ICS Flashcards
what is inflammation?
It is hard to define a reaction to injury or infection that involves neutrophils and macrophages.
When can inflammation be good?
Infection and injury
When is inflammation bad?
- Autoimmunity
- When there is over-reaction to a stimulus
How is inflammation classified?
- Acute
- Chronic
What is acute inflammation clasifed by?
- Sudden onset
-Short duration - Usually resolves
Example appendicitis
What are the cells involved in Inflammation
- Neutrophils
- Macrophages
- Lymphocytes
- Endothelial cells
- Fibroblasts
What are neutrophil polymorphs?
They are short lived cells that are first on the scene of acute inflammation
They contain cytoplasmic granules that are full of enzymes used to kill bacteria.
They will usually die at the site of an infection but release chemicals to signal other inflammatory cells such as macrophages
What are macrophages?
They are long lived cells (weeks to months) that have phagocytic properties.
They ingest bacteria and debris and carry them away
Can present antigens to lymphocytes
What are Lymphocytes?
Longest living cells involved (years)
They produce chemicals which will attract other inflammatory cells, they have memory for past infections and antigens
What are endothelial cells?
They line capillary blood vessels in areas of inflammation
How are endothelial cells involved in inflammation
They become sticky in areas of inflammation so cells like macrophages and neutrophils stick to them
They become more porous to allow cells to flow in
They grow into areas of damage to form capillaries so more cells can get to area
What do fibroblasts do in acute inflammation?
Long lived cells
Form collagen in areas of chronic inflammation and repair.
What are the steps of acute inflammation
- Initial reaction of tissue to injury
- Vascular component-dilation of vessels
- Exudative component- vascular leakage of protein rich fluid
- Cellular exudate
What are causes of acute inflammation?
- microbial infections e.g., pyogenic bacteria, viruses
- Hypersensitivity reaction e.g., TB, parasites, allergens
- Physical agents e.g., physical trauma, ionising radiation, heat
- Chemicals
- Bacterial toxins
- Tissue necrosis
Macroscopic appearances of acute inflammation
Rubor- redness due to dilation of small blood vessels
Calor- increase in skin temperature, due to increased blood flow and vascular dilation. Also, fever
Tumor- swelling results from fluid from exudate accumulating in extravascular space
Dolor- Pain
Reduced function
What are the outcomes of inflammation?
- Resolution
- Suppuration
- Organisation
- Progression to chronic inflammation
What is resolution?
The problem goes away
What us suppuration?
Pus formation
What is organisation?
There is healing by fibrosis (scar formation) when there is substantial damage lack of ability for the cells to regenerate.
Dead tissue and inflammatory exudate are removed from the area
Defect becomes filled with specialised vascular growth tissue
What happens in the early stages of acute inflammation?
Oedema fluid, fibrin and neutrophil polymorphs accumulate in the extracellular spaces of damaged tissue. The presence of the cellular component (neutrophil polymorph) is essential to the diagnosis.
What is the acute inflammatory response process?
- Changes in vessel calibre and increased vessel flow
- Increased vascular permeability and formation of fluid exudate (cells leaking out of blood vessels into surrounding tissue)
- Formation of cellular exudate- emigration of NP’s into EV space
How is blood flow regulated in inflammation?
By smooth muscle at precapillary sphincters ,in acute inflammation they relax which increases blood flow
Why does fluid accumulate in inflammation?
Increased capillary hydrostatic pressure forces more fluid out at aretiloar end and also forces proteins out which reduces oncotic pressure so less fluid is absorbed in the venous end
What causes the increased vascular permeablity?
- Immediate transient-chemical mediators, e.g. histamine, NO, C5a
- Immediate sustained- severe direct vascular injury
- Delayed prolonged- endothelial injury
What are the four stages of neutrophil polymorphs accumulation?
- Margination of neutrophils- increase in plasma viscosity due to fluid loss means NP flow closer to endothelial cells
- Adhesion of neutrophils- the NP adhere to endothelial cells process known as pavementing
- Neutrophil emigration- cells leave through the gap created between the endothelial cells
- Diapedsis- Red blood cells also may escape, the presence of a large number of RBCs mean severe vascular injury
What are the four stages of neutrophil polymorph accumulation?
- Margination of neutrophils- increase in plasma viscosity due to fluid loss means NP flow closer to endothelial cells
- Adhesion of neutrophils- the NP adhere to endothelial cells process known as pavementing
- Neutrophil emigration- cells leave through the gap created between the endothelial cells
- Diapedesis- Red blood cells also may escape, the presence of a large number of RBCs means severe vascular injury
What cells are the main source of histamine?
Mast cells (basophils, eosinophils and platelets)
What is the role of the lymphatic system in acute inflammation?
Lymphatics channels become dilated and drain away the inflammatory exudate, this limits the extent of oedema in tissues. Antigens carried to lymph nodes for recognition by lymphocytes.
What is chronic inflammation classified by?
- slow onset or sequel to acute an inflammatory process in which lymphocytes, plasma cells and macrophages predominate
- Long duration
- may never resolve
Example TB
Give 4 causes of chronic inflammation.
- Primary chronic inflammation.
- Transplant rejection.
- Recurrent acute inflammation.
- Progression from acute inflammation.`
Is chronic inflammation usually primary or following on from acute?
Usually primary
What are causes of primary chronic inflammation?
- Resistance of ineffective agent to phagocytosis and intracellular killing e.g., TB Leprosy
- Endogenous, necrotic adipose tissue, uric crystals
- Exogenous materials e.g., Asbestos fibres, suture fibres
- Autoimmune disease
- Diseases such as Crohn’s and sarcoidosis
- Transplant rejection
What are the macroscopic appearances of chronic inflammation?
- Chronic ulcer
- Chronic abscess cavity
- Thickening of hollow organ cavity
- Fibrosis
What do b lymphocytes do in chronic inflammation?
They are in contact with the antigens and become transformed into plasma cells
What is the role of T lymphocytes in chronic inflammation
They are responsible for cell mediated immunity. Thye produce cytokines which recruit and activate other cells
What is the role of macrophages?
They ingest a wide range of materials and being long living they can harbour organisms for a long time e.g., mycobacterium tuberculosis and leprae. This can result in delayed hypersensitivity reaction.
What is a granuloma?
An aggregate of epithelioid histocytes
What are the causes of chronic inflammation?
- Primary chronic inflammation.
- Transplant rejection.
- Recurrent acute inflammation.
- Progression from acute inflammation.
What are examples of granuloma causing diseases?
TB, leprosy, Crohn’s and sarcoidosis
What cell can form when several macrophages try to ingest the same particle?
Multinucleate giant cell.
What is the difference between resolution and repair?
Resolution is when the initiating factor is removed, and the tissue is able to regenerate. In repair, the initiating factor is still present, and the tissue is unable to regenerate.
Name 5 types of cells capable of regeneration
- Hepatocytes.
- Osteocytes.
- Pneumocytes.
- Blood cells.
- Gut and skin epithelial cells.
Name 2 types of cells that are incapable of regeneration.
- Myocardial cells.
- Neuronal cells.
What is a thrombosis?
The solidification of blood contents that forms within the vascular system during life (clot is outside the vascular system/after death)
What prevents thrombosis from forming all the time?
-Laminar flow, cells flow through the middle of vessels and don’t touch the side
- Endothelial cells aren’t sticky when healthy
What cells are platelets derived from?
Megakaryocytes
What do platelets contain?
Alpha granules and dense granules
When are platelets activated?
When they come into contact with collagen, they release their granules
What processes result in thrombus formation?
-Platelet aggregation they release chemicals which cause them to stick to each other- is a positive feedback loop so hard to stop.
-Fibrin makes a mesh between platelets preventing RBCs from escaping
-
What three main factors are thrombosis formed by (Virchow’s triad)?
- Change in vessel wall
- Changes in blood flow
- Changes in blood constituents
Not all three factors are needed and any one of them may result in thrombosis. Usually, a combination though
What are the two types of thrombosis?
Arterial and venous
What causes an arterial thrombus to form?
Usually through the formation of an atheromatous plague-result in changes to blood flow and vessel wall
Describe the process of arterial thrombus formation
- Plaque results in raised streak on vessel surface
- This plaque will grow and cause turbulent blood flow
- This causes a loss in intima cells and exposes the plaque to platelets
- The turbulence results in fibrin deposition and platelet clumping and they will settle on exposed collagen- this will form first layer of the thrombus
- This structure will now protrude further into the vessel and cause further turbulence to blood flow
- Thrombi will continue to grow, they will grow in the direction of blood flow propagation
What can an arterial thrombus lead to?
Can lead to MI/stroke
What is the treatment for an arterial thrombus?
Anti-platelets e.g., aspirin
Where do most venous thrombi begin?
At valves
Why is venous thrombosis most likely to occur at valves
As they protrude into the vessel lumen and cause turbulence
When is venous thrombosis most likely to occur?
- When there is a fall in blood pressure after surgery or after MI as flow is slower through the vessels.
- During normal flow (laminar) the blood cells are kept away from damaged valves or diseased walls
What else can result in venous thrombosis?
Venous return from the legs is very reliant upon calf contraction and relaxation this massages the veins and return blood towards the heart.
- So, during periods of immobilisation DVT’s are more likely to occur
What can a venous thrombus lead to?
A deep vein thrombosis/pulmonary embolism
What is the treatment for a venous thrombus?
An anti-coagulant e.g., warfarin
What are the clinical effects of Arterial thrombosis?
-Loss of pulse distal to the thrombus
- Area becomes cold, pale and painful
- Eventually tissue will die and become gangrenous
What are the clinical effects of venous thrombosis?
- Area will become tender due to developing ischaemia
- Area will become reddened as blood will continue to flow the tissue but can’t be drained away
- Area will become swollen
What are the 4 fates of thrombi
- Best case scenario- Resolution
- Organisation- macrophages clear way thrombus and fibroblasts replace it with collagen results in slight narrowing of lumen
- Recanalization- small capillaries grow into thrombus and fuse to form larger vessels this will allow blood to flow again via a different route
- Embolism- fragments break off and enter the circulation
A thrombus can also cause death by effecting a vital centre before the body or clinicians can make an intervention
What is an embolism?
A mass of material in the vascular system able to lodge in a vessel and block its lumen
What is the most common cause of an embolism?
A thrombus e.g., a DVT of the leg breaks off and embolises through the large veins and into the ride side of heart or lungs
What happens to an arterial embolism?
- It can travel anywhere downstream of its entry point
- Mural thrombi in the left ventricle can go anywhere
- Cholesterol crystals from an atheromatous plaque in the descending aorta can go to any lower limb/renal artery
What are the casues of an arterial embolism?
- Most of the thrombi that result in a systemic embolism originate from the heart or an atheromatous plaque
- In the heart thrombi may occur as a result of MI which will damage the endothelial lining of the cardiac muscle and expose the collagen to circulating platelets
- Another common cause of thrombosis is AF the ineffectual movement of blood will cause it to stagnate and form a thrombus
What are the causes of an arterial embolism?
- Most of the thrombi that result in a systemic embolism originate from the heart or an atheromatous plaque
- In the heart thrombi may occur as a result of MI which will damage the endothelial lining of the cardiac muscle and expose the collagen to circulating platelets
- Another common cause of thrombosis is AF the ineffectual movement of blood will cause it to stagnate and form a thrombus
What are the effects of a small venous emboli?
- They may go unnoticed (lysed in the lungs)
- Can cause idiopathic pulmonary hypertension as it becomes organised and over time damages the lungs
What are the effects of a large venous emboli?
- Can result in acute respiratory or cardiac problems that may resolve slowly with or without treatment
- Symptoms are chest pain and shortness of breath
- Lung function will be impaired after recovery and higher risk of future embolism
What are the effects of a massive emboli?
- Sudden death
- Usually derived from long thrombi in legs
- Often impair the bifurcation of the pulmonary arteries
What is ischaemia?
The reduction in blood flow to a tissue caused by constriction or blockage of the blood vessels supplying it
What areas are most vulnerable to ischaemia?
Cardiomyocytes and cerebral neurons (attacks are brief are effects are reversible)
What is infarction?
The necrosis of part of the whole of an organ that occurs when the artery supplying it becomes obstructed
What type of event is an infarction?
Usually, a macroscopic event caused by thrombosis
Why are most organs susceptible to infarction?
Thye only have one artery which supplies them so if there is a blockage in that artery, they will become infarcted
Which organs have dual blood supply and thus are less likely to be infarcted?
- Liver- portal vein and hepatic artery
- Lung- pulmonary venous and bronchial artery
- Brain- the circle of willis has multiple artery supplies
What is a reperfusion injury?
Most of the damage in an area occurs when blood flow is returned as the damage is oxygen dependant
What is gangrene?
When whole areas if a limb or region of the gut have their arterial supply cut off and large areas if mixed tissue die in bulk
What are the two types of gangrene?
- Dry gangrene where tissue becomes mummified, and healing occurs above it. This area will drop off
- Wet gangrene due to bacterial infection gangrene spreads proximally and patient will die from sepsis
What is atherosclerosis?
The formation of atherosclerotic plaques in the intima of large and medium-sized arteries e.g. coronary arteries
What can atherosclerosis cause?
Often can be asymptomatic
But can cause life-threatening damage is a thrombus is formed from a disrupted plaque
- Cerebral infarction
- Carotid atheroma leading to TIA’s
- MI
- Aortic aneurysm
- Peripheral vascular disease
- Gangrene
In what vessels does atherosclerosis occur?
Systemic not pulmonary due to the highger presuure
How do atherosclerotic plaques form?
- High levels of LDL in the blood will accumulate on the arterial wall
- Endothelial cell dysfunction (lots of cholesterol damages cell walls, also nicotine and carbon monoxide)
- Macrophages are attracted to the site of damage and take up lipids to form foam cells
- The activated macrophages will release growth factors and cytokines
- This will form a fatty streak
- There will be smooth muscle proliferation around the lipid core, and this will form a fibrous cap that could occlude blood flow
- This process will continue until artery becomes fully occulded.
What are the risk factors for atherosclerosis?
- Hypercholesterolemia
- Smoking
- Hypertension
- Diabetes
- Male sex
- Increasing age
What is apoptosis?
A physiological cellular process in which a defined and programmed sequence of intracellular events leads to the removal of a cell without the release of products harmful to surrounding cells
What process does apoptosis work alongside?
- Apoptosis is essentially programmed cells death
- Works alongside mitosis to ensure a continuous renewal of cells enabling tissue to be more adaptable to environmental demands
What are the characteristics of apoptosis?
- Energy dependant
- Involves enzymatic digestion of nuclear and cytoplasmic contents
- Phagocytosis of resultant breakdown products still retained within the cell membrane
Where is apoptosis common?
In the gut/duodenum, where cells are regularly replcaed
What diseases is poorly regulated apoptosis implicated in?
- Defective apoptosis is important ion neoplasia, i.e cancer, whereby there is a lack of apoptosis resulting in cells living longer
- Disturbances in apoptosis, i.e AIDS, Neurodegenerative disorders and anaemia of chronic disorders`
List the 4 inhibitors of apoptosis
- Growth factors
- Extracellular cell matrix
- Sex steroids
- Some viral proteins
List the 8 inducers of apoptosis
-Growth factor withdrawal
- Loss of matrix attachment
- Glucocorticoids
- Some viruses
- Free radicals
- Ionising radiation
- DNA damage
- Ligand binding at death receptors
What are the two main apoptosis pathways?
Extrinsic and intrinsic (both converge upon a final common effector pathway characterised by the activation of proteases and DNAses)
Describe the intrinsic apoptosis pathway
- Uses the pro/anti-apoptotic members of the BCL-2 family
- BCL-2 can inhibit many factors that induce apoptosis vs Bax, which forms Bax-Bax dimers which enhance apoptotic stimuli
- Thus, the ratio of BCL-2 to Bac determines the cells’ susceptibility to apoptotic stimuli
- The pathway responds to growth factors and biochemical stress
What is the p53 gene?
-It induces cell cycle arrest and initiates DNA damage repair
- If damage is more difficult to repair, then p53 can induce apoptosis via activation of pro-apoptotic members of the BCL-2 family
Describe the extrinsic apoptosis pathway
- Ligand-binding at death receptors on the cell surface
- This results in the clustering of receptors of receptor molecules in the cell surface and the initiation of the signal transduction cascade
- This pathway is used by the immune system to eliminate lymphocytes
What proteins carry out apoptosis?
Caspases
What is necrosis?
Traumatic cell death which induces inflammation and repair
What is necrosis characterised by?
- Bioenergetic failure, i.e. failure to produce ATP
- The loss of plasma membrane integrity
What are the 4 types of necrosis?
- Coagulative (most common)
- Liquefactibe
- Caseous
- Gangrene
What is coagulative necrosis?
- Most common type
- Caused by ischaemia
- Can happen in most organs
- Tissue will become soft due to digestion by macrophages
- Presence of necrotic tissue will evoke an inflammatory response
What is liquefactive necrosis?
- Occurs in the brain due to its lack of substantial supporting stroma meaning necrotic neural tissue may totally liquefy
What is caseous necrosis?
- Where dead tissue becomes structureless, almost like soft cheese
- Normally associated with TB
What is hypertrophy?
- An increase in cell size without cell division
- Muscle hypertrophy is seen in athletes
- Uterine hypertrophy is seen in pregnancy
What is hyperplasia?
- An increase in cell number by mitosis
- This can only happen in cells that divide i.e., it can’t happen in myocardial cells or nerve cells
- Hyperplasia of bone marrow cells can be seen in those living at high altitude
What is atrophy?
- The decrease in the size of an organ or cell by reduction in size or number often involving apoptosis
- Occurs naturally during the development of the GU tract
- Occurs in disease e.g., muscle atrophy in ALS due to lack of innervation
What is metaplasia?
-The change in differentiation of a cell from one fully differentiated cell type to another
- Occurs in response to alterations in cellular environment
- E.g., Squamous epithelium of the oesophagus can become columnar in response to stomach acid (Barett’s oesophagus)
What is dysplasia?
- Morphological changes seen in cells in the progression to becoming cancer (not cancer but could become cancer
Why do we age?
- Our cell’s ability to divide decreases the older we get
- Our fetal cells have the greatest potential for division
- Ageing is influenced by genetic and environmental factors
What is telomeric shortening?
- At the tip of each chromosome, there is a non-coding, randomly repetitive DNA sequence this is the telomere
- The telomeric sequences are not fully copied during DNA synthesis as a result, during each mitosis, the telomere is shortened
What is sarcopenia?
- Muscle loss due to ageing
- Begins from 40 onwards but accelerates from 80 onwards
- Due to decreased growth hormone, decreased testosterone and increased catabolic cytokines
Name some other age-related conditions.
- Deafness
- Dementia
- Cataracts
- Osteoporosis
- Impaired immunity
What is carciogenesis?
The transformation of normal cells into neoplastic cells through permanent genetic alterations or mutations.
What is neoplasm?
A lesion resulting from the autonomous or relatively autonomous abnormal growth of cells which persists after the intimating stimulus has been removed
What 4 things define neoplasia?
- Autonomous
- Abnormal
- Persistent
- New growth
What are carcinogens?
- An environmental agent participating in the causation of tumour
Name some carcinogens and cancer which they cause
- Smoking and lung cancer
- B-naphthylamine (dyes and rubber industry) can cause bladder cancer
- Soot exposure can cause scrotal carcinoma
- HPV and cervical cancer
Classify a benign tumour
- Does not invade the basement membrane
- Exophytic (grows outwards)
- Low mitotic activity
- Circumscribed
- Necrosis and ulceration rare
Classify a malignant tumour
- Invades the basement membrane
- Endophytic
- High mitotic activity
- Poorly circumscribed
- Necrosis and ulceration common
What cells can neoplasms not arise from?
Erythrocytes as they have no nucleus so have no DNA. But can arise from precursor’s e.g., erythroblasts
What makes neoplasms a more common occurrence?
- Spontaneous mutations during normal DNA replication are common but rectified through repair mechanisms
- The probability of a neoplastic transformation increases with the number of cell divisions experienced by a cell- hence the incidence increases with age
- Carcinogens increase the probability of mutational events
What is a tumour?
- Any abnormal swelling
This includes neoplasm, inflammation, hypertrophy, hyperplasia
Name the 5 classes of carcinogens
- Chemical
- Viruses
- Ionising and non-ionising radiation
- Hormones, parasites and mycotoxins
- miscellaneous
What are epithelial cell tumours called?
Carcinoma
What are connective tissue tumours called?
sarcomas
What are lymphoid cell tumours called?
Leukaemia/lymphomas
How are tumours histological graded?
Grade is based on the extent to which the tumour resembles its original histology
Grade 1- Well differentiated (most closely resembles parent tissue)
Grade 2- Moderately differentiated
Grade 3- Poorly differentiated
Classify a malignant tumour
- Invades basement membrane
- Endophytic
- High mitotic activity
- Non circumscribed
- Necrosis and ulceration rare
Give 5 carcinoma’s that can spread to the bone
- Breast.
- Kidney.
- Lung.
- Prostate.
- Thyroid.
Give an example of a carcinoma that can spread to the axillary lymph nodes.
Breast carcinomas.
What is required for a tumour to invade through a basement membrane?
- Proteases.
- Cell motility.
What complications can a benign tumour cause?
- Pressure on adjacent structures
- Obstruction to flow of fluid
- Production of a hormone
- Transformation into a malignant neoplasm
- Anxiety and stress
How do malignant tumour cause issues?
- Pressure on and destruction of adjacent tissue
- Formation of secondary tumours
- Blood loss from ulcerated surfaces
- Obstruction of flow
- Hormone production
- Weight loss
Name some benign tumours
- Lipoma tumour is of adipocytes
- Rhabdomyoma is of straited muscle
- Leiomyoma is of smooth muscle
- Chondroma is of cartilage
- Osteoma is of bone
- Angioma is of vessels
- Neuroma is of nerves
Suffix is always oma
Name some malignant tumours
- Liposarcoma tumour is of adipocytes
- Rhabdomyosarcoma is of straited muscle
- Leiomyosarcoma is of smooth muscle
- Chondrosarcoma is of cartilage
- Osteosarcoma is of bone
- Angiosarcoma is of vessels
Why do neoplastic cells proliferate so much and why are they immortal?
- Autocrine growth stimulation due to abnormal expression of genes, intracellular signalling proteins, inactivation of genes
- Reduced apoptosis
- Telomerase prevents telomeric shortening
What percentage of cancers are due to environmental factors?
85%
What does a neoplasm release in order to initiate angiogenesis?
Vascular endothelial growth factors.
Why does necrosis often occur in the centre of a neoplasm?
The neoplasm grows quickly and outgrows its vascular supply.
What are the two ways in which neoplasms can be classified?
1.Behavioural classificationq
2. Histogenetic classification
What is the behavioural classification of neoplasms?
Neoplasms can be classified as benign, malignant or borderline. Borderline tumours (e.g., some ovarian lesions) defy precise classification.
What is the histogenetic classification of neoplasms?
Histopathological tests specify tumour type by determining the cell of origin of a tumour. If the origin is unknown the tumour is said to be anaplastic.
What is essential for neoplasm growth?
Angiogenesis.
Why wont a ductal carcinoma spread to the rest of the body?
- It is surrounded by a band of collagen, so wont spread into the rest of the body. No access to blood vessels/lymphatics
- Once a tumour leaves the duct, then its bad, as it can get through the extracellular matrix and then vessels
What do cancer cells in a duct need to do in order to spread through the body
get through the basement membrane - by producing enzymes that will break down the collagen (collagenases)
what does a tumour bigger than one 1mm need in order to survive?
Its own blood supply
How do cancer cells invade the host immune defence?
- Aggregation with platelets
- Adhesion to each other
- Shedding of surface antigens
Give 3 inhibitors of tumour angiogenesis. How can this be used?
1.Angiostatin.
2. Endostatin.
3. Vasculostatin.
Use medications like these to stop angiogenesis so tumours cannot make their own blood supply, so they can’t exceed more than 1mm in size
Give an example of carcinomas that can spread to the liver.
Colon, stomach and pancreatic carcinomas can spread to the liver via the portal vein
Give an example of a malignant tumour that often spreads to the lung
breast carcinoma
Tumours from where commonly metastasise to bone?
Prostate, breast, thyroid, lung and kidney
define cell motility
Cellular motility is the spontaneous movement of a cell from one location to another by consumption of energy.
Cancer cells need this in order to spread (obvs)
what is an invasive carcinoma?
Invasive cancer means the cancer cells have broken out of the lobule where they began and have the potential to spread to the lymph nodes and other areas of the body.
Name some things that cancer cells that are in situ need in order to spread through the body
Proteases
Collagenases
Cell motility
Adhesion receptors, so it can leave the blood stream
Describe the process of metastasis
- Detachment of tumour cells from their neighbours
- Invasion of surrounding connective tissue
- Intravasation into the lumen of vessels
- Evasion of host defence cells
- Adherence to endothelium in remote location
- Extravasation of the cells from the vessel lumen into surrounding tissue
- Tumour cells proliferate into the new environment
What is the most common way for grading tumours?
TMN
T- refers to primary status (Size)
N- refers to node status (Degree of lymph node involvement)
M- refers to metastatic status (Extent of distant metastasis) `
What is haematopoiesis?
Formation of red and white blood cells
Describe innate immunity
- Non-specific
- Resistance is not improved by repeat infections
- Rapid response
- Instinctive
- No lymphocytes (Phagocytes and natural killer cells)
- Lysosome, complement interferon protect uninfected cells and activate macrophages
What types of barriers make up the innate immune response
- Chemical barriers e.g., stomach acid and lysosomes in tears
- Physical barriers e.g., epithelium in stomach and gut and cilia lining airways
Describe the role of neutrophils
- They make up 65% of WBC
- Lifespan 6-12 hours
- They play an important role in innate immunity (phagocytosis)
What 2 main intracellular granules do neutrophils contain?
- Primary lysosomes (myeloperoxidase, muramidase, acid hydrolases and proteins). They combine with phagosomes which contain microbes to digest pathogens
- Secondary granules (lactoferrin and lysozyme). They have Fc and complement receptors and can kill microbes by secreting toxic substances
Describe the role monocytes
- Make up 5% of blood
- Lifespan: months
- Play an important role in innate (phagocytosis) and adaptive (antigen presentation) immunity
How do monocytes contribute to the immune response?
- They differentiate into macrophages in the tissues
- Main role is to remove anything foreign or dead
- Have lysosomes containing peroxidases that can kill microbes
- Have Fc, complement receptors, pattern recognition receptors, toll-like receptors and mannose receptors and can bind to all kinds of microbes
Describe the role of macrophages
- Lifespan: Months/years
- Examples include: Kupffer cells and microglia
- Play important role in innate (phagocytosis) and adaptive (antigen presentation) immunity
What role do macrophages play in the immune response?
- The first line of non-self-recognition
- Main role is to remove foreign (microbes) and self (dead/tumour cells)
- Present antigens to T cells
- Release cytokines to attract other immune cells
What is the difference between a macrophage and a monocyte?
Monocytes are found in the blood and then differentiate into macrophages or dendritic cells in tissue
Describe the role of eosinophils
- Make up 5% of blood
- Lifespan: 8-12 days
- Mainly associated with parasitic and allergic reactions
- Phagocytic (more so than basophils due to bigger size)
What do the eosinophil granules contain?
Major basic protein (MBP)
What does MBP do?
- It is potent toxin for helminth worms
- Activates neutrophils
- Induces histamine release from mast cells
- Provokes bronchospasm
Describe the neutrophil innate immune response
- Engulf pathogens using phagocytosis
- Form a phagosome inside the cell
- Granules in neutrophil fuse with phagosome to form phagolysosome causes it to become acidic (kills 2% of pathogens)
- Neutrophil continues to engulf more pathogens
- Once neutrophil is full an oxidative burst occurs
- These highly reactive oxygen species kill neutrophil but also the pathogens engulfed
What to myeloid progenitor cells develop in to?
- Neutrophil (granulocyte)
- Eosinophil (granulocyte)
- Basophil (granulocyte)
- Mast cell
- Dendritic cells
- Macrophage
- Monocyte
All part of the innate immune response
Describe the role of basophils
- Make up 2% of blood
- Lifespan: 2 days
- Similar to mast cells involved in allergic reactions
How are basophils involved in allergic reactions?
- They have high affinity IgE receptors
- Binding of IgE to receptor results in de-granulation releasing histamine
What is one major difference between eosinophils and basophils?
Eosinophils are phagocytic
What is the difference between mast cells and basophils?
Mast cells are in fixed tissue, whereas basophils are able to circulate around the body
Describe the role of mast cells
- Only found in tissues
- Very similar to basophils
What cells is known as the professional antigen presenting cells
Dendritic cells
Describe how dendritic cells are involved in the immune response to a pathogen
- They are excellent at phagocytosis
- Once they are mature, they break up pathogens into small amino acid chains
- Will move through lymph to nearest node and perform antigen presentation to T cells they are the best at this
What is called when a T cell with a specific receptor binds to an antigen on a macrophage
Priming
What do lymphoid progenitor cells become?
- B cells
- T cells
- Natural killer cells
Describe the role of T lymphocytes
- Make up 10% of blood
- Lifespan: hours-years
- Play a major role in adaptive immunity
- Can’t secrete receptors
Where do T lymphocytes originate and mature
They originate in bone marrow and mature in the thymus
What is an advantage and disadvantage of the adaptive immune response
- Advantage immunological memory
- Disadvantage can take a few weeks
What do T cells require for its receptors to bind to an antigen
Antigens need to be presented on a major histocompatibility complex (MHC)
What are natural killer cells (NKC’s)?
- Large lymphocytes with granules
- They target cells infected with intracellular organisms e.g., virus
- They also target cancer cells
How do NKC’s kill target cells?
By releasing cytotoxic granules
How do cytotoxic granules kill target cells?
They punch holes in cell membranes creating pores or they enter cells and cause apoptosis
What are B cells?
- Have receptors on surface but don’t need MHC
- Can bind to any antigen that has shape specific to their receptors
- Can also perform phagocytosis and antigen presentation
- Contain MHC II
What happens when a T cell gets activated
It helps a B cell to transform into a plasma cell
What do plasma cells secrete
Antibodies
How long does it take for antibody levels to peak?
A few weeks
What are antibodies
B cell receptors in the secreted form (humoral immunity)
What are the two main types of T cell
- CD4+
- CD8+
What CD are all T cells positive for?
CD3
What are CD4+ cells called and what do they do?
-They are called helper T cells
- They secrete cytokines that coordinate immune response
- Can only see antigens presented on an MHC II molecule
What are CD8+ cells called and what do they do?
- They are called cytotoxic T cells
- They kill target cells
- Very specific killing (only kill cells with antigen presented on MHC I molecule)
What is an antibody comprised of?
- Two heavy chains
- Two light chains
What are the two different regions of an antibody?
- Fragment antigen binding (Fab) (A variable region)
- Constant fragment (fc) (stays the same)
What chains determine the class of antibody?
Heavy chain
What are the 5 classes of antibodies?
- IgG
- IgA
- IgM
- IgE
- IgD
GAMED
What is valence?
How much antigen binding occurs basically how many Fab fragments the antigen contains
What is IgM?
- Makes up 4% of antibody population in serum
- 1st antibody response made
- Monomer (valence 2) / pentamer (valence 10)
- Can be made without T cell response
- Most effective at activating complement pathway
What is IgG?
- Most abundant antibody in serum makes up 75%
- Monomer (valence of 2)
- Four types: IgG1, IgG2, IgG3, IgG4
- Serves as an opsonin: helps phagocytes bind to pathogen and makes it easier for phagocytosis to occur
- Activates the common complement pathway
- Helps NKC’s to kill viruses
What is IgA?
- Makes up 20% of antibody population in serum
- Monomer (valence of 2)/ dimer (valence 4) at mucosal sites
- Serves as an opsonin
- Main antibody found in mucosal sites and prevents pathogens entering the body
- Forms IgA1 and IgA2
- Babies receive lots if IgA in breastmilk
What is IgE?
- Makes up 0.004% of antibody population in serum
- Monomer (valence of 2)
- Associated with allergic and anti-parasitic responses
- Triggers granule release when binding to basophils, Eosinophils and mast cells
- Triggers inappropriate release of histamine granules in allergic reactions
What is IgD?
- Makes up 1% of the serum antibody population
- Monomer (valence 2)
- Found with IgM antibodies and serves as a signal they are ready to leave the bone marrow
What are complement factors?
A group of 20 serum proteins that need to be activated in order to work
How do complement factors contribute to the immune system?
- Direct lysis (MAC) (C5b + chain)
- Attract more leukocytes to site of infection (C3a and C5a)
- Coat invading organism (opsonisation C3b)
What are cytokines?
Proteins secreted by the immune system that coordinate the immune response
What do interferons do?
Induce a state of antiviral resistance in uninfected cells
What are interleukins?
- Can be pro inflammatory (IL1) or anti-inflammatory (IL10)
- Can cause cells to divide and differentiate and to secrete factors
What do colony stimulating factors do?
Involved in the direction of division and differentiation in bone marrow
What are TNF’s?
Tumour necrosis factor, they mediate inflammation and cytotoxic reactions
What do chemokines do?
They attract leukocytes
How do we sense pathogens?
- In the blood, monocytes and neutrophils will detect
- In tissue will be macrophages, dendritic cells
These cells have pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs) on pathogens.
What are the 3 antigen-presenting cells?
- Macrophages
- B cells
- Dendritic cells
What are the two types of antigens?
Intrinsic and extrinsic
What MHC do intrinsic cells use?
MHC I (this will stimulate CD4+ T cells)
What MHC do extrinsic cells use?
MHC II (this will stimulate CD8+ T cells)
What is the main type of PRRs?
Toll-like receptors
Describe the process of a T helper cell binding to a B cell.
A B-cell antibody binds an antigen -> phagocytosis -> epitope is displayed on the surface of the B-cell bound to an MHC2 -> TH2 binds to B-cells -> cytokine secretion induces B-cell clonal expansion -> differentiation into plasma cells and memory B cells
What activates the alternative pathway?
Bacterial cell walls and endotoxin.
Name 3 receptors that make up the PRR family.
- Toll-like receptors (TLR).
- Nod-like receptors (NLR).
- Rig-like receptors (RLR).
What is the main function of TLR’s?
TLR’s send signals to the nucleus to secrete cytokines and interferons. These signals initiate tissue repair. Enhanced TLR signalling = improved immune response.
What is the main function of NLR’s?
NLR’s detect intracellular microbial pathogens. They release cytokines and can cause apoptosis if the cell is infected.
What disease could be caused by a non-functioning mutation in NOD2?
Crohn’s disease.
Give examples of diseases that can be causes by PRR’s failing to recognise pathogens.
- Atherosclerosis.
- COPD.
- Arthritis.
Give examples of 3 extracellular PRR.
- Mannose receptors.
- Scavenger receptors.
- TLR’s.
What proteins make up the classical complement pathway?
C1-C9
What does C1 do? (Classical pathway)
- C1q binds to antibody-antigen complex
-This causes c2a and c4b to bind to surface of the pathogen forming C3 convertase - This activates C3
What does C3b do? (Classical pathway)
- C3b is an opsonin, helps with phagocytosis
- Forms C5 convertase
- This activates C5
What does c5 do? (classical pathway)
- Binds with C6,7,8
- This complex penetrates through pathogen membrane
- C9 joins with them, and this forms the membrane attack complex (MAC)
What is the difference between the lectin binding pathway and the classical pathway?
The LBP uses mannose binding lectin protein instead of C1 to activate C2 and C4 to form C3 convertase
What regulates the alternative pathway?
C1 inhibitor
What TLR’s are found on the cell surface and what do they bind to?
1,2,4,5,6 and they bind to extracellular PAMPs (peptidoglycan, lipopolysaccharide, flagella) on pathogens
Which TLR’s are found inside the cell and what do they do?
3,7,8,9 and they bind to intracellular PAMPs (viral RNA)
What do TLR’s do when they are activated?
They activate NF-kB which stimulates inflammatory cytokines e.g., IL-1, IL-6 and TNF-a
What antibody is involved in a type 1 hypersensitivity reaction?
IgE
What’s the first exposure to an allergen called?
Sesitisation
What’s more the serious subsequent exposures or an initial exposure?
Subsequent exposures
What is a T-helper that has never seen an antigen before called?
A naive T-helper cell
In an allergic reaction what do the T-helper cells differentiate in to?
Th2 cells
What interleukins help a T-helper cell to differentiate into a Th2 cell
IL-4, IL5, IL-10
What interleukin released by TH2 cells causes B-cells to release IgE antibodies?
IL-4
What interleukin released by TH2 cells stimulates production of eoisnophils?
IL-5
What receptors do IgE receptors bind to on mast cells?
Fce
fc epsilon
What happens when a sensitised mast cell binds to a previously seen antigen e.g., pollen
It degranulates and releases pro-inflammatory molecules e.g, histamine
What receptors does histamine bind to?
H1
What does binding of histamine to H1 receptors do?
-Bronchoconstriction
- Vasodilation
- Increased vascular permeability (which causes swelling and hives and redness)
What happens 8-12 hours after an allergic reaction?
- Leukotrienes LTB3, LTB4 are secreted by immune cells
- Cause smooth muscle contraction
- Causes signalling to other immune cells to aggregate in the area
What is a feature of type II hypersensitivity?
It is usually organ specific
What is it called when immune cells that are reactive to self get destroyed?
Central tolerance
What cells are the primary cause of a type II hypersensitivity reaction?
B-cells
What antibodies are secreted in type II hypersensitivity reaction?
IgG, IgM
What are the two types of antigens attacked on cells by antibodies in a type II hypersensitivity?
- Intrinsic (antigens normally produced)
- ## Extrinsic (things that have become attached to cells e.g., drugs)
What is it called when an antibody binds to an antigen? When is this a problem?
Antigen-antibody complex, is an issue when this happens to host tissue
What is the first cytotoxic mechanism of a type II reaction?
Activation of the complement system (will kill host cell)
What can a penicillin mediated type II hypersensitivity reaction cause?
Haemolytic anaemia, Thrombocytopenia, neutroepenia
What can a penicillin mediated type II hypersensitivity reaction cause?
Haemolytic anaemia, Thrombocytopenia, neutropenia
What is the 2nd cytotoxic mechanism in a type II reaction?
The membrane attack complex of the complement system (which causes cell lysis)
How do you test for autoimmune haemolytic anaemia?
Coomb’s test
When is an indirect coombs test performed?
To test for antibodies against an antigen before exposure
What is the 3rd cytotoxic mechanism of a type II reaction?
When there is opsonisation by c3b and subsequent phagocytosis
What is the 4th cytotoxic mechanism of a type II reaction?
- Antibody-dependant cell-mediated cytotoxicity,
- Complex gets recognised by NKCs which cause cell death
What is a non-cytotoxic type II mechanism?
- Antibody-mediated cellular dysfunction
- Changes normal functioning of cell e.g., myasthenia gravis (block binding site of Ach )and graves’ disease
What are the three fundamental things that define a type II reaction?
- Antibody-mediated
- (generally) Cytotoxic
- Tissue specific
When do type III reactions occur?
When antigen-antibody complexes get deposited in blood vessel walls
What is major difference between type II and type III reactions?
Type II involves antigens on cell surfaces. Whereas type III involves solouble antigens
What is a good example of a type III reaction?
Lupus
Are small antigen-antibody complexes (found in type III reactions) more or less immunogenic (attractive to other parts of the immune system)?
Less
What is the consequence of the small antigen-antibody complexes being less immunogenic?
- They stay in the blood stream for longer and
- Make their way to basement membrane of blood vessels
Is the complement system more or less active in type III compared to a type II reaction?
Type III
What is the last major difference between type II and type III reaction?
Damage in type III occurs where the complexes deposit not where they were made
What are the mediators of a type IV reaction?
T-cells
What interleukin causes a CD4+ cell to differentiate into a Th1 cell?
IL-12
How long does it usually take for a type IV reaction to occur?
48-72 hours
What diseases are type IV reactions implicated in (CD4+)?
- Rheumatoid arthritis
- Multiple sclerosis
- IBS
What is another common form of type IV reaction?
Skin rashes e.g., poison ivy, TB, Nickel
What type IV reactions do CD8+ cells cause?
- Type 1 diabetes
- Hashimoto thyroiditis
What are the main features of anaphylaxis?
- Rapid onset
- Rash with blotches
- Swelling
- Wheeze
- Hypotension (anaphylactic shock)
- Cardiac arrest
