BMS106 Pathobiology - Gokhale and Sahal Flashcards
What are the two ways in which cells can die?
Necrosis and apoptosis
When does necrosis occur?
Due to physical trauma (e.g. cuts and burns or extreme temperatures - frostbite) or toxins such as snake venom or bacterial toxins internally. Or acute hypoxia or ischaemia (restricted blood supply to certain tissues) e.g. stroke
When does apoptosis occur?
Physiological situations:
- Tissue size maintenance
- Developmental cell loss
- senescence
- removal of immune cells
Pathological situations:
- DNA damage, e.g. due to radiation or oxidative stress
- Virally infected cells
What are the characteristics of reversible necrosis?
Membrane integrity compromised
Organelle and cell swelling
What are the characteristics of irreversible necrosis?
Increased intracellular calcium Autolysis (destruction of tissue by own enzymes) Cell bursting (lysis) Inflammatory response
What are characteristics of apoptosis?
- Cell shrinkage
- Nuclear breakdown
- Apoptotic bodies
- Phagocytosis
- No inflammatory response
- Requires energy
Why might apoptosis occur at the edge of necrotising tissues?
To restrict spread of cell death
How does apoptosis occur in young frogs?
A surge in thyroid hormone in the blood initiates tail apoptosis in tail cells during metamorphosis
What are neuronal connections refined by?
Survival factors. Not enough survival factor = apoptosis
What are ced genes involved in?
Apoptosis. From recognition of apoptotic signals to the engulfment of apoptotic cells by phagocytes. They can be pro-apoptotic or anti-apoptotic
What are caspases?
Executioners of cell death. C = cysteine at active site asp = aspartic acids - cleavage site in target proteins irreversible pathway 10+ ced3 homologues
What are the 2 types of caspases?
Initiator - activated by apoptotic signals and activate executioner caspases - 1 initiator can activate multiple executioner caspases (amplifying proteolytic cascade)
Executioner - Cleave >1000 proteins
What are 3 main targets of caspases?
Nuclear lamina (cause breakdown of nuclear structure) Prevent DNA repair by cleaving DNA repair enzyme PARP. Cause cytoskeletal changes, e.g. breakdown of actin
What are the two main pathways of apoptosis initiation?
Intrinsic and extrinsic
Describe the extrinsic apoptosis pathway
Indirectly activate initiator caspases. 6 related receptors (the death receptors). Tumour necrosis factor family.
Caspase-8 = initiator caspase
Triggered by DEATH LIGANDS
Describe the intrinsic apoptosis pathway
Triggered by stress signals, such as DNA damage, and development signals.
Caspase-9 = initiator caspase.
Cytochrome c release by mitochondria
In intrinsic apoptosis, what decides whether cytochrome c or other intermembrane mitochondrial proteins are released?
The balance between pro- and anti-apoptotic factors known as Bcl2 family proteins.
Ced9 is anti-apoptic
EGL-1 is pro-apoptotic
When an where was the first case of HIV?
1981 Los Angeles - 30 yr old homosexual man had PCP (rare lung infection) - within 5 months 5 cases documented - flood of similar reports across USA
+ cluster of cases of rare and unusually agressive Kaposi’s sarcoma (a cancer)
By end of 1981 270 reported cases of sever immunodeficiency among homosexual men
Where is HIV most prevalent?
East and Southern Africa, the western and central Africa.
Dramatic increase in Russia in recent years (60% increased)
What is the HIV prevalence in Swaziland?
27%
How is HIV transmitted?
Blood and blood products Vaginal mucus and secretions Semen Any body fluid mixed with infected blood Sometimes breast milk
Is there an asymptomatic period of HIV?
Yes - person will feel and look completely healthy - can last up to 15 years
What are some symptoms of AIDS?
Lip warts Shingles Kaposi's sarcoma PCP Thrush Severe weight loss
What does AIDS stand for?
Acquired Immunodeficiency Syndrome
What does HIV stand for?
Human Immunodeficiency Virus
What is ART?
Anti-Retroviral therapy.
Controls viral replication, allows immune system to recover, allows individuals with HIV to live healthy and productive lives - doesn’t cure HIV infection - controls spread of HIV
How many classes of anti-retroviral drugs are used to prevent the formation of HIV DNA?
3 - integrase inhibitors prevent HIV DNA integration into host DNA - protease inhibitors prevent new viruses being formed
Which cells can be used to give an indication of the immune system’s health?
CD4 cells - HIV uses CD4 as a place to multiply and damages their normal function in immunity
What are CD4 cells normally used for?
Binding of macrophages to helper T cells - stabilises antigen presentation to T-h cell. HIV uses CD4 to invade T-helper cells
What do most strains of HIV need to enter helper T cells? How can this be altered to prevent HIV binding?
Co-receptor called CCR5. ∆32 mutation prevents HIV binding
Where is there a greater frequency of the CCR5-∆32 mutation?
European populations
What does vaccination aim to do?
Protect from infectious disease by producing riskless immunity and immunological memory - very specific to a single antigen
What are the two types of immunity?
Passive and active
What is active immunity?
Protection is provided by the person’s own immune system and takes days or weeks to develop, but is usually permanent. It can be natural or acquired
What is passive immunity?
Protection is transferred from one human or animal to another by the transfer of an antibody (IgG)
- provides immediate but short term protection (weeks to months).
It can be natural or acquired
What are the four formulations of vaccinations providing active immunity?
- Live attenuated pathogens
- Killed micro-organisms
- Microbial extract conjugates (antigens)
- Toxoids
What is the first eradicated disease? When was the last wild case?
Smallpox
Eradicated in 1977 (somalia)
Why was eradicating smallpox so successful?
No animal reservoir (as in ebola, swine flu etc.)
Subclinical cases are rare (If you have the disease it is clear)
Infectivity does not precede overt symptoms
One variant
Effective vaccine providing lifelong immunity
Major commitment by governments
What are some potential problems with developing vaccines?
Different viruses may cause similar disease, e.g. the common cold
Alteration to viruses (e.g. antigenic drift or antigenic shift (2 viruses combine antigens))
Immune system cannot detect viral antigens
HIV and influenza particularly difficult due to their rapidly changing properties
Why is subsequence response more rapid after a primary infection?
memory B cells - produce antibodies more efficiently
What is the first antibody to respond during infection?
Immunoglobulin M (IgM)
What is the most common antibody, representing around 75% of serum antibodies in humans?
Immunoglobulin G (IgG)
How much does CVD cost the UK economy each year?
Estimated £19bn
What can vascular occlusion (venous or arterial) result from?
Thrombosis (blood clot), embolism (clot, fat globule, bubble of gas), atherosclerosis (plaques of fat, cholesterol calcium), external compression
What does the consequence of vascular occlusion depend on?
- Type of tissue (major artery or minor vein)
- How quickly the occlusion occurs
- Availability of collateral circulation (more common in venous system)
What is a thrombus?
A solid mass of blood formed within the CVS involving endothelial cells, platelets and fibrin (coagulation cascade). Arterial more age-dependent, may be caused by smoking or diabetes
Why does a thrombus form (3 main reasons)
Hypercoagulable blood (e.g. due to cancer, thrombophilia, inflammatory disease, increased cells, platelets and plasma proteins), stasis of blood (immobility, venous obstruction), vessel wall injury (due to surgery, chemical irritation, inflammation)
What is propagation in terms of CVD?
Accumulation of additional platelets and fibrin, making the clot larger.
What are lines of Zahn?
Bands of fibrin in clots, alternating white blood cells and platelet deposits
What is pulmonary embolism?
From venous emboli that pass through the right side of the heart into the pulmonary artery - function of the lungs is to trap and dissolve small clots
What is systemic embolism?
From the arterial system to a variety of organs
Where does atherosclerosis occur?
Where does arteriosclerosis occur?
Inner surface of artery
In artery wall
What might arteriosclerosis lead to?
Decreased elasticity (hardening), increased wall thickness, hypertension (because of reduced vessel compliance)
What might atherosclerosis lead to?
Narrowing of vessel, obstruction, thrombosis, disease of the intima
Atheromatous plaque
What are the major components of an atheromatous plaque?
Fibrous cap (smooth muscle, collagen, elastin and proteoglycans) Cellular layer (Macrophages, T-lymphocytes, smooth muscle) Necrotic core (lipid, cellular debris, cholesterol clefts, foam cells) Often calcification
What are the major processes in plaque formation?
Endothelial activation and dysfunction promotes lipid accumulation
Inflammatory response and immune cell recruitment - macrophages ingest lipids to become foam cells
Recruitment and proliferation of smooth muscle cells and extracellular matrix synthesis
What is CHD?
Coronary Heart Disease (Ischaemic) - the most common CVD. Due to a narrowing of the coronary arteries - angina is caused by pain from this narrowing. Complete blockage leads to myocardial infarction (heart attack)
What is the leading cause of death worldwide?
CHD
What are the risk factors of CHD?
Age, being male, family history (fixed)
Smoking, diabetes, obesity, hypertension, hyperlipidaemia (modifiable)
What happens in myocardial infarction?
A lack of nutrients and oxygen lead to cardiac muscle cell death
What is arteriogenesis?
Collateral vessel formation due to occlusion
What is PCI?
Percutaneous coronary interventions - angioplasty (balloon opens blocked vessel) and stenting (with a wire mesh)
What is a limitation of PCI?
It is not permanent as the vessel closes up again. Anti proliferative and healing agents (such as Taxol from the Yew tree) help to prevent this - result in reduced restenosis. Called drug-eluting stents
What are the main causes of cancer?
- Environmental causes/carcinogens (e.g. smoking, diet, alcohol, radiation)
- Viral infection (Rous sarcoma virus, Kaposi’s sarcoma (HIV), EBV, HPV 16 &18)
- Inherited factors - (e.g. retinoblastoma, breast cancer, FAP)
Genetic instability (chronic myeloid leukaemia - small chromosome named the philadelphia chromosome (Ph) - 1st evidence for a consistent chromosome change (genomic instability) in cancer)
What causes Ph translocation?
The fusion of two genes: ABL (a proto-oncogene that encodes a nuclear tyrosine kinase protein that is a positive regulator of cell growth) and BCR (increases tyrosine kinase activity, leading to increased proliferation and malignant growth)
What are some other examples of oncogenes?
Ret and Myc (as well as BCR/ABL)
What do most cancer-causing viruses contain?
An oncogene - probably evolutionary capture and mutation of proto-oncogene
Many cancers arise from defects in the machinery that regulates cell growth and/or cell death
How common is cancer incidence?
1 in 3 individuals at some point in their life will develop cancer
(but 1 in 9x10^15 cells)
Cells have to acquire a number of functional capabilities before they can become cancerous. What are these?
Self-sufficiency in growth signals, insensitivity to anti-growth signals, tissue invasion and metastasis, limitless replicative potential, sustained angiogenesis (blood vessel formation), evading apoptosis (controlled cell death)
What are the plasias?
Hyperplasia - tissue containing excessive numbers of cells
Metaplasia - displaced but otherwise normal cells
Dysplasia - cells appear abnormal
Neoplasia - Invasive abnormal tissue growth
What is the difference between benign and malignant tumours?
Benign tumours are confined and well-defined structures, malignant tumours involve dysplasia, anaplasia and invasion metastasis.
Describe a benign tumour
Grows locally, usually well-differentiated and surrounded by a basement membrane/capsule and does not spread to other sites.
Describe a malignant tumour
One that breaks through its basement membrane and spreads (metastises) to distant parts of the body - usually poorly differentiated
Tend to end in carinoma (epithelial tissue) or sarcoma (connective tissue)
What is anaplasia?
Very poor cell differentiation (associated with stage four malignant cancer)
How many “hits” are required for retinoblastoma tumours?
2
Inherited - 1 in germ cell, 1 in somatic during mitotic recombination
Not inherited - 2 hits in somatic cells during mitotic recombination
What are the differences between oncogenes and tumour suppressor genes?
Oncogenes: Activating, gain of function, dominant, one allele required, enhanced effect on the protein product
Tumour suppressor genes: Inactivating, loss of function, recessive, two alleles required, reduced effect on the function of the protein produce
Decreased apoptosis, increased cell division
What does p53 do?
Arrests cell when DNA is damaged
Turns on transcription of DNA repair genes and genes that arrest cell cycle
Turns on apoptosis when all else fails
“the guardian of the genome”
Most cancer cells are defective in apoptotic response. How?
Increased anti apoptotic proteins or decreased anti-apoptotic proteins
Decreased t-cell recognition sites mean that t-lymphocytes and natural killer cells cannot kill the cancer cells
What do sarcomas generally spread via?
The bloodstream
Where do carcinomas (e.g. breast carcinomas) generally spread first via?
The lymphatic system
How is cancer treated?
Surgery Radiotherapy Chemotherapy Endocrine related treatments Immunotherapy (interferons, vaccinations) Molecular mechanism-based therapies
What is metastasis promoted by?
Decreased cell adherence, increased cell motility, tumour angiogenesis, defective basement membrane, evasion of host immune system
What is Her2?
A receptor tyrosine kinase that regulates cell growth and its amplification is involved in 25-30% of breast tumours - status is essential for targeting therapy - not responsive to standard therapies - do respond to a new drug called Herceptin
An effective screen should…
Be affordable to the healthcare system, be acceptable to all social groups, have good discrimination between benign and malignant lesions, and show a reduction on mortality from the cancer
e.g. Her2 probe screening
How does Herceptin work?
- Monoclonal antibody binds to erbB2 receptor sites, inhibits receptor function and the cell cycle is arrested (in the G1 phase).
- Angiogenesis is suppressed using increased antiangiogenic factors and decreased proangiogenic factors.
