MODULE 6: immunology Flashcards
innate immune system: types of initial response
- first barrier against infection
- can be mechanical, chemical, or microbiological
mechanical:
- longutidunal flow of air
- skin and gut
- constant flow –> bacteria cannot settle in one place - movement of mucus by cilia
- lungs
- bacteria trapped in mucus, cilia transport mucus into throat, swallow mucus
chemical:
- skin, gut, eyes and nose
- breaks down bacteria in various ways
- fatty acids, enzymes, low pH
microbiological:
- skin and gut
- bacteria must out-compete normal flora for resources
innate immune system: immune cells
next level of defence after initial barrier
immune cells come from bone marrow (hematopoietic stem cells)
—> lymphoid lineage (T/B/NK cells)
—> myeloid lineage
—> granulocyte/megakaryocyte
acute inflammation mechanism
blood vessels during inflammation
macrophages sitting underneath skin
macrophages recognise pathogens
—> sends out chemical signals
—> phagocytosis of pathogens
chemical signals effect blood vessels, binding to receptors on epithelial cells
—> blood vessels dilate = more blood flow
—> inside wall of blood vessel releases adhesion molecules to become stickier = immune cells stick
—> tight junctions btw cells loosen up = cells and fluids move out into tissue
neutrophils leave blood stream and attracted to tissue sight
—> phagocytosis of pathogens
changes to blood vessels in inflammation:
- dilation –> increased blood flow –> redness
- changes in adhesion molecules –> blood sticks to site –> accumulation of cells –> swelling
- increased permeability –> blood cells move into tissue –> blood sent direct from heart –> heat –> blood cells interact with nerves –> pain
how are pathogens recognised by phagocytes?
PAMP receptors = pathogen associated molecular pattern
binding of PAMPs to receptors results in activation and secretion of inflammatory mediators
types of macrophages in the body (5)
- microgilia:
- found in brain
- phagocytose dying neurones - alveolar macrophages:
- found in the lungs
- respond to local irritants via cytokine release - spleen macrophages
- found in the spleen
- immune function
- phagocytosis of naturally dying cells, clearance of agents, etc - kuppfer cells
- found in the liver
- exposed to gut microbial products - synovial A cells
- found in joints
- cytokines in arthritis etc
stages of phagocytosis
(1) Binding of pathogen to surface receptors e.g. PAMP receptors
(2) Engulfment into vacuole/phagosome
(3) Fusion of phagosome with lysosome
(4) Killing and degradation of bacterium by lysozyme, proteases, acid hydrolases, free radicals
secreted factors after macrophage activation (3)
macrophages ingest and degrade bacteria and are activated by LPS to secrete cytokines
*IL = inter-luekin, transferred between leukocytes
1. IL-1 local effects: - activates vascular endothelium - activates lymphocytes - increases access to effector cells systemic effects: - fever - production of IL-6
2. IL-6 local effects: - activates lymphocytes - increases antibody production systemic effects: - fever - acute protein production
3. TNF-alpha local effects: - activates vascular endothelium and increases vascular permeability - results in increased entry of IgG - increased fluid drainage to lymph nodes systemic effects: - fever - mobilisation of metabolites - shock
- fever for ~24hours is good –> fever burns brown fat –> decrease rate of bacterial growth
neutrophils
main line of defence against invading bacteria –> first cells to bind to inflamed tissue
primary function is phagocytosis and killing of pathogens
neutrophils must gain access to tissues from the bloodstream –> move via chemotaxis
complement system
complement cascade pathways
set of plasma proteins that act together as a defense against pathogens in extracellular spaces
functions:
- inactive enzymes float in cytoplasm –> attach to bacteria to alert immune system –> recruitment of inflammatory cells
- kill pahogens
- coats microbes with molecules (opsonins) that enhances their phagocytosis
complement cascade:
- classical:
- antibody attaches to bacterium
- recruits complement protein t surface
- first complement protein binds, chopped to become active enzyme
- active complement protein chops next in line
- accumulate onto bacteria surface - mb-lectin:
- proteins bind to sugar groups uniquely found on pathogen
- activates complement cascade - alternative
- pathogen surfaces recognised by complements
mast cells
primarily responsible for type 1 hypersensitivity (immediate)
certain allergens invoke an IgE response –> then bind to mast cells (and basophils)
Fc~RI are high affinity receptors for IgE on the surface of mast cells
when cross-linked by allergen-antibody complexes, mast cells respond by degranulation
natural killer (NK) cells antibody dependent cell-mediated cytotoxicity (ADCC)
develop in the bone marrow from common lymphoid progenitor cells.
larger than T cells with distinctive cytoplasmic granules
recognise infected cells or tumour cells and destroy them.
- -> form synapses with infected cell
- -> -degranulate cytotoxic components across synapse
- -> these kill infected cell via apoptosis
activation state controlled by +/- signals on their cell surface (inhibitory dominates over activation)
ADCC:
- antibody binds antigens on surface of target cell
- fc receptors on NK cells recognise bound antibody
- cross-linking of fc receptors signals NK cell to kill target cell
- target cell dies via apoptosis
T cells: MHC1 vs MHC2
T cells recognise a combination of peptide (sampling of inside cell) and the MHC (not foreign) –> gives very high specificity
MHC1
- T-cells with short peptides bind MHC1
- MHC1 derived from cytoplasm
- Viral proteins invoke MHC1 response
- MHC1 = aplha 1, 2, 3 + beta2
- CD8 stabilises
MHC2:
- T-cells with long peptides bind MHC2 (ends open to fit longer peptide in groove)
- MHC2 derived from extracellular/vesicle proteins
- Extracellular bacteria invoke MHC2 response
- MHC1 = aplha 1, 2 + beta 1, 2
- CD4 stabilises
Describe how T-cells are activated
1) T-cells develop in thymus as naive T-cells
2) A cell digests bacteria and loads polypeptides onto MHC1 or MHC2
3) Once naive T-cell receives both signal 1 (TCR engagement) and signal 2 (MHC), becomes effector T-cell
4) Active effector T-cell releases growth signal to induce proliferation and differentiation
5) Active T-cell triggers effector function at infection site
T-cell selection
STRONG AFFINITY for self peptides —> too autoreactive —> negative selection —> undergoes apoptosis
WEAK AFFINITY for self peptides —> high affinity for foreign peptides —> positive selection
VERY WEAK AFFINITY for self peptides —> death by neglection
CTL killing mechanism
facilitated by CD8 + T-cell (MHC1)
kill virally infected cells by secreting cytokines
PRIMARY MECHANISM
- T-cell receptor (TCR) triggering leads to directed secretion of preformed lytic granules
- Lytic granules contain two main proteins:
- —–> perforin: polymerises to form pore in target cell membrane
- ——> granzymes: >3 serine proteases activate apoptotic pathways in target cell cytoplasm
- Lytic granules target cell for death
SECONDARY MECHANISM
- TCR receptor causes T-cell membrane to express Fas-ligand
- Fas crosslinks on target cell and triggers apoptosis
