Introductory Clinical Sciences Flashcards
What is inflammation?
A reaction to injury or infection involving cells such as neutrophils and macrophages
Give 5 cardinal signs of inflammation.
- Redness (rubor).
- Swelling (tumor).
- Pain (dolor).
- Heat (calor).
- Loss of function.
Give a disadvantage of inflammation.
Inflammation can produce disease and can lead to distorted tissues with permanently altered function.
When is inflammation bad?
- Autoimmunity
- When it’s an overreaction to the stimulus
What is the expected outcome of acute inflammation?
The complete elimination of a pathogen followed by resolution of damage, disappearance of leukocytes and regeneration of tissue.
Acute inflammation features
- Sudden onset
- Short duration
- Usually resolves
Give 6 causes of acute inflammation.
- Microbial infections (bacteria and viruses).
- Chemicals (corrosives, acids/alkalis).
- Physical agents (trauma, burns, frost bite).
- Hypersensitivity reactions (TB).
- Bacterial toxins.
- Tissue necrosis.
Chronic inflammation features
- Slow onset or sequel to acute
- Long duration
- May never resolve
What is chronic inflammation?
Persistent, unresolved inflammation.
Give 4 causes of chronic inflammation.
Primary chronic inflammation.
Transplant rejection.
Recurrent acute inflammation.
Progression from acute inflammation.
Give examples of primary chronic inflammation.
- Infective substances having resistance to phagocytosis e.g. TB, leprosy.
- Endogenous materials e.g. uric acid crystals.
- Exogenous materials e.g. asbestos.
- Autoimmune diseases e.g. chronic gastritis, rheumatoid arthritis etc.
- Other chronic inflammatory diseases e.g. chronic inflammatory bowel disease.
Which one of the following is a chronic inflammatory process from its start?
A. Appendicitis
B. Cholecystitis
C. Infectious mononucleosis
D. Lobar pneumonia
C. Infectious mononucleosis
What cells are involved in acute inflammation?
- Neutrophil polymorphs
Give 3 endogenous chemical mediators of acute inflammation.
Bradykinin.
Histamine.
Nitric Oxide.
Features of neutrophil polymorphs
- Short lived cells
- First on the scene of acute inflammation
- Cytoplasmic granules full of enzymes that kill bacteria
- Usually die at the scene of inflammation
- Release chemicals that attract other
inflammatory cells such as macrophages
What are 4 systemic effects of acute inflammation?
Fever.
Feeling unwell.
Weight loss.
Reactive hyperplasia of the reticuloendothelial system.
What cells are involved in chronic inflammation?
Macrophages and plasma cells (B and T lymphocytes).
Features of macrophages
- Long lived cells (weeks to months)
- Phagocytic properties
- Ingest bacteria and debris
- May carry debris away
- May present antigen to lymphocytes
What cell can form when several macrophages try to ingest the same particle?
Multinucleate giant cell.
What are some macroscopic features of chronic inflammation?
Chronic ulcer.
Chronic abscess cavity.
Granulomatous inflammation.
Fibrosis.
Features of lymphocytes
- Long lived cells (years)
- Produce chemicals which attract in other inflammatory cells
- Immunological memory for past infections and antigens
Plasma cell function and features.
- B cell antibody production
- Lots of endoplasmic reticulum to make protein.
Endothelial cells features
- Line capillary blood vessels in areas of inflammation
- Become sticky in areas of inflammation so inflammatory cells adhere to them
- Become porous to allow inflammatory cells to pass into tissues
- Grow into areas of damage to form new capillary vessels
What happens to the arterioles and capillary beds during inflammation?
In acute inflammation, the precapillary sphincters open, causing blood to flow through all capillaries. This is good in localised areas.
Define exudate.
A protein rich fluid that leaks out of vessel walls due to increased vascular permeability.
Why does inflammation lead to oedema
- Normally, fluid leaves the arteriole end and enters through the venous end.
- In acute inflammation, the sphincter is open and there is a higher pressure in the arteriole end and capillaries are more porous.
- There is a net loss of fluid together with plasma protein into the extracellular space.
- This leads to oedema
Fibroblasts features
- Long lived cells
- Produce collagenous connective tissue in scarring following some types of inflammation
What occurs during acute appendicitis? (eg of acute inflammation)
– Unknown precipitating factor
– Neutrophils appear
– Blood vessels dilate
– Inflammation of serosal surface occurs
– Pain felt
– Appendix either surgically removed or inflammation resolves or appendix bursts with generalised peritonitis and possible death
What are the 4 outcomes of inflammation?
- Resolution.
- Suppuration.
- Organisation (scar tissue formation).
- Progression onto chronic inflammation.
What occurs during tuberculosis? (eg of chronic inflammation)
– No initial acute inflammation
– Mycobacteria ingested by macrophages
– Macrophages often fail to kill the mycobacteria because of the cell wall
– Lymphocytes appear
– Macrophages appear
– Fibrosis occurs
What are granulomas?
A aggregation of epithelioid histocytes surrounded by lymphocytes
What is granulation tissue?
Granulation tissue is composed of small blood vessels in a connective tissue matrix with myofibroblasts. It is important in healing and repair.
What is a chronic granulomatous disease (CGD)?
Give 4 examples of granulomatous disease.
An inherited disorder that occurs when the white blood cells (phagocytes) do not work properly. Therefore, the phagocytes cannot protect the body from bacterial or fungal infections.
TB, leprosy, Crohn’s disease and sarcoidosis.
The activity of what enzyme in the blood can act as a marker for granulomatous disease?
Angiotensin converting enzyme.
How would you treat inflammation?
List 5 things
- Ice
- Antihistamine for insect bites: histamine drives inflammation
- Aspirin, ibuprofen: inhibits prostaglandin synthetase, prostaglandins are chemical mediators of inflammation
- Corticosteroids: inhibitors of inflammation down regulate chemical mediators of inflammation
What leads to thrombus formation in arteries ?
Endothelial cell injury -> exposing collagen -> platelets aggregate -> Turbulent flow -> fibrinogen polymerises to fibrin -> blood clot
What are the 3 factors that can lead to thrombosis formation?
- Change in vessel wall.
- Change in blood constituents.
- Change in blood flow.
Define thrombosis.
Formation of a solid mass from blood constituents in an intact vessel in the living.
Give 2 reasons why thrombosis formation is uncommon.
- Laminar flow.
- Non sticky endothelial cells.
What drug can be used to prevent Thrombosis?
Aspirin. Inhibits platelet aggregation
How is COVID-19 related to thrombosis
- COVID virus causes massive inflammation boosting cytokines
- Increases the liver’s production of clotting factors
- Leads to thrombosis.
Define embolus
Mass of material in the vascular system able to become lodged within vessel and block it.
Most commonly, thrombus
What are the consequences of an arterial embolus?
An arterial embolus can go anywhere! The consequences could be stroke, MI, gangrene etc.
What are the consequences of a venous embolus?
An embolus in the venous system will go onto the vena cava and then through the pulmonary arteries and become lodged in the lungs causing a pulmonary embolism. This means there is decreased perfusion to the lungs.
Through which blood system would an embolus have travelled if it resulted in a pulmonary embolism?
Venous system.
What are the effects of thrombosis and embolism
Can lead to ischaemia and infarction.
Define ischaemia.
Decreased blood flow.
What complication may happen if ischaemia is rectified?
Re-perfusion injury can occur due to the release of waste products.
Define infarction.
Decreased blood flow with subsequent cell death.
What are most organs in the body supplied by. What issue does this cause?
Most organs are supplied by the end arterial supply. If it blocks, can lead to infarction.
What organs have more than one supply?
The lungs (bronchial arteries and pulmonary veins), liver (hepatic arteries and portal veins), and some parts of the brain (circle of Willis).
What is the difference between resolution and repair?
Resolution
–initiating factor removed
–tissue undamaged or able to regenerate
Repair
–initiating factor still present
–tissue damaged and unable to regenerate
What prevents the liver from regenerating in patients with alcoholic liver disease?
Initiating factor not taken away (patient still drinking), leads to cirrhosis where the liver repairs instead of regenerates.
What damages occur in lobar pneumonia and severe COVID lung damage?
- Pneumocytes can regenerate, but alveolar cannot.
In lobar pneumonia the lungs can regenerate and can completely recover. In severe cases of Covid, the alveolar cannot regenerate, lungs can only repair.
What are abrasion skin wounds?
Superficial skin wounds that have only damaged the top layer of the epidermis, will heal up normally.
What happens when healing by 1st intention?
Edges by skin are closely re-approximated.
What happens when healing by 2nd intention?
Occurs in traumatic wounds when skin lost and cannot heal through edges. Blood vessels have to grow in from either side. Takes longer to heal.
Define repair.
- replacement of damaged tissue by fibrous tissue
- collagen produced by fibroblasts
List 3 examples of repair in the human body.
–heart after myocardial infarction
–brain after cerebral infarction
–spinal cord after trauma
Name 6 types of cells capable of regeneration.
- hepatocytes
- pneumocytes
- all blood cells
- gut epithelium
- skin epithelium
- osteocytes
Name 2 type of cells that don’t regenerate?
- myocardial cells
- neurones
Man aged 30 takes a large overdose paracetamol overdose and doesn’t come to hospital for 2 days. He spends a few days on ITU with liver failure but then recovers.
What will be happening in his liver - resolution or repair?
Resolution!
Only 1 overdose, and hepatocytes are capable of regeneration.
A child aged 3 falls off a climbing frame onto his hand, he fractures his clavicle. He has his arm in a sling for 4 weeks and is very good about keeping it in the sling
What will be happening in his clavicle - resolution or repair?
Resolution!
The patient is keeping the sling in and osteocytes are capable of regeneration.
A child aged 3 falls off a climbing frame onto his hand, he fractureshis clavicle. He has his arm in a sling for 4 weeks but won’t keep the sling on and moves his arm a lot
What will be happening in his clavicle - resolution or repair?
Repair!
The patient won’t keep the sling on and keeps moving his arms about. Body unable to regenerate because it becomes fibrous and only repair can occur.
Give a benefit of inflammation.
Inflammation can destroy invading micro-organisms in injuries and can prevent the spread of infection.
What do viral infections result in?
Cell death due to intracellular multiplication.
What does bacterial infection result in?
The release of exotoxins (involved in the initiation of inflammation) or endotoxins.
Define abscess.
Acute inflammation with a fibrotic wall.
Define atherosclerosis.
Inflammatory process characterised by accumulation of fibrolipid plaques in the intima of a vessel wall. It causes a huge amount of illness by reducing the blood flow in important areas.
What is the time course of atherosclerosis?
- Birth - no atherosclerosis
- Late teenage/early 20s - fatty streaks in aorta, may not progress to established atherosclerosis
- 30s/40s/50s - development of established atherosclerotic
plaques - 40s-80s - complications of atherosclerotic plaques e.g. thrombosis, intraplaque haemorrhage
What is the distribution of atherosclerosis plaques?
It is common in high pressure systems such as aorta and systemic arteries, never in pulmonary circulation.
What is in an atherosclerosis plaque?
- Lipid core.
- Necrotic debris.
- Connective tissue.
- Fibrous cap.
- Lymphocytes.
List 5 risk factors of atherosclerosis.
- Cigarette smoking
- Hypertension
- Poorly-controlled diabetes mellitus
- Hyperlipidaemia
- Lower social economic status
What secondary preventative measure can a GP introduce to a patient post myocardial infarction, known ischaemic disease or known peripheral arterial disease? List 5 examples.
- Statins 80mg (primary prevention would be 20mg)
- Aspirin 75mg
- ACE inhibitors
- Beta blockers
- Control BP with anti-hypertensives
What is the endothelial damage theory
- Endothelial cells are delicate, they require oxygen to produce lots of nitric oxide.
- If they are in any way impaired will not produce nitric oxide and die.
Describe the main stages involved in the formation of an atherosclerotic plaque
- Macrophages form foam cells from lipids in arterial wall - fatty streak formation (platelets) > intermediate lesion
- Plaque protrudes into artery lumen and disrupts laminar flow - medial thinning and platelet aggregation
- Secondary platelet plug forms fibrin mesh over itself and traps red blood cells
- Fibroblasts form smooth muscle ‘fibrous cap’ over this
- Continuous formation of secondary platelet plug, this is a stable atheroma - plaque stabilisation/( fibrous cap formation)
How does cigarette smoke cause damage to the endothelial cells
Free radicals, nicotine and carbon monoxide can damage endothelial cells.
How does hypertension damage the endothelial cells?
High blood pressure has shearing forces exerted on endothelial cells and this can lead to damage
How does poorly-controlled diabetes mellitus damage endothelial cells.
Super oxide anions present and glycosylation products both
cause oxidative stress and endothelial injury.
What does cumulative damage to the endothelium lead to?
Endothelial ulceration -> microthrombi -> eventual development of established atherosclerotic plaques
Complete block to an artery will mean no blood flow to the organ and infarction can occur.
Give 6 examples of complications of atherosclerosis?
- Cerebral infarction
- Carotid atheroma
- Myocardial infarction
- Aortic aneurysms
- Peripheral artery disease with intermittent claudication
- Gangrene
What is the anatomy of a normal artery and which part of it is important with regards to atherosclerosis?
- Intima, media and adventitia
- Intima is the most important with regards to ACS. It is formed of only a single layer of endothelium – this is involved in the immune response, releases antithrombotic molecules
to prevent clots, releases vasodilators and constrictors
Where does the left and right coronary arteries arise from?
The aortic sinuses
How can occlusion of coronary arteries be detected and treated?
Occlusion of any of the coronary arteries can be seen on ECG and via coronary angiogram. It is diagnostic and relieving treatment. Immediate treatment can be done = coronary angioplasty = balloon & stent.
Define apoptosis
Programmed cell death of a single cell.
What is the role of p53 protein?
Cells can detect DNA damage using p53 protein which can then trigger apoptosis.
What protein can switch on apoptosis if DNA damage is present?
p53 protein.
How does a cell apoptose?
The cell triggers a series of proteins which lead to the release of caspases within the cell which can turn on apoptosis.
Activation of what receptor can activate caspase and therefore apoptosis?
FAS receptor.
Give an example of a disease where there is a lack of apoptosis.
Cancer; mutations in p53 mean cell damage isn’t detected.
Give an example of a disease where there is too much apoptosis.
HIV
Define necrosis.
Unprogrammed death of a large number of cells due to an adverse event.
Give 5 examples of events that can lead to necrosis.
- Infarction due to loss of blood supply e.g. myocardial infarction, cerebral infarction
- Frostbite
- Toxic venom from reptiles and insects
- Avascular necrosis of bone
- Pancreatitis
Give 3 differences between apoptosis and necrosis.
- Apoptosis is programmed cell death whereas necrosis is unprogrammed.
- Apoptosis tends to effect only a single cell whereas necrosis effects a large number of cells.
- Apoptosis is often in response to DNA damage. Necrosis is triggered by an adverse event e.g. frost bite.
Which one of the following is not an example of apoptosis?
A. Loss of cells from tips of duodenal villi
B. Loss of cells during embryogenesis
C. Renal infarction
D. Graft versus host disease
C. Renal infarction.
Necrosis not apoptosis
How does the spinal cord form?
- Initial epithelium
- Columnar base
- Invagination
- Tube formation and closure
What are the types of spina bifida?
a congenital defect of the spine
- Spina bifida occulta
- Meningocele
- Myelomeningocele
What genes control how cells migrate and differentiate?
Homeobox genes
Define congenital.
Present at birth.
Give an example of a disease which is congenital but not genetic.
Club foot.
Why do people with Down syndrome tend to have earlier dementia?
This is because they have trisomy 21, this leads to excessive beta amyloid being produced which can clump together to form plaques between neurons.
Define polygenic inheritance.
Polygenic inheritance refers to inheritance in which the trait is produced from the cumulative effects of many genes.
Give an example of a congenital acquired disease.
Foetal alcohol syndrome.
Is dwarfism inherited?
Yes, caused by genetic inheritance leading to growth hormone deficiency.
Is gigantism inherited?
No, it’s caused by growth hormone excess from pituitary adenoma.
Define hypertrophy.
Increase in the size of a tissue due to an increase in the size of constituent cells.
Why are cows able to grow muscle despite a grass-fed diet?
Mutation in the myostatin gene
Define hyperplasia.
Increase in the size of a tissue due to an increase in the number of constituent cells.
Define atrophy.
Decrease in the size of a tissue due to a decrease in the size of the constituent cells OR due to a decrease in the number of constituent cells.
Define metaplasia.
A change in the differentiation of a cell from one fully differentiated cell type to another fully differentiated cell type.
Give an example of a disease that demonstrates metaplasia.
Barrett’s oesophagus - the cells at the lower end of the oesophagus change from stratified squamous cells to columnar.
Define dysplasia.
Morphological changes seen in cells in the progression to becoming cancer.
Dysplasia is sometimes used to refer to developmental abnormalities. Give an example of this.
Focal cortical dysplasia.
What happens to a cell when the telomere gets too short?
It can no longer divide.
What is the limit to how many times a human cell can divide called?
The Hayflick limit.
What are the effects of ageing on skin? What is the cause of it?
Dermal elastosis is caused by UV-B light causing cross-linking of the proteins, especially collagen, in the dermis.
How can osteoporosis be prevented?
Can be prevented by hormone replacement therapy at menopause and calcium/vitamin D supplements.
Give 6 examples of ageing in different body parts?
- Wrinkling of skin (dermal elastosis)
- Eyes - cataracts
- Osteoporosis
- Dementia
- Loss of muscle (sarcopaenia)
- Deafness
Why does ageing cause osteoporosis?
Lack of oestrogen post menopause leading to increased bone resorption and decreased bone formation
What are the effects of ageing on the eyes? What is the cause of it?
Cataracts - caused by UV-B cross-linking of proteins in the lens causing opacity.
How can cataracts in old age be prevented and treated?
Can be prevented by wearing sunglasses that cut out UV light.
Can be treated by replacement of the lens with a plastic implant.
Cause of sarcopenia in old age?
Reduced levels of growth hormone and testosterone, increased catabolic cytokines in later life.
How can sarcopenia be prevented?
Regular exercise including resistance/weight training
What causes deafness in old age?
The hair cells in the cochlear do not divide so if they are damaged by high volumes they will die and not be replaced eventually producing deafness.
Which one of the following is an example of atrophy?
A. Biceps of a body builder
B. Uterus in pregnancy
C. Brain in dementia
D. Prostate in older age
C. Brain in dementia
Give an example of:
a) a dividing tissue.
b) a non dividing tissue.
a) Gut or skin tissue can divide.
b) Brain tissue is non dividing.
Why can excision be used as a cure for basal cell carcinoma?
Because BCC only invades locally and doesn’t metastasise.
Define carcinoma.
Malignant epithelial neoplasm
Why can’t excision be used as a cure for leukemia?
Leukemia is systemic, it circulates and always spreads all around the body, therefore excision can’t be used.
Suggest a treatment that could be used for leukemia?
Chemotherapy
Where can the majority of breast carcinomas spread to?
Breast cancers can spread to the lymph nodes that drain the site of the carcinoma.
Which 5 carcinomas commonly spread to bone?
- Breast
- Kidney
- Lung
- Prostate
- Thyroid
PORTABLE
PO=prostate, R=renal, TA=thyroid, B=breast, LE=lung
How would you plan for treatment of breast cancer?
- Confirm diagnosis of breast cancer. (eg core biopsy needle)
- Confirm whether it has spread to the axilla to decide whether axillary node clearance is needed. (eg ultrasound of the axilla)
- Confirm whether its has spread to the rest of the body. (eg bone scan)
- If cancer has spread to rest of body, systemic therapy needed. If not, then surgery with, or without axillary lymph node clearance can take place.
Even if a tumour is completely excised, what complications may there be? What can be used to treat these patients?
Micro metastases could be present.
Adjuvant therapy (extra treatment given after surgical excision) can be used to suppress secondary tumour formation.
What common treatment is given to patients who have undergone lumpectomy?
Radiotherapy to the breast.
What secondary treatment is given to breast cancer patients who test oestrogen receptor positive?
adjuvant anti-oestrogen therapy
What secondary treatment is given to breast cancer patients who test positive for amplified HER2 gene?
Herceptin (Trastuzumab)
Define carcinogenesis.
The transformation of normal cells to neoplastic cells through permanent genetic alterations or mutations.
What does oncogenesis cause?
Cause the development of benign and malignant tumours
What is the difference between carcinogenic and oncogenic?
carcinogenic = cancer causing
oncogenic = tumour causing
What percentage of cancer risk is due to environmental factors? What problems does this have?
85% of cancer risk is environmental
Rest are chance, genetics, micro-organisms
Problems:
- latent interval may last decades
- complexity of environment
- ethical constraints
Chemical carcinogens: what types of cancer do polycyclic aromatic hydrocarbons cause?
Skin cancer and lung cancer.
Chemical carcinogens: what types of cancer does Beta-Naphthylamine cause?
Bladder cancer.
Chemical carcinogens: what can expose people to polycyclic aromatic hydrocarbons?
Smoking cigarettes and mineral oils.
Chemical carcinogens: what types of cancer do aromatic amines cause?
Bladder cancer
Chemical carcinogens: what types of people are more susceptible to bladder cancer caused by aromatic amine exposure?
People who work in the rubber/dye industry.
Chemical carcinogens: what types of cancer do nitrosamines cause?
Gut cancer
Chemical carcinogens: what types of cancer do alkylating agents cause?
Leukaemia; the risk is small in humans.
Chemical carcinogens: what types of cancer does radioactive iodine cause?
Thyroid cancer (seen during Chernobyl)
Name the 5 different classes of carcinogens.
- Viral.
- Chemical.
- Ionising and non-ionising radiation.
- Hormones, parasites and mycotoxins.
- Miscellaneous e.g. asbestos and metals.
List 4 features of chemical carcinogens.
- No common structural features
- Some act directly
- Most requires metabolic conversion from procarcinogens to ultimate carcinogens
- Enzyme required may be ubiquitous or confined to certain organs
What percentage of all cancers are made up by viruses?
10-15% of all cancers are caused by viruses. Most oncogenic viral infections don’t results in cancer.
Name 5 viral DNA carcinogens and the cancer they cause.
- Human Herpes Virus 8 (HHV8) - Kaposi sarcoma
- Epstein Barr Virus (EBV) - Burkitt lymphoma, Nasopharyngeal carcinoma
- Hepatitis B Virus (HBV) - Hepatocellular carcinoma
- Human papillomavirus (HPV) - Squamous cell carcinomas of the cervix, penis, anus, head and neck
- Merkle cell polyomavirus (MCV) - Merkle cell carcinoma
Name 2 viral RNA carcinogens and the cancer they cause
- Human T-lymphotrophic virus (HTLV-1) - Adult T-cell leukemia
- Hepatitis C Virus (HCV) - Hepatocellular carcinoma
Features of radiant energy carcinogens.
- Ionising radiation
- Long term effect
- Skin cancer in radiographers
- Lung cancer in uranium miners (radon gas)
-Thyroid cancer in Ukrainian children
What biological agents cause cancer?
- Hormones such as oestrogen (mammary/endometrial cancer) and anabolic steroids (hepatocellular carcinoma)
- Mycotoxins such as aflatoxin B1 (hepatocellular carcinoma)
- Parasites such as Chlonorchis sinensis (cholangiocarcinoma) and Shistosoma (bladder cancer)
Give 5 host factors that can affect cancer risk.
- Ethnicity.
- Diet.
- Constitutional factors (gender, age).
- Premalignant conditions.
- Transplacental exposure.
Host factors - premalignant conditions. Name 3 identifiable local abnormalities which are associated with increased risk of malignancy at that site
- Colonic polyps
- Ulcerative colitis
- Cervical Dysplasia (CIN)
Give an example of a situation when transplacental exposure lead to an increase in cancer risk.
The daughters of mothers who had taken diethylstilboestrol for morning sickness had an increased risk of vaginal cancer.
A 72 year old man from Singapore has smoked for all his adult life, placing the lit end of his cigarettes in his mouth. ‘Reverse smoking’ increases the risk of developing which cancer?
Oral cancer
A 42 year old woman has recently returned from Uganda. She continued her hobby of fresh water swimming during her trip. She now complains of an itchy rash and a fever. Her doctor suspects she may have schistosomiasis. Left untreated, this parasitic infection increases the risk of which cancer?
Bladder cancer
A 51 year old woman with HIV presents to her doctor with multiple purple bruise-like lesions on the skin of her face, torso and limbs. A biopsy confirms the diagnosis of Kaposi sarcoma. Which virus causes Kaposi sarcoma?
Human Herpes Virus 8 (HHV8)
A 27 year old man is worried about his alcohol consumption and seeks advice about the effect it might have on his health. Which cancer can be caused by excess alcohol consumption?
Colon cancer
A 32 year old man is admitted to hospital with abdominal pain. The pain is in his right iliac fossa. A scan is performed and his appendix is removed by laparoscopic surgery. The appendix is sent for histopathology examination. What is the predominant cell that the pathologist sees on microscopic examination?
Neutrophil polymorphs
Pathologist finds a white area of scarring in the myocardium and takes a sample for histology. What is the predominant cell the pathologist will see in the white area?
Fibroblasts
What is carcinoma in situ?
When the carcinoma hasn’t reached the basement membrane, thus it can’t enter the lymphatic system or blood vessels and cannot spread.
What do you call carcinoma that has reached the basement membrane?
Invasive carcinoma
What is micro-invasive carcinoma?
Carcinoma that has invaded through the basement membrane, but only by a little. Potentially, it could spread through the body, but the risk of it spreading is extremely low.
What properties help the carcinoma invade the basement membrane? (intravasation)
- proteases - matrix metalloproteases
- cell motility
How does the invasive carcinoma metastasise?
- Tumour invades basement membrane and stroma
- Tumour has to enter system (ie lymphatic vessels, venules, transcoeleomic, arteries though unlikely)
- Tumour cells have to resist immune response in the lymphatic fluid or venous blood as the lymphocytes and macrophages would act against it
- Tumour cells have to exit and invade the extracellular matrix and start growing
What is required for a tumour to exit the blood stream (extravasation)?
- Adhesion receptors.
- Collagenases.
- Cell motility.
Give 2 promoters of tumour angiogenesis.
- Vascular endothelial growth factors.
- Fibroblast growth factors.
Give 3 inhibitors of tumour angiogenesis.
- Angiostatin.
- Endostatin.
- Vasculostatin.
What 3 mechanisms do tumour cells use to evade host immune defence?
- Aggregation with platelets
- Shedding of surface antigens
- Adhesion to other tumour cells
What kind of drugs can be used in targeted chemotherapy?
Monoclonal antibodies (MAB) and small molecular inhibitors (SMI).
MAB can be used to treat constitutive activation of receptors.
SMI can be used to treat overexpression of receptors.
Give an example of a malignant tumour that often spreads to the lung.
Sarcoma (via venae cava -> heart -> pulmonary arteries).
Give an example of carcinomas that can spread to the liver.
Colon, stomach, pancreas, carcinoid tumours of intestine can spread to the liver via the portal vein.
What are the common cancers to metastasise to the bone?
PORTABLE
Po – Prostate
R – Renal
Ta – Thyroid
B – Breast
Le – Lung
Conventional chemotherapy: how does vinblastine work?
In order for cells to divide cells have to replicate. Binds to the microtubules and prevents them working.
Conventional chemotherapy: how does etoposide work?
In order for cells to divide cells have to replicate. Etoposide inhibits topoisomerase II
Conventional chemotherapy: how does ifosamide work?
Ifosamide binds directly to DNA
inhibits DNA synthesis by cross linking
Conventional chemotherapy: how does cisplatin work?
Cisplatin binds directly to DNA and inhibits DNA synthesis by cross linking
Give an advantage and a disadvantage of conventional chemotherapy.
Advantage: works well for treatment against fast dividing tumours e.g. lymphomas.
Disadvantage: it is non selective for tumour cells, normal cells are hit too; this results in bad side effects such as diarrhoea and hair loss.
What type of tumours are conventional chemotherapy good for? List 5 examples
Fast dividing tumours
- germ cell tumours of testis
– acute leukaemias
– lymphomas
– embryonal paediatric tumours
– choriocarcinoma
What type of tumour is conventional chemotherapy not good for?
Slow dividing tumours - some tumour cells increase by mitigating apoptosis.
What is the histogenetic classification of neoplasms?
Histopathological tests specify tumour type by determining the cell of origin of a tumour.
Name two genetic drivers of carcinogenesis?
- Proto-oncogenes: genes that promote cell growth and survival
- Tumour suppressor genes: genes which inhibit cell growth and proliferation
How would you diagnose bronchial carcinoma (small and non small)?
- Sputum
- Radiology-guided biopsy
- Bronchoscopy
What is tumour grading and staging?
Tumour grading:
How much the tumour cells resemble their normal counterparts
Tumour staging:
How much the tumour has spread. Involves assessment of lymph nodes, extent of spread to other organs and tissues.
What is the name of a malignant tumour of straited muscle?
rhabdomyosarcoma
What term describes a cancer that has not invaded through the basement membrane?
Carcinoma in situ
What is the name of a benign tumour of glandular epithelium?
Adenoma
What is the name of a benign tumour of fat cells?
lipoma
What is the name of a malignant tumour of glandular epithelium?
adenocarcinoma
True or False: Ovarian cancer commonly spreads in the peritoneum.
True
A 27 year old woman presents to the Accident and Emergency Department with abdominal pain. She says that it started the day before when she felt non-specifically unwell and felt pain in the middle of her abdomen. She slept rather fitfully and woke up this morning with a more severe pain that had moved to her right groin region. A diagnosis of acute appendicitis is made and her appendix is removed during a laparoscopic operation. The appendix is sent to the Department of Histopathology where it is sampled and microscopic slides are produced. The Consultant Histopathologist looks at the lumen of the appendix on a high power lens on her microscope.
What is the predominant type of inflammatory cell that she sees?
- Eosinophil
- Lymphocyte
- Macrophage
- Mast cell
- Neutrophil polymorph
Neutrophil polymorph - acute inflammation
Define neoplasm
An autonomous, abnormal, persistent new growth.
What are the 3 commonest causes of cancer death in males?
- Lung cancer
- Prostate cancer
- Bowel cancer
What are the 3 commonest causes of cancer death in women?
- Lung cancer
- Breast cancer
- Bowel cancer
What is the structure of a neoplasm?
- Neoplastic cells.
- Stroma.
Describe neoplastic cells.
- Derived from nucleated cells.
- Usually monoclonal
- Growth pattern and synthetic activity is related to the parent cell.
Describe the stroma of a neoplasm.
- Connective tissue composed of fibroblasts and collagen; it is very dense.
- There is a lot of mechanical support and blood vessels provide nutrition
What is essential for neoplasm growth?
Angiogenesis.
Why does central necrosis occur in neoplasm?
The neoplasm grows quickly and outgrows its vascular supply.
What are the two ways in which neoplasms can be classified?
- Behavioural classification.
- Histogenetic classification.
What are the 5 features of a benign neoplasms.
- non invasive, localised
- slow growth rate
- well-circumscribed or encapsulated
- low mitotic activity
- close resemblance to normal tissue
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.
List 4 histological features of benign neoplasms.
- Nuclear morphometry often normal
- Necrosis rare
- Ulceration rare
- Growth on mucosal surfaces usually exophytic
What are the 5 complications of benign neoplasms?
- Pressure on adjacent structures
- Obstruct flow
- Produce hormones
- Transform to malignant neoplasm
- Anxiety
What are the 5 features of malignant neoplasms?
- Invasive
- Metastases
- Rapid growth rate
- Variable resemblance to normal tissue
- Poorly defined or irregular border
List 5 histological features of malignant neoplasms.
- Hyperchromatic nuclei
- Pleomorphic nuclei
- Increased mitotic activity
- Necrosis and ulceration common
- Growth on mucosal surfaces and skin often endophytic
List 7 complications of malignant neoplasms?
- Destruction of adjacent tissue
- Metastases
- Blood loss from ulcers
- Obstruct flow
- Produce hormones
- Paraneoplastic effects
- Anxiety and pain
What is a papilloma?
A benign neoplasm of non-glandular non-secretory epithelium
What is an adenoma?
Benign tumour of glandular or secretory epithelium.
What are carcinomas of glandular epithelium called?
adenocarcinomas
What is a leiomyoma?
A benign smooth muscle neoplasm.
What is a neuroma?
A benign neoplasm of nerves.
What is a chondrosarcoma?
A malignant neoplasm of cartilage.
What is a liposarcoma?
A malignant neoplasm of adipose tissue.
What is a melanoma?
A malignant neoplasm of melanocytes.
What is a lymphoma?
A malignant neoplasm of lymphoid cells.
What is a mesothelioma?
A malignant neoplasm of mesothelial cells.
Carcinomas and sarcomas are further classified according to the degree of differentiation. Is a carcinoma/sarcoma with a close resemblance to normal tissue classified as well differentiated or poorly differentiated?
A carcinoma/sarcoma with a close resemblance to normal tissue is classified as well differentiated. These types of neoplasms are low grade and have a better prognosis.
What is the neoplasm called if its cell of origin is unknown?
Anaplastic
What are teratomas?
A teratoma is a rare type of neoplasm that may contain immature or fully formed tissue, including teeth, hair, bone and muscle.
A 43 year old woman is referred to a gynaecologist with a history of pain during sexual intercourse and vaginal bleeding after intercourse and in between her periods. The gynaecologist takes a biopsy of the ectocervix which reveals a primary malignant neoplasm. What is the likely diagnosis?
Squamous cell carcinoma
- As the ectocervix is lined by stratified squamous epithelium. Malignancy of stratified squamous epithelium is squamous cell carcinoma.
A 46 year old woman undergoes an elective hysterectomy to treat severe menorrhagia (heavy period). The pathologist examining the specimen reports the presence of multiple benign smooth muscle neoplasms within the myometrium. What are these neoplasms called?
Leiomyomas
A 72 year old man undergoes a biopsy of his colon. The biopsy reveals a disease process that is not neoplastic or due to an infection. What is the likely abnormality?
Granuloma (chronic inflammation)
What are the 7 hallmarks of cancer?
- Growth self-sufficiency
- Evade apoptosis
- Ignore anti-proliferative signals
- Limitless replication potential
- Sustained angiogenesis
- Invade tissues
- Escape immune surveillance
What is cancer immunosurveillance?
When the immune system recognises and destroys transformed cells, this is an important host protection process.
What is cancer immunoediting?
Immune responses can change tumours to be hidden from recognition by the immune system and tumours can promote immune suppression
What are the two types of tumour antigens and where are they found?
- Tumour specific antigens
- Only found on tumour cells.
- As a result of point mutations or gene rearrangement
- Derive from viral antigens - Tumour associated antigens
- Found on both normal and tumour cells, but are overexpressed on cancer cells
- Developmental antigens which become derepressed. (CEA)
- Differentiation antigens are tissue specific
- Altered modification of a protein could be an antigen
List 5 evidence for human tumour immunity
- Spontaneous regression
- Regression of metastases after removal of primary tumour
- Infiltration of tumours by lymphocytes and macrophages
- Lymphocyte proliferation in draining lymph nodes
- Higher incidence of cancer after immunosuppression, immunodeficiency (AIDS, neonates), aging, etc.
What is tumour escape?
Immune responses change tumours such that tumours will no longer be seen by the immune system.
What is immune evasion?
Tumours change the immune responses by promoting immune suppressor cells
How can we kill tumours without killing normal cells?
To induce an immune response against the tumour that would discriminate between the tumour and normal cells: Adaptive immunity
What are the two types of immunotherapy?
- Active immunotherapy
- Passive immunotherapy -
List 6 examples of active immunotherapy.
Vaccines!
- Killed tumour vaccine
- Purified tumour antigens
- Professional APC-based vaccines
- Cytokine- and costimulator-enhanced vaccines
- DNA vaccines
- Viral vectors
List 2 examples of passive cancer immunotherapy.
- Adoptive Cellular Therapy (T cells)
- Anti-tumour Antibodies (Her-2/Neu, CD20, CD10, CEA, CA-125, GD3 ganglioside)
Features of cell-based therapy.
- Cellular therapies can be used to activate a patient’s immune system to attack cancer.
- They can also be used as delivery vehicle to target therapeutic genes to attack the tumour
- They do not act directly on cancer cells. Instead, they work systemically to activate the body’s immune system.
What 2 cell types are commonly used for cell-based therapy?
- Dendritic cells
- T cells
Features of dendritic cells.
- Antigen presenting cells
- Found throughout the body (0.1-0.5%)
- Interstitial cells (Liver, heart, liver), Langerhans cells of the epidermis.
- Detect and chew up foreign “invader” proteins and then “present” piece of the invaders on their surface.
How would you create a dendritic cell cancer vaccine?
To make a DC vaccine, the blood of the cancer patient is collected and enriched to increase the population of DC.
How would you create a T cell cancer vaccine?
eg for melanoma
- Tumour biopsy
- Isolation: tumour fragments and tumor infiltrated lymphocytes (TILs) are isolated
- Cultivation: TILs propagated on tumour fragments and cultivated
- Expansion: expansion of melanoma reactive TILs
- T cell infusion
What is tumour hypoxia?
Hypoxia is a prominent feature of malignant tumours. The inability of the blood supply to keep up with growing tumour cells can lead to hypoxic tumour cells that have adapted to low oxygen
What are the problems with tumour hypoxia?
Tumour hypoxia usually means poor patient prognosis.
- Stimulates new vessel growth
- Suppresses immune system
- Resistant to radio- and chemotherapy (repopulate the tumour)
- Increased tumour hypoxia after therapy
Why is hypoxia a prominent feature of a lot of malignant tumours?
Malignant tumours grow rapidly and so outgrow their blood supply
What are the 3 types of vaccines traditionally used?
- whole-killed
- toxoid
- live attenuated
Define passive immunisation.
The administration of pre-formed “immunity” from one person or animal to another person
Limitation of passive immunisation.
Only humoral (antibody) mediated
(will not work if cell mediated!)
What are the advantages and disadvantages of passive immunity
Advantages
- Gives immediate protection
- Effective in immunocompromised patients
Disadvantages
- Short-lived
- Possible transfer of pathogens
- “Serum sickness” on transfer of animal sera
Give 4 examples of passive immunisation
Specific Immunoglobulin (Ig)
- Human Tetanus Ig (HTIG) Rapid protection of exposed individuals
- Human Rabies Specific Ig - Used after exposure to rabies to give protection until vaccine becomes effective
- Human Hepatitis B Ig (HBIG)
- Varicella Zoster Ig (VZIG)
What are the 3 main approaches to making a vaccine for active immunisation?
- Using a whole virus or bacterium
- Using parts that trigger the immune system
- Using just the genetic material
List 3 features of the whole microbe vaccine
- Bacteria or viruses grown in vitro and inactivated using agents such as formaldehyde or Β-propionolactone.
- Non-living vaccines do not cause infection, but the antigens contained in it induce an immune response that protects against infection – by non-self antigen recognition.
- Non-living vaccines can also be cell-free toxoids - inactivated toxins
List 4 problems and limitations of whole killed vaccines.
- The organisms must be grown to high titre in vitro (viruses and some bacteria difficult/expensive to grow in the lab)
- Whole pathogens can cause excessive reactogenicity (i.e., adverse reactions, excessive immunological responses)
- Immune responses are not always close to the normal response to infection, e.g., no mucosal immunity, no CD8 Tc responses
- Usually need at least 2 shots
Gives examples of bacteria that have been used in active vaccine.
- Diphtheria - formaldehyde treated toxin - rendered a non-toxic “toxoid”
- Tetanus - toxoid, causes muscle contractions/spasms - treat purified toxoid in the lab with formalin leading to loss of toxicity but NOT epitopes
- Pertussis (whooping cough) - killed whole bacteria (Bordetella pertussis) given with the two above as DTP. 3-doses. UK has now moved to acellular pertussis (aP)
- Cholera - heat-killed bacteria (Vibrio cholerae)
Give examples of viruses that have been used in active vaccine.
Polio vaccine (Salk) - inactivated virus-IPV
Influenza vaccine - inactivated virus
Hepatitis A vaccine - inactivated virus
Rabies vaccine - inactivated virus
SARS-Co-V2 (Valneva) - inactivated virus
How do Live Attenuated Vaccines work?
The organisms replicate within the host and induce an immune response which is protective against the wild-type organism but does not cause disease.
Define attenuation.
Where an organism is cultured in such a way that it does not cause disease when inoculated into humans.
It has lost its pathogenicity but retains its antigenicity – (i.e., shape).
List 4 advantages of Live Attenuated Vaccines.
- Immune response more closely mimics that following real infection because its not fixed – no shape change.
- Better immune response so lower doses are required, so the scale of in vitro growth needed is lower.
- Route of administration may be more favourable (oral).
- Fewer doses may be required to provide protection.
Problems and limitations of live attenuated vaccines.
- Often impossible to balance attenuation and immunogenicity
- Reversion to virulence
- Transmissibility
- Live vaccines may not be so attenuated in immunocompromised hosts
Give 2 examples of live attenuated bacterial vaccines.
Bacille Calmette-Guérin (BCG) Mycobacterium bovis grown over many passages in vitro. Gives some protection against TB (tuberculosis)
Salmonella typhi - temperature sensitive strain given orally.
Give 3 examples of viral live attenuated vaccines.
Poliomyelitis (Sabin) - widely used to bring polio to the brink of eradication
Vaccinia virus - used in billions of doses to eradicate smallpox due to cross-reactivity between itself and the variola virus
Measles, Mumps and Rubella - 3 given together as MMR
In this day and age, why do so many pathogens still do not have a vaccine? List 4 possible reasons.
- Pathogen too difficult to grow
- Killed pathogen not protective (shape change)
- Impossible to obtain attenuated and suitably immunogenic strain
- Too many strains causing disease etc.
Recombinant proteins are a novel approach in creating vaccines. How are they created?
Genetically engineered and produced from bacteria, yeast, insect or mammalian cells
What are the advantages and disadvantages of recombinant protein vaccines
Advantages:
Avoid the problem of having to grow pathogen in vitro
Disadvantages:
Major difficulties are finding a protein or proteins that are protective and generate a strong enough immune response
Give examples of recombinant proteins
Hepatitis B Surface Antigen
HPV vaccines Cervarix and Gardasil (HPV16 and 18)
SARS-Co-V2 – Novavax (recombinant spike protein produced by moth cells in culture, these are purified, assembled into a synthetic nanoparticle for injection – 14 spike proteins per particle)
What are synthetic peptides
Peptides synthesized directly using a machine - avoids the need for pathogen growth
Problems with synthetic peptides.
Difficulties
- Identifying protective epitopes
- Inducing a strong response
- Inducing a broad response
What are live attenuated vectors – viral vector
Composed of a safe living attenuated viruses that have inserted genes encoding foreign antigens, which are displayed to the immune system.
How do viral vectors work?
When injected the virus is taken up by an APC, the viral DNA is released and enters the nucleus. The viral DNA is transcribed to mRNA and translated to a protein – some of this spike protein is presented with MHC II on the cell surface as a foreign antigen. This is recognised by T-cells and initiates an immune response to the spike protein.
The virus is replication deficient and can not replicate in human cells limiting its spread.
What are DNA vaccines?
A mammalian plasmid containing DNA that encodes for the foreign protein of interest is injected directly.
This requires a lipid nanocarrier to get the DNA into a human cell. The DNA goes to the nucleus, gets transcribed and the foreign protein expressed with MHC to stimulate the immune response.
Advantages and disadvantages of DNA vaccines.
- Avoid the need to grow the pathogen, viral vector
- No live organism involved
- DNA is cheap to produce
- Problem is often poor immunogenicity
What are mRNA vaccines
mRNA of the target foreign protein is synthesized in vitro. It is complexed with lipid nanoparticles that stabalise and protect the mRNA from degradation and allow the mRNA to cross the plasma membrane.
The mRNA is translated in the cytoplasm and the protein presented on the surface of the cell with MHC
Stimulating the immune response.
Advantages of mRNA vaccines
- Avoid the need to grow the pathogen, viral vector
- No live organism involved
- mRNA is relatively cheap to produce
- Quick to make new variations of vaccine
Features of T-Independent Antigens
Bacterial capsular polysaccharides cannot be processed and presented on MHC class II
No T cell help
Antibody response of low magnitude
Low affinity
Predominantly IgM
Little or no boosting on secondary exposure
Infants respond especially poorly and are major target group for these vaccines
Haemophilus influenzae
Neisseria meningitidis
Streptococcus pneumoniae
Examples of conjugate vaccines.
Neisseria meningitidis type C
polysaccharide-protein conjugate vaccine
Streptococcus pneumoniae
23-valent polysaccharide vaccine or 7-valent conjugate
Haemophilus influenzae type B (HiB)-Polysaccharide protein conjugate vaccine
What are recent changes to the vaccination programme in children?
The addition of a pneumococcal conjugate vaccine (PCV) at 2, 4 and 13 months of age;
A dose of MenC vaccine at 3 and 4 months;
A booster dose of Hib and MenC vaccine (given as a combined Hib/MenC vaccine) at 12 months of age.
HPV vaccine for teenage girls and boys soon
BCG no longer routinely given to teenagers. Targeted on at risk infants.
Why do people not trust vaccines?
Misinformation and hearsay on the internet/social media that are not based on any science
Religion – its un-natural
Studies linking immunisation with contraction of other diseases/conditions
Japan – HPV vaccine with neurological disorders
UK – MMR and autism
Describe innate immunity
- 1st line of defence
- Instinctive
- Non-specific does not depend on lymphocytes
- Present from birth
- Slow response
- No memory
- Provides barrier to antigen
Describe adaptive immunity.
Specific ‘Acquired/learned’ immunity, requires lymphocytes, antibodies.
Response specific to antigen
Learnt behaviour
Memory to specific antigen
Quicker response
What are both innate and adaptive immunity made up of?
Cells and soluble factors (humoral)
What is haematopoiesis?
The commitment and differentiation processes that leads to the formation of all blood cells from pluripotent haematopoietic stem cells.
Where does haematopoiesis take place?
Bone marrow (10^11 new cells each day)
How do the pluripotent haematopoietic stem cells decide what to differentiate into?
Stem cells in the bone marrow are stimulated by colony stimulating factors (soluble proteins) that bind to receptors on the stem cell.
What 2 are the two pathways the pluripotent haematopoietic stem cells can split into?
- Myeloid pathway
- Lymphoid pathway
Which 3 types of cells are polymorphonuclear leukocytes?
- Neutrophils (70% of wbcs in body)
- Eosinophils
- Basophils
Which 3 types of cells are mononuclear leukocytes?
- Monocytes: differentiates into macrophages when entering tissue.
- T-cells
- B-cells: differentiates into plasma cells which produce antibodies.
What process are mast cells important in?
Allergic reactions - have histamines
What are natural killer cells important for? (Type of T cell)
Anti tumour responses
What are dendritic cells important for?
Immune surveillance
Which 3 soluble factors make up the immune system?
- Complement
- Antibodies
- Cytokines and chemokines
Define complement.
Group of ~20 serum proteins secreted by the liver that need to be activated to be functional.
What are the 3 modes of actions of complement?
- Direct lysis
- Attract more leukocytes to site of infection
- Coat invading organisms
What are antibodies?
Antibodies (also called immunoglobulins) are soluble glycoproteins that recognize and bind antigens, specifically.
Antibodies (Ab) can also be called immunoglobulins (Ig) What are the 3 features of immunoglobulins?
- soluble
- secreted
- bound to B cells as part of B-cell antigen receptor
What are the 5 distinctive classes of Ig?
IgG (IgG1-4)
IgA (IgA1 & 2)
IgM
IgD
IgE
Describe the basic structure of an antibody (IgG).
Antibodies have a basic structure of four polypeptide chains – two identical light chains and two identical heavy chains. Each chain contains a variable region (fab region).
The chains are held together by disulphide bonds.
The C-terminal (Fc) regions of the light and heavy chains form the constant regions which determine the effector functions of an antibody.
In an antibody what does the Fc region and Fab region bind to?
Fc region binds to receptors on the surface of wbcs.
Fab region bind to non-self elements, they are very specific.
Which is the most predominant Ig in the human serum?
IgG: accounts for 70 - 75% of Igs in human serum
List 5 features of IgM.
- Accounts for 10% of Igs in serum.
- Pentamer, formation requires J chain.
- Mainly found in blood – too big to cross endothelium.
- Mainly primary immune response, initial contact with Ag.
(First responder during immune response) - The monomeric form (mIgM) is present as an antigen-specific receptor on B cells - which is important for the adaptive immune response.
List 3 features of IgA
- Accounts for 15% of Igs in serum
- In humans 80% of serum IgA is as a monomer (in most animals serum IgA is a dimer)
- The predominant Ig in mucous secretions such as saliva, colostrum, milk, bronchiolar & genitourinary secretions
Called Secretory IgA (sIgA)
sIgA is held together with a J chain and a secretory component
List 2 features of IgD.
Accounts for 1% of Ig in serum
A transmembrane monomeric form (mIgD) is present on mature B cells
List 5 features of IgE
Accounts for only ~0.05% of Ig in serum
Basophils and Mast Cells express an IgE-specific receptor that has high affinity for IgE
Basophils and Mast Cells are continually saturated with IgE
Binding Ag triggers release of histamine by these cells
Associated with hypersensitivity allergic response and defence against parasitic infections
What is an epitope?
Each antibody binds to a restricted part of the antigen called an epitope.
What are the functions of an antibody?
Antibodies acts as an adaptor that links a microbe to a phagocyte.
1. Neutralise toxins.
2. Opsonisation.
3. Activate classical complement system.
What are cytokines?
Proteins secreted by immune and non-immune cells.
Name 4 types of cytokines.
- Interferons.
- Interleukins.
- Colony stimulating factors.
- Tumour necrosis factors.
Cytokines: Function of interferons (IFN)
Induce a state of antiviral resistance in uninfected cells & limit the spread of viral infection
Cytokines: Function of interleukins (IL)
- Can be pro-inflammatory (IL1) or anti-inflammatory (IL-10)
- Can cause cells to divide, to differentiate and to secrete factors
- Produced by many cells, over 30 types
Cytokines: Function of Colony Stimulating Factors (CSF)
- Involved in directing the division and differentiation on bone marrow stem cells – precursors of leukocytes.
Cytokines: Function of Tumour Necrosis Factors (TNFa & b)
Proinflammatory molecules. Mediate inflammation and cytotoxic reactions.
What are chemokines?
Chemotactic cytokines
Group of approx 40 proteins that attract leukocytes to sites of infection from the bloodstream into the tissues or lymph organs by binding to specific receptors on cells
What are the 4 subclasses of chemokines?
CXCL – mainly bind to neutrophils
CCL – monocytes, lymphocytes, eosinophils, basophils
CX3CL – mainly T lymphocytes & NK Cells
XCL – mainly T lymphocytes
What is innate immunity composed of?
- Physical and chemical barriers
- Phagocytic cells (neutrophils and macrophages)
- Blood proteins (complement, acute phase)
Give examples of physical and chemical barriers used in innate immunity?
- Lysozymes in tears
- Skin
- Low pH and commensals of vagina
- Mucociliary escalator
- Gastric acid
Sometimes physical barriers are breached leading to tissue damage (trauma) or infection. This will induce an inflammatory response. What response is the body aiming for during inflammation?
- Coagulation: stop bleeding.
- Acute inflammation (leukocyte recruitment).
- Kill pathogens, neutralise toxins, limit pathogen spread.
- Phagocytosis: clear pathogens/dead cells.
- Proliferation of cells to repair damage.
- Remove blood clot – remodel extracellular matrix to maintain homeostasis.
What are the 3 hallmarks of inflammation?
- Increased blood supply
- Increased vascular permeability
- Increased leukocyte transendothelial migration ‘extravasation’
Name 3 pattern recognition receptors (PRR) that can sense microbes?
- Toll-like receptors (TLR).
- Lectin receptors.
- Scavenger receptors.
What kind of immunity are PRR’s and PAMP’s associated with?
Innate immunity.
What are PRR’s a receptor for?
PAMP’s (on microbes)
What happens when a PAMP binds to a PRR?
The innate immune response and inflammatory response is triggered.
What are C-Type lectin receptors?
Expressed by Macrophages and DC, can recognise foreign carbohydrates.
What are scavenger receptors?
They are a very large family of receptors - They mainly recognise foreign lipids on bacteria. (ie LPS in Gram -ve bacteria)
What are toll-like receptors?
TLRs recognise Pathogen-Associated Molecular Patterns expressed by microbes. Different TLRs activate different signalling cascades depending on the pathogen being detected.
TLRs and their targets
TLR2: Gram positive bacteria and mycobacteria (inc fungi)
TLR4: Gram negative bacteria and lipopolysaccharides
TLR5: Bacteria and flagellin
TLR7: Single-strand RNA
TLR9: Non-methylated DNA
What are the 3 different activation pathways that make up the complement system? How are they activated?
- Classical: Antibody bound to microbe.
- Lectin: Mannose binding lectin bound to microbe.
- Alternative: Complement bound to microbe.
Which complement plasma proteins are chemoattractants that recruit leukocytes to the site of infection.
C3a and C5a.
Which complement plasma proteins have opsonic properties (insert itself into the membrane of bacterium “coating it” to increase its susceptibility to ingestion by phagocytosis) when bound to a pathogen?
C3b, C4b.
Which complement plasma proteins make up the membrane attack complex (MAC) and are responsible for the cytolytic function?
C5b-9
What is extravasation?
Leukocyte (WBC) migration across the endothelium.
What do macrophages at the tissues secrete to initiate extravasation?
TNF alpha.
Describe the process of extravasation.
- Macrophages at tissues release TNF alpha.
- The endothelium is stimulated to express adhesion molecules and to stimulate chemokines.
- Neutrophils bind to adhesion molecules; they roll, slow down and become stuck to the endothelium.
- Neutrophils are activated by chemokines.
- Neutrophils transmigrate through the endothelium to the tissue to help fight infection.
