectional)
DC cells: IL-12 and IL-18
T cells: IFN-g and T-bet (transcription factor)
Are all 3 signals needed for dendritic cell mediated activation of T cells to occur?
Yes
CO-STIMULATION must occur in order for the T cell to be activated
If this does not occur, no further action occurs but T cells may become unresponsive and be later destroyed by apoptosis
What is phagocytosis?
= cell eating
- pathogens
- damaged cells
- dead cells
- nutrients
mechanism of the IIS
What are the main roles of phagocytosis?
protection from pathogens
disposal of damaged/apoptotic cells
processing and presentation Ag
- activation adaptive IIS
What are the main steps within phagocytosis?
- chemotaxis (to site of infection/injury)
- recognition + attachment to target cells/debris
- engulfment
- killing of ingested material
What does the CHEMOTAXIS step in phagocyte mobilisation involve?
movement of phagocytes towards infection site
guided by chemoattractants
chemocractants are released by pathogens, inflammatory cells or damaged tissues
What are the key chemoattractants released by bacteria?
N-formyl-methionine-leucine-phenylalanine peptides (fMLP)
What is the main chemoattractant released by neutrophils?
IL-8
What are chemoattractants?
chemical messengers
serve as cues for infiltrating immune cells of IIS
Released by pathogens or other native cells present in the infection site (provides a siren)
How to inflammatory mediators aid the delivery of immune cells to the infection site?
Inflammatory mediators released by tissue-resident APCs or blood vessels or pathogens
e.g. histamine, 5-HT/serotonin
these cause vasodilation of blood vessels, and therefore increased permeability (between endothelia)
easier access for immune cells to enter affected tissues
What are the main steps of phagocytosis itself?
- actin cytoskeleton arrangement
- pseudopod mediated PM rearrangement
- engulfment (endocytosis)
- phagosome formation
- fusion to create phagolysosome
- pathogen destruction by lytic enzymes
What is the function of the phagolysosome? Why is it important for it to be encased within a double membrane?
= digestion and degradation of ingested material
double membrane means that phagocyte is not exposed to the lytic enzymes within lysosome and therefore exposed to damage or death
What are the oxygen-INDEPENDENT mechanisms of pathogen killing in phagocytes?
LYSOSOMES
- proteolytic enzyme (cathepsin): degrade microbes
- lysosyme: breaks down cell wall
- lactoferrin: binds iron and therefore disrupts bacterial metabolism (chelation?)
- defensins: destroys bacterial walls
What are the oxygen-DEPENDENT mechanisms of pathogen killing in phagocytes?
occurs within activated phagocyte
Oxidative burst = ROS generation
- assembly of phagocyte oxidase
- generation of superoxide anion (O2-)
Why is the oxidative burst/ROS generation considered a last resort mechanism for phagocyte-mediated pathogen killing?
ROS production is very unstable
And can be damaging to phagocyte itself
This means that the phagocyte is likely to die in the process of killing the pathogen
What are the main ROS generated through phagocyte oxidase (oxygen-dependent mechanisms)?
superoxide hydrogen peroxide (H2O2) hydroxyl radicals (OH-) nitric oxide (NO) peroxynitrite radicals
What physiological mechanisms are in place to restrict the impact of ROS on normal tissues?
scavenger receptors
Can mop up extra ROS that may have escaped from the phagocyte for e.g.
However, if there is mass ROS production, these receptors may struggle to contain the detrimental effects of ROS
= oxidative stress and damage
What is opsonisation? How does it aid phagocytes?
coating of microbes with opsonins
Provides a more efficient phagocytosis process
What are opsonins?
- proteins of the complement system (C3b, C4b)
- Antibodies (e.g. Ig)
What is the clinical consideration with opsonisation?
Encapsulated pathogens require opsonisation with Ab (Ig) to be effectively phagocytosed
Why does opsonisation make phagocytosis more effective?
- recognition of microbes (via opsonins)
- facilitates phagocytosis because of opsonin receptors
( Ig receptor = Fc, complement = complement receptor)
What are NK cells?
= natural killer cells
- kill virus-affected cells
- kill malignancy transformed cells (tumours)
- express cytotoxic enzymes which can lyse target cells
Why do encapsulated bacteria require opsonisation?
encapsulated bacteria can evade normal phagocytosis
opsonisation provides a specific method for identification and attachment
What soluble molecules are involved in the IIS?
- complement system
- plasma proteins (C1-C9)
- activated by microbes
- direct killing of microbes
- coating of microbes - facilitates process
- stimulates inflammation - Inflammatory cytokines
- TNFa, IL-1, IL-6
How does complement activation lead to microbe elimination?
- Complement activation
i) microbe opsonisation -> increased phagocytosis
ii) inflammation -> recruitment + activation of leukocytes
iii) lysis of microbes
What are the main characteristics of adaptive immune response?
- acquired following exposure to infection
- needs exposure to microbes
- lag time (exposure to max response, days)
- better at eliminating infection
- very specific
- memory of pathogens
- better/faster with each repeated exposure
What are the main components of the adaptive immune response?
Cells
- T lymphocytes: cellular immunity
- B lymphocytes: humoral immunity (Ab)
Soluble molecules
- cytokines
- Ab
What subtypes of cells comprise the adaptive immune response?
T cells: helper (Th), cytotoxic (CTL), regulatory (Treg)
B cells: humoral - memory and plasma cells
What are the functions of the different T cell subtypes?
T helper cells (CD4+)
- activate macrophages
- help B cells to produce Ab
Th1, Th2, Th17
CTLs (CD8+)
- kill cells infected with microbes
- kill tumour cells
Treg cells
- inhibit function of other T cells and immune cells
- terminate auto-reactive T cells
- control/mediate closure of immune response
What are PAMPs?
= Pathogen Associated Molecular Patterns
- present on pathogens and host cells (infected)
- essential for survival of pathogen
- shared by class of pathogens
Why are PAMPs essential for pathogen survival?
prevents evasion of immune system
ds viral RNA (replication)
LPS (structure of bacterial membrane)
Give examples of common types of PAMPs
LPS (gram -ve) lipoteichoic acid (gram +ve) peptidoglycan unmethylated CpG (bacterial DNA) ss/ds viral DNA glucans (fungi)
What are pattern recognition receptors (PRRs)?
present on all cells of the IIS
+ some epithelial cells
recognise PAMPs and other conserved Ag on pathogen surfaces
detect foreign invaders and/or damaged cells
What are some common types of PRRs?
= pattern recognition receptors
- toll-like receptors (TLRs)
- C-type lectin receptors (CTLRs)
- NOD-like receptors (NLRs)
- RIG-like helicase receptors (RLRs)
- scavenger receptors
What are toll-like receptors (TLRs)?
type of pattern recognition receptor (PRR)
- evolutionary conserved
- role in IIS
- stimulates inflammatory cytokine production
- recognises PAMPs
How is immune recognition mediated in the adaptive immune system?
Ag receptors on B and T cells e.g. Fc-gamma-III?
- can recognise virtually any microbial structure
- not germline encoded
- can distinguish Ag on different and on the same microbes
- self vs non-self Ag (defect: autoimmunity)
Which immune cells are derived from a lymphoid lineage?
NK cells
B cells
T cells
Which immune cells are derived from a myeloid lineage?
monocytes (macrophages, dendritic cells)
eosinophils
basophils
mast cells
What are giant cells?
- mass formed by fuse of several distinct cell types
- most commonly originate as macrophages
- distinct to granulomas
