Immune system Flashcards
Erythropoiesis
Making of red blood cells in red bone marrow
How long do RBCs last?
120 days
Process of erythrocyte differentiation
Haematopoietic stem cells > Common myeloid progenitor > Proerythroblast > Reticulocyte > Erythrocyte
Reticulocyte loses its nucleus to become erythrocyte.
What happens to bone marrow as we age?
Red bone marrow is converted to yellow bone marrow, 100% red in children and 50% in adulthood
How is erythropoiesis regulated?
Kidneys produce erythropoietin in response to hypoxia
What does erythropoietin do?
Stimulates red bone marrow to produce red blood cells
What cells do all blood cells come from?
Haematopoietic stem cells
Where do innate immune cells come from?
Common myeloid progenitor cells, except natural killer cells which come from common lymphoid progenitor cells
Where do adaptive immune cells come from?
Common lymphoid progenitor cells
Where do basophils, eosinophils, neutrophils and monocytes come from?
Myeloblasts
Where do macrophages come from?
Monocytes
Where do platelets come from?
Megakaryocytes
Innate immune response
First response to infection - provides the first and second lines of defence
Involves physical and chemical barriers
Occurs quickly within the first 12 hours of infection
What are the proteins involved in the innate immune response?
CRP
Complement
What is CRP
C reactive protein, produced by the liver. It is an oponising protein
What are the physical barriers in the innate response?
Skin
Mucosal membranes
removal of particles by cilia
What are the chemical barriers in the innate response?
Normal flora in GI tract which occupy the biological niche
Lysozymes in tears
Stomach acid
What do mast cells do?
Degranulate to cause leaky tight junctions in endothelium. This allows other immune cells to enter and plasma to leave causing oedema. Release IL-1, TNF-alpha and CXC18 for chemotaxis
What do dendritic cells do?
Recognise PAMPs and DAMPs on their PRRs. Engulf pathogenic peptides and transport them to lymph nodes. Present peptides on MHC 2 molecules
What do neutrophils do?
Recognise PAMPs, carry out oxidative burst. Form a pseudopodia and then a phagosome around the pathogen. Granules are released to kill the pathogen.
What do macrophages do?
Clear up debris by phagocytosis.
Kupffer cells = liver
Langerhans = skin
Dust cells = alveoli
Adaptive immunity
Specific line of defence, but takes longer to occur. Works by recognising non-self from self antigens. Involved in development of immunological memory. Specific responses tailored to maximally eliminate a specific pathogen.
What are the 2 types of immunity that make up adaptive response?
Cell-mediated
Humoral
Extracellular pathogen response - TH2/ humoral response
Bacteria infect and proliferate the body
LPS of bacteria acts as a PAMP
activates the complement pathway
Activates the complement cascade
C3a and C5a cause degranulation of mast cells
release of histamine
causes inflammation
C3b opsonises
macrophages, dendritic cells and neutrophils carry out phagocytosis
Macrophages recognise PAMPs and release cytokines
C5a causes chemotaxis
so more immune cells are drawn to the site of infection
dendrites present pathogen peptide on their MHC 2 molecules and migrate to the local lymph node
Naive T cells are recruited to the lymph node and recognise the MHC 2 pathogen protein
T cells bind to the MHC 2 molecule
This causes the T cells to release IL-4
IL-4 causes TH2 cells to be formed
This is the humoral response
Plasma cells are formed and release IgM antibodies, then IgG and IgA antibodies.
Memory B cells are formed
Intracellular immune response - TH1
The virally infected cell produces IFN-alpha
Neighbouring cells produce antiviral proteins to prevent them being infected
IFN-alpha attracts natural killer cells
NKs check the MHC 1 molecules and kill abnormal/ absent ones
After the cells burst and the viral particles are released the dendritic cells pick the viral particles up and take them to the local lymph nodes
Dendritic cells present the antigen on their MHC 2 and CD28 molecules
Dendritic cells produce IL-12 to form CD4 TH1 cells
TH1 cells release IFN gamma and IL-2 which activates CD8 cytotoxic cells
CD8 cells check MHC 1 molecules and kill the abnormal/ absent ones
They make holes in the cell using perforin and inject granzymes which kill the cells .
Clean up following an adaptive immune response
T regulatory cells are activated by TNF-beta and IL-10. They downregulate TH1 or TH2 cells depending on the type of infection. Macrophages and neutrophils clear away the debris.
What is isotype switching?
Change in the B cell’s production of an antibody from one class to another
Cytokines released by naive Th cell
Activate naive T helper cell produces IL-12 or IL-4, IL-12 produces TH1 cells and IL-4 produces TH2 cells.
What cytokines are released by TH1 cells
IFN-gamma which activates macrophages and NK cells and costimulates CD8 activation with Antigen presentation. TNF-beta activates macrophages and NK cells.
What are the stages of wound healing?
Haemostasis
Inflammation
Proliferation
Remodelling
Process of haemostasis
- Damage to vessel wall exposes underlying collagen and chemical factors from the damaged endothelium. Vascular spasm - blood vessels constrict in response to shock to reduce blood loss
- Platelet adhesion - platelets adhere to the damaged collage which involves von Willebrand Factor, it activates the platelets so they undergo a structural change that helps them adhere together.
- Activated platelets release Thromboxane, ADP and Serotonin which causes vasoconstriction and activates more sticky platelets
- Platelet plug is formed from platelets sticking together and the coagulation cascade is triggered
- Coagulation cascade converts fibrinogen into fibrin
- Fibrin reinforces the platelet plug and forms a mesh work that forms a clot
Why does the platelet plug not spread all the way along the vessel?
Prostacyclin and nitric oxide from intact endothelium inhibit platelet adhesion and aggregation
What are clotting factors?
Proteins in the blood that control bleeding. They are inactive unless needed.
How does the clotting cascade work?
Activated form of each factor acts as a catalyst for the next reaction in the cascade. Calcium ions and vitamin K are necessary for activation of some of the reactions
What is the purpose of the coagulation cascade?
To make thrombin which converts fibrinogen into fibrin to form a mesh .
Fibrin
Is factor 1, it is insoluble so doesn’t circulate in the blood as it would form blood clots so fibrinogen is the inactive soluble form
What are the pathways of the coagulation cascade?
Extrinsic = activated by tissue damage through release of tissue factors and causes the intrinsic pathway to kick in.
Intrinsic pathway = gets most of the coagulation done
Which stages of the coagulation cascade are vitamin K dependent?
II,VII, IX, X
where is vitamin K synthesised?
By bacteria in large intestine
Coagulation cascade
Learn the coagulation cascade!!!!
Coagulation cascade drugs
Thrombolytics
Antiplatelets
Anticoagulants
Thrombolytic drugs
Break down fibrin
e.g. tPA, Urokinase
Antiplatelet drugs
Aspirin - inhibits COX
Clopidogrel - inhibits platelet aggregation
Ticagrelor
Anticoagulants
Heparin - makes anti-thrombin very active, low molecular weight heparin acts on thrombin and unfractionated heparin works on Xa
Warfarin - vitamin K agonist (acts on 10,9,7 and 2)
These have to be stopped before surgery
Hemophilia
Type A = . factor VIII deficiency, X-linked recessive disease
presentation depends on severity. Presents early in life or after surgery/ trauma.
what can Excessive bleeding do?
Into joints can cause arthropathy and into muscles can cause hematomas
increase in pressure can cause nerve palsies and compartment syndrome
Treatment of hemophilia
Avoid NSAIDs and intramuscular injections
minor bleeding - pressure and elevation
major bleeding - give recombinant factor VIII
Type B hemophilia
Factor IX deficiency and behaves clinically like type A
Liver disease
Liver makes vitamin K and so liver disease causes a complex bleeding disorder with the decreased synthesis of clotting factors. Decreased absorption of vitamin K and abnormalities in platelet function.
Malabsorption of vitamin K
Less uptake of vitamin K
Treat with IV vitamin K
Inflammation
Non-specific defensive response to tissue damage .
How does inflammation occur
Damaged cells release cytokines and histamines causing vasodilation. Neutrophils phagocytose bacteria and debris. Macrophages carry out debridement/ matrix turnover. Tissue fluid moves into the area providing cells and nutrients.
Scab
Blood clot and dead macrophages
Signs of inflammation and their causes
Heat - capillary widening causing increased blood flow
Redness - increased permeability causing fluid release into tissues
Swelling - increased permeability causing fluid release into tissues
Tenderness - Attraction of leukocytes and extravasation (movement) of them to site of injury
Pain - systemic response, fever and proliferation of leukocytes
Acute inflammation
Usually lasts <3 weeks
Accumulation of neutrophils
Purulent = pus (bunch of dead neutrophils)
Increases ESR (sedimentation rate) and CRP
Chronic inflammation
Defined as lasting longer than 6 weeks
Significant tissue destruction - a typical feature
CRP will be less raised
Accumulation of macrophages and leukocytes
Proliferation of wound healing
Days to weeks timescale
Angiogenesis - oxygen needed for growth
Fibroplasia - fibroblasts move to the site and grow - forms collagen
Epithelialisation - making new skin
Contraction - fibroblasts form myofibroblasts, which produce contractile proteins which pull the edges of the wound together
What is the dominant cell type at wound edges in the first week?
Macrophages/ mast cells
What is granulation tissue?
Collagen and proteoglycans deposited by fibroblasts which hold epidermal cells together
Remodelling
Formation of new granulation tissue stops
Collagen composition changes from type 3 to 1
Fibrous scar forms due to collagen cross linking
The new blood vessels formed are no longer required and so are removed by apoptosis
What local factors impair wound healing?
Poor blood supply infection oedema movement foreign material moisture
What systemic factors impair wound healing?
Diabetes atherosclerosis nutrients immunosuppression connective tissue disorders smoking age alcohol drugs - steroids and antiplatelets
Maggots
Can be used to differentiate between live and dead tissue in a wound as they eat the dead tissue - allows debridement without surgery
Core body temperature
36.5 - 37.5
can be altered by menstrual cycle and circadian rhythms
Hypothermia = <35
Hyperthermia = >38 - pyrexia/ fever
Thermoreceptors
Cold receptors - in the peripheries, it is conducted by myelinated A fibres (fast)
Warm receptors - central in hypothalamus
Pain receptors - nociceptors
Response mechanisms to temperature changes
Physiological, behavioural, neurological and hormonal
Behavioural responses to temperature change
Voluntary actions to increase muscle activity
Moving out of the environment you are in
Physiological responses to temperature change
Involuntary effecting heat loss and production
Hormonal responses to temperature change
Thyroxine, T3 and adrenaline will increase metabolism to generate heat
Nervous system responses to temperature change
Activation of either the sympathetic or parasympathetic NS and motor system can cause shivering
Responses to cold
Cold receptors in skin signal to hypothalamus.
Heat loss is reduced by warm clothing and vasoconstriction
Heat production is increased by thyroxine/ T3 release, shivering and catecholamine release (adrenaline) .
Responses to hot
Warm receptors detect it in the hypothalamus .
Heat loss is increased by sweating, vasodilation and exposure
Heat production is decreased by decreased activity
How to treat heat stoke?
Ice cold IV saline
Who is at high risk of hypothermia?
Neonates
People who have experienced near drowning, major trauma or those who have taken drugs/ alcohol
Why are neonates at greater risk of hypothermia?
They have a high surface area to weight ration and cannot make behavioural changes. They have brown fat found between the scapulae that is especially to be metabolised to produce heat and doesn’t produce ATP as oxidative phosphorylation is uncoupled
Why are people who experience major trauma at risk of hypothermia?
Blood loss is replaced with cold fluids
Hypothermia impairs blood clotting
Why are people who nearly drown at risk of hypothermia?
Heat loss via conduction to water
Why are intoxicated people at risk of hypothermia? (Drugs/ alcohol)
They cannot make behavioural changes
Function of lymph
Draining excess interstitial fluid
Transport of dietary lipids and lipid soluble vitamins
carrying out immune response
returns lost plasma proteins into circulation
What allows transport of lymph?
Skeletal muscle pump
Respiratory pump - pressure changes
When you breath in pressure in the abdomen increases, drawing lymph into thorax
Lymphatic capillaries
Larger than blood capillaries
When pressure in interstitial spaces is higher than the capillaries the cells fluid enters the lymph system due to anchoring filaments being pulled.
Endothelial cells overlap = one way valve
Passage of lymph
Capillaries Vessels Nodes Trunks Ducts
What are the 5 trunks and what do they drain?
Jugular - head and neck Subclavian - upper limbs Bronchomediastinal - thoracic wall, lungs and heart Intestinal Lumbar - lower limb and pelvic organs
What drains the right upper quadrant of the body?
The right lymphatic duct:
- right jugular
- right bronchomediastinal
- right subclavian
What drains most of the body?
Thoracic duct:
- lumbar
- intestinal
- left jugular
- left subclavian
- left bronchomediastinal
Venous angle
Site where the lymph drains into the venous system
It is the junction of the subclavian and internal jugular vein bilaterally .
virchow’s node
In left supraclavicular area that drains lymph from the gut. When it is enlarged it can be an early sign of intra-abdominal malignancy. It is located at the venous angle .
Primary lymphatic organs
stem cells which become immune cells
red bone marrow
Secondary lymphatic organs
Essential for an efficient immune response and surveillance
e.g. peyers patches, spleen, tonsils and MALT and lymph nodes
Thymus
soft triangular organ in the mediastinum, enlarges during childhood then atrophies. T cells mature in the thymus, where they undergo tolerance .
Spleen
Main storage site of T independent B cells, e.g. the T independent B cells that produce the IgG2 antibody - eliminates encapsulated bacteria.
Contains fixed macrophages.
Huge network of capillaries with a long transmit time through the organ so encapsulated bacteria are exposed to the spleen’s fixed macrophages for a longer time so the body has a greater chance of defending itself.
Why are encapsulated bacteria difficult to fight?
They are difficult to recognise as non-self pathogens because of their thick capsule.
Tolerance
Mechanism to remove immune cells that attack self tissue - autoimmunity.
T cells undergo central and peripheral tolerance.
Positive selection
Makes sure T cells can recognise MHC molecules - MHC I = CD8 and MHC II = CD4
Negative selection
Occurs after positive selection. If the cells bind strongly to self peptides being displayed on MHC molecules they will undergo apoptosis to remove them.
Lymphatic drainage of bladder
External iliac
Lymphatic drainage of prostate
Internal iliac
Lymphatic drainage of penis
superficial inguinal
Lymphatic drainage of Scrotum
superficial inguinal
Lymphatic drainage of testes
para aortic - enlargement is a sign of testicular cancer
Lymphatic drainage of Ovaries
Lateral and pre-aortic
Lymphatic drainage of Uterus
Fundus = para-aortic
Body and cervix = internal and external iliac
Lymphatic drainage of Vagina
Upper 1/3 = external and internal iliac
Middle 1/3 = internal iliac
Lower 1/3 = superficial inguinal
Antibodies
5 classes
all have the same basic structure
What do antibodies do?
Prevent toxins from damaging tissue
prevent pathogens from entering cells
highlight the pathogen to phagocytes and help phagocytosis
important for encapsulated bacteria and viruses
antibodies can cause activation of complement so activate mast cells
What are the different types of immunity?
Natural passive
Artificial passive
Natural active
Artificial active
What are the different antibody classes?
IgG IgA IgM IgD IgE
IgG
monomer important in secondary response pass through the placenta to the fetus have the ability to traverse the blood vessels to tissues most abundant of circulating antibodies
IgA
found in GI tract and respiratory tract - mucus membranes
high concentration in breast milk
help in transferring immunity to the new born infants
IgM
Produced in the primary immune response. They are restricted to the blood stream due to high mass . They are important in the primary response .
IgD
Present on the surface of B cells where they function as receptors for antigens .
IgE
Important in protection against parasites. They are involved mainly in the development of allergic responses. They release histamine which causes contraction of smooth muscles and stimulates secretion of mucus .
What are the different types of pathogens?
Bacteria, viruses, fungi, protozoa, metazoa and prions
What are prions?
Misfolded proteins with the ability to transmit their misfolded shape onto normal variants of the same protein
Bacterial replication
DNA is replicated
DNA is pulled to separate poles of the bacterium as it increase in size to prepare for splitting
The growth of a new cell wall begins to separate the bacterium
New daughter cells have tightly coiled DNA, ribosomes and plasmids, DNA gyrase and polymerase
Spores
Allow the bacteria to exist in a dormant state
complex multi-layered coat that is resistant to heat, drying, alcohol and UV
bacteria are able to return to a vegetative state when conditions are favourable
Biofilms
Community of bacteria attach to surfaces in extracellular polymeric substances
It protects them against desiccation and chemical attack
can occur on living or inanimate structures
Why are viruses easier to remove from the environment than bacteria?
They don’t form spores or biofilms
Cleaning
Removal of physical debris from a surface that microorganisms might be supported by. Involves handwashing .
Disinfection/ antiseptics
Removal of microorganisms
doesn’t remove everything
antisepsis = disinfection of living tissues
Sterilisation
Process of destroying all micro-organisms destroys spores pressure and heat in an autoclave blast with gamma rays super fine filters gas
Gram staining
Flood with crystal violet
Flood with iodine
Decolourise with gram’s alcohol
flood with safranin counterstain
Interpreting gram staining
Purple = gram postive
Pink = gram negative
oblong shape = rod
Sphere = cocci
PCR
Makes it possible to detect pathogenic viruses or bacteria
Process of PCR
95 degrees - denaturation
55 degrees - Annealing
72 degrees = Taq polymerase joins free nucleotides to template
What is the bacteria that commonly causes UTIs
Enterbacteriacae
When does testing for microorganisms need to be done?
From site of infection when the patient is acutely ill - start of the infection
When does testing antibodies need to be done?
When the patient is recovering, later on and from the blood .
What are the 4 main classes of receptor?
Endocrine
Paracrine
Synaptic
Contact-dependent
Endocrine signalling
hormones produced by endocrine cells
secreted into the bloodstream
act on distant tissues and cells
Paracrine signalling
hormones/ signals are released by various types of cells secreted locally (not into bloodstream) and diffuses between cells act on cells in near vicinity - short distance
what are the 3 types of surface receptors?
Ion channel coupled receptors
G protein coupled receptors
receptor tyrosine kinases - enzyme linked
Ion channel coupled receptors
Ligand binds to receptor (ion channel)
causes a conformational change
allows movement of specific ions
change in relative ion concentration across the cell may cause other changes
G protein coupled receptors
Absence of the ligand - GPCR is inactive
GPCRs bind to G proteins which are a trimeric protein - alpha, beta and gamma subunits
G proteins bind GDP when the GPCR is inactive but GTP when active.
When GTP binds the trimeric protein splits into 2 signals
The G protein hydrolyses the GTP to GDP to inactivate GPCR
Enzyme linked receptors
Ligand binds to 2 adjacent receptors which then dimerise
Receptors phosphorylate each others intracellular domain
Initiates a downstream signalling cascade
Most receptor tyrosine kinases activate Ras which cause GDP to become GTP
This initiates downward signalling
Contact dependent signalling
requires direct contact between 2 cells e.g. through gap junctions or through cell surface molecules .
Gap junctions
Hexameric channels that allow diffusion of small molecules between the 2 connected cells
usually smaller molecules - ions
all coordinated contraction of cardiac muscle cells
Cell-surface molecules
signalling molecule is not secreted, it is bound to the surface of the signalling cell
there is a receptor on the surface of the target cell
cells need to be in close vicinity to make a molecular contact
what is the difference between gram positive and negative bacteria?
Gram positive has a thick peptidoglycan cell wall and no outer lipid membrane but gram positive bacteria has a thin peptidoglycan cell wall and an outer lipid membrane . The gram positive retain the crystal violet stain, making them purple, but the gram negative are only coloured by the safranin counterstain as they cannot retain the crystal violet.
What is peyers patches
Small masses of lymphatic tissue found in the small intestine. They monitor intestinal bacteria
