Pathobiology Flashcards
What is the definition of a Disease?
A disease is a state in which the health of the human organism is impaired
What is the definition of Homeostasis?
The biological process that maintains a physiological steady state of the internal environment, despite changes in the external environment
What is the definition of Pathogenesis?
The pathological mechanism which results in clinically evident disease
What is the definition of Aetiology?
The specific cause of a disease
What is the definition of a Predisposition to a disease?
A susceptibility to a disease which, given the right circumstances, will manifest as clinically evident disease
What is the definition of a Risk Factor for a disease?
A factor associated with an increased probability of developing a particular disease
What is the Genotype of an organism?
The inherited, genetic constitution of an organism
What is the Phenotype of an organism?
The physical and behavioural characteristics of an organism that are a result of the interaction between the Genotype and the Environment
What are the 2 factors that cause disease?
- Intrinsic factors
2. Extrinsic factors
Give 4 examples of intrinsic causes of disease.
Give an example of a disease for each type of cause.
- Genetic - sickle cell
- Cellular - Alzheimer’s
- Metabolic - Diabetes
- Structural - Spina Bifida
Give 4 examples of extrinsic causes of disease.
Give an example of a disease for each type of cause.
- Physical - Bone fracture
- Chemical - Asthma
- Biological - AIDS
- Nutritional - Malnutrition
What are the 4 steps in the course of a disease?
- Aetiologic agent
- Pathogenic mechanism
- Pathological process
- Overt disease
What is the definition of a Manifestation of a disease?
How are they detected?
- The functional consequences of the morphologic changes that occur in the disease process
- Clinical signs and symptoms
- May require tests such as blood tests and x-rays
Who is the founder of biochemical genetics?
Archibald Garrod
What disease did Archibald Garrod first discover was inherited a classic mendelian trait?
What are the symptoms of this disease?
What this disease dominant or recessive?
- Alkaptonuria
- Homogentisic acid accumulates in joints causing cartilage damage and back pain
- Also precipitates as kidney/prostate stones
- Autosomal recessive trait
What are the 4 patterns of inherited human diseases?
- Autosomal recessive - Alkaptonuria
- Autosomal dominant - Huntington’s disease
- Autosomal co-dominant - Sickle Cell Anaemia
- X-Linked - Duchenne’s Muscular Dystrophy
What is the molecular cause of sickle cell anaemia?
What does this result in?
- Single point mutation in the codon for amino acid 6 in the Beta-globin subunit of haemoglobin
- This changes the normal Glutamine to Valine, which results in the formation of large insoluble polymers which distort RBC shape
Why is the frequency of the Sickle Cell allele so high in sub-saharan countries?
Heterozygous carriers of the Sickle Cell allele have increased resistance to malaria
What is Karyotyping?
How can the banding pattern of chromosomes be used to identify human disease genes?
- Karyotyping is a technique used to map out and distinguish each chromosome
- Abnormalities in banding pattern can be identified and associated with specific diseases, therefore the genes which cause the disease must be located on that specific chromosome
Which protein did DNA sequencing show was mutated in Duchenne’s Muscular Dystrophy?
What does this protein do in the Wild type?
In which pattern is Duchenne’s Muscular Dystrophy inherited?
- Dystrophin
- Part of a bridging complex that connects muscle fibres to the ECM
- X-Linked inheritance pattern
What is the molecular cause of Huntingtons disease?
What does this result in?
What are the symptoms of Huntingtons disease?
- Expansion of a CAG repeat sequence in the Huntington gene increases the size of the Huntington protein
- This protein is now toxic to neurones and results in their death
- Dementia, lack of movement control and neuronal loss in basal ganglia
Are mutant alleles in oncogenes of viruses that cause cancer:
- Dominant or Recessive
- Gain of function or Loss of function
- Dominant
- Gain of function
What is a proto-oncogene?
How can chromosomal rearrangements affect them?
What can this cause?
- A normal gene that could become an oncogene (cancer) due to mutations
- Chromosomal rearrangements can disrupt, truncate or reassemble proto-onocogenes
- This can cause cancer
How can loss of function mutations cause cancer?
What is an example of a cancer that can develop from a loss of function mutation?
- They can inactivate tumour suppressor genes
- Retinoblastoma
Are unilateral retinoblastoma’s hereditary or non-hereditary?
They can be either hereditary or non-hereditary
Are bilateral retinoblastoma’s hereditary or non-hereditary?
They are always hereditary
What did Alfred Knudson hypothesise was the cause of retinoblastoma’s?
Mutations in tumour suppressing genes that normally prevent cells from becoming cancerous
What did Alfred Knudson hypothesise was the cause in non-hereditary retinoblastoma’s?
- Retinoblastoma requires inactivation of both alleles of a tumour suppressing gene
- First somatic retinoblastoma mutation occurs in retinal cell
- Second somatic retinoblastoma mutation occurs in retinal cell resulting in retinoblastoma
What did Alfred Knudson hypothesise was the cause in hereditary retinoblastoma’s?
- Retinoblastoma requires inactivation of both alleles of a tumour suppressing gene
- There is an inherited retinoblastoma mutation in all cells
- First somatic retinoblastoma mutation occurs in retinal cell resulting in retinoblastoma
In what genes do dominant, gain of function mutations cause cancer?
Proto-oncogenes
In what genes do recessive, loss of function mutations cause cancer?
Tumour supressor genes
What are some examples of diseases caused by multiple genes interacting with both each other and the environment?
- Heart disease
- Diabetes
- Cancer
What are single nucleotide polymorphisms (SNPs)?
How are they distributed throughout the genome?
What do they provide?
- A variation in the sequence of single nucleotides in DNA
- They are distributed randomly throughout the genome
- They provide a map of DNA sequence variation across the genome
How can single nucleotide polymorphisms (SNPs) be used to identify DNA sequences associated with common diseases?
Genome Wide Association Studies
- Genomes are analysed to catalogue all of the SNPs present in each individual
- Can then compare the SNPs present in affected individuals with the SNPs present in healthy individuals
- SNPs that are more common in affected individuals may be associated with the disease and may be the cause
What are Genomic Imprints?
Structural modifications to specific regions of particular chromosomes that prevent the transcription of genes within such regions
What is an example of a genomic modification for imprinting?
Methylation of DNA sequences
How can genomic imprints in germ cells of parents affect somatic cells in offspring?
- Patterns of DNA methylation in chromosomes of sperm/egg are conserved in the somatic cells of offspring
- If there are defects in the imprinted genomic regions then this can result in disease in the offspring
What happens to patterns of DNA methylation in germ line development of an embryo?
- They are removed and then reapplied in a pattern dependent on the sex of the embryo
Give 2 examples of parent-of-origin specific diseases.
- Prader-Willi Syndrome
2. Angelman Syndrome
How does maternal/paternal imprints cause Prader-Willi Syndrome?
- The gene involved is called SNORD116 et al
- This gene carries a maternal imprint so only the paternal copy of the gene is expressed
- If the paternal allele is mutated then there will be no functional gene product from SNORD116 et al resulting in Prader-Willi syndrome
How does maternal/paternal imprints cause Angelman Syndrome?
- The gene involved is called UBE3A
- This gene carries a paternal imprint so only the maternal copy of the gene is expressed
- If the maternal allele is mutated then there will be no function gene product from UBE3A resulting in Angelman syndrome
Are maternal/paternal imprints permanent epigenetic changes?
No they are stable but not permanent epigenetic changes
How are parent-of-origin specific diseases caused in heterozygous offsprings?
When a loss of function mutation in a non-imprinted allele is combined with a wild type imprinted allele, then neither allele produces the wild type gene product and the clinical phenotype results
What is epidemiology?
What are the 2 assumptions that epidemiology is based upon?
- The patterns of disease frequency in human population
1. Disease does not occur randomly
2. Disease has identifiable causes
What 3 things make up the epidemiological triangle?
- Host (intrinsic factors)
- Environment (extrinsic factors)
- Agent (disease cause)
What are some examples of environmental (extrinsic) factors that can cause disease?
- Physical
- Socioeconomic
- Nutrition
- Pollution of atmosphere
How did John Snow’s epidemiological study identify the cause of cholera in London?
- He looked at the similarities between those getting infected by cholera
- Found that they all used the same water pump, which was contaminated with sewage
- Identified this was the cause of cholera
What is pulmonary emphysema?
How does smoking increase the likelihood of developing it (macrophages)?
- Pulmonary emphysema is enlargement of the alveolar airspaces with destruction of elastin in walls
- Compounds in smoke irritates alveolar macrophages which then recruit neutrophils and releases chemotactic factors
- This activates proteases which breakdown the elastic tissue of the alveolar walls and replaces it with scar tissue
How does smoking affects levels of alpha-1 antitrypsin and how can this increase likelihood of developing emphysema?
- Oxidants in smoke reduces the levels of alpha-1 antitrypsin
- This decreases the protection for alveolar walls from proteases
- Proteases breakdown the elastic tissue of the alveolar walls and replaces it with scar tissue
How does smoking affect the action of cilia in the respiratory system andhow can this increase likelihood of developing emphysema?
- Smoking decreases the action of cilia in the respiratory system
- This means that bacteria-rich mucus cannot be moved and the risk of infection is increased
- This results in tissue damage of the alveolar walls
What are the 2 broad responses to occupational toxic agents?
- Allergic
2. Pneumoconiosis
How do occupational toxic hazards result in an allergic response?
- Allergen is inhaled
- It then interacts with mast cells via immunoglobulins
- This causes mast cells to degranulate and secrete histamines
- Histamines cause bronchoconstriction and excessive mucus secretion
What is Pneumoconiosis?
What are some examples of its causes?
- Lung disease caused by the inhalation of dusts
- Coal-miners
- Asbestos
- Extrinsic allergic aleveolitis
- Lung carcinomas
How is asbestosis caused?
- Asbestos fibres become coated in Iron and Calcium to form a ferruginous body
- These are ingested by macrophages and causes them to release growth factors
- This stimulates fibroblasts to secrete collagen which decreases the elasticity of lungs
What are the 4 types of infectious pathogens?
- Bacteria
- Viruses
- Protozoans
- Fungi
What are obligate pathogens?
Pathogens that can only survive in host - usually very specific to host species
What are facultative pathogens?
Pathogens present in the environment waiting for host
What are opportunistic pathogens?
Pathogens that are normally benign but cause disease in compromised host
What type of genes cause 2 closely related species to be pathogenic or harmless?
Virulence genes
What is an example of a species that is harmless but can be morphed into a pathogen?
- Cholera bacteria must be infected by a bacteriophage to become virulent
- The bacteriophage transfers genes that encode the cholera toxin to the bacteria
- This toxin causes diarrhoea by dehydrating the cells of the intestines
Give an example of a fungal life cycle that shows dimorphism.
How can this cause disease in humans?
- In soil, fungi grows as a mould
- In warm body, it switches two the yeast morphology
- The yeast are then consumed by macrophages where they grow a germ tube
- This pierces the macrophage from the inside, and results in death of the macrophage
Give an example of a life cycle of a protozoa (malaria).
- Protozoa often have more than one host e.g. mosquito and humans in malaria
- Protozoa are transferred to humans from salivary glads of mosquito when its sucks blood
- Protozoa then replicate in the liver and infect red blood cells
- They produce gametes which are picked up by mosquitos when they suck blood
- The gametes are fertilised in the gut of mosquitos and the cycle continues
What are 3 ways that epithelia are specialised to form a barrier for protection against pathogens?
- Epithelia are densely populated with bacterial and fungal flora to form a barrier to infection
- Epithelial cells are linked by tight junctions to prevent pathogens squeezing through spaces between cells
- Epithelia secrete mucus that traps pathogens and this is then cleared and destroyed
How do some bacteria use adhesins to overcome epithelial barriers?
Some bacteria use adhesin proteins to bind to receptors on epithelial cells to anchor themselves so they aren’t flushed away
What 2 reasons do pathogens need to breach the cell membrane?
- To replicate inside cells
2. To inject toxins into the cell
What 2 reasons do pathogens use toxins to kill host cells?
- Killing host cells provides nutrients for pathogen
2. Killing white blood cells help pathogens evade the immune system
What do E.coli cells do to host cells to hold them in place?
They make the host cell form an actin pedestal that holds them in place so they cannot be flushed away
How can do many bacteria pass toxins into host cells?
They have type III secretion systems that act like syringes that pierce the cell membrane of the host cell
Why do some pathogens hide in host cells?
To evade the immune system of the host
In what 3 ways can bacteria invade cells to evade the hosts immune system?
- They can be phagocytosed by macrophages
- Zipper mechanism - bacteria use adhesin proteins to bind to receptors on host cell surface
- Trigger mechanism - bacteria use secretion systems to actively rearrange the cell membrane of host cells
How do Listeria bacteria enter and replicate within a cell?
How do they then enter other cells?
- Listeria bacteria attach and enter cell by Zipper mechanism within a phagosome
- Listeria then secrete hemolysin, which causes the membrane of the phagosome to breakdown
- Listeria then replicate within the cell cytoplasm
- Listeria assemble actin tails to push them into neighbouring cells
How do antibiotics stop bacterial growth?
They disrupt bacterial cellular processes
What are some examples of cellular process that antibiotics stop in bacteria?
- Cell wall synthesis
- Folic acid biosynthesis
- DNA replication
- DNA transcription
- Protein synthesis
What is the structure of a virus?
A simple genome encapsulated in a coat protein called a capsid
What are lytic and lysogenic viruses?
- Lytic viruses replicate and transcribe DNA to form proteins to make new viruses (shut down cellular processes not related to their replication)
- Lysogenic viruses integrate into the host cell DNA where they can lay dormant for many months/years
What are the 4 entry strategies for viruses?
Give an example of a virus that uses each strategy.
- Fusion with plasma membrane - HIV
- Fusion with membrane after endocytosis - Influenza
- Pore formation - Poliovirus
- Endosomal membrane disruption - Adenovirus
How do viruses bind to host cells in order to enter?
Viruses have viral surface proteins that bind to virus receptors on the surface of host cells
How can the papillomoavirus cause cancer in humans?
- Virus can infect epithelial cells and cause benign genital warts
- Proteins produced by the viral genome up regulate DNA replication and proliferation by the host cell to allow more production of viral genome
- Viral genome contains oncogenes with gene products that promote uncontrolled proliferation
- Accidental integration of virus into host chromosome can result in too much proliferation and can give rise to malignant tumours
How can retroviruses cause cancer?
- Retroviruses cause cancer by incorporating human proto-onocogenes into their own genome
- This is occurs when there are mistake integrating the viral genome into the human genome
- Proto-oncogenes encode proteins involved with cell proliferation and these are normally down-regulated in humans
- The proto-oncogenes products are less controlled in viral genome and this results in uncontrolled proliferation and tumour formation
What is the function of the innate immune system?
Non-specific defence against infection during first hours/days of exposure to a new pathogen
In what 2 ways do epithelial surfaces form physical barriers to pathogens?
- Tight junctions between epithelial cells prevents passage of pathogens between cells
- Keratinized epithelia forms thick barrier
In what 2 ways do epithelial surfaces form chemical barriers to pathogens?
- Sweat discourages attachment and entry of pathogen
2. Sebaceous glands in skin secrete fatty acids and lactic acids which inhibit bacterial growth
What are defensins?
what is their function?
- Antimicrobial molecules secreted by epithelia
- They are positively charged peptides that bind to and disrupt membranes of many pathogens
What 2 ways can the epithelia of internal tissues/organs form a barrier to pathogens?
- Mucus secretions in respiratory and GI tract prevent adhesion of pathogens to epithelia
- Cilia action and peristaltic movements moves mucus along tract to be destroyed/excreted
What 2 ways do the harmless bacteria in the body form a barrier to pathogens?
- They compete with pathogens for nutrients
2. They secrete antimicrobial peptides that inhibit pathogen proliferation
If a pathogen breaks the epithelial barrier, how do cells underneath recognise the pathogen as foreign?
They have receptors that bind to microbe associated molecules that are not normally present in the host
What is the name given to microbe associated molecules that are detected by cell-surface receptors?
Pathogen Associated Molecular Patterns (PAMPs)
What is the name of receptors that bind to Pathogen Associated Molecular Patterns (PAMPs)?
Pattern Recognition Receptors (PRRs)
What 3 ways can Pattern Recognition Receptors (PRRs) be located?
What is there function in each location?
- On the cell surface of Macrophages and Neutrophils
- Mediate uptake of pathogen by phagocytosis - Intracellularly
- To detect pathogens such as viruses - Secreted to bind to surface of pathogens
- Marks them for destruction by phagocytes
What are 3 examples of Pathogen Associated Molecular Patterns (PAMPs)?
- F-met - involved in protein synthesis of prokaryotes
- Lipopolysaccharide - found on surface of gram -ve prokaryotes
- Foreign nucleic acids
What are the 2 major phagocytic cells in the innate immune system?
- Macrophages - resident phagocytes that reside in tissues permanently
- Neutrophils - recruited to areas of infection by chemokine secreted by macrophages
How is phagocytosis of a pathogen carried out?
- Phagocytes have cell surface receptors that recognise and bind to complement proteins or antibodies bound to pathogen
- Binding of pathogen to phagocyte initiates phagocytosis
- Once inside the pathogen is attacked in the phagolysosome
What is the respiratory burst?
A rapid rise in O2 consumption by phagocytes to produce toxic chemicals such as hydrogen peroxide and superoxide
What are the 3 pathways of the complement system?
- Classical pathway
- Lectin pathway
- Alternative pathway
What do all of the pathways of the complement system result in?
Sequential cleavage of proenzymes which results in recruitment of neutrophils, stimulation of adaptive immune response and coating of pathogens for phagocytosis
What is the Classical pathway of the complement system activated by?
Antibodies bound to surface of pathogen
What is the Lectin pathway of the complement system activated by?
Presence of mannose residues on the surface of pathogen membrane
What is the Alternative pathway of the complement system activated by?
Molecules on the surface of pathogen itself
What are membrane attack complexes formed by the complement system?
What do they cause?
Large aqueous pores formed in the membrane of pathogens that make them leaky and can cause lysis
What are interferons?
When are they produced?
- Anti-viral cytokines
- When a cell recognises viral double-stranded RNA
What 2 ways do they block viral genome replication?
- Degrade all single-stranded RNA
2. Inactivate protein synthesis in infected cells
How do Natural Killer cells cause infected cells to die?
They induce them to undergo apoptosis
What type of surface proteins do Natural killer cells use to identify infected cells?
Class 1 MHC proteins
How do Natural killer cells use class 1 MHC proteins to identify cells that need to be killed?
- NK cells have cell-surface inhibitory receptors that monitor levels of class 1 MHC proteins on surface of cells
- Healthy cells have high levels of class 1 MHC proteins
- Infected cells have low levels of class 1 MHC proteins
What is an example of a Pattern Recognition Receptor (PRR)?
Toll-like receptors
What are the 4 characteristics of inflammation?
- Heat
- Redness
- Swelling
- Pain
What changes in local blood vessels occur during inflammation (3 changes)?
- Blood vessels dilate
- Blood vessels become more permeable to fluid and proteins
- Endothelial cells stimulated to express adhesion proteins to promote the attachment and escape of `WBC’s
What is the function of megakaryocytes (2 functions)?
- Form platelets which play a critical role in clotting
- Secrete pro-inflammatory cytokines
What is the function of monocytes?
What is the function of the cell they differentiate into?
- They migrate to injured/infected tissues and differentiate into macrophages
- Macrophages phagocytose pathogens and are involved in antigen presentation
What is the function of basophils?
They release histamines and prostaglandins to cause dilation and increase permeability of capillaries
What is the function of mast cells?
Release heparins and histamines in allergic responses
What is the function of eosinophils (2 functions)?
- Present antigens to the adaptive immune system
- Kill cancer cells
What is the function of neutrophils (2 functions)?
What happens when they die?
- Phagocytose pathogens
- Release antimicrobials
- When neutrophils die they form pus in areas of infection
What are 8 examples of chemical mediators involved in inflammation?
- Histamine
- Serotonin
- Prostaglandins
- Cytokines
- Nitric Oxide
- Platelet-activating factor
- Clotting factors
- Complement systems proenzymes
What is the duration of acute inflammation like?
What leukocytes are involved in acute inflammation?
What changes occur to the local tissue?
- Short duration
- Neutrophils
- Vascular changes (e.g. vasodilation etc)
What is the duration of chronic inflammation like?
What leukocytes are involved in chronic inflammation?
What changes occur to the local tissue?
- Long duration
- Lymphocytes, plasma cells and macrophages
- Angiogenesis and fibrosis
What is the impact of an increase in permeability of vessels during inflammation?
What condition can result from increased permeability of vessels?
- Increased fluid influx to tissues that leads to swelling
- Oedema
What 2 processes does reduction in blood velocity during inflammation promote?
What happens in these 2 processes?
- Margination - process by which WBC exit blood stream and initiate WBC and endothelial interactions
- Diapedesis - passage of blood cells through the intact walls of the capillary
During the immediate-transient inflammatory response:
What blood vessels are affected?
What chemical mediators are involved?
What are examples of causes of this type of response?
- Small vessels are affected
- Histamine, Nitrous Oxide, Platelet-Activating Factor and Leukotrienes
- Causes include nettle sting and insect bites
During the immediate-persistent inflammatory response:
What blood vessels are affected?
What chemical mediators are involved?
What are examples of causes of this type of response?
- Any vessels can be affected
- Bradykinins, Nitrous Oxide, Platelet-Activating Factor and Leukotrienes
- Causes include severe direct injuries such as Burns
During the delayed-persistent inflammatory response:
What blood vessels are affected?
What are examples of causes of this type of response?
- Capillaries and venules affected
- Radiation damage to endothelial cells through sunburn or radiotherapy
What chemical mediators is Arachidonic Acid used as a precursor for?
- Prostaglandins
- Leukotrienes
What are 2 general indicators of infection?
- Increased C-reactive protein
2. Increased Hypothalamic/Pituitary/Adrenal hormones
What is an indication of bacterial infection?
Increased neutrophil levels
What is an indication of viral infection?
Increased lymphocyte levels
What is an indication of parasitic infection?
Increased eosinophil levels
What are 5 examples of chronic inflammatory illnesses?
- Tuberculosis
- Rheumatoid Atrhritis
- Syphilis
- Leprosy
- Osteomyelitis
What are the 2 broad classes of adaptive immune response?
- Antibody response
2. T Cell mediated immune responses
What cells are involved in the antibody response?
How do antibodies stop and result in the destruction of pathogens?
- B cells are activated to proliferate into Plasma cells
- Antibodies specifically bind to antigens on pathogens and prevent them from binding to cells
- They also mark the pathogens for destruction by phagocytes and complement system
What type of protein do T cells recognise that have foreign antigens bound?
How do these proteins allow T cells to identify cells infected by a pathogen intracellularly?
Once an infected cell has been identified, what does a T cell do?
- MHC proteins
- MHC proteins carry fragments of pathogen proteins from inside a host cell to the surface, allowing T cells to detect pathogens hiding inside cells
- T cells can either kill the infected cell or stimulate phagocytes and B cells to eliminate pathogens
Where do B cells develop?
Bone marrow
Where do T cells develop?
Thymus
What type of cell do B and T cells originate from?
What type of stem cell does this progenitor cell originate from?
- Lymphoid progenitor cell
- Haematopoietic stem cells
What are 2 examples of central (primary) lymphoid organs?
- Bone marrow
2. Thymus
What are 3 examples of peripheral (secondary) lymphoid organs?
- Lymph nodes
- Spleen
- Epithelium-associated lymphoid tissues (e.g. in GI and Respiratory tract)
Are B and T cells activated in central or peripheral lymphoid tissues?
Peripheral lymphoid tissues
What effector cells do B cells proliferate and mature into after activation?
What is their function?
- Plasma cells
- Secrete antibodies
How can B and T cells respond specifically to such an enormous diversity of foreign antigens?
- As each lymphocyte develops in a central lymphoid organ, it becomes committed to react with a particular antigen before it has ever been exposed to it
- They express this commitment in the form of cell surface receptors that specifically bind to antigens
What is the process of Clonal Expansion?
- Once an antigen binds to a lymphocytes complimentary receptor, it activates the lymphocyte and causes proliferation
- This produces many more cells with the same receptor for this particular antigen
What is the course of a primary immune response?
- After 1st exposure to an antigen, an immune response is detected after several days
- It rises rapidly and exponentially and then gradually declines
What is the course of a secondary immune response?
- After 2nd exposure to an antigen, the lag period is much shorter because there are pre-existing B and T cells with specificity for that antigen
- Immune response is greater and more efficient
In the peripheral lymphoid tissue, what are the 3 stages of maturing lymphocytes?
- Naïve cells
- Effector cells
- Memory cells
What are Naïve cells?
Lymphocytes that have never been exposed to an antigen
What are effector cells?
When Naïve cells are exposed to their antigen they proliferate and differentiate into effector cells that carry out the immune response
What are memory cells?
When Naïve cells are exposed to their antigen some differentiate into memory cells which are more easily and quickly induced to become effector cells in the case of a second infection
What 2 mechanisms ensure that the adaptive immune system does not respond to self molecules?
Describe each mechanism.
- Receptor editing - developing B cells that recognise self molecules change antigen receptors so they no longer recognise self molecules
- Clonal deletion - potentially self reactive B and T cells die by apoptosis
When do autoimmune diseases occur?
What is an example of an autoimmune disease and what happens during this disease?
- When mechanisms fail to prevent B and T cells responding to self molecules
- Myasthenia Gravis - make antibodies against ACh receptors on their own skeletal muscle which are required for normal contraction
What happens to the first Immunogobulin’s produced by B cells?
What structures do they become?
- They are not secreted, they are inserted into the plasma membrane of the B cell
- They form B cell receptors (BCRs) and serve as receptors for the antigen
What is the typical structure of an immunoglobulin?
- Bivalent, with 2 antigen binding sites
- 4 polypeptide chains - 2 heavy and 2 light
What do the N terminal parts of the light and heavy chains form in an immunoglobulin?
- Antigen binding sites
What do the C terminal parts of the heavy chains form in an immunoglobulin?
What is the function of this part of the Ig?
- Tail of immunoglobulin
- Can activate complement or bind to receptor proteins on phagocytes
What are the 5 major classes of immunoglobulins?
What is the main structural difference between them?
- IgA
- IgD
- IgE
- IgG
- IgM
- They all have their own class of heavy chain
What is the function of IgM?
When is it released?
- IgM is the first class of Ig that a developing B cell produces
- It forms the B cell receptors on the surface of immature B cells
- Also secreted in the early stages of primary immune response to activate complement system
When are IgD produced?
How are these similar to IgM?
- IgD are produced once the B cell leaves the bone marrow
- They have the same antigen binding sites as IgM and are also inserted into the plasma membrane to form BCRs
Where is IgG most commonly found?
What is the function of IgG?
- IgG is the major antibody of the blood
- It is involved in activating the complement system and binds to receptors on neutrophils and macrophages for phagocytosis
What is the function of IgE?
What does binding of antigen to IgE cause?
- IgE bind to receptors on mast cells and eosinophils to act as membrane receptors
- When an antigen binds to IgE it causes release of cytokines from mast cells/eosinophils e.g. Histamine
What is the function of IgA?
Where is it commonly found?
- It helps guide secretions to their target
- It is found in secretions such as saliva, milk and GI secretions
What is the structure of amino acids like in the constant region of heavy and light chains?
It is a constant sequence of amino acids at C-terminus of heavy and light chains
What is the structure of amino acids like in the variable region of heavy and light chains?
What does this structure form the basis of?
- It is a variable sequence of amino acids at N-terminus of heavy and light chains
- Forms the basis of diversity in antigen binding sites
In what regions is the greatest diversity found in variable regions of heavy and light chains?
Hypervariable regions
How many amino acids form an antigen binding site?
5-10 amino acids
What do T cells require in order to be activated?
The antigen must be displayed to them by Antigen Presenting Cells (APCs)
What is the main type of Antigen Presenting Cells (APCs)?
Dendritic cells
What are the 3 main classes of effector T cells?
- Cytotoxic T cell
- Helper T cell
- Regulatory T cell
What is the function of a cytotoxic T cell?
It directly kills cells that are infected with viruses
What is the function of a helper T cell?
Help stimulate responses of other immune cells (e.g. B cells, macrophages and neutrophils)
What is the function of a regulatory T cell?
Suppress the activity of other immune cells
What is the function of MHC proteins?
They capture and display protein fragments of foreign proteins for presentation to T cells
What are the 2 main classes of MHC proteins?
What cells do these present protein fragments to?
- Class 1 MHC Proteins - present to cytotoxic T cells
2. Class 2 MHC Proteins - present to helper and regulatory T cells
What cells express Class 1 MHC Proteins?
All nucleated cells
What cells express Class 2 MHC Proteins?
Only antigen presenting cells (APCs)
How do cytotoxic T cells induce infected cells to kill themselves?
Cytotoxic T cells store toxic proteins in secretory vesicles that it releases and these induce infected cells to undergo apoptosis
What are 2 examples of toxic proteins that cytotoxic T cells use to kill infected cells?
How do they both do this?
- Perforin - forms transmembrane pore in infected cell
2. Granzymes - enter through these pores and activate caspases to induce apoptosis
What are the 2 mechanisms of cell death?
- Necrosis
2. Apoptosis
What are the characteristic features of Necrosis? (5 features)
- Loss of cell components by lysis
- Inflammation
- Autolysis
- Debris (pus)
- Calcification
What are the characteristic features of Apoptosis? (4 features)
- Shrinkage of cells
- Nuclear breakdown
- Phagocytosis
- Requires protein synthesis
What is necrosis associated with (4 things)?
- Physical damage
- Infection
- Acute toxicity
- Acute hypoxia/ischaemia
What is necrosis associated with (5 things)?
- Developmental cell loss
- Chronic toxicity
- Aging
- Removal of growth factors
- Detachment from substrate
How does apoptosis contribute to the formation of digits in embryonic development?
Hands and feet start out as spade-like structures, and individual digits only separate as the cells between them die by apoptosis
How does apoptosis contribute to the loss of tail in tadpoles during metamorphosis?
When a tadpole changes into a frog, the cells in the tail die and tail which is no longer needed disappears
What is apoptosis triggered by?
Specialised intracellular proteases, which cleave specific sequences in numerous proteins inside the cell
What is the name of proteases that trigger apoptosis in cells?
Caspases
What are the 2 major classes of apoptotic caspases?
- Initiator caspases
2. Executioner caspases
What are the 2 main activation mechanisms of apoptosis?
- Intrinsic pathway
2. Extrinsic pathway
What is the name of the receptors that trigger the extrinsic pathway of apoptosis?
What family of receptors do they belong to?
- Death receptors
- Tumour necrosis factor (TNF) receptors
What is the death-inducing signalling complex (DISC)?
How is it involved in the extrinsic pathway of apoptosis?
- When death receptors are activated they recruit adaptor proteins on the cytosolic domain which bind caspases
- This forms death-inducing signalling complex (DISC)and is involved in activating the executioner caspases for apoptosis
What is the intrinsic pathway of apoptosis involving cytochrome c?
- Cytochrome C is released from the inter membrane space of mitochondria into the cytoplasm
- It binds to an adaptor protein called Apaf1 and causes it to form a apoptosome
- This then recruits caspases to initiate apoptosis
In what 5 fluids can HIV be transmitted?
- Blood and blood products
- Vaginal mucus and secretions
- Semen
- Any body fluid mixed with infected blood
- Breast milk
Is HIV symptomatic straight after infection?
No there is a latent period that can last up to 15 years
What is the current therapy for HIV?
What does this do?
- Combination anti-retroviral therapy
- Controls viral replication of HIV and allows immune system to recover
What type of genetic material is found in HIV?
What is the function of the following enzymes found in HIV for infection:
- Reverse Transcriptase
- Intergrase
- Proteases
- 2 single strands of HIV RNA
- Reverse transcriptase generates double stranded HIV DNA
- Intergrase integrates HIV DNA into the host DNA where it is replicated and produces more HIV to infect more cells
- Proteases involved in viral protein synthesis to assemble new HIV
How does HIV infect host cells?
It integrates its genome into the host genome to produce more viruses to spread infection
What are the 3 phases of progression of HIV infection?
- Acute phase
- Chronic phase
- AIDS phase
What occurs during the acute phase of HIV infection?
- HIV replicates rapidly and directly kills CD4 T cells
- The immune system then mounts a response and the virus numbers drop
- CD4 T cell count rises again
What occurs during the chronic phase of HIV infection?
- Lasts for several years and is marked by slow and steady increase in HIV numbers and slow and steady decrease in CD4 T cell count
- T cells are both lysed by the virus and killed by the immune system
What occurs during the AIDS phase of HIV infection?
- Begins when T cell count drops below 200 cells per mm3 of blood
- AIDS is characterised by persistent infections by fungal and bacterial pathogens that are not normally seen in individuals with normal immune systems
What receptors does HIV use to invade T cells?
CD4 receptors
Which protein does HIV use to bind to CD4 receptors to invade T cells?
gp120
How do mutations in CCR5 genes affect course of HIV infection?
Individuals with CCR5 mutations tend to have longer latency periods
What is active immunity?
Protection produced by the persons own immune system
What is passive immunity?
Protection transferred from another person or animal as an antibody
What are the 5 formulations of active vaccines?
- Live pathogens
- Killed microorganisms
- Microbial extracts
- Vaccine conjugates
- Toxoids
Why was eradicating smallpox successful?
- No animal reservoir
- Effective vaccine
- Lifelong immunity
- Major commitment by governments
What is the definition of hypertension?
High blood pressure
What is the definition of thrombosis?
What 3 things are involved?
- Formation of a solid mass of blood that occludes vessels
1. Endothelial cells
2. Platelets
3. Coagulation cascade
What is the definition of embolism?
Detached blood clot that occludes a blood vessel
What is the definition of atherosclerosis?
What is damaged and what does it cause?
- Disease of the tunica intima
- Damage to endothelium can cause narrowing of vessel, obstruction and thrombosis
What is the definition of arteriosclerosis?
What does it cause?
- Disease of the tunica media
- Increased wall thickness and decreased elasticity that can cause hypertension
What are the 3 components of Virchow’s triad?
- Alteration to blood constituents
- Damage to endothelial lining
- Changes to normal blood flow
How are the 3 components of Virchow’s triad affected in thrombosis?
- Alteration to blood constituents - increased cells, platelets and plasma proteins
- Damage to endothelial lining - endothelial damage and loss
- Changes to normal blood flow - turbulent flow
What are the differences between arterial and venous thrombosis?
- Arterial - often occur in middle/old age in individuals with circulatory disorders or diabetic/smokers
- Venous - can occur at any age and often caused by immobility
During thrombus formation, what are the Lines of Zahn?
Alternating red and white cell deposits
What are the 4 major components of an atherosclerotic plaque?
- Cells - smooth muscle, macrophages
- ECM - collagen, elastin
- Lipids - Cholesterol
- Calcifications
What are the 2 major processes in atherosclerotic plaque formation?
- Intimal thickening
2. Lipid accumulation
What are 4 complications of Myocardial Infarction?
- Arrhythmia
- Ventricular Aneurysm
- Rupture of myocardium
- Acute/Chronic pump failure
What are the major risk factors for myocardial infarction?
- Smoking
- Hypertension
- Diabetes
- Hypercholesterolaemia
- Lack of exercise
- Family history
What do mutations in Sonic Hedgehog cause?
- Limb defects
- Cyclopia
- Basal cell carcinoma
TIR is a protein produced by E. Coli and causes host cells to form actin pedestals. What 3 things does it do during infection?
- Rearranges actin filaments in host cell
- Inserts itself into host cell membrane
- Binds to a protein called Intmin expressed in the membrane of E. coli
What is the definition of hyperplasia?
Tissue growth containing excessive numbers of cells
What is the definition of hypertrophy?
The enlargement of an organ or tissue from the increase in size of its cells
What is the definition of metaplasia?
Tissue growth containing displaced but otherwise normal cells
What is the definition of dysplasia?
Tissue growth where cells appear abnormal
What is the definition of neoplasm?
Invasive, abnormal tissue growth
What is the definition of a benign tumour?
One that grows locally, usually well differentiated and surrounded by a basement membrane and does not spread to other sites
What is the definition of a malignant tumour?
One that breaks through its basement membrane and spreads (metastasises) to distant parts of the body and is poorly differentiated
What are the stages of cell differentiation at each of the 4 grades of malignant tumours?
- Well differentiated
- Moderately differentiated
- Poorly differentiated
- Nearly anaplastic
What are the 4 causes of cancer?
- Environmental causes/carcinogens
- Viral infection
- Inherited factors
- Genetic instability
What are the following genes examples of?
- Rb
- P53
- WT-1
- Ptc
- BRCA-1
- APC
Tumour suppressor genes
What is the function of P53 protein?
- Arrests cell cycle in cells that have DNA damage
- Turns on transcription of DNA repair genes
- Turns on apoptosis if all else fails
How do lung and colon cancer cells avoid apoptosis?
They secrete decoy molecules that bind and inactivate type 1 MHC proteins so cytotoxic T cells and NK cells cannot induce apoptosis
What are the 5 ways a tumour spreads?
- Direct
- Via lymphatics
- Field change
- Via bloodstream
- Transcoelomic
How are metastases formed?
- Cells grow as benign tumour
- Cells become invasive and enter capillary
- Cells adhere to blood vessel wall
- Cells escape from blood vessel to form micrometastases
- Cells multiply to form full-blown metastases
What are metastases promoted by?
- Decreased adherence between cells
- Synthesis of defective basement membrane
- Increased cell motility
- Secrete growth factors
- Secrete alternative ECM
- Secrete proteases
What is Herceptin?
What type of cancer is it used to treat?
- Monoclonal antibody that binds to erbB2 receptor sites and represses tyrosine kinase function
- Used to treat breast cancers