ICS Flashcards
What are the main cells involved in acute and chronic inflammation?
Also, give examples of acute and chronic inflammations (broadly)
Acute inflammation - infections, hypersensitivity
Main cells involved - neutrophils
Chronic inflammation - Autoimmune diseases, recurrent infections
Main cells involved - macrophages (may present antigen to lymphocytes for long lived immunity) and lymphocytes
Endothelial cells and fibroblasts also involved.
What is the function of fibroblasts in inflammation?
They form collagen in areas of chronic inflammation and help with repair
How is damaged tissue repaired? E.g heart after MI
Damaged tissue is replaced by fibrous tissue e.g. collagen - produced by fibroblasts
e.g. heart after MI
Brain after cerebral infarction
Spinal cord after trauma
What are the 5 cardinal signs of inflammation? And what are their causes?
Rubor - Redness (vasodilation of arteries/capillaries near the site of injury)
Dolor - Pain (caused by chemical mediators of inflammation e.g. histamine)
Calor - Heat (vasodilation –> increased blood flow –> heat)
Tumor - Swelling (leakage of plasma fluids –> oedema)
Loss of function (generally caused by swelling and pain)
What are the stages of inflammation?
1) Increased vessel permeability –> (blood vessels adjacent to the injury first dilate, blood flow increases. The endothelial cells contract to increase the space between them, thus increasing permeability of the vascular barrier)
2) Fluid exudate –> Fluid leaks out from the vascular space into the interstitial space resulting in oedema (tumour)
3) Cellular exudate –> The increased fluid acts as a medium for inflammatory proteins to migrate through. Whole cells (RBC, WBC) leave the vessel as well. (e.g neutrophils leave to go to the site of injury)
What is the main cell involved in acute inflammation and what are the 3 stages of migration?
What happens at the site of inflammation?
- Neutrophils
1) Margination - Neutrophils line up against the endothelium
2) Adhesion- Selectins (produced by endothelium) bind to the neutrophils causing them to ROLL along the margin (slowing down)
3) Emigration - Neutrophils interact with CD31 molecules and chemokines, becomes static and move through the wall to the affected area up the chemokine concentration gradient(DIAPEDESIS - movement of leukocytes from the blood vessel to sites of tissue damage) - form of cellular exudate
(Migration of neutrophils to the site of inflammation stimulated by chemokines)
At the site
1) Neutrophils begin phagocytosis
2) Formation of a phagolysosome –> bacteria killing
3) Macrophages clear the debris (and pathogens)
Neutrophils usually die at the site of infection after performing their job. may be cleared by macrophages.
What are the possible outcomes following acute inflammation?
Check with lectures
1) Complete resolution - Total repair (back to normal) - RESOLUTION
2) Abscess formation - Localised collection of PUS (neutrophils) surrounded by granulation tissue - this will over time, be replaced by scar tissue- (SUPPORATION)
3) Fibrosis and scar fomation - Occurs in cases of significant inflammation - (ORGANISATION) e.g. liver cirrhosis
4) Chronic inflammation - from a persistent insult/cause (Progression)
What are granulomas?
(what combines to form them in chronic inflammatin)
They are aggregates of epitheloid histiocytes (clusters of immune cells)- that form in response to the presence of foreign substances (in chronic inflammation, macrophages and lymphocytes can combine to form a granuloma)
What diseases would you see granulomas in?
What would be a blood marker?
Tuberculosis - where central necrosis is present
Leprosy - caesation necrosis
Sarcoidosis, vasculitis, crohn’s disease - where central necrosis is not present
ACE would be a blood marker for Sarcoidosis, crohn’s disease, tuberculosis and other granulomatous diseases
What is a thrombus?
A solid mass of blood constituents formed in an intact vessel in a living person. (blood clot)
What is an embolism?
A mass of material travelling in the vascular system which becomes lodged within vessel and blocks it.
What is venous thromboembolism (VTE)
A condition that occurs when a blood clot forms in the vein. It encompasses Deep vein thrombosis and pulmonary embolism (DVT can lead to PE) - clot from DVT, typically starting in the leg, lodges in the pulmonary arteries.
What is a venous thrombosis and what can it be caused by?
How is it treated?
If not treated, what can it lead to?
A condition that occurs when a blood clot forms in the vein. (usually leg)
Caused by:
- Venous stasis (DVT)
- Disease or injury to veins in the leg
- A fracture
- Autoimmune disorders that make it more likely for your blood to clot
- Medicines that increase your risk of clotting.
Treated with anticoagulants (warfarin) (you would also administer low dose subcutaneous heparin and have early mobilisation after operation)
Can lead to a PE if not treated
What is an arterial thrombosis and what can it be caused by?
How is it treated?
If not treated, what can it lead to?
A condition that occurs when a blood clot forms in the artery.
Caused by:
- Atherogenesis (process of plaque buildup)
- Atherosclerosis - arteries become narrowed by plaque buildup
Treated with antiplatelets (aspirin)
If occurs in coronary arteries - MI
If occurs in a blood vessel in the brain - Stroke (Ischemic stroke)
What is ischemia and infarction?
The inadequate supply of blood to an area due to the blockage of the blood vessels supplying the area.
- Reduction in blood flow (e.g. TiA)
Infarction
- A reduction in blood flow with subsequent death of cells. (e.g. ischemic stroke)
How are arterial and venous thrombosis treated? Why are they treated differently?
Venous thrombosis treated with anticoagulants. (Warfarin)
- In a venous thrombosis when there is stasis, the level of coagulation factors and thrombin is high – thrombin breaks down fibrinogen into fibrin –> fibrin traps red blood cells.
Anticoagulants target the coagulation cascade, they inhibit the formation and growth of the (fibrin) clot, reducing risk of embolisation.
Arterial thrombosis treated with antiplatelets. (Aspirin)
- Arterial thrombosis are platelet rich clots which develop at sites of artherosclerotic plaques (as fatty deposits damage the endothelial lining. Antiplatelets are taken to inhibit platelet aggregation and activation.
(Essentially tailored to the type of clot, fibrin rich clot or platelet rich clot)
What are the possible fates of thrombi (clots)?
Resolution –> The clot degrades and results in normal physiological outcome
Organisation –> Leaves scar tissue
Embolism –> Fragments of thrombi break off and lodge in distal circulation
What/Where are the most common arterial and venous thrombus and resulting emboli?
Not sure if the most COMMON but should know this?
Arterial emboli
–> Lodges in the systemic circulation (from left heart)
E.g. Due to irregular heart rhythm in Atrial fibrillation, sluggish blood flow can lead to the formation of clots –> Atrial fibrillation thrombi. –> Part of the clot can break loose and lodge in the carotid artery leading to ischemic stroke
Venous emboli
–> Lodges in the pulmonary circulation (from right heart)
e.g. DVT thrombus lodges in the pulmonary artery leading to a PE.
Differences between an arterial and venous ulcer
Location
Arterial- usually on the tips of toes and lateral malleolus of ankle
Venous - usually on the medial malleolus and inner calf
Exudate
Arterial - punched out hole (deeper) with little exudate
Venous - less demarcated punched out hole appearance (shallower) with a lot of exudate
Colour
Arterial - pale cool skin (or yellowish-grey base)
Venous - Reddish base
Skin changes
Arterial - hair loss, thickened toenails, weak distal pulse of affected limb
Venous - Varicose veins, itchy skin, eczematous (stasis dermatitis)
What is virchow’s triad and what are its components?
The formation of a thrombus is dependent on any one of Virchow’s triad being present
1) Abnormal blood flow (stasis/decreased blood flow) - due to e.g. periods of immobility (long flights/being bed bound) –> Most common caused of DVT
2) Abnormal blood components (Hypercoagulability - excessively easy clotting of blood) –> alterations in the constitution of blood caused by smoking, sepsis (reaction to an infection), malignancy/cancer – can be due to genetics also - Gene mutations like in essential thrombocythemia (high number of platelets in blood)
3) Abnormal blood vessel wall (Endothelial injury) –> can be from NICOTINE (smoke), atheroma formation (Fatty substance build up in arteries), inflammatory response, surgery, direct trauma, etc.
atheroma = plaque
What are some risk factors of developing a venous thromboembolism?
Need to check with lecture notes
Obesity,
hormone replacement therapy, increasing age
injury/trauma
Smoking
Prolonged immobilisation
What is atherosclerosis?
- The accumulation of fibrolipid plaques in systemic arteries. It narrows the arteries, reducing blood flow to important areas and thus cause illness e.g. MI of the heart
Take note: not really found in low pressure systems (pulmonary arteries). common in high pressure systems (aorta/systemic arteries)
What are plaques that build up in arteries composed of?
Lipid, smooth muscle, macrophages + foam cells (macrophages that ingest LDLs), platelets, calcium, fibroblasts, T lymphocytes
Lipid, necrotic core, connective tissue, fibrous cap.
Describe the formation of an atherosclerosis
Look into lectures about smooth muscle cap.
1) Fatty streak –> Precursor turns into plaque (late teenage/early 20s) (consists of lipid laden macrophages and T lymphocytes within the INTIMAL layer of the vessel wall)
2) Lipid accumulation –> Endothelial damage initiates an INFLAMMATORY response. This results in monocytes and macrophages being recruited to phagocytose LDLs to become foam cells, which contribute to plaque formation.
3) Platelet aggregation (due to damage of endothelial lining) –> Accumulated lipids lead to plaque protruding into the artery lumen, causing platelet aggregation
4) Smooth muscle cells contribute to the formation of the fibrous cap over the plaque by releasing fibroblast growth factor producing collagen and elastin. (stabilising the plaque - stable atheroma)
atheroma=plaque
What is a risk in an advanced stage of atherosclerosis?
- Unstable atheroma (plaque)
The fibrous cap covering the plaque may weaken or rupture. If it ruptures, exposing the plaque’s contents, it will trigger platelet activation which leads to platelet aggregation at the site of the plaque disruption –> leading to the formation of clots within the arterial lumen –> impedes blood flow –> can lead to acute cardiovascular events (MI, stroke)
What are some risk factors for atherosclerosis?
Smoking, diabetes, hypertension, obesity, hyperlipidemia increased age, males
(Also risk factors for MI)
Briefly what is the pathogenesis of atherosclerosis?
ENDOTHELIAL DAMAGE THEORY
Endothelial cells are delicate and can be damaged by cigarette smoke (free radicals released), shearing forces at arterial divisions, hyperlipidemia (lipids taken up by macrophages, forming foam cells which lead to plaque forming) and glycosylation products
(Where blood flow is turbulent or low at arterial branch points, that area is more susceptible to plaque buildup)
What are the complications of atherosclerosis when there is single and dual arterial supply?
If an atherosclerotic plaque completely blocks an artery (which can be due to a rupturing of the plaque leading to the formation of a thrombus), then no blood will flow to the organ supplied by that artery and unless there is second arterial supply e.g. the brain, the organ will infarct (die).
Name a few possible complications of atherosclerosis
- Cerebral infarction
- Myocardial infarction
- Emboli (when pieces of the atherosclerotic plaque break off and travel downstream to smaller vessels) –> can cause transient ischemic attacks or cerebral infarcts if in the carotid artery (carotid atheroma)
- Aortic aneurysm (if atherosclerosis occurs in the aorta, it can weaken the wall of the aorta causing it to be less elastic and causing turbulent blood flow.
- Gangrene (lack of blood flow and lack of oxygen to extremities can lead to necrosis)- body tissue dies (usually starts in the toes)
- Intermitted claudication (muscle pain due to lack of oxygen)
State 4-5 differences been apoptosis and necrosis
for point 4 need to check with lectures
Apoptosis –> Non inflammatory, programmed cell death
Necrosis –> Inflammatory, traumatic cell death (due to injury, disease initiated, etc)
Apoptosis –> Cell membrane remains intact
Necrosis –> Disrupted cell membrane (loss of membrane integrity)
Apoptosis –> Cell shrinks (nucleus condenses)
Necrosis –> Cell swells (and bursts)
Apoptosis –> Chromoatin is unaltered. Pyknosis (condensation of chromatin) and Karyorrhexis (fragmentation of the nucleus)
Necrosis –> Chromatin is altered - degrades and fragments(could mutate). Pyknosis, karyorrhexis and karyolysis occurs (dissolution of cytoplasm)
Apoptosis –> Energy dependent process (and therefore controlled)
Necrosis –> Energy independent
How does a cell apoptose?
The cell triggers a series of proteins which lead to the release of enzymes like caspases which autodigest the cell.
Cascade of activated enzymes.
What is polygenic inheritance?
The inheritance of a trait (e.g. height, skin colour) influenced by more than one gene.
How does a cell decide to apoptose?
Why does this not work in cancer cells?
What happens in HIV?
- Via the amount of DNA damage within the cell. p53 is a protein that can detect DNA damage and can then trigger apoptosis.
- In cancer cells, there is a mutation of the p53 protein so it can no longer detect DNA damage and induce apoptosis.
- In HIV, the HIV virus can induce apoptosis in CD4 helper cells which reduce their numbers, resulting in an immunodeficient state.
What kind of DNA damage results in apoptosis of cells?
- Single stranded break
- Double stranded break
- Base alteration
- Cross linkage
(other forms of damage to cellular systems –> accumulation of toxic by-products of metabolism, telomere shortening, damage to mitochondrial DNA, free radical generation)
Name 3 specific types of ageing in parts of the body
Wrinkling of the skin (dermal elastosis) - caused by UV-B light (component of sunlight) cross linking proteins, especially collagen in the dermis - can be reduced by avoiding too much sun exposure/using sun screen.
Cataracts of the eye - caused by UB-B cross-linking proteins in the lens causing opacity. - Prevented by wearing sunglasses that cut out UV light.
Osteoporosis in post menopausal women - loss of bone matrix is due to a significant decline in estrogen levels which help maintain bone density (increased bone resorption, decreased bone formation). - prevented by hormone replacement therapy and vitamin D supplements.
Deafness - Hair cells in the cochlear do not divide. If they are damaged by high volumes, they will die and not be replaced, thus producing deadness. - Prevented by avoiding high volume sounds throughout life.
What is caseous necrosis?
A distinct form of necrosis recognised by its cheese-like crumbly appearance. It is associated with granulomatous infections like tuberculosis - tissues cellular material breakdown (stain for mycobacteria).
What are the 3 apoptosis pathways (mechanisms)?
Intrinsic, extrinsic and cytotoxic
Describe the apoptosis intrinsic pathway.
Occurs due to internal stimuli (DNA damage, biochemical stress, lack of growth factors)
- Pathway modulated by the molecules Bcl-2 (inhibits Bax) and Bax (promotes cytochrome C release)
- Cytochrome C activates caspases - the executioners of apoptosis
Describe the apoptosis extrinsic pathway
Occurs due to external stimuli
- Ligands bind to receptors on the cell surface
Tumour necrosis factor receptor (TNFR) binds to TNF ligand. FAS receptor binds to FAS ligand –> these interactions activate caspases for apoptosis.
Describe the apoptosis cytotoxic pathway
Cytotoxic T cells release granzyme B and perforin which activate caspases for apoptosis. (perforin creates pores or channels in the target’s cell membrane for granzyme B to enter the cell and activate caspases)
Definition of hypertrophy
Give examples
Hypertrophy –> Increase in size of an organ caused by an increase in the size of its constituent cells (without an increase in number)
(occurs in organs where cells cannot divide)
Examples –> skeletal muscle in athletes/body builders
Definition of hyperplasia
(What is mixed hypertrophy/hyperplasia)?
Examples
Hyperplasia –> Increase in size of an organ caused by an increase in the number of its constituent cells(via mitotic replication)
occurs in organs where cells can divide.
e.g. benign prostatic hyperplasia, endometrial hyperplasia (irregular thickening of uterine lining)
Take note - mixed hypertrophy/hyperplasia - is an increase in the size of an organ due to increases in the size and number of its constituent cells (e.g. smooth muscle cells of the uterus during pregnancy)
Definition of metaplasia and dysplasia
Metaplasia - The change in cell differentiation from one fully differentiated type to another fully differentiated type
e.g. Barrett’s oesophagus (squamous to glandular/columnar), bronchial epithelium from ciliated columnar to squamous epithelium due to continuous cigarette smoke
(Usually due to a consistent change in the environment of an epithelial surface)
Dysplasia - basically ABNORMAL GROWTH/DEVELOPMENT OF CELLS - morphological changes that may be seen in cells in the progression on to development of cancer (dysplastic cells are considered pre cancerous)
Metaplasia –> dysplasia –> carcinoma in situ (pre-invasive stage of cancer development - has not breached membrane) –> invasive carcinoma (malignant, it has the potential to invade and damage surrounding tissues)
What is a common pathway with chronic inflammation?
Chronic inflammation –> metaplasia –> dysplasia –> carcinoma in situ (hasn’t breached membrane) -> invasive carcinoma
Definition of atrophy
Examples
- A decrease in the size of an organ due to a decrease in the size or number of its constituent cells via dying(or both)
Main thing is a decrease in the size of an organ/tissue
Example - Alzheimer’s dementia (cortex becomes smaller), quadriceps muscle following knee injuries or immobilisation
What does it mean to have a congenital, inherited or acquired disorder?
Congenital - present at birth
Inherited - caused by an inherited genetic abnormality
Acquired - caused by non-genetic environmental factors
What is the hayflick limit and why is it a thing?
Hayflick limit - The limit to which a human cell can divide.
There is a limit because at each cell division, the telomere region at the end of chromosomes shortens and eventually becomes so short that it is not possible for chromosomes to divide and replicate. (telomere length appears to be paternally inherited)
Definition of carcinogenesis and neoplasm
Carcinogenesis –> The transformation of normal cells into neoplastic cells (cancer cell) through permanent mutation leading to uncontrolled/abnormal growth (possibly into a tumour subsequently)
Neoplasm –> The Autonomous, abnormal, persistent new growth of cells
What does the structure of a neoplasm consist of?
Neoplastic cells + stroma.
(Cancer cell)
A type of nucleated cell that has undergone genetic mutations that lead to uncontrolled or abnormal growth. These cells divide and proliferate in an unregulated manner forming a mass of of cells - Tumour. They are monoclonal. (growth pattern and synthetic activity are related to parent cell)
A vascular stroma which provide mechanical support and nutrition for the neoplastic cell grows based on growth factors released by the neoplastic cell. (a connective tissue framework)
(They arise from NUCLEATED cells)
What are the characteristics of a neoplastic cell?
Autocrine growth stimulation - due to overexpression of growth hormone and mutation of tumour suppression genes. - very fast growth
They can evade apoptosis
They have telomerase - Prevents telomere shortening with each replication
Sustained angiogenesis - They have their own blood supply
Difference between benign and malignant tumour (behavioural classification of neoplams- benign, borderline, malignant)
Benign - localised and non invasive - (no basement membrane invasion)
Malignant - metastases and invasive - basement membrane invading
Benign - Slow growing due to low mitotic activity
Malignant - Fast growing due to high mitotic activity (hyperdense nucleus)
Benign - Well circumscribed (or encapsulated) (restricted)
Malignant - Poor circumscription (or encapsulation) (poorly defined or irregular border of the neoplasm)
Benign - Exophytic - grows upward and outward from surface epithelium
Malignant - Endophytic - grows inward from surface epithelium
Benign - Rare ulceration (breach in mucosal surface) and necrosis
Malignant- Common ulceration and necrosis
Benign - Nuclear shape often normal
Malignant - Hyperchromatic and pleomorphic nuclei (can take different shapes)
What are the 3 main histogenesis (need microscope) classes of tumours? - Describe them slightly
Carcinomas- Epithelial tumours. Cancer that starts in cells that make up the skin or tissue lining organs.
Sarcomas - Mesenchymal tumours.
Cancer of soft tissues, connective tissue or bone (invade the LUNGS commonly)
Lymphoid - Cancer of the lymph system or blood cells (lymphoma and leukemia)
lymphoma - malignant neoplasm of lymphoid cells.
(melanoma, mesothelioma –> malignant neoplasms)
What are tumours called when they are non/glandular benign/malignant?
They are Epithelial tumours
Papilloma - non glandular benign
Carcinoma - non glandular malignant
Adenoma - glandular benign
Adenocarcinoma - glandular malignant
What are sarcomas? Give examples
Cancer of soft tissue, connective tissue or bone - MESENCHYMAL tumours
Lipoma and liposarcoma - adipocytes
Rhabdomyoma (benign) and rhabdomyosarcoma (malignant)- striated muscle
Leiomyoma and leiomyosarcoma - smooth muscle
Chrondroma and chondrosarcoma - cartilage
Osteoma and osteosarcoma - bone
Angioma - Vascular/blood vessels
Neuroma - Nerves
What are lymphoid tumours - give examples
Cancer of the lymph system or blood cells
Leukemia and lymphoma (always malignant) –> Blood disease
Describe melanoma and mesothelioma
Melanoma - melanocyte malignancy (skin cancer)
Mesothelioma - Cancer of the mesothelium, typically pleura of the lungs (associated with ASBESTOS - microscopic particles that can be inhaled - long term exposure can cause cancer)
Both malignant
How are tumours graded?(in terms of differentiation to parent cell)
They are graded based on their similarity to the parent cell
1) Well differentiated (>75% cells resemble the parent)
2) 10-75%
3) Poorly differentiated (<10% cells resemble parent)
State some classes of carcinogens
- agents capable of causing cancer
1) Chemicals - e.g. paints, dues, rubber, soot. (most require metabolic conversion from pro-carcinogen to ultimate carcinogens)
2) Viruses - e.g. HPV (cervical cancer), EBV (burkitt lymphoma) - causes 10-15% of cancer
3) Ionising + non-ionising radiation - UVB (or UVA) (skin cancer) - basal cell carcinoma, squamous cell carcinoma (increased risk of xeroderma pigmentosum)
4) Hormones, parasites, mycotoxins - mycotoxins can be found in food/fungi/mold (aflatoxin - hepatocellular carcinoma)
5) Abestos (fibrous minerals that are microscopic and can be inhaled)
What are the 3 main methods of tumour spread?
1) Haematogenous - Via the bloodstream –> common in cancers that spread to the bones, lungs and liver - breast cancer. prostate cancer
(Carcinomas spread to the bone via blood)
2) Lymphatic –> spread via the lymphatic vessels - they travel in lymphatic fluid to lymph nodes –> seen in breast cancer, melanoma
(carcinomas spread to the lymph nodes that drain the site of the carcinoma)
3) Transcolemic –> Cancer cells spread within body cavities (e.g pleural, peritoneal) - via exudative fluid accumulation (pleural, peritoneal, pericardial effusions)
- they form tumour deposits on the surface of organs and tissues –> ovarian cancer (peritoneal cavity)
A direct metastases is the spread of cancer cells from a primary tumour to nearby tissues of organs. (This is without travelling through the bloodstream or lymphatic system)
What are the 5 main metastasis to bone? (Cancers that commonly spread to bone)
BLT.KP
Breast, lung, thyroid, kidney, prostate
Which path of metastases do sarcomas and carcinomas mostly spread through?
Sarcomas - haematogenous
Carcinomas - lymphatic (exceptions- follicular thyroid, RCC, HCC)
What do the stages of a cancer describe? (TNM)
Tumour grading - How differentiated the tumour cell is. - well differentiated resembles its original counterpart. (well differentiated tumours have a better prognosis as they tend to grow and spread more slowly)
Tumour staging - How much the tumour has spread (TNM system)
T - size and extent of invasion of the main tumour
N - number of nearby lymph nodes that are involved (have cancer) - extent of lymph node metastases
M - whether the cancer has metastasised - extent of spread to other parts of the body
Which is the exception of histogenesis tumour class that is not measured via the TNM system?
Which system is used to describe the severity of it?
Lymphomas –> uses Ann Arbour Staging system (stages 1-4 and A or B)
A - asymptomatic, B - presence of B symptoms
1-4 (extent of disease and degree of metastases)
TNM more for solid tumours
What are 2 specific mutations involved in colorectal cancer?
- FAP (familial adenomatous polyposis) –> mutated APC (adenomatous polyposis coli) gene, can result in thousands and millions of colorectal adenomas forming - benign polyps that have potential to become cancerous
- HNPCC (lynch syndrome) –> mutated MSH2 gene (DNA mismatch repair gene)
Both autosomal dominant
What layer of prevention is screening?
What kind of cancers are being screened in the UK and what is the method?
What is the Heel prick test used for and when is it done?
Secondary prevention - method of early detection which makes management easy
- Cancers screen include: Breast (mammogram), Cervical (cervical swab), Colorectal (Fecal occult)
- Heel prick test done at birth is to test for sickle cell anaemia, cystic fibrosis, hypothyroidism, etc.
Draw the multipotential hematopoietic stem cell pathway (hemocytoblast)
refer to phase 2a ics document
What are dendritic cells and what is their origination?
Dendritic cell - Antigen presenting cells that initiate the adaptive immune response.
They are mesenchymal in origin and not hematopoietic.
Which cells are responsible for innate immunity, parasites, allergy and active immunity?
Innate immunity - Neutrophils (short lived 2-3 days) and macrophages (long lived months to years)
Parasites - Eosinophil
Allergy - Basophil
Adaptive immunity - T cells and B cells (plasma cells)
What are primary and secondary lymphoid organs (name some examples)?
Primary –> Where immune cells originate, mature or develop
- Bone marrow (all cells originate here including T cells) - B cells mature here
- Thymus - development and maturation of T cells (thymic tolerance)
Secondary –> Where immune responses are initiated and coordinated
- Lymph nodes - antigen presenting cells and T/B cell interactions –> filters lymphatic fluid allowing immune cells to encounter and respond to antigens
- Spleen - RBC recycling, bacteria killing - it has lymphocytes and macrophages which can respond to infections
What is thymic tolerance and where does it occur?
A critical process that occurs in the thymus where T cells are developed to recognise and respond to foreign antigens while remaining tolerant to the body’s own tissues thus preventing autoimmune reactions. (T cell selection)
Positive selection - If the T cells recognise the thymus Major histocompatibility complexes (MHCs 1 and 2), then they are selected for
Negative selection - If the T cells produce an immune response (by recognising self antigens as foreign, they are selected against.)
What are tertiary lymphoid organs?
This is pathological and only found in sites of chronic inflammation
They are specialised collections of immune cells that form in response to chronic inflammation or infection.
They sustain immune responses - allowing the continual combating of chronic inflammation
There are germinal centres within, where lymphocytes undergo rapid proliferation (differentiation and antibody productioin)
How are CD8+ and CD4+ cells allocated for and what are their functions?
T cells that interact with MHC 1 become CD8+ cells (Cytotoxic T cells) INTRINSIC
–> They function to kill
T cells that interact with MHC 2 become CD4+ cells (Helper T cells)
EXTRINSIC
–> They promote the immune response
Elaborated more in a different flash card
What is the function of CD8+ cells?
Cytotoxic T cells –> involved in eliminating target cells
1) They secrete perforin which creates pores in the target cell’s membrane, allowing Granzyme B to enter and induce apoptosis.
2) They express the Fas ligand which bind to Fas receptors on the cell’s surface, activating caspases which are the main executioners of apoptosis.
What is the function of CD4+ cells?
T regulatory cells
(T cells that interact with MHC 2)Helper T cells –> Promotes immune response
cytokines - signalling molecules
1) T helper 1 cells secrete the cytokine Interferon-y, which activates natural killer cells and macrophages (increases innate immune response)
2) T helper 2 cells secrete the cytokine interleukin 4 (5 and 10), which activates B cells to differentiate into plasma cells (increases adaptive immune response) - they also activate eosinophils and induce b cells to make IgE to promote release of inflammatory mediatory - important in helminth (parasitic) infections and allergies.
-
They also help with development of cytotoxic T cells
3) T regulatory cells also referred to as CD4+ cells
- Suppress immune responses (helps with preventing autoimmunity)
What is a naive T cell?
A T cell that has not encountered an antigen or has not matured
Describe the innate immune system
1) Non specific and rapid immune response with no memory involved
2) Neutrophils and macrophages are primarily involved
3) Killing occurs via the complement system: Activation of inflammation, opsonization of pathogens, phagocytosis and killing of target cells, by lysis
4) Includes physical barriers like the skin, mucus and cillia
and chemical barriers like lysozyme in tears and stomach acid, saliva.
Describe the 5 main immunoglobulins
IgG
- The most abundant
- Key in SECONDARY immune response
- Found in bacterial and viral infections
IgA
- Secreted in breast milk and mucosa
- Defends mucosal surfaces
- Forms dimer (effective in defending mucosal surface)
IgM
- The first antibody produced in response to foreign pathogens
- Forms pentamer
IgE
- Antibody that is produced in response to allergies (type 1 hypersenstivity)
IgD
- Unknown function but presumably B cell activation
Describe neutrophil, macrophage, eosinophil, basophil and natural killer cells.
Neutrophil
- 70% of all WBCs
- Key mediators of acute inflammation
- Act in hours - days
- They express CD 66 which allows neutrophils to adhere to blood vessel walls and migrate to sites of infection.
Macrophage
- Clear apoptotic debris
- Act in months - years –> can be circulating or resident (e.g. kupffer cells, alveolar macrophages)
Eosinophil
- Contain major basic protein
- Often seen in parasitic infection
Basophil/mast cells (resident version of basophil)
- Induces type 1 hypersensitivity reaction (allergy)
- Via IgE binding –> degranulation –> histamine release (promotes inflammation)
Natural killer cells
- Key role in viral cell killing via secretion of perforin
What are the 2 scenarios that can happen when dendritic cells present foreign antigens to helper T cells?
- Stimulation of helper T cell proliferation
- Stimulation of B cell production and differentiation to form antibodies
3 differences between innate and adaptive immunity
Innate - non specific, rapid response with no memory
Adaptive- specific, slow response with memory involved
Innate - Neutrophils and macrophages primarily involved
Adaptive - T cells and B cells are primarily involved
Innate - Killing via complement system
Adaptive - Killing is antibody mediated
Type 1 hypersensitivity
Anaphylaxis
- IgE mediated
IgE binds to basophils and mast cells –> upon re-exposure, degranulation of mast cells –> release of histamine which causes vasodilation, bronchoconstriction and increased permeability of vascular endothelium
(urticaria, angio-oedema)
Timing - Immediate (within an hour)
Causes an inflammatory response
Example - Atopy (genetic tendency to develop allergic disease), hayfever, asthma, eczema
Occurs when an individual is sensitised to a specific allergen and upon re-exposure of the allergen, IgE antibodies are produced which trigger the release of histamine
Type 2 hypersensitivity
(Antibody involved, process, timing, examples)
Antigen-antibody complex
Antibody - IgM, IgG
Cytotoxic response
Antibody binds to the antigen (e.g. drug that is combines with a protein) –> antibodies activate the complement system. Degranulation of neutrophils (and release of their antimicrobial contents) –> oxygen radicals are released (respiratory burst) leading to the destruction of the cell.
Timing - hours to days
Examples - Good pastures syndrome, pernicious anemia, rheumatic fever
Basically –> categorised by the binding of IgM or IgG to antigens on the surface of target cells. It triggers an immune response that results in the destruction of the cell via the complement system
Type 3 hypersensitivity (Antibody, process, timing, examples)
Immune complex formation
Antibody - IgG
Difference between type 2 and 3 - type 2 involves antigens that are cell bound (ABO to RBC) while type 3 involves soluble antigens
The antibody and antigen bind, move somewhere downstream and activate the complement system at the site of deposition.
Timing - 7-21 days
E.g. SLE (Systemic lupus erythematosus), farmer’s lung, malt worker’s lung
Type 4 hypersensitivity
T cell mediated
When antigens enter the body, it is processed by antigen presenting cells and presented to a Th1cell –> activating the T cell which releases chemokines to recruit macrophages and cytokines e.g. interferon-y to activate them
Timing- Days-weeks
DELAYED response
e.g. tuberculosis, type 1 diabetes mellitus, MS, guillain barre syndrome.
What are symptoms that may present with anaphylactic shock (an acute medical emergency)?
- Severe hypotension
- Tachycardia + dyspnoea
- Pale
- Cold extremities
- Puffed up face + tongue
- Itching
- Urticaria (Hives)
- Central cyanosis (lips are blue)
How would you manage a person with anaphylactic shock?
Airway - are they breathing? Are there any signs of airway obstruction? Secure the airway with intubation PRN.
Breathing - any signs of respiratory distress? Wheezing? SPO2<94%? Provide oxygen if required (salbutamol can help with wheezing)
Circulation - Check pulse and BP. Are they pale or cold? Provide an IV bolus PRN - start CPR if appropriate and needed. (IV bolus improves circulation by rapidly delivering a concentrated dose of a substance into the bloodstream)– saline solution can restore fluid balance and increase blood volume (also addresses dehydration)
Disability - Assess patients level of consciousness and mental state - lie patient flat to improve cerebral perfusion (may need to inject drugs to help e.g. epinephrine) A sitting position may help to make breathing easier
Exposure - Look for visible signs of an allergic reaction e.g. urticaria, flushing, angioedema → remove any triggers.
As soon as symptoms are recognised, administer 500mcg of IM adrenaline.
Consider antihistamine (Chlorphenamine) - not for first line but for skin symptoms,
What is immune tolerance?
A safeguard mechanism to prevent the production of autoreactive cells (where autoreactive B and T cells infiltrate and attack healthy tissues and organs - producing antibodies with high affinity for self antigens)
Split into
Central tolerance - which occurs in primary lymphoid organs. Thymus for T cells and bone marrow for B cells (where they mature)
Peripheral tolerance - occurs in secondary lymphoid organs e.g. Spleen (in the event faulty T and B cells evade central tolerance)
What is autoimmunity? What are the 2 categories?
System of immune responses of an organism against its own healthy cells, tissues, organs, etc.
It can either be organ specific or non organ specific.
What is organ specific autoimmunity?
Examples
- It affects a main organ
e.g.
1) Type 1 diabetes mellitus - affected endocrine pancreas where beta cells producing insulin are destroyed
2) Multiple sclerosis - Oligodendrocytes which myelinate cells of the CNS are attacked
3) Graves disease - Thyroid stimulating hormone receptors are stimulated (by TSH receptor antibodies) –> causing the secretion of thyroid - Hyperthyroidism.
4) Myasthenia gravis - antibodies attack acetylcholine receptors on muscle cells (neuromuscular junction) (interferes with transmission of nerve signals to muscles thus leading to muscle weakness and and fatigue)
What is non organ specific autoimmunity?
Examples
Autoimmunity having a generalised effect.
E.g. Systemic lupus erythmatosus
- The immune system attacks multiple organs and tissues.
- In SLE, individuals produce anti-DNA antibodies which forms an immune complex with DNA molecules. These circulate and deposit in various tissues and organs, triggering inflammation, leading to tissue damage. (joint inflammation, skin rashes, etc) Also affects lungs, brain, kidney, etc.
Immunodeficiency can be acquired or inherited, give examples of both.
Inherited (genetic) - Defects in T cells e.g. SCID- severe combined immunodeficiency (caused by adenosine deaminase deficiency, where infants lack the enzyme required for T-cell survival)
Acquired- HIV (Unprotected sex, sharing injection drug equipment)
What are some examples of how you may be immunodeficient? (patterns of immunodeficiency)
- In HIV, there is a decrease in helper T cells, increasing your susceptibility to diseases. (present with TB, pneumocystic pneuomonia - alveoli attacked)
- B cells can be deficient
- Neutrophil and macrophage deficiency (required for phagocytosis and acute inflammation)
- Complement deficiency - Low C3 and C4 proteins which are required for activation of the complement cascade (innate immune killing of bacteria) –> Associated with systemic lupus erythmatosus
- Hyposplenism - Lack of function of the spleen - less RBC cycling, less killing of encapsulated bacteria
What are covid 19 vaccines (pfizer and moderna) made of?
mRNA
What are the differences between active and passive immunity?
Active
- our own immune system produces immunoglobulins to protect us against a pathogen
- Immunological memory - memory cells produced for long term protection
- Secondary response (upon re-exposure to pathogen)
Passive - The administration of PRE-FORMED immunity from one person or animal to another person
- Immunoglobulin passed to host (only antibody mediated, not cell mediated)
- No memory
- Primary response - immediate and temporary effect
- Short lived
What are examples of active natural, passive natural, active artifical and passive artificial immunity?
Active natural - Body encounters pathogen and produces memory cells against it (after the infection)
Passive natural - Maternal antibodies/immunoglobulins are passed onto feeding baby in breast milk
Active artificial - Vaccine mimics encountering pathogen and stimulates immunoglobulin production
Passive artificial - Antivenom (injection of immunoglobulin from another organism)
What are the methods of drug administration?
Enteral (via the GI tract)
1) Oral - mouth
2) Suppositories - via the rectum
Paranteral (bypasses the GI tract)
3) Injection
- Intramuscular - injected directly into muscle
- Subcutaneous - drug injected directly under the skin
- Intravenous - injected directly into bloodstream
4) Inhalation - vapour
5) Skin patches/topical - transdermal
6) Eye/ear drops
What are the 4 main drug targets?
1) Receptors (Majority)
2) Enzymes
3) Transporters
4) Ion channels
Where drugs target receptors, the ligands can either be agonists or antagonists. What is the difference in terms of affinity and efficacy with the receptor?
What is the most common type of receptor?
Agonists - full affinity (binds well to receptor) and full efficacy (fully activates the receptor)
Antagonists - full affinity and zero efficacy (inactivates the receptor)
(Can competitively or non competitively inhibit receptors)
(irreversible antagonist – won’t come off the receptor and will never become available for an agonist)
Most common receptors are G-protein coupled receptors.
What is the definition of efficacy and potency?
Efficacy- The maximum effect a drug can produce, regardless of dose (the ability of a drug receptor complex to produce a maximum functional response)
Potency - How much of a drug is needed to elicit a response in the body
How is potency and efficacy of a drug/agonist affected by a competitive and non competitive antagonist?
Competitive –> Potency is decreased, efficacy is not. Ligand concentration is rate limiting.
Thus, an increase in agonist concentration can overcome this.
Non competitive –> Both potency and efficacy is decreased. Ligand concentration is not rate limiting.
Examples of non-selective/selective beta blocker/agonist.
Non-selective beta blocker –> binds to all beta receptors (B1 and B2) - Propanolol
Selective beta blocker –> binds to a specific beta receptor (B1) - Atenolol, bisoprolol
Non-selective beta agonist –> B1, B2 - Epinerphrine, isoprenaline (so efficacy and potency for B2 and B1 will be similar)
Selective beta agonist (B2) - Salbutamol (Efficacy is similar but potency for B2 receptors is higher then B1)
Describe the function of COX1 and ACE Inhibitors. And what kind of drugs target them.
COX-1 - Important function in producing prostaglandins which protect the stomach lining. (it is also important in blood clotting pathways - production of thromboxane A2)
NSAIDS - inhibit COX-1 and COX-2, decreasing prostaglandins production.
Inhibiting COX-1–> decreased prostaglandins–>decreasing gastric mucosal protection, decreasing stomach pH resulting in gastric ulcers (and risk gastrointestinal bleeds). Inhibiting COX-2 –> Decreased prostaglandins –> has an anti-inflammatory effect
(basically both COX-1 and 2 are responsible for producing prostaglandins but for different things)
ACE inhibitors – inhibit the conversion of angiotensin 1 to angiotensin 2 –> results in an antihypertensive response, reduced aldosterone, hyperkalemia (as principal cells no longer secrete as much potassium)
How are transporters targeted by drugs?(which pumps/channels do they act on)
Proton pump inhibitors e.g omeprazole –> irreversibly inhibits H+ K+ ATPase pumps (decreasing gastric pH)
Diuretics (reduces fluid buildup by promoting the excretion of NaCl and water)
- Loop diuretics act on the symporter in the ascending loop of henle to inhibit the reabsorption of sodium, chloride and potassium (NKCC2) e.g. furosemide
- Thiazide diuretics inhibit the sodium chloride cotransporter in the DCT (increasing excretion of sodium and potassium)
Spironolactone diuretics - Aldosterone receptor antagonist. A potassium sparing diuretic which acts on ENaC channels of the collecting duct, causing the excretion of sodium and water.
What are some ion channels targeted by drugs?
Calcium channel blockers (muscle + glial cells)- cause vasodilation and decreased contractility. It slows the heart rate - amlodipine.
Local anaesthesia - e.g. Lidocaine blocks Na+ voltage gated channels in nerve cells, preventing the propagation of nerve impulses.
Potassium channel blockers - e.g. Repaglinide, nateglinide lower blood glucose levels by blocking potassium channels to stimulate insulin secretion. –> Type 2 diabetes treatment
