ToB Sessions 7-11 Flashcards
Where is the diaphysis of a long bone?
Narrow section in the middle i.e. shaft of humerus
Where is the metaphysis of a long bone?
Where the bone widens between the diaphysis and epiphysis
Do bones increase in girth as epiphyseal growth plates move apart?
No, only length
What is the first stage in converting the embryonic hyaline cartilage skeleton model into bone?
Collar of periosteum bone around diaphysis
As the central cartilage calcifies at the same position as the hyaline cartilage in endochondral ossification, what penetrates the precursor bone?
Artery to supply osteogenic cells
Where does the primary ossification centre of a long bone form?
At the diaphysis
What forms after the primary ossification centre has formed in endochondral ossification?
Growth plates
Secondary centres of ossification
Where are the secondary centres of ossification located in a long bone undergoing endochondral ossification?
Epiphyses
What does medulla turn into during endochondral ossification?
Cancellous bone
What causes lengthening of the bone in endochondral ossification?
Epiphyses ossifying and growth plates moving apart
What are epiphyseal growth plates replaced by?
Bone
How is old bone externally remodelled?
Epiphysis enlarges by growth of cartilage and replacement of bone
Spicules of bone form
Bone reabsorbed and added to narrow and give shape
How is young bone externally remodelled?
Cartilage grows
Columns extend from growth plate
Columns mineralised
What are the zones of bone remodelling?
Bone and calcified cartilage Zone of reserve cartilage Zone of proliferation Zone of hypertrophy Zone of calcified cartilage Zone of resorption Bone, osteoclasts, BV and osteoblasts
What halogens in the zone of reserve cartilage in bone remodelling?
Matrix produced
What happens to cells in the zone of proliferation during bone remodelling?
Divide
Columns and cells enlarge
Matrix synthesised
What happens in the zone of hypertrophy in bone remodelling?
Cells enlarge
Matrix is formed
Cells arrange in linear bands
What happens in the zone of calcified cartilage in bone remodelling?
Degeneration
Matrix calcifies
What mixes in the zone of resorption during bone remodelling?
Spicules and bone marrow
In which direction does bone grow in bone remodelling?
Towards zone of reserve cartilage
What is the calcified matrix in direct contact with in the zone of resorption?
Marrow cavity
What invades the dying chondrocyte region in bone growth?
Small BV and CT
Where does intramembranous ossification take place?
W/in condensations of mesenchymal tissue
What happens in intramembranous ossification?
Mesenchyme cells –> osteoblasts –> osteocytes –> osteocytes linked by canaliculi
What bones are formed by intramembranous ossification?
Flat bones
Give some examples of flat bones.
Skull, maxilla, mandible, pelvis, scapula
What is unique about the formation of the clavicle?
Its medial end undergoes endochondral ossification and its lateral end undergoes intramembranous ossification so it is the first to start and last to finish ossifying
Does intramembranous ossification increase girth or length?
Girth
What happens to the mineral deposits in intramembranous ossification?
Radiate w/in trabeculae from the earlier primary ossification centre
What can be seen in section of intramembranous ossification?
Newly formed woven bone Osteoblasts, osteocytes, osteoclasts Bony spicules connected to form trabeculae Vascularised mesenchymal tissue Periosteum w/osteoprogenitor cells
What makes the bone formed by intramembranous ossification indistinguishable from that formed by endochondral ossification during postnatal development?
Presence of osteocytes, osteons, Haversian and Volkmann’s canals
What is Osteogenesis Imperfecta?
Autosomal dominant group of inheritable disorders of CT
What do mutations in the gene for type I collagen as seen in Osteogenesis Imperfecta affect?
Skeleton Joints Ears Ligaments Teeth Sclerae Skin
What can be visible on X-Ray in Osteogenesis Imperfecta?
Thin, attenuated long bones
Fracture calluses
Why is type II Osteogenesis Imperfecta a lethal perinatal disease?
Almost all bones are fractured during delivery/by uterine contractions
Why does a diagnosis of Osteogenesis Imperfecta have medicolegal importance?
Fractures can appear to be caused by deliberate injury
Where is growth hormone synthesised and stored?
Anterior pituitary gland
What does high levels of growth hormone before puberty cause?
Promoted epiphyseal growth late activity –> gigantism
What does high levels of growth hormone in an adult cause?
Increase in bone width –> acromegaly
What is acromegaly usually a result of?
Benign tumour of pituitary gland
Why is there no increase in bone length with raised GH in adulthood?
Epiphyseal plates have ossified
What feature of bone development do sex hormones influence?
Development of ossification centres
Why do sex hormone producing tumour retard bone growth?
Premature closing of epiphyseal growth plates
What is seen in the bones when there is a sec hormone deficiency?
Epiphyseal plates persist –> tall stature
Are androgens and oestrogens present in both males and females?
Yes
What gives rise to the pubertal growth spurt and induces secondary sexual characteristics?
Sex hormone
How is neonatal hypothyroidism readily reversed?
Prompt administration of thyroxine
What does untreated neonatal hypothyroidism lead to?
Cretinism and short stature
What is osteoporosis?
Metabolic bone disorder where mineralised bone is creased in mass to the point where it can no longer provide adequate mechanical support
What is osteopenia?
Precursor to osteoporosis defined as bone density one standard deviation below that of a 30 y.o. white female
What causes osteoporosis?
Osteoclasts outcompete osteoblasts
How does osteoporosis in the cortical nine compare to in the trabecular bone?
Cortical bone usually remains thick enough but trabeculae become narrow and prone to #
What is osteoporosis characterised by?
Pits in bone dug out by osteoclasts that are not repaired
Why do osteoporosis patients often stoop?
Compression #s occur in vertebral bodies and continue down spine to cause wedging of vertebrae
What is type 1 osteoporosis?
Increased osteoclast number in post menopausal women caused by oestrogen withdrawal (also decreased osteoblasts stimulation)
What is type 2 osteoporosis?
Senile: males and females over 70 have attenuated osteoblasts function
What are the risk factors for osteoporosis?
Lack of exercise - no osteoblasts stimulation Insufficient calcium absorption Insufficient calcium intake Insufficient vitamin D Cigarette smoking Genetics
What is achondroplasia?
Most common form of short limb dwarfism
What inheritance pattern does achondroplasia show?
Autosomal dominant
What is the mentation and lifespan like in achondroplasia?
Normal
What causes achondroplasia?
Point mutation in fibroblast growth factor receptor 3 gene (FGFR3) causing decreased endochondral ossification, inhibited proliferation of chondrocytes in growth plate, decreased cellular hypertrophy and decreased cartilage matrix production
What is sealed off in achondroplasia?
Epiphyseal growth plate
What is rickets?
Childhood deficiency of vitamin D causing insufficient calcium deposition
Where is vitamin D obtained from?
Diet
Synthesised in skin by UV light
Where does vitamin D undergo hydroxylation?
First in liver
Then in kidney
What does PTH stimulate?
Bone degeneration
Calcium absorption by kidney
What is the purpose of hydroxylation get vitamin D twice?
To form active D3 to increase calcium absorption by the bowel and promote bone mineralisation
What is osteomalacia?
Adult form of vitamin D deficiency which causes insufficient calcium deposition
What changes in bone composition are seen in osteomalacia?
Too much non-mineralised bone –> thicker osteoid layer but a normal amount of bone matrix
What can cause osteomalacia?
Liver/kidney disease
Intestinal malabsorption
Poor diet
Lack of sunshine
What are the common #s seen in osteomalacia?
Femoral neck
Public ramus
Spine
Ribs
What is the consequence of two parents affected by achondroplasia having a homozygous child?
Child will not survive
How do most bones in the body develop?
Endochondral ossification from hyaline skeleton in foetus
What is myalgia?
Muscle pain
What is myasthenia?
Weakness of the muscles
What is myoclonus?
Sudden muscle spasm
Why is myopathy?
Any disease of the muscle
How is muscle tissue classified?
Striated or non-striated
Describe the structure of cardiac muscle.
Short, branched cylinders Single central nuclei in myocytes Junctions join myocytes end to end 50-100 micrometers in length 10-20 micrometers in diameter
What type of muscle has an involuntary, intrinsic autonomy rhythm which is lifelong and variable?
Cardiac
Describe the structure of skeletal muscle.
1 mm-20 cm cell length 10-100 micrometers cell diameter Long parallel cylinders Multiple peripheral nuclei Fascicles bundles and tendons present
What controls skeletal muscle contraction?
Somatic motor neurones under voluntary control
What type of contraction can skeletal muscle generate?
Rapid and forceful
Describe the structure of smooth muscle.
Spindle shaped myocytes w/tapering ends and single central nucleus Gap and demosome-type junctions 5-10 micrometer diameter 20-200 micrometer length Connective tissue
How is the slow, sustained/rhythmic contraction of smooth muscle cells brought about?
Involuntary, autonomic, intrinsic activity or local stimuli
How does skeletal muscle develop?
Mesoderm ally derived multipotent myogenic stem cells –> myoblasts –> primary myotube –> newly synthesised actin and myosin filaments
How does development of cardiac and smooth muscle differ to skeletal?
Myoblasts do not fuse but develop ago junctions at a very early stage
What is characteristic of the primary myotube in skeletal muscle development?
Has multiple central nuclei
How are three types of skeletal muscle fibre identified?
Staining for reaction to NADH in mitochondria
What do the proportions of the different types of fibres seen in skeletal muscle depend on?
Function
Which type of skeletal muscle fibre has the largest diameter, poor vascularisation and myoglobin levels, few mitochondria and gives a fast and strong contraction?
White
What are the three types of skeletal muscle fibre?
Red
Intermediate
White
Which type of skeletal muscle fibre has a smaller diameter, is rich in vascularisation and myoglobin, has numerous mitochondria and gives a slow, repetitive, weak contraction?
Red
Which type of skeletal muscle fibre fatigues the quickest?
White
How do the enzymes in red and white skeletal muscle fibres vary?
Red: rich in oxidative, poor in ATPase
White: poor in oxidative, rich in ATPase
Which type of skeletal muscle fibre has more neuromuscular junctions and is found in the extraocular muscles and fingers?
White
Where are red skeletal muscle fibres typically found?
Limbs
Postural muscles
What is the gross structure of skeletal muscle?
Myofibrils –> muscle fibre –> fascicle –> muscle
What surrounds each muscle fibre?
Endomysium
What surrounds each fascicle in skeletal muscle?
Perimysium
What surrounds the entirety of a skeletal muscle?
Epimysium
What is found in the perimysium?
Nerves and BV
Where can circular, convergent and parallel structured skeletal muscles be found?
Circular: round the mouth
Convergent: pectorais major
Parallel: sartorius
Where can unipennate, bipennate, multipennate and fusiform muscle be found?
Unipennate: extensor digitorum longus
Bipennate: rectus femoris
Multipennate: deltoid
Fusiform: biceps brachii
What is the difference between extrinsic and intrinsic skeletal muscle?
Extrinsic attach to bones via tendons and allow changes of position. Intrinsic allow change of shape as they are not attached to bone
What allows retraction and side to side movement of the tongue?
Protusion of extrinsic muscles
What allows the tongue to changes shape?
Intrinsic muscles
How is MHAZI related to myofilament arrangement?
M line in H zone which is in the A band
Z disc is in the I band
What is a sarcomere?
Length of muscle fibre form Z-line to Z-line
What is the ultra structural appearance of skeletal muscle?
In TS enclosures w/dots show myofibrils w/myosin filaments
Abundant mitochondria
Period ally positioned nuclei
How do the bands change in the sliding filament model of muscle contraction?
A band is constant
I band shrinks
What forms the thin filaments of skeletal and cardiac muscle?
Actin, tropomyosin and troponin molecules in a complex
Which part of the thin filament is useful for assays to investigate chest pain?
Troponin - cardiac specific I and T
Which three troponin said form the troponin complex seen in thin filaments?
I, C and T
What is the structure of the thin filament of skeletal and cardiac muscle?
Actin forms helix
Tropomyosin molecules coil round actin helix
Troponin complex attached to each tropomyosin molecule
What is the structure of thick filaments in skeletal and cardiac muscle?
Many myosin filaments whose heads protrude at opposite ends of the filament
Where are the thick filaments devoid of myosin heads?
In the centre of the sarcomere
What is rigor configuration?
Lack of ATP perpetuates tight binding of myosin head to actin molecule (in death –> rigor mortis)
Describe the myosin-actin interaction in the first stage of contraction?
Myosin head in high-energy conformation - ADP and Pi bound
Myosin cross bridge attaches to actin myofilament
What happens in the working stroke of muscle contraction?
ADP and Pi released
Myosin head pivots and bends as it pulls on actin filament sliding towards the M line
What happens to the myosin head when it is in the low energy configuration during contraction?
New ATP attaches and cross bridge detaches
What happens to ATP when the myosin head is cocked during contraction?
Hydrolysed
What is the role of ionic calcium in the contraction mechanism?
Bind to TnC of troponin complex to cause a conformational change to move tropomyosin away from the binding site of actin so myosin can bind
What is the neuromuscular junction?
Small terminal swelling of the axon containing vesicles of ACh
Why are calcium and sodium ions needed in the neuromuscular junction?
Calcium for ACh vesicle fusion and release
Sodium needed in muscle for general depolarisation to release calcium for contraction
What causes depolarisation of the sarcolemma at the NMJ?
Nerve impulse along motor neurone axon prompts release of
ACh into synaptic cleft
How does depolarisation spread over the sarcolemma?
V-G sodium channels open, general depolarisation spreads over
T-tubules
How does depolarisation over the sarcolemma cause initiation of the contraction cycle?
Voltage sensor proteins change conformation so calcium is released from terminal cisternae into sarcoplasm and bind to TnC in troponin
What happens to calcium after it has initiated the contraction cycle?
Returned to terminal cisternae of sarcoplasmic terminal
How are T-tubules arranged in skeletal muscle?
Triads of 2 terminal cisternae of the SR + tubule itself at every AI junction (so twice in every sarcomere)
What is the function of T-tubules in skeletal muscle?
Allow wave of general depolarisation to move across the SR so calcium are released
What features identify cardiac muscle in longitudinal section?
Striations
1 or 2 centrally positioned nuclei per cell
Intercalated discs
Branching
What is the function of intercalated discs in cardiac muscle?
Substitute Z bands and have gap junctions for electrical coupling and adherens-type junctions to anchor cells and provide anchorage for actin filaments
How does cardiac muscle appear in transverse section?
Central nuclei
Capillary rich endomysium
Lobular profiles from emergence of branches
What is the purpose of branching in cardiac muscle?
Helps w/synchronised contraction
How does the ultrastructure of cardiac muscle appear in transvers section?
Continuous mass of actin and myosin
Mitochondria and SR penetrate b/w myofilaments
How does the position of T tubules in cardiac muscle differ to in skeletal muscle?
Lie in register w/ Z bands no AI junction are organised as diads
How are action potentials generated in the SAN spread across the heart?
Pass to AVN then ventricles via distal conducting cells of Purkinje fibres
What are Purkinje fibres?
Large, modified myocytes w/less actin and myosin, abundant glycogen and extensive gap junction sites that conduct action potentials much more rapidly than cardiac muscle fibres
Why are actin and myosin filaments arranged diagonally and spiralling along longitudinal axis of smooth muscle cells?
So smooth muscle contracts in twisting way
What is the function of intermediate filaments in smooth muscle cells?
Attach to dense bodies scattered throughout sarcoplasm
Occasionally anchor to the sarcolemma
Is calcium needed for contraction in smooth muscle cells?
Yep
How does the contraction of smooth muscle compare to that of skeletal/cardiac?
Slower
More sustained - can stay contracted for hours-days
Needs less ATP
What is the relationship between stretch and strength of contraction in smooth muscle cells?
More stretched, stronger it contracts
What causes smooth muscle contraction?
Nerve signals
Hormones
Drugs
Local blood gas concentrations
What is the clinical significance of smooth muscle?
Often form contractile walls of passageways or cavities so their volume can be modified
What are the two types of modified smooth muscle cells?
Myofibroblasts
Myoepithelial cells
What is the role of myofibroblasts?
Produce collagenous matrix at sites of wound healing - abundant actin and myosin
Pull sides of wound together
What is the role of myoepithelial cells?
Stellar cells form basketwork around secretory units of some exocrine glands and assist secretion
Dilate pupil in ocular iris
How is most smooth muscle innervated by the ANS?
Releases neurotransmitters from variscoties into a wide synaptic cleft
How does skeletal muscle repair?
Satellite cells increase mitotic activity and fuse w/existing muscle cells to cause skeletal muscle hypertrophy
How does cardiac muscle repair?
Can’t regenerate so after damage fibroblasts invade, divide and lay down scar tissue
How does smooth muscle repair?
Has mitotic activity so can undergo hyperplasia
Where can hypertrophy and hyperplasia of cells in combination be seen physiologically?
Pregnant uterus
Which clinical conditions are associated with smooth muscle?
Hypertension Dysmenorrhea Abnormal gut mobility Atherosclerosis Asthma
What is skeletal muscle needed for?
Movement
Posture
Stability of joints
Heat generation
Which component of myocytes can increase and decrease in number?
Actin and myosin myofilaments
What is remodelling in skeletal muscle?
Continuous process by which contractile proteins are replaced within two weeks
What are the effects of exercise on skeletal muscle?
Metabolic adaptation - increased ATPase Sarcoplasmic reticulum swells Increased volume of mitochondria Increased Z band width Increased density of T tubules Increased number of contraction proteins
How does endurance exercise such as jogging change muscle?
Stimulate synthesis of mitochondrial proteins
Vascular changes for greater oxygen utilisation
Increase endurance w/out hypertrophy
Does atrophied muscle have more nuclei than normal?
No, just appears so due to less cellular volume meaning more cells in one area
How does high resistance exercise change muscle?
Stimulates contractile protein synthesis
Fatter muscle fibres and larger muscle
Increases muscle mass and strength
Hypertrophy by satellite cells
What happens to muscle in denervation atrophy?
Loss of protein
Reduced fibre diameter
Loss of power
What is the time scale of nerve repair if a nerve is split?
Want to rejoin ends to allow axon to grow done centre w/in 3 months but will not happen 2+ years after injury
What are the signs of denervation atrophy?
Weakness
Flaccidity
Muscle atrophy
What does sustained stretching do to skeletal muscle?
Adjusts muscle length and alters CT arrangement
How is muscle length adjusted?
Unknown - potentially addition of sarcomere a
At high motor neurone firing rates what percentage of ACh receptors need to be occupied for the muscle to remain contracted?
25
What terminates ACh in the NMJ?
Acetylcholinesterase
What is myasthenia gravis?
Autoimmune destruction of ACh receptors and junctional folds at end plate
What are the S/S of myasthenia gravis?
Drooping of eyelids, double vision, unable to hold arm out for long
Why are small muscles affected first in myasthenia gravis?
Loss of few muscle fibres is greater proportion so is more noticeable
What causes symptoms to fluctuate in myasthenia gravis?
General state of health
Fatigue
Emotion
How is myasthenia gravis treated?
AChE inhibitors
Immune suppressants
Plasmapheresis
Thyrectomy if thymus problems present
What in the motor neurone can be affected by toxins that affect the NMJ?
Sodium channels
Calcium channels
ACh release
Potassium channels
What do tetanus and botulinum toxin interfere with?
ACh release
What can be affected by toxins acting on muscle in the NMJ?
Sodium channels
AChR channel
AChE
What is Duchenne-type muscular dystrophy?
Complete absence of dystrophin chain in cell allowing muscle fibres to create tearing force on contraction and calcium entry into cell causing necrosis
What causes pseudohypertrophy in DMD?
Replacement of cells by fat and CT
What are the S/S of DMD?
Early onset Gower’s sign
Contractures
What causes contractures in DMD?
Imbalance b/w agonist and antagonist muscles
What can be used to measure muscle damage in DMD?
Creatine (phospho) kinase
What is the treatment for DMD?
Short term steroids (they cause muscle damage)
Gene therapy?
What is the mutation in the most common and noticeable type of muscular dystrophy?
Altered truncated dystrophin in Becker-type muscular dystrophy
What are the 7 types of muscular dystrophy?
Duchenne-type Becker-type Enary-Dreifuss Limb girdle Fascioscapulohumeral Distal Occulopharyngeal
Which muscles are particularly affected in DMD?
Shoulders
Upper arm
Thigh
Lateral leg
What skeletal muscle disorder does hypoparathyroidism cause?
Hypocalcaemia –> tetany
What skeletal muscle disorder can arise under general anaesthetic?
Malignant hyperthermia - high calcium levels
What can cause primary muscle disease?
Systemic disease
Electrolyte imbalances
Inflammation
Muscular dystrophies
How does thyrotoxicosis cause skeletal muscle disorders?
Increases protein catabolism and BMR
Why are pathogens?
Disease causing organisms
What are Protozoa, bacteria, viruses, fungi and worms all made of?
Proteins, carbohydrates and lipids
What causes food poisoning?
Campylobacter jejuni
How does the immune system detect pathogens?
Identifies their different amino acid sequences
Why have pathogens evolved to damage the host if it alerts the immune system?
Break through barriers to move to more prosperous region so damage and subsequent alert is inevitable
What is the first line of defence against infection?
Epithelial cells
What roles do epithelial cells have in protecting against infection?
Block entry of microorganisms
Produce natural antibiotics
Some possess motile cilia and produce mucin
Produce cytokines and chemokines
Transport antibodies from ‘inside’ to ‘outside’
What natural antibiotics are produced by epithelial cells?
Cationic bacterial peptides - defensins and catheliadins
What are cytokines?
Proteins that alter the behaviour of other cells
What are chemokines?
Proteins that attract other cells
How are pathogens cleared from epithelial surfaces?
Mucociliary escalator Sneezing Coughing Regular urine flow Nasal hairs Ear wax Flow of tears Blinking Peristalsis Sebum Digestive enzymes Vomiting
What are the constituents of sebum?
Lactic and fatty acid at a pH of 3-5
What do epithelial cells do when activated by pathogen attack?
Release cytokines
What do inflammatory mediators promote?
Increased permeability of the BV
What is humoral escape?
Cell and fluid migration out of BV that have increased permeability
What follows after humoral escape in pathogen attack?
Opsonisation and phagocytosis
What happens to antibodies and complement at the site of infection?
Extravasation of antibodies and complement
What happens to the macrophages and neutrophils during cell and fluid migration in response to pathogen attack?
Increased microbiocidal activity
What are the five cardinal signs of inflammation?
Heat Redness Swelling Pain Loss of function
Which cells are specific to the adaptive immune response?
B and T lymphocytes
What is the function of antibodies?
Block entry
Opsonise
Neutralise
Activate complement
What governs the innate immune response?
Tissues
Myeloid cells
What governs the adaptive immune response?
Lymphocytes
Is the adaptive immune system cell mediated or humoral immunity?
Both
What is the innate immune response?
Inbuilt immunity to resist infection which is native, natural and present from birth
Why is the innate immune response not enhanced by a second exposure?
Has no memory so gives same response
How are the innate and adaptive immune responses linked?
They are poorly effective w/out each other, innate is involved in triggering and amplifying adaptive
Which cells are involved in the innate immune system?
Macrophages Monocytes Neutrophil Polymorphonucelar leucocytes Eosinophils Basophils Mast cells Natural killer cells
What is adaptive immunity?
Immunity established to adapt to infection which is ‘specific’ or ‘acquired’ and learnt by experience
Why is the adaptive immune system enhanced by second exposure?
It has memory and confers pathogen-specific immunity
Which cells are involved in the adaptive immune system?
Lymphocytes
What is the role of eosinophils?
To attack parasites when activated by IgE presence
Assoc. w/allergy
What is the first event of inflammatory response?
Arrival of neutrophils
How are neutrophils specialised?
Can work in the anaerobic conditions found in damaged tissues
What happens to neutrophils once they are activated?
Can not make more granules so they use the ones they have and die
What will patients with neutrophil deficiency suffer from?
Recurrent infections, often from microbes of the normal commensal flora
How do neutrophils bind to bacteria in order to engulf and digest them?
Express lipopolysaccharide receptors for many bacterial constituents
Can macrophages continue to generate more lysosomes as needed?
Yep
Are macrophages short-lived or long-lived?
Long-lived
What act as professional antigen presenting cells in the development of adaptive immunity to break up pathogen and present parts so it can be recognised by T lymphocytes?
Macrophages
What is opsonisation?
Coating of a microorganism by antibodies or complement to render it recognisable as foreign by phagocytes
What does binding of an antibody to a bacteria cause?
Activation of complement and bonding of C3b to bacteria
What mediates engulfment of a bacterium following opsonisation?
Fc and complement receptors
How are bacteria killed following opsonisation?
Granules fuse w/phagosomes to release toxic oxygen metabolites
Which cells are phagocytes?
Macrophages and neutrophils
What can phagocytes do in the event of parasite infection?
Release lysosome contents on the outside of the large pathogen
Which cells release chemical mediators that stimulate NK cell activation?
Mast
Macrophages
Which cells do NK cells closely resemble?
T and B lymphocytes - need staining to distinguish
What is the function of NK cells?
Recognise and kill abnormal cells by directly inducing apoptosis in virus-infected cells
How do NK cells kill virus-infected cells?
Pump proteases through pores they make in the target cell to directly induce apoptosis
What are NK cells an analogue of?
Cytotoxic T cells
What do NK cell deficient patients suffer from?
Persistent viral infection, esp. Herpes which cannot be cleared despite adaptive immune response
What do viral infections induce cells to secrete?
Burst of cytokines
What do cytokines do to NK cells?
Induce proliferation and their activation
What does the slower cytotoxic T cell response do?
Develops to help clear the infection
What are the secretory molecules of the innate immune system?
Interferon Lysozyme Fibronectin TNF-alpha Transferrin/lactoferrin
Where are complement proteins ubiquitous?
Blood and lymph
Where are complement proteins synthesised?
Liver and some epithelial tissues
What is the role of membrane attack complexes?
Assemble to make pore in membrane and punch holes in plasmamlemma
Which role of the complement system is most important for host defence against infection?
Recruitment of inflammatory cells
What enhances complement activation?
Antibodies
What can be used immediately after infection begins and long before any pathogen specific antibody is made?
Complement proteins
What is Type III immune complex disease?
Inherited complement deficiency of C1, 2 and 4 which results in aggregations of toxins bound by antibodies to not be cleared from the blood
What does an inherited deficiency of C3 cause?
Recurrent bacterial infection
What does an inherited C5-9 deficiency cause?
Recurrent Neisserial infections which will only present clinically w/meningitis and gonorrhea
What can be said about the activity of T and B lymphocytes?
Inactive until exposed to antigens
Which type of cell do B cells give rise to?
Plasma cells
What is the function of plasma cells?
Produce antibodies
What do plasma cells need to function?
Permission from T helper cells
Which types of cell can T lymphocytes give rise to?
T helper
Cytotoxic T lymphocytes
What is the role of T helper cells?
Activate B cells and macrophages by releasing cytokines upon activation
What do T helper cells need to function?
Antigen presenting cells
What is the role of cytotoxic T lymphocytes?
Present endogenous antigen to major histocompatibility complex which directly kills virus infected cells
In which three ways can antibodies protect the host from infection?
Neutralisation
Opsonisation
Complement activation
Why is the adaptive immune response said to have a clonal nature?
Each naive lymphocyte bearing a unique receptor is the potential progenitor of a genetically identical clone of daughter cells
What are lymphocytes of a particular specificity too infrequent to mount an effective response in adaptive immunity?
Clonal distribution
What is the function of clonal selection?
Increase clonal frequency of cells w/particular antigen specificity
What happens in the process of clonal selection?
Antigen interaction
Lymphocyte activation
Daughter cells bear identical specificity
Proliferation induced
Effector cell frequency increases which allows for memory
Secondary response has more antibodies
How is memory seeded in the adaptive immune response?
Clonal selection and expansion –> differentiation to effector cells –> humoral and cell mediated immunity –> T and B cell apoptosis but lots remain for memory seeding
Which cell do cells of the adaptive immune response originate from?
Common lymphoid precursor
What does the notochord stimulate?
Neural tube formation
What does the notochord define?
Midline
What happens to the neural plate during neurulation?
Differentiates, thickens and folds to form the neural tube
What differentiates to form the brain and spinal cord?
Neural tube
What limits signalling by the notochord?
Diffusion of signal molecules
What creates the proud, slipper-shaped neural plate?
Notochord releasing signals which cause overlying ectoderm to thicken
What happens to the neural plate to form the neural tube?
Edges elevate out of the plane of the disc and curl towards each other
What does the mesoderm give rise to?
Largest number of derivatives in the body
What are the three types of mesoderm present in the trilaminar disc?
Intermediate
Somatic
Splanchnic
What is found between the somatic and splanchnic mesoderm in the trilaminar disc?
Intraembryonic coelom
What do the different types of mesoderm give rise to?
Intermediate: uritogenito tract
Somatic: body
Splanchnic: viscera
What forms somites?
Organisation of paraxial mesoderm into segments
How do somites appear?
Sequentially w/first pair at day 20 and subsequently at 3 pairs a day
Why can somites be used for aging an embryo?
Sequence of presentation is regular
Why do some somites disappear?
So that 31 are left in total which corresponds to the number of pairs of spinal nerves
What is organised degeneration of the somites?
Ventral walls break down to form sclerotome
Dorsal wall forms dermomyotome of which the myotome proliferates and migrates and the dermatome disappears
What does the dermomyotome give rise to?
Back muscles Dermis Myotomes Ventral body wall muscles Limb muscles
What does the sclerotome give rise to?
Proximally: vertebral body
Distally: vertebral arch
Vertebrae
Ribs
What is a dermatome?
Strip of skin supplied by a single spinal nerve
What is a myotome?
Single/group of muscles supplied by a single spinal nerve
What does the paraxial mesoderm give rise to?
Axial skeleton
Dermis
Some limb muscles
What is embryonic folding driven by?
Neural tube formation
What happens in cephalocaudal folding?
Head folds first then tail
What follows cephalocaudal folding?
Lateral folding
What drives lateral folding of the embryo?
Expansion
What is the result of folding of the embryo?
Only ectoderm can be seen irrespective of direction of view
How does a cavity form in the embryo?
Pinched off an incorporated by cephalocaudal folding
What happens to the amniotic sac in folding of the embryo?
Moves from sitting on top of the embryo to enclosing it
What do the lateral edges of the developing embryo do during folding?
Push downwards
What happens to the somatic and splanchnic mesoderm during embryonic folding?
They open further
How does embryonic folding draw together the margins of the embryonic disc?
Creates a ventral body wall
Pulls amniotic membrane around disc
Pulls connecting stalk ventrally
What are the results of embryonic folding?
Embryo suspended within amniotic sac
Primordium of gut created from yolk sac
Heart and diaphragm primordium in right place
Forms new cavity within the embryo
What are the three main events in week 4 of embryonic development?
Neurulation
Organisation of the mesoderm
Segmentation
What has happened by the end of the fourth week of development?
Nervous system has started to form
Segments have appeared assigning specific tasks to specific cells
Embryo folded so entirely covered by ectoderm and there is a cavity inside
Everything is in the right place
What is the lifespan of a RBC?
120 days
What is the lifespan of a platelet?
10 days
How do the lifespans of WBC differ?
Neutrophils: 2-4 days
Lymphocytes: 1 day - years
Where are RBCs, platelets and most WBCs produced?
Bone marrow
Which system removes RBCs from the circulation?
Reticuloendothelial
Which organs are involved in the reticuloendothelial system?
Spleen mainly but other organs can take over if spleen is compromised
How does the bone marrow in the infant compare to in the adult?
Extends into periphery but retracts w/age
How can cell trails be examined to see if red and white precursors are normal?
Take bone from iliac crest and decalcify
Where can bone marrow predominantly be found in the adult?
Pelvis Sternum Skull Ribs Vertebrae
How does the production of RBCs, platelets and granulocytes compare?
RBCs and platelets produced at 2.5 bn cells/kg/day
1 bn granulocytes produced /kg/day
What is haemopoiesis?
Process by which all blood cells are derived from progenitor stem cells
What drives haemopoiesis?
Cytokines such as erythropoietin, thrombopoietin, G-CSF, GMSCF, IL-6 etc
What do all blood cells derive from?
Haemocytoblasts
What precursor do megakaryocytes, erythrocytes, mast cells and myeloblasts all derive from?
Common myeloid progenitor
What do myeloblasts give rise to?
Basophils
Neutrophils
Eosinophils
Monocytes
What can a monocytes become within a tissue?
Macrophage
Where do all myeloblasts derivatives transform?
In tissues
What does myeloid mean?
Generally WBC but anything not lymphoid
What stimulates transformation of megakaryocytes into thrombocytes?
Thrombopoietin
GM-CSF
What do common lymphoid progenitor cells transform into?
Small lymphocytes
Natural killer cells
What is a B lymphocyte?
Transformed small lymphocyte plasma cell not seen in the circulation
What name is given to a small lymphocyte which has passed through the thymus?
T lymphocyte
What plays a major role in the development of lymphoid cells?
Interleukins
Tumour necrosis factors
How much can one unit of blood raise the haemoglobin levels of an individual?
10/L per unit
What are RBCs?
Bacon cave flexible discs with a diameter of 8 micrometers which carry oxygen in its reduced (ferrous) state to tissues
What must enzymes in the RBCs do?
Maintain osmotic equilibrium so that they can move through the microcirculation
How do RBCs generate ATP?
Anaerobic glycolytic pathway
What makes up the membrane of an RBC?
Actin and spectrin structure with glycophorins, glycoproteins and antigens
What maintains elasticity of the RBCs?
Actin and spectrin structure
Which pathways are used in RBC metabolism?
Embolen Meyerhof which metabolises glucose to lactate
Hexose monophosphate pathway to metabolise G6P
What do the globin chains in haemoglobin protect the haem molecule from?
Oxidation
When does beta-haemoglobin chain production start?
~3-6 months
What transition occurs in early life which causes a shift of the oxygen dissociation curve to the left?
Switch from HbF –> HbA
What are delta-haemoglobin chains good for?
Thalassaemia diagnosis but nothing else
Where are primitive oxygen carriers formed in the developing embryo?
Yolk sac
Is oxyhaemoglobin the R or T state of haemoglobin?
Relaxed R state
How are RBCs broken down?
RBCs –> haemoglobin –> heam –> bilirubin
Where can bilirubin go from the liver?
Straight to kidney
Stored in gall bladder –> small intestine then large and into kidneys
What is bilirubin that passes to the kidneys called?
Urobilinogen
What is sterobilin?
Bilirubin excreted from the GI tract
What happens in erythropoiesis?
Kidney senses hypoxia
Increases endogenous erythropoietin production
Erythropoietin acts on E-progenitor cells in BM
RBCs maturation and release
Hb and p(oxygen) increase detected by kidney and decreases erythropoietin production
Where is hypoxia sensed in the kidneys?
Interstitial peritubular cells
How are platelets formed?
Magakaryocytes increase in size and replicate DNA
TPO causes platelets to bud off from the cytoplasm
What are platelets?
2-3 micrometer diameter cell fragments w/no nuclei, mostly stored in the spleen
What is the structure of a platelet?
Phospholipid membrane
Glycoprotein receptors
Glycoprotein alpha granules
Dense bodies of 5HT, ADP, catecholamines and calcium
What is the function of the dense bodies present in platelets?
ADP release for aggregation
What is the function of the glycoprotein receptors in the membrane of platelets?
Platelet adhesion
What does primary platelet aggregation cause?
Activation of the clotting cascade
What does secondary aggregation of platelets cause?
Fibrin mesh to form in clot formation
What is the purpose of the fibrin mesh in clot formation?
Trap platelets and RBCs
How does platelet aggregation occur?
Damage to vessel wall exposes underlying tissue and platelets can bind to blood glycoprotein von Willebrand factor
Why must platelets be kept moving in clinical practice?
Keep them agitated so they will work
What are the stages of neutrophil maturation?
Myeloblast –> promyelocyte –> myelocyte –> metamyelocyte –> bond –> neutrophil
How can neutrophils be identified on histological examination?
Multiplied nucleus w/granular cytoplasm
What is the effect of GCSF on neutrophils?
Increase production
Decreases time for release from BM
Enhances chemotaxis
Enhances phagocytosis and killing of pathogens
What do neutrophils use to destroy pathogens?
Hypochlorous acid and lysozymes
What is the role of monocytes?
Migrate to tissues and become macrophages
Respond to inflammation and antigenic stimuli
Phagocytosis and pinocytosis
What do lysosomes w/in monocytes contain to stimulate production of more monocytes?
Lysozyme Complement Interleukins Arachidonic acid CSF
How do monocytes enter tissues?
Diapedesis (roll)
What is the function of eosinophils?
Spend 3-8 hrs in circulation to migrate to epithelial tissues to phagocytise antigen-antibody complexes and mediate hypersensitivity reactions such as asthma and skin inflammation
What do the granules in eosinophils contain?
Arginine
Phospholipid
Enzymes
What is the lifespan of an eosinophil?
8-12 days
What do basophils resemble on histological examination?
Blackberries
What is the function of basophils?
Active in allergic reactions
Which are the least common of the circulating leucocytes which have a half life of 2.5 days?
Basophils
What do the dense granules in basophils contain?
Histine
Heparin
Hyaluronic acid
Serotonin
Are lymphocytes active in the circulation?
Nope
Which type of cells use the same mechanism of using peroxide to kill cells by cytotoxic activity?
T cells and natural killer cells
What do CD4+ helper cells do?
Induce proliferation and differentiation of T and B cells as well as activate macrophages
What do CD8+ suppressor cells do?
Induce apoptosis in infected cells
What happens when T lymphocytes migrate to the thymus?
Undergo receptor gene rearrangement
Can B lymphocytes recirculate?
Yes
Which lymphocytes are part of humoral immunity?
B lymphocytes
What do B lymphocytes do when they interact with T lymphocytes?
Transform to plasmablasts or memory cells within lymph nodes
What do plasmablasts do?
Migrate from lymph nodes to BM to form plasma cells which produce antigen specific antibodies
Which type of lymphocytes are involved in cellular immunity?
T
What do NK cells carry?
Membrane receptors for functional end of Ig
