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MS 2 POD > Exam 1 - Week 2 > Flashcards

Exam 1 - Week 2 Flashcards

1
Q

Define all parameters and equation for calculation

  1. Bioavailability
  2. Half-life
    - how many half life to eliminate drug from body?
  3. Clearance
  4. Volume of distribution
  5. Elimination constant
  6. Steady state concentration
  7. Pharmacokinetics
A
  1. • Bioavailability - fraction of UNCHANGED DRUG that reach systemic circulation after administration
    • All values are 1 or less.
    • F=1 is the higher bioavailability that you can get
    • E.g statins (that lower cholesterol) - work in liver - 30% bioavailability
    • Determine first pass effect or changes in absorption
    •to calculate; Administer drug twice (IV and PO)
    • F= AUCoral/AUCiv
    • Oral has lower bioavailability
  2. • Time it takes for half of drug to be eliminated out of the body - HALF LIFE ; amount it takes for 50% of drug in plasma to decrease/eliminated - by metabolism or excretion
    • T1/2 = 0.693/Ke
    - 4 half life’s to eliminate drug
  3. Clearance is the volume of blood from which a
    drug is totally removed in a given time (L/hr or ml/min)
    - due to metabolism or excretion
    - total clears is sum of all clearance methods
    - CL = Ke x Vd = 0.693 x Vd / t1/2
  4. • APPARENT volume of distribution (Vd = dose/Co)
    • E.g warfarin - 9L Vd - greater than plasma. Thiopental Vd 140L - very lipophilic and redistributes to fat and brain
    • Lead toxicity - high affinity for bone so you now make lead phosphate instead of calcium phosphate
    • Liver failure - low albumin (warfarin now free to go into tissues)
  5. Ke = 0.693/ t1/2
  6. • Peaks and trough level up - equilibrium
    • Steady state - equilibruim between what you take it and what goes out
    • Steady state concentration - rely on constant. It is average plasma concentration once you reach steady state (balance between intake and output)
    • Remember it takes 4 half life’s to get to 94% steady state (CSS)
  7. How to predict the concentration of drug you need to give to get a pharmacological effect (relationship between absorption, distribution and elimination as a function of time)
    - changes in blood concentration influence effect of the drug
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2
Q

Define the 2 different compartmentment models and look at the graphs

    • Dose - central compartment - elimination (metabolism or excretion).
    • Double dose - double tissue concentration where it goes to. **Plasma and tissue drug concentration MAY BE DIFFERENT
    • A drug doesn’t necessarily go to all tissues (neostigmine used in myasthenia gravis does not cross the BBB). In places that drug goes- increase plasma conc lead to increased tissue concentration
  2. First go to tissues (distribution) before elimination (excretion or metabolism)
    - Semi log plot vs linear plot?
A
  1. One - compartment model (first order)
    - in drug distribution, equilibrium so fast that body acts as one compartment
    - Drug rapidly equilibrates between plasma and
    tissues relative to elimination rate
    - Semi-log plot; STRAIGHT LINE - 1 COMPARTMENT
    - linear plot; CURVED LINE
  2. Two compartment model - 2 phases (zero order)
    - drug takes longer to equilibrate between plasma and tissues
    - First go to tissues (distribution) before elimination (excretion or metabolism)
    - Semi-log plot - 2 COMPARTMENT - CURVED LINE (distribution and elimination phase/line)
    - linear; STRAIGHT LINE
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3
Q

Zero vs first order kinetics

    • Constant FRACTION eliminated per hour
    • semilog plot is linear
    • unsaturated enzymes
    • constant AMOUNT eliminated per hour
    • semilog is curved
    • saturated enzymes
  • *give examples
  • what is Ke
A
  1. First order
    • 99% of drugs follow first order
    • Rate (conc/time) of decrease in drug conc is directly proportional to amount of drug in the body (conc)
    • CONSTANT FRACTION
    • Ke - K of elimination (value unique for every drug). Does not depend on the amount of drug given. E.g 10% of Advil dose is eliminated per hour (constant fraction) . 200mg dose - first hour eliminate 20mg, second hour 18mg (10% loss each hour)
    • A constant fraction is eliminated becuase ENZYMES ARE NOT SATURATED (phase 1 and phase 2 enzymes - previous lecture)
    • Linear graph - curved. Semi-log graph - straight line
  2. ZERO ORDER - alcohol, aspirin (arthritis). **If you use aspirin for headache it is first order
    • CONSTANT AMOUNT of drug is eliminated (dont matter how much you take) e.g elimination rate is 10 ug/L/hr no matter the dose
    • DRUG CAN ACCUMULATE (you can only eliminate a constant amount)
    • Saturation kinetics - SATURATED ENZYMES
    • Linear graph; straight line
    • Semi-log; curved
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4
Q

Relationship between clearance, half life, volume of distribution and plasma drug concentration

**what is CSS directly proportional to? Inversely proportional to?

A
  1. Clearance CL = Ke x Vd = 0.683/half life x Vd
  2. T1/2 = 0.693/ke
  3. Vd= Clearance x 0.693 / half life
4. Plasma drug conc = C 
A = C x Vd 
A = amount of drug 
C = plasma conc of drug 
Vd= volume of distribution
  • *Remember
  • Css directly proportional to dose, half life,
  • Css inversely proportional to Vd, clearance
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5
Q

Predict change in steady state drug concentration if a change occurs in another pharmacokinetics parameter

  1. Maintenance dose
  2. IV infusion
  3. Loading dose
  • *why you need loading dose?
  • *why you need maintenance dose?
A
  1. Css = MD/CL
  2. Css = Infusion rate/CL
  3. Css = loading dose x F / Vd
  • Constant IV infusion - NO VARIABILITY (no peak and trough). You are giving the drug at steady state
  • Do In people who need steady rate (don’t want overdose)

Need loading dose; gets people to steady state immediately
• you then need to give maintenance dose (IV or oral) next to keep them at steady state

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6
Q

More formulas

  1. Is rate of decrease of drug directly proportional to amount of drug ?
  2. Fraction eliminated
  3. Fraction in body
  4. When do you calculate Css (what graph?)
A 
1. Yes Dc/Dt direct proportion to amount of drug 
A = C x Vd 
A = amount of drug 
C = plasma conc of drug 
Vd = volume of distribution
  1. Fraction eliminated = 1- 1/2^n
    Where n is number of half lives
  2. Fraction in body = 1/2^n
  3. Css calculated only in FIRST ORDER KINETIC
    - cant do in zero order kinetics (constant amount eliminated)
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7
Q
  1. What is peak and trough and how does this affect maintenance dose
    - give 300mg dose a day (300mg daily vs 100mg 3x daily); is CSS affected? Variability in peak and trough?
A
  1. • Trough is lowest veils
    • Peak is highest level
    • Blue SID - same amount drug taken every day - more variability
    • Orange - 3x daily (less variability) but steady state concentration is the same
    • As you increase dosing interveal - the bigger the variability between pea and trough
    • Give drug more times a day so that peak and trough are closer
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8
Q

Identify 4 types of cellular adaptation to physiologic and pathologic conditions

  1. Cell shrinkage
  2. Increase in cell SIZE - lead to enlarged organs
  3. Increase in cell NUMBER in organ or tissue
  4. Transformation or replacement of one adult cell type with another

A. Which cells can increase in size but not number?

A

Ways cell adapts due to stress. If they can’t adapt - lead to cell injury - if can’t recover - cell death (necrosis)

  1. Atrophy (decrease in size)
  2. Hypertrophy (increase in size)
  3. Hyperplasia (increase in number)
  4. Metaplasia (change/transform/replace cell line )
  • *Dysplasia - mix of different cells
  • *controlled by complex molecular mechanisms

A. Permanent cells (cardiac, neurons, skeletal) - undergo hypertrophy not hyperplasia because they can’t divide

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9
Q

What are the following

  1. The capacity of cells to adjusting their structure and functions in response to various physiological and pathological conditions.
  2. Certain changes that cells undergo when they are unable to adjust/adapt to stress
    - 2 types?
  3. Necrosis vs apoptosis
    - 2 types of necrosis
A
  1. Cell adaptation ; response to stress
  2. Cell injury; response to adaptation failure
    A. Reversible; mild, transient injury so cell bounce back - recover from injury
    B. Irreversible; cell may die if it can’t recover - necrosis
  3. A. Necrosis - irreversible cell injury lead to changes produced by enzymatic digestion of dead cellular elements
    1) COAGULATION necrosis; KINDEY INFARCT - maintain/preserve the normal architecture of necrotic tissue for several days after cell death
    2) LIQUEFACTIVE necrosis; always in BRAIN INFARCT OR ABCESS. No preservation

B. Apoptosis; vital process that eliminates unwanted cells - internally programmed series of events affected by dedicated gene products

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10
Q

Cellular adaptation
1. Atrophy
A. Identify stressor ; physiological vs pathological atrophy
1. Due to decreased workload or endocrine stimulation
2. Nutritional deficiency

  • *match the following examples
  • loss of innervation (enervation atrophy)
  • low estrogen
  • muscle atrophy/disuse
  • uterine atrophy after pregnancy
  • starvation
  • aging/senile atrophy

**how does loss of brain substance affect gyri and sulci?

A
  1. Physiological atrophy
    - decreased estrogen levels in menopause lead to atrophy of endometrium, vaginal epithelium and breast
    - uterus decrease in size after pregnancy
    - aging (senile atrophy); cell loss in tissue containing permanent cells like heart and brain
  2. Pathological
    - disuse
    - cerebral atrophy (decreased blood supply)
    - decreased nutrients from starvation
    - enervation atrophy; skeletal muscle depend on nerve supply
    - tissue compression with an enlarging bending tumor go through cell atrophy

**loss of brain substance NARROWS GYRI and WIDENS SULCI

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11
Q
  1. What is the difference between atrophy and cell death
  2. What is the mechanism of atrophy (4).
    - what enzyme pathway is important to note?
  3. What is the marker for atrophy? (Called what type of atrophy?)
  4. Increase in what also accompany atrophy?
    - cells eat themselves
A
  1. Atrophy is Not cell death. It is cell trying to conserve energy so you DECREASE CELL SIZE AND NUMBER
  2. Breaking down stuff - lead to cell shrinkage
    A. Increased catabolic activity
    B. Decreased protein synthesis and increase protein degradation C. UBIQUITIN-proteasome pathway - UB LIGASE
    D. Increased autophagy (Self Eating)
  3. LIPOFUSCIN GRANULES
    - aka BROWN ATROPHY
    - undigested lipids are stored as residual bodies (lipofuscin granules)
  4. Increased autophagy vacuoles
    - autophagy is when starved cells eat its own components to reduce nutrient demand to match the supply
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12
Q

Identify cellular adaptation

Stressor; increased workload induced by growth factors produced in response to mechanical stress or other stimuli - occurs in tissues incapable of cell division

Identify Physiological vs pathological

  • heavy workout (massive biceps)
  • hypertension or faulty valves state
  • uterus increase size in pregnancy
A

HYPERTROPHY

  1. Physiological; increased functional demand or stimulation by hormone or growth factor
    - skeletal muscle hypertrophy (heavy workout)
    - uterine hypertrophy ( estrogen hormones act on smooth muscle - increase smooth muscle proteins and increase cell size)
  2. Pathologic
    - CARDIAC HYPERTROPHY from chronic hemodynamics overload from HYPERTENSON or faulty valve stress
    - if left untreated can become maladaptive and lead to - heart failure, arrhythmia and sudden DEATH
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13
Q

Mechanism of hypertrophy

  1. Actions from what 3 things integrate to activate a complex signal transduction pathway
  2. Which 2 are more important in cardiac hypertrophy?
  3. What does signal pathway activate? - work coordinately to increase the synthesis of muscle proteins that are responsible for hypertrophy
  4. Actions of #3 (3)
A
  1. A. Mechanical stretch (increased work load)
    B. Agonists ( alpha adrenegic hormones, angiotensin)
    C. Growth factors (IGF-1, fibroblast growth factor)
  2. A. Agonist
    C. Growth factors
  3. Transcription factors (Myc, Fos, Jun)
  4. A. Introduction of embryonic/fetal genes - cardiac, alpha actin, ANF - increase mechanical performance and decrease work load
    B. Increase synthesis of contractile proteins - increase mechanical performance
    C. Increased production of growth factors
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14
Q

Identify the cellular adaptation based on mechanism below

  • result of growth factor - driven proliferation of mature cells and in some cases by increased output of new cells from tissue stem cells
A

HYPERPLASIA

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15
Q

Identify physiological or pathological hyperplasia in the following examples

  • increased RBC
  • proliferative phas eof endometrial Menstrual cycle
  • breast development
  • hepatica regeneration
  • excess hormone stimulation
  • endometrial or prostatic hyperplasia (BPH)
  • papillomavirus causing skin warts
A
  1. Physiologic hyperplasia
    - increased RBC
    - proliferative phas eof endometrial Menstrual cycle
    - breast development
    - hepatica regeneration
  2. Pathological hyperplasia
    - excess hormone stimulation
    - endometrial or prostatic hyperplasia (BPH)
    - papillomavirus causing skin warts
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16
Q

Identify cellular adaptation

  • result form chronic irritation
  • precede development of cancer in some instances
  • arise from reprogramming of stem or undifferentiated cells that are present in adult tissue

**Give examples (2)

A

METAPLASIA
E.g
1. CILIATED Columnar to squamous cells ( RESPIRATORY TRACT) - in smoking of Vit A deficiency
2. Squamous to columnar (BARRETT ESOPHAGITIS) - gastric acid \, stones in salivary glands, pancreas or bile ducts

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17
Q

Identify 7 causes of cell injury

A
  1. Oxygen deprivation; hypoxia, ischemia, hypoxemia, perfusion defects, loss of oxygen carrying capacity of blood (Co poisoning and anemia)
  2. Physical agents
  3. Chemical agents and drug reaction
  4. Infectious agents
  5. Immunologic reactions (autoimmune)
  6. Genetic derangement (sickle cell anemia)
  7. Nutritional imbalances
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18
Q

What are the 4 major targets and biochemical mechanisms of cell injury?

**arrange from immediate occurrence like 1 hr to 10-12 hours)

A
  1. Mitochondria and their ATP/ROS under pathologic conditions; no ATP and increased ROS
  2. Damage to cellular (plasma and lysosomal) membranes ; failure of membrane functional integrity
  3. Disturbance in calcium homeostasis (entry of calcium)
  4. Damage to DNA and misfolding of proteins

**Once you damage membrane - IRREVERSIBLE

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19
Q

What nucleus changes are seen during cell death

Necrosis vs Apoptosis

  • blebs
  • dissolved
  • condensed
  • fragmented
A
  1. Apoptosis
    - Apoptotic fragments; BLEBS
  2. Necrosis
    A. Pyknosis - Condense (nuclear shrinkage and increased basophilia)
    B. Karyorrhexis - Dissolved (breakup/fragment of nucleus that disappear in 2 days)
    C. Karyolysis - Fragmented (fading of basophilic chromatin of nucleus)
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20
Q

Identify the various types of necrosis

    • conditions of ischemia (coagulated or clotted)
    • any INFARCT/ischemia except brain
    • bacteria abcess and fungi of any organ
    • brain INFARCT (CVA/stroke)
    • digestion of tissue by hydrolytic enzymes
    • severe trauma not due to lipases
    • pancreatic enzymes (lipases)
    • chalky white saponification
    • occur where fat is present
    • immune reactions involving blood vessels
    • prominent when complexes of antigen and antibodies are deposited in walls of arteries
    • deposition of fibrin like material (smudgy and eosinophilic)
    • TUBERCULOSIS and fungi
    • chronic inflammation
    • lack of oxygen from gangrene and infection
A
  1. Coagulative necrosis
  2. Liquefactive necrosis
  3. Fat necrosis
  4. Fibrinogen necrosis
  5. Caseous necrosis
  6. Gangrenous necrosis - can cause liquefactive necrosis
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21
Q

Identify type of cell death

    • enlarged cell size
    • nucleus (pyknosis, karyorrheis, karyolysis)
    • disrupted plasma membrane
    • enzymatic digestion leakage of cellular content
    • frequency inflammatory response
    • mainly pathological role
    • cell shrinkage
    • fragmentation into nucleosome size fragment
    • intact plasma membrane
    • no leaked - may be released in apoptotic body
    • do not provoke inflammation
    • often physiological
A
  1. Necrosis
    - organ damage (whole organ affected)
  2. Apoptosis
    - cell damage (individual cell affected)
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22
Q

What is the most common and important cause of acute cell injury underlying human disease ? (2)

A

Hypoxia and Ischemia

Hypoxia; deficiency of oxygen - cause injury by reducing oxidative respiration (deplete ATP)

Causes of hypoxia; Ischemia (blood loss), cardiorespiratory failure, anemia, CO poisoning (reduced oxygen carrying capacity of blood), severe blood loss

  • *cells can adapt - e.g in narrowed artery vessels can shrink in size (atrophy)
  • *more sever cell injury lead to injury and cell death
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23
Q

There are 4 biomechanical mechanisms of cellular injury.

List all and describe mitochondrial damage in detail

A
  1. MITOCHONDRIAL DAMAGE - ATP low and ROS high.
    ◦ Ox phos down - ATP low - anaerobic glycolysis UP - excess lactic acid, low glycogen, low pH - clumping of nuclear chromatin
    ◦ ATP low - low Na pump - efflux of K+ - influx of sodium, calcium and water - cell swell up (REVERSIBLE - fix with oxygen)
    - ATP low - detachment of ribosomes - low protein synthesis
    ◦ ATP low - loss of membrane potential - No ATP - necrosis
    - ATP low - cytochrome C - apoptosis

◦ ROS - free radicals; generated in several ways - affect lipids and proteins
◦ Free radicals produced by inflammation, radiation, chemicals, reperfusion injury
◦ Removal of free radicals by antioxidant; SOD (mitochondria), glutathione peroxidase (mitochondria) and catalase (peroxisomes)

  1. CALCIUM HOMEOSTASIS IMBALANCE
  2. DNA DAMAGE (misfolded proteins)
  3. MEMBRANE DAMAGE (plasma and lysosomal membranes)
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24
Q

There are 4 biomechanical mechanisms of cellular injury.

  • what contribute to membrane damage?

**Is this reversible?

A
  1. ROS; by lipid peroxidation
  2. Decreased phospholipid synthesis
  3. Increased phospholipid breakdown (increased action of phospholipase by increased cytosolic calcium)
  4. Cytoskeleton damage (by protease activation due to increased cytosolic calcium)

**IRREVERSIBLE - cell can’t fix itself ??

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25
Q

There are 4 biomechanical mechanisms of cellular injury.

Describe influx of calcium and loss of calcium homeostasis

A
  • normally there is low cytosolic calcium. Most calcium in ER and mitochondria
  • during cell injury, there is increases membrane permeability which lead to influx of calcium, sodium and water to cell that result in cell swelling
  • increased cytosolic calcium activates;
    1. Phospholipases - destroy phospholipid - MEMBRANE DAMAGE
    2. Protease - disrupt membrane and cytoskeletal proteins - MEMBRANE DAMAGE
    3. Endonuclease - NUCLEAR DAMAGE (chromatin fragmentation)
    4. ATPase - deplete ATP
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26
Q

When Is cell injury irreversible? Reversible?

**lab signs of heart attack

**lab signs of HTN

A

Cell swelling - reversible
Once there is membrane injury - irreversible

  1. Membrane injury - intracellular release and activation of lysosomal enzymes - decreased basophilia (RNP), nuclear changes, protein digestion
  2. Membrane injury (from ischemia) - loss of phospholipids, cytoskeleton alterations, free radicals, lipid breakdown - increased leakage of enzymes (CK, LDH), increased cytosolic calcium
  • *ISCHEMIA (Heart attack) - elevated cardiac muscle creatinine kinase MB, increased troponin (early signs of MI)
  • troponin; indicates myocardial necrosis
  • CK-MB levels; increase within 3-12 hrs onset of chest pain, reach peak within 24 hrs, return to baseline after 48-72 hours.
  • increased LDH (lactate dehydrogenase)

**Hypertension - increased ANP

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27
Q

What is reperfusion injury

**WHAT 3 CAUSES

A

When you restore blood supply to someone that has ischemia, there may be increase in production of ROS and free radicals (oxidative stress)

  • aggravated calcium overload - favor opening of mitochondrial permeability - further depletion of ATP
  • ischemic injury - inflammation - danger signals - cytokines recruit neutrophils
  • **Neutrophils attack by spitting out FREE RADICALS
  • superoxide free radicals
  • increased cytosolic calcium
  • NEUTROPHILS
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28
Q

What type of free radical injury is this?

  • swelling of the smooth ER
  • disaggregation of ribosomes
  • decline in hepatic protein synthesis
  • reduced lipid export from hepatocytes
  • inability to synthesize apoprotein
  • fatty liver of CCl4 (carbon tetrachloride) poisoning
A

CCL4 converted to CCl3 in LIVER by P-450

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29
Q

Identify the following conditions (examples) of intracellular accumulation

  1. Inadequate removal of normal substance secondary to defects in mechanisms of packaging and transport (e.g alcoholism, diabetes mellitis)
  2. Genetic or acquired defects in protein folding and transport (endogenous accumulation)
  3. Enzyme deficiency so can’t degrade metabolite
  4. Accumulation of exogenous substance - can’t degrade substance or transport it
A
  1. Fatty liver - Steatosis (build up of TRIGLYCERIDES in parenchyma cells )
  2. Alpha 1 antitrypsin
  3. Lysosomal storage disease
  4. Accumulation of carbon or silica
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30
Q

Different endogenous pigment From extracellualr pigment \

  • which is lipofuscin? Marker for?
  • which is coal dust or dust cell ? Marker for?
A
  1. Endogenous pigment
    E.g LIPOFUSCIN; gaining pigment composed of lipids and phospholipids with proteins
    - marker for atrophy
  2. Exogenous
    E.g coal worker’s PNEUMOCONIOSIS
    - phagocytosis of black anthracotic pigment (coal dust) by alveolar macrophages
    - pigmented alveolar macrophages called “dust cell”
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31
Q

2 types of pathologic calcification - abnormal deposition of calcium salts with small amounts of iron, magnesium and other mineral

A

• Abnormal deposition of calcium salts

  1. DYSTROPHIC - NORMAL SERUM calcium, CALCIFIED dead tissues - tissue that has suffered NECROSIS (plaque, aortic stenosis, bicuspid aortic stenosis)
    * *diagnostic radiology
  2. METASTATIC - HIGH SERUM calcium, NORMAL CALCIFICATION (lung, kidney, gastric mucosa)
    - hypercalcemia from hyperparathyroism or malignancy induced
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32
Q

Difference between pharmacokinetics and pharmacodynamics

*what is therapeutics

A
  1. Pharmacokinetics
    - what body does to drug
    - absorption, distribution, biotransformation and excretion of drugs
  2. Pharmacodynamics
    - what drug does to the body
    - mechanism of action and effects of drug
  3. Therapeutics
    - use of drug in treatment of disease
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33
Q

What is this?

  • the primary mechanism of action (pharmacodynamics) involve drugs interacting with macromolecules like lipids, proteins, enzymes etc
  • *what are these macromolecules called?
  • *give 6 examples
  1. 3 important of receptor
  2. Identify 2 types of drug receptors
A

DRUG RECEPTOR

  1. Membrane receptors
  2. Intracellular receptors
  3. Ion channels
  4. Enzymes
  5. Carrier or transport proteins
  6. Other macromolecules (e,g membrane lipids and nucleic acid)
  7. Importance of receptor
    A. Determine quantitative relationships between dose or conc of drug and its effect
    B. Responsible for selectivity of drug action
    C. Mediate actions of antagonists
  8. A. Ligand binding domains; selective. Drug compete for ligand binding site
    B. Ligand-effector domains; effector domains interact with signal transduction pathways
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34
Q

Basis of drug selectivity vs specificity

  1. Act through single receptors type or subtype
    (Single mechanism)
    • exert single effect

Is any drug absolutely specific/selective?

A
  1. Specificity
  2. Selectivity
    - depends on specificity/receptor distribution

**No drug is absolutely specific/selective - that why you have side effects

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35
Q

Signal transduction mechanisms

  1. What is the largest family of receptors
    - how does it work?
  2. What is the mechanism of Gs, Gi and Gq
    Activated by ?
    Cellular effects?
  3. Purpose of G proteins and 2nd messengers?
  4. How does cAMP work as 2nd messenger
    - how is it activated? Inactivated?
  5. The cGMP is made from GTP (distinct forms of guanyly cyclase). What are 2 types of guanyly cyclase? What stimulate which?
  6. What is another examples of 2nd messenger? How is it made?
A
  1. GPCR - largest family
    • receptor activates G protein - GTP bind to G protein (G alpha subunit) - G beta and gamma separate out.
    • Cell can have 20 different G proteins that have different cellular effects - at least 3 main types (Gs, Gi and Gq)
    **SECOND MESSENGERS
  2. A. Gs
    - activated by; beta adrenergic, histamine, serotonin
    -effects; stimulate adenylate cyclase and activate calcium channels

B. Gi

  • activated by; alpha 2 adrenergic, muscarinic, opioids
  • effects; inhibits adenylate cyclase and activates potassium channels

C. Gq

  • activated by; muscarinic, serotonin
  • activates phospholipase C
  1. AMPLIFY AND STRENGTHEN THE SIGNAL
    - Binding is only for a millisecond - imparts a signal
    - Adenylate cyclase activate cAMP.
    - The cAMP is the 2nd messenger - active for longer period
  2. Gs - adenylate cyclase - cAMP - PKA - phosphorylate protein (insulin, glucocorticoid
    - inactivated by PDE
  3. 2 types of guanyly cyclase
    A. Soluble GC (NO stimulates soluble GC)
    B. Particulate GC (ANP, guanyly s stimulate this)
    - GC regulates PKG - platelet inhibition and smooth muscle relaxation
  4. Calcium (Ca2+)
    • PLC cleaves PIP2 to IP3 and DAG
    • IP3 releases Ca2+ from ER
    • DAG activates PKC
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36
Q

Define receptor up regulation and receptor down regulation

A
  1. Receptor upregulation
    - SUPERSENSITIZTION
    - SUSTAINED ANTAGONIST activity
    - increase number of receptors
    - decrease down regulation - withdrawal of antagonist - ELEVATED RECEPTORS (exaggerated response)
  2. Receptor downregulation
    - DESENSITIZATION
    - SUSTAINED AGONIST activity - TACHYPHYLAXIS (no response)
    - endocytosis
    - recycling or degradation - synthesis of new protein - incorporation into membrane
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37
Q

Drug receptor interactions

  1. strength of interaction between drug and its receptor (binding ability)
  2. what happens when drug and receptor interacts (cellular/biological/pharmacological response)
  3. simulate endogenous ligands and bind to receptor e.g muscarine is agonist of and bind to muscarinic acetylcholine receptor
  4. interact with receptor but have no response (prevent binding of agonist to receptor) e.g atropine is agonist of MAR
  5. partial response no matter the dose you give
  6. confused with antagonist. Higher affinity to inactive form move equilibrium to inactive. Affinity is 1 but intrinsic is btw 0 and -1?
  7. intrinsic activity
A
  1. AFFINITY; binding ability of drug to receptor
  2. INTRINSIC ACTIVITY; inherent property of drug to impart cellular response
  3. AGONIST; bind to and stimulate receptor
  4. ANTAGONIST; interact with receptor but have no response (prevent binding of agonist to receptor) e.g atropine is agonist of MAR
  5. PARTIAL AGONIST; partial response no matter the dose you give
  6. INVERSE AGONIST; stabilize receptor in it’s inactive conformation
  7. SIGNAL TRANSDUCTION; receptor binding initiate cascade of biochemical events that lead to physiological response
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38
Q

Which drugs don’t need receptors (4)

A
  1. ANTACID is weak base
  2. MANNITOL change osmotic pressure
  3. WELCHOL prevent absorption of cholesterol (soak excess cholesterol)
  4. many ANTIBIOTICS
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39
Q

IDENTIFY

    • when genes mirror geography - all individuals has to be born same town parents were born in
    • *DECTECT ANCESTRY NOT RACE
    • study of the nature and distribution of genes within populations
  2. Inheritance of traits due to multiple genes and their interaction and also environmental effects (everything except the DNA)
    - All result in variable expression
    - **study of the degree of different traits
A
  1. POPULATION GENETICS
  2. Quantitative genetics
    - quantity not quality of the degree of differences in traits
40
Q

IDENTIFY

  1. SINGLE position on a chromosome - position may be that of allele, gene or segment of chromosome
    - each position present once in haploid - twice in diploid
  2. alternate forms of DNA at specific locus of chromosome (different forms of the same gene - sequence variation, length polymorphism., protein expression)
  3. Any normal individual has 2 of #2. If you have more than 2 in population of locus is called?
A
  1. Locus
  2. Allele
    ◦ Any given individual only has 2 alleles
    ◦ 2 identical alleles - HOMOZYGOUS
    ◦ 2 different alleles - HETEROZYGOUS
  3. Genetic polymorphism
    - more than 2 alleles in population of given loci
41
Q

Define

  1. Condition in which the heterozygote express a trait in same manner as homozygote
  2. Allele that is only expressed in homozygous condition
  3. Most common phenotype
A
  1. Dominance
  2. Recessive
  3. Wildtype
42
Q
  1. What is proteins in humans that are drug metabolizing enzymes and enzymes responsible for the synthesis of cholesterol, steroids and other important lipids such as prostacyclins and thromboxane A2.

**major role in drug interactions

  1. Gene that is not functional in any human in the population
    - some can function in mice but not in human
  2. What is precision medicine
  3. How can you trace your ancestry with polymorphism
A
  1. Cytochrome P450
  2. Pseudogene
  3. Individualized care - more efficient but costly
  4. Most occur one in every generation (one time mutations)
43
Q

Give example of prodrug and how it works

  • what happens if you delete CYP2D6
  • what happens if you duplicate?

**explain phenocopies

A

• CODEINE is a prodrug. It must be converted to morphine (by CYP2D6 in the liver) before it can have good pharmacological effect
◦ Gene deletion - no CYP2D6 - no morphine (poor metabolizer)
◦ Gene duplications - multiple CYP2D6 - overdose on morphine (ultra rapid metabolized)

• codiene/morphine story - why it works
◦ It is MONOGENIC
◦ THERAPEUTIC WINDOW has to be NARROW - safe concentration of drug
◦ ***Phenocopies; environmental factors (maybe on another drug like statins that interacts)

44
Q
  1. What are the 3 classes do pharmacogenes

2. Give exmpales of prodrug vs active agent?

A
  1. Drug metabolizing enzymes
  2. Drug transporters
  3. Drug target
  4. Prodrug - CODEINE (needs to be change to morphine but CYP2D6 in liver to be active)
    Active agent - WARFARIN
45
Q

Describe in detail the 3 classes of pharmacogenes

  1. Drug metabolizing enzyme
    - what happens if you have mutated enzyme so can’t metabolize drug? For Prodrug vs active agent
  2. Drug transporter
    - what is important here? Why (2)
    - do they result in reduced function or loss of function?
  3. Drug target
    - polymorphism in target affect what?
A

CLASS OF PHARMACOGENES
1. Drug metabolizing enzyme
A. EXAM. In drug metabolizing enzymes; for POOR METABOLIZES determine if it is a prodrug (no death just no benefit) vs an active agent (DEATH!!!! Due to toxicity)
2. Drug transporters
A. LOCATION OF TRANSPORTER IS IMPORTANT. Can CHANGE PHENOTYPE and REDUCE FUNCTION (transporters are complicated)
B. There are often multiple transporters.
C. Transporter variants are generally not loss of function (just reduced function)
3. drug target
A. Polymorphism in target can affect drug response (resistance or lack of response) - pharmacokinetic ( what body does in response to drug?)

46
Q

On a dose response graph - compare

  1. When curve goes to left
  2. When curve goes to right?
  3. Formula for therapeutic ratio or index
  4. Differentiate between synergism and potentiation
A
  1. Potentiation
  2. Competitive antagonist
    - has affinity but no intrinsic affinity
  3. Therapeutic ratio/index = LD50/ED50
    - the larger the ratio, the safer the drug
  4. A. Synergism; combine 2 drugs and get greater effect than if you give drug individually
    B. Potentiation; the drug itself has little or no efficacy but it will enhance the biological response induced by an agonist. SHIFT CURVE TO THE LEFT
47
Q

If you have a break in epithelial/mucosal surface and get exposed to and infected by pathogen, how does your body respond with the first 4 hours

  1. How is pathogen recognized? Removed? (3)
  2. Is it effective? Is there inflammation?
A

Ubiquitous/Immediate Innate response

  1. Recognized by preformed non-specific effector molecules and resident effector cells in infected tissues
    - resident tissue macrophages and DCs
    - resident complement proteins in all tissues
    - antimicrobial peptides
  2. It is effective most of time with NO INFLAMMATION
48
Q

If you have a break in epithelial/mucosal surface and get exposed to and infected by pathogen, if your body can’t eliminate pathogen in first 4 hours, how does your body respond by 4 hours - 4 days

  1. How is pathogen recognized? Removed? (3)
  2. Is there adaptive response? Is there inflammation?
A

INDUCED INNATE RESPONSE

  1. Activation of cells resident in infection site - Recruitment of effector cells to site of infection - inflammation/fever/acute-phase response
    Then you,
    Recruit soluble effector molecules and effector cells to infected tissues to recognize and attack pathogens
    - pro-inflammatory cytokines
    - interferons (Type 1)
    - neutrophil infiltration
  2. ACUTE INFLAMMATION with little or no adaptive response
49
Q
  1. Now infection has lasted 4-5 days with no elimination/relief. What now?
  2. Still no elimination of bug?
A
  1. ADAPTIVE RESPONSE (day 4 till infection gone)
    - transport antigen to secondary lymphoid organs
    - recognition by naive B and T cells in secondary lymphoid organs (bone marrow, spleen, lymph nodes)
    - Clonal proliferation and differentiation to effector cells (B cells can function anywhere but T cell has to go to infection site)
    - remove infectious agen
  2. Chronic inflammation
50
Q

Adaptive immune response consists of what 2 types of immunity?

  • mediated by? activated by?
  • effector mechanisms?
  • directed against intracellular or extracellular pathogens?

**do B cells require help? From who? Why?

A
  1. Cell mediated immunity
    A. Mediated by T-lymphoid (thymic derived) cells activated by antigen processed and presented by APCs
    B. Effector mechanisms - CD4 (helper T cells) and CD8 (cytolytic T cells)
    C. In most cases, CMI directed against intracellular virus and bacteria
  2. Humoral immunity
    A. Mediated by antibodies generated by bone marrow derived B cells. B cells need help from T cells and APCs in order to make antibody
    B. Effector mechanism; antibody
    C. Antibody used in innate immune system against pathogens both intracellular and extracellular and also toxins
51
Q
  1. Adaptive immune system was developed by the acquisition of what gene in jawed vertebrates?
  2. Adaptive immunity is characterized by what 2 things?
  3. What is the HALLMARK of adaptive immunity?
A
  1. RAG - Recombinase Activating gene
    - RAG 1 and 2 form BCR and TCR from series of recombination events
  2. A. CLONAL DISTRIBUTION AND SELECTION; of receptors from random and diverse specificities
    B. MEMORY ACQUISITION; memory T or B cells generated following resolution of an immune response to a pathogen
  3. MEMORY
52
Q

The multiplication of lymphocytes after their activation by antigen, so that large clones of rare antigen specific lymphocytes are generated to eliminate the pathogen

A

CLONAL PROLIFERATION/expansion

  • during development, progenitor cells give rise to large numbers of lymphocytes each with a different specificity
  • during infection, lymphocytes with receptors tat recognize the pathogen are activated
  • proliferation/differentiation give effector cells that terminate the infection.
  • effector cells then eliminate pathogen
53
Q

Differentiate innate immunity vs adaptive immunity

  1. What do receptors bind to?
  2. Is response to pathogen fast or slow?
  3. Responding cells express how many receptor types for pathogen?
A
  1. Receptors bind to;
    A. COMMON microbial structure (innate) - *there are only 10 TLR that bind PAMP
    B. UNIQUE pathogen specific structures (adaptive) - there are many 10^13,10^16 BCR and TCR that bind antigen/epitope
  2. Response to pathogen
    A. Fast (innate)
    B. Slow (adaptive)
  3. Responding cells express
    A. NUMEROUS receptor types for pathogen (innate)
    B. SINGLE receptor type for pathogen (adaptive)
54
Q

What are the benefits of adaptive immunity?

A
  1. Numerous BCR and TCR; allow host to respond to argue number of pathogen derived epitopes
  2. Adaptation to mutated pathogen; if pathogen mutates, BCR and TCR contain cells that recognize the change and adapt to the response
  3. Memory cells; small numbers of B and T cells become memory cells for potential future infection

**You can respond to multiple pathogens at the same time

55
Q

Important things to consider in immune response

  1. Is pathogen extracellualr or intracellular?
    - what immunity respond to each?
  2. How do you turn on the response to antigens expressed by pathogens (what do you do first before you can start doing immune response?)
  3. In intracellular pathogen - distinguish between normal from infected cell
    How?
  4. Effector cells - to clear pathogen (types?)
A
  1. A. Extracellular; humoral adaptive immunity
    B. Intracellular; Cell mediated immunity (CMI)
  2. Antigen presentation by APCs (macrophage, DCs, B cell) to what receptors?
    A. Extracellular; TLR, MHC, TCR, BCR**
    B. Intracellular; TLR, MHC, TCR
  3. MHC (major histocompatibility complex)
    - MHC class I and II
  4. Effector cells
    A. Cytokines - direct differentiation, proliferation and maintenance of response (T helper cells)
    B. Cytotoxic T cells - kill cells infected with intracellular pathogen
56
Q

Innate and adaptive immunity work together to eliminate pathogens

  • identify what is responsible for communication in the immune system
  • 4 types (least to most numerous)
A

CELLULAR RECEPTORS

4 TYPES
TCR > BCR > MHC > TLR

57
Q

Differentiate the 4 types of cellular response according to the following

  1. TLR
    A. Type of immunity (innate, acquired)
    B. Pathogen (inside or outside cell)
    C. Diversity (limited, very or extremely)
    D. Expression (constitutive or only when needed)
    E. Where (what cell is it located)
    F. Types of antigen (pathogen, soluble ag, allo-transplant)
    G. Effector mechanism
A 
1. TLR 
A. Innate and acquired immunity 
B. Extracellular and intracellular 
C. Limited diversity 
D. Constitutively expressed 
E. All cells but our interest is APCs (macrophages, DC, B cell)  
F. Pathogens
G. CYTOKINE RELEASE and INFLAMMATION
58
Q

Differentiate the 4 types of cellular response according to the following

  1. BCR
    A. Type of immunity (innate, acquired)
    B. Pathogen (inside or outside cell)
    C. Diversity (limited, very or extremely)
    D. Expression (constitutive or only when needed)
    E. Where (what cell is it located)
    F. Types of antigen (pathogen, soluble ag, allo-transplant)
    G. Effector mechanism
A 
2. BCR 
A. Innate and acquired 
B. EXTRACELLULAR pathogen 
C. Extremely diverse 
D. Constitutively 
E. B cell 
F. Pathogen and soluble antigen 
G. ANTIBODY PRODUCTION
59
Q

Differentiate the 4 types of cellular response according to the following

  1. TCR
    A. Type of immunity (innate, acquired)
    B. Pathogen (inside or outside cell)
    C. Diversity (limited, very or extremely)
    D. Expression (constitutive or only when needed)
    E. Where (what cell is it located)
    F. Types of antigen (pathogen, soluble ag, allo-transplant)
    G. Effector mechanism
A 
3. TCR 
A. ACQUIRED 
B. Intracellular and extracellular 
C. Extremely diverse 
D. Constitutively expressed 
E. T cell 
F. Virus, bacteria, tumor, allo-transplant 
G. HELPER, CYTOTOXIC, SUPPRESSOR T CELLS
60
Q

Differentiate the 4 types of cellular response according to the following

  1. MHC
    A. Type of immunity (innate, acquired)
    B. Pathogen (inside or outside cell)
    C. Diversity (limited, very or extremely)
    D. Expression (constitutive or only when needed)
    E. Where (what cell is it located)
    F. Types of antigen (pathogen, soluble ag, allo-transplant)
    G. Effector mechanism
A
  1. MHC
    A. ACQUIRED
    B. Intracellular and extracellular
    C. Very diverse
    D. Constitutively but can be up-regulated (class I by y-interferon in brain, kidney and liver)
    E.
    -CLASS I; All nucleated cells (not in RBC - no nucleus)
    -CLASS II; APCs (macrophage, DCs, B cell)
    F. Virus, bacteria, tumor and allo-transplant
    G. HELPER, CYTOTOTIC, SUPPRESOR T CELL
61
Q
  1. What is located in transmembrane region of TCR
    - common progenitor to CD4, CD8etc
    - what chain acts as signal?
  2. Identify 2 classes of TCR
    - which is more diverse?
A
  1. CD3
    - ZETA CHAIN signals
  2. A. Alpha and beta chain; huge diversity (viral infection?)
    - TCR recognize antigen (MHC:peptide)
    - CD3 complex signals ZETA CHAIN KEY
    - Effector mechanism; CD4 helper - cytokines, CD8 kill - CTL

B. Gamma and delta chain; limited diversity (innate? Has NK receptor- infected epithelial cell die by APOPTOSIS)

62
Q

Explain concept of MHC restriction

A

MHC restriction

  • T cell receptor (TCR) binds to BOTH PEPTIDE and MHC molecule
  • will not recognize a different peptide
  • *
  • TCR recognize antigen (MHC:PEPTIDE)
  • CD3 complex signals ZETA CHAIN KEY
  • Effector mechanism; CD4 helper - cytokines, CD8 kill - CTL

**MHC RESTRICTION; TCR Requires a specific class 1 or class 2 MHC and peptide to bind

63
Q
  1. What is the cellular requirement that enable you to recognized viral infected cell vs normal cell? (5)
  2. Difference in innate vs adaptive effector mechanism)
A
  1. APC; express MHC class 1 or 2 with peptide derived from pathogen (MHC:Peptide)
  2. CD4 helper T cell; CD3+αβ+CD4+
  3. CD8 cytolytic T cell; CD3+αβ+CD8+
  4. CD4 suppressor T cell; CD3+αβ+CD4+CD25+
  5. Infected cell must express MHC class 1 protein and pathogen derived peptide (MHC:Peptide)
  6. A. Innate
    - complement, preformed antibodies, tissues macrophages, mast cells, cytokines and chemokines

B. Adaptive
- APCs (DCs) and antigen specific lymphocytes (B cell and T cell)

64
Q

T cells function by making contact with other cells and inducing them to change. Identify 3 cells that T cell make contact with and is the effect?

A
  1. CD8 T cell + virus infected cell
    - direct cell contact
    - lethal hit lead dead viral infected cell
  2. CD4 T cell + macrophage
    - release cytokine (gamma interferon) that activate macrophage
    - activated macrophage release cytokines (TNF alpha - inflammation, apoptosis, T cell activation)
  3. CD4 T cell + B cell
    - release cytokine (IL 4,5,6,21) that proliferate and differentiate B cell to plasma cell
    - plasma cell make antibodies (neutralization of toxin and foreign cell, ADCC, opsonization, memory cells? )
65
Q
  1. What is the structural similarity between MHC class I and II
  2. What gene stabilize the MHC class I and result in immunodeficiency if the gene if absent/mutated?
  3. The HLA (human leukocyte antigen) is a gene on chromosome 6 expressed by MHC. Both class I and II HLA are inherited by an individual on a single chromosome
    - identify the Antigen presenting genes in Class I vs Class II? Are they coded on same or different chromosome?
A
  1. A. Class I; alpha 1, alpha 2, alpha 3, beta 2 immunoglobulin
    B. Class II; alpha 1, alpha 2, beta 1, beta 2
  2. Beta 2 immunoglobulin - stabilize MHC class I
  3. A. AP genes Class I; HLA-A > HLA-B > HLA-C
    - B2 microglobulin is coded on a different chromosome
B. AP genes Class II; HLA DP, DQ, DR 
- both chains for class II are coded on same chromosome

**An individual co-expresses both alleles for each MHC gene (maternal and paternal)

66
Q
  1. How do TCR recognize peptide antigens produced by degradation of proteins
  2. APCs simultaneously express 2 forms of MHC molecules (*remember MHC class III has no functional gene)
    - MHC class I vs Class II bind peptides from what pathogen (intracellular or extracellular)
    - the peptide is then presented to what T cell type?
A
  1. A. Dendritic cell take up pathogen for degradation (by lysosomes - protein cut into smells peptides)
    B. Peptide bing to MHC and complex go to surface of dendritic cell (DC is a professional antigen presenting cell)
    C. TCR bind to MHC:peptide compels on dendritic cell surface
  2. A. MHC class I bind peptides from INTRACELLULAR pathogens
    - peptide then presented to CD8 T cell (lethal hit)
    B. MHC class II bind peptides from EXTRACELLULAR pathogens
    - peptide then presented to CD4 T cell (release cytokines)
67
Q

Identify MHC class

  1. • TURNS ON IMMUNE RESPONSES - CD4.
    • ***Only want it on APCs - DCs, B cell, macrophages
    • LOW IN BRAIN
  2. • BILL BOARD (identify self from non self) - CD8 .
    • can be upregulated during infection in liver, kidney,brain or downregualted.
    • occur in ALL NUCLEATED CELLS (not on RBC)
    • Types; HLA A,B,C. A presents the most. Single HLA can bind different peptides
    • Amino acid residues (1,2, and 9 position) - T cell receptor binds the class 1 peptide
A
  1. Class II
  2. Class I
    - target cells use class I (upregulated by gamma interferon in liver, brain, kidney)
    - need beta 2 immunoglobulin to stabilize it
68
Q
  1. How can 6 class I molecules and 16 class II molecules display all possible antigenic peptides in nature?
A

ANCHOR RESIDUES
- promiscuous binding specificity
- only certain amino acid residues in peptide binding groove are critical for a peptide to bind to an HLA molecule
E.g amino acid residues on 1,2 and 9 position bind to class I peptide

69
Q

MHC class I vs class 2

  1. What cells highly express BOTH class I and II (3)
  2. What can upregulate BOTH classes (2)
  3. Where can you find class I?
  4. Where you find class II?
  5. Where will you not find either class I or II?
A
  1. APCs; macrophages, B cell, dendritic cell
  2. Gamma interferon and TNF upregulate both
  3. Class I - intracellular - CD8; all nucleated cells - APCs, T cells, liver hepatocytes, kidney epithelium, brain
  4. Class II - extracellualr - CD4; APCs only - B cell, macrophages, dendritic cell
  5. Both not found in RBC - erythrocytes (not an APC and has no nucleus)
70
Q

Differentiate antigen processing from presentation

A
  1. Antigen processing; break up the protein into peptide (in DC) and MHC specific class with bind to peptide (MHC:peptide)
  2. Antigen presentation; MHC:peptide presented to cell surface of DC for TCR to bind
71
Q

Identify the function of

  • DC
  • Macrophage
  • B cell

**co-stimulatory molecule

A

3 important cells (ALL APCs - DC, B cell, macrophages)
1. Dendritic cell; professional APC (antigen presenting cell). Antigen processing occur in macrophages (how it becomes activated) and B cells
A. DC turns on helper cells (CD3); CD4, CD8
B. Class I MHC working in DC is also working/processing/presenting in infected and uninflected nucleated cells (to differentiate infected from non-infected).
2. Macrophages; antigen processing
3. B cells; antigen processing

**Costimulatory cells (DANGER SIGNAL- PRR/PAMP) - makes checks and balances in DC. If danger signal not there (pathogen not signaled), T cell doesn’t get turned on

72
Q
  1. Class I bind what type of peptide?

2. Class II bind what type of peptide

A
  1. Class I molecules bind and present peptides derived from CYTOPLASMIC sources of pathogens (INTRACELLULAR pathogens)
    - viral protein is from cytoplasm (protein is broken up by proteasome into peptides in cytoplasm) - class I bind the peptide in the ER then - complex go to dendritic cell surface to be recognized by CD8 (cytolytic T cell) - kill infected cell
  2. Class II molecules bind and present peptides derived from EXTRACELLULAR space (extracellular pathogens)
    A. macrophage engulf and degrade bacteria to produce peptides - bound MHC:peptide to to cell surface - CD4 release cytokines to activate macrophages
    B. Antigen processing by B cells - extracellular antigen via class II - utilize surface immunoglobulin to capture antigen - MHC:peptide recognized by TCR which turn on Th2
73
Q

Identify the type of adaptive immunity

1. 
•  Antigen Presenting Cells	
•  Thymic derived lymphocytes	 
•  Helper (cytokine release)	 
•  Cytotoxic	(Kiss of death)
  1. •  Antigen Presenting Cells
    •  Thymic derived lymphocytes (Helper, cytokine releas
    •  Bone marrow derived lymphocytes (B cells, antibody production
A
  1. CMI (cell mediated Immunity)

2. Humoral Immunity

74
Q

Effective immune response required interactions between multiple cell types

What sites do the following occur?

  1. Cell development (2)
  2. Activation by antigens and microbes (2)
  3. Destruction of antigens (1)
A
  1. Cell development
    - thymus
    - bone marrow
  2. Activation - T cell, B cell, DC, macrophages
    - spleen (white pulp)
    - lymph nodes
  3. Destruction of antigens/microbes
    - site of infection
75
Q

Identify cell

  • capture antigen in PERIPHERY
  • undergo maturation process IF TLR IS ENGAGED
  • danger signal
  • upregulate MHC and COSTIMULATORY molecules
  • Migrate to lymph noses and present antigen to naive T cell?
    • how is it different from its immature form?
    • what makes this cell mature?
A

Dendritic cell

  1. Immature DC
    - highly phagocytic
    - low to NO COSTIMULATORY MOLECULES
    - sampling environment

**Antigen promotes dendritic cell MIGRATION and DIFFERENTIATION

76
Q

Microbial products enhance APC function of macrophage and dendritic cells

  1. What happens in absence of infection
  2. During infection?
    * *what is engulfed? Receptor? B7? Signal 2? T cell activated?
  3. What 2 things need to be present to activate T cel?
A
  1. Absence of infection
    - self proteins engulfed
    - No PRRs engaged
    - No B7 (CD 80/86) induced
    - No signal 2
    - No T cell activation
  2. During infection
    - microbial proteins engulfed
    - PRRs stimulated
    - B7 costimulatory expression induced (bind CD28)
    - signal 2 can be delivered
    - T cells can be activated
  3. Specific antigen and Co-stimulator
77
Q

Differentiate between peripheral tolerance and central thymic tolerance

A
  1. Central thymic tolerance (during development of T cell in thymus)
    - T cells that recognize self die by apoptosis
    - T cell that recognize non self proliferate/differentiate
  2. Peripheral tolerance (other tissues and lymph nodes)
    - self reactive T cell that escaped thymic selection sees self antigen but no costimulation
    - T cell becomes anergic (inactive)
    - once anergic stays anergic
78
Q

Intracellular vs extracellular pathogen

  1. Protein broken down to peptide where?
  2. Peptide bind to what class of MHC
  • *
    3. How can cross presentation occur?
A
  1. A. Intracellular - proteosome (in cytoplasm)
    B. Extracellular - phagolysosome
  2. A. Intracellular - peptide bind to Class I and presented to CD8
    B. Extracellualr - peptide bind to class II and presented to CD4
  3. Cross presentation; APC express both class I and II
    - small peptides coming from Class II (in RER) leak out to class I
    - occur mainly with dendritic cells
    - so DC can turn on CD4 and CD8
79
Q
  1. What do naive T cells utilize to enter secondary lymphoid tissues (spleen and lymph nodes)
  2. What is the process called when lymphocytes leaves blood and enter lymph node?
    - what do they use to enter lymph node?
  3. Overall movement into target/infected cell called?
A
  1. Non-specific cell adhesion molecules
    - once within LN, naive T cells bind to APCs via INTEGRINS and Ig superfamily molecules
  2. Diapedesis
    - through HEV?
  3. Extravasation
80
Q

Remember than 1 peptide and 1 MHC class is required for TCR to recognize antigen (MHC:peptide).

  1. What 2 signals are required for T cell to be activated/proliferated
  2. Signal 1 required what 3 points of contact
  3. Why will both signals not directly lead to T cell proliferation
  4. What 3 signals do APCs deliver to naive T cells
A
  1. Signal 1 - TCR (CD3 zeta chain signals once there is MHC:peptide?)
    Signal 2 - costimulation; CD28/B7
  2. antigen/peptide, MHC class 1/2, CD4/CD8
  3. Combination of an antigen-specific signal and a co-stimulatory signal is required to activate a naive T cell
    * *remember - As a result of infection, TLR binding PAMP, DC matures (Danger signal delivered) and costimulatory molecules expressed.
    • activation
    • survival
    • differentiation
81
Q
  1. Activation of naive antigen-specific T cells lead to the synthesis of what cytokine?
  2. What 3 nuclear transcription factors are required to activate transcription of IL2 gene?
    - immunosuppressive drug (cyclosporine A) blocks what?
A
  1. IL2 and high affinity IL2 receptors
    - made by CD4 helper T cells (Th1)
    - IL2 is tightly controlled and only expressed after signal 1 and 2
    - mature DC can turn on T cell
    * *Binding of IL2 to high affinity receptor send signal to T cell to induce proliferation
    * *AUTOCRINE OR PARACRINE stimulation of proliferation
    • NFAT (cyclosporine A blocks this)
    • NFkB
    • AP1
82
Q

Identify cell

  1. SIGNALS
  2. Accessory/ADHESION molecule that modulate T cell receptor signalling? (What are the 2 types - which is naive? Mature?)
  3. Produce cytokines; activate CTL, macrophages, help in antibody production, maintain inflammation, get rid of parasites
  4. Give rise to subsets based on cytokines encountered in micro-environment
A
  1. CD3
  2. CD45
    A. Ra positive (naive)
    B. Ro positive (more mature)
  3. CD4 (helper T cell)
  4. Th0
    - precursor for Th1, Th2, Th17, Tfh, Tregs
83
Q

Dendritic cell cytokines determine the pathway of CD4 helper T cell differentiation

  • *identify the individual cytokines that induce differentiation of the following helper T cells and what cytokines do the T cells release and function
    1. Th1 effector
    2. Th2 effector
    3. Th17 effector
    4. Treg effector
    5. Tfh
  1. T cell proliferation
  2. T cell memory
A
  1. Th1 effector
    DCs - IL12 or gamma interferon
    T cells - Gamma interferon
    Action - angry macrophage/ CTL
  2. Th2 effector
    DCs - IL4
    T cell - IL 4/5
    Action - Ab isotype switch, Ab to parasites
  3. Th17 effector
    DCs - IL23
    T cell - IL17
    Action - mediate inflammation and enhance neutrophils
  4. Treg effector
    DCs - TGF beta
    T cell - TGF beta and IL10
    Action - suppress T cells
  5. Tfh
    DC - IL6/21
    T cells - IL 21
    Action - B cell maturation
  6. IL2 - T cell proliferation ‘
    IL7 - T cell memory
84
Q
  1. What 2 cytokines can help in dendritic cell production?
  2. What upregulate vs down regulate class I MHC expression? Why?
  3. What proinflammatory cytokines help in neutrophil mobilization and mediate signs of inflammation with effect on liver
  4. Which cytokines are active in early anti viral immunity
  5. What cytokines stop inflammation
A
  1. IL4 and GMCSF - DC is derived from CD14+ monocytes
2. Gamma interferon - upregulate Class I 
Viral infected cells - down regulate Class I expression; to avoid CTL kiss of death 
** NK cells however can recognize low class I expression and lyse viral infected cell
  1. IL1 and IL6 - proinflammatory
    • alpha and beta interferon
    • IL12 activate NK cells
  3. IL4, IL10, TGF beta
85
Q
  1. Name 3 effector function of CTL
  2. What must be recognized on target cells in order for effector function to occur?
  3. Do you need costimulation for CTL function?
  4. Where do the following occur
    A. Recognition of antigen
    B. Proliferation and differentiation
    C. Effector function
A
    • Kill cells harboring intracellular pathogens
    • Distinguish uninflected from infected cells
    • Can also secrete cytokines
  2. MHC class 1:peptide
  3. NO
    - costimulation only needed to activate T cell not for effector function
  4. A. Secondary lymphoid tissue
    B. Secondary lymphoid tissue
    C. Infection site
86
Q

Identify
1.
- Rapid, not blocked by inhibitors of protein
synthesis.
- Requires cell:cell contact
•  Uni-directional killing (Apoptosis of target)
•  Killer T cell could kill multiple targets
•  Bystander cells unaffected
–  Local, directed mechanism of killing

    • Initial contact independent of antigen (Mg
      dependent)
      –  MHC/TCR binding; Accessory molecule binding
      (LFA-1:ICAM; CD2:LFA-3)
      –  Granule reorientation
A
  1. CTL mediated killing

2. CTL target cell binding

87
Q

Identify the 2 types of cell death

  1. Lead to inflammation and wound repair. Injury to cells and oxygen deprivation
    • induced by CTL, NK cells
    • plasma membrane blebbing
    • changes in distribution of membrane lipids
    • enzymatic fragmentation of chromosomal DNA (nucleases cleave DNA btw nucleosomes)
A
  1. Necrosis

2. Apoptosis

88
Q

Identify the following protein in granules of cytotoxic T cells

  1. Aids in delivering contents of granules into cytoplasm of target cells
  2. Serine proteases, activate apoptosis once in cytoplasm of target cell
  3. Has antimicrobial actions and can induce apoptosis
A
  1. Perforin
  2. Granzymes
  3. Granulysin
89
Q
  1. Name 2 routes that naive T cell can use to enter the lymph node
  2. How does dendritic cell enter?

**how do they exist back to blood if ever?

A
  1. A. In blood (HEV)
    B. Afferent lymph
    **Irrelevant T cells that don’t see any antigen in lymph node leave lymph node by efferent lymph and go to blood by thoracic duct
    **relevant T cells bind to mature DCs - become activated and proliferate - once adequate number reached - leave lymph node via efferent lymphatic - go to site of infection to deliver effector function (helper or cytotoxic)
  2. Afferent lymph
    * *rare for dendritic cell to get back into blood
90
Q
  1. What turns off or inactivates T cells once pathogen is cleared
  2. What can counter this inhibitor?
A
  1. Checkpoint inhibitors (CTLA4)
    - once T cell begins to express CTLA4 as well as CD28
    - CTLA4 binds with higher affinity to CD80/86 (so that CD28 don’t bind)
    - further T cell activation is inhibited
  2. Anti-CTLA4 antibody (kertruda)
    - blocks the binding of CTLA4 to CD28
    - allow for persistent T cell activation (useful in cancer treatment)
91
Q
  1. What 2 cells can inhibit a T cell response? How?
  • which release TGF beta
  • which secrete arginase
  • which is derived from thymus? Which is induced?
A
  1. A. Suppressor T cells (Tregs)
    - secrete IL10 and TGF beta
    - suppress many function like; antigen processing, presentation or inhibit effector T cell function like cytokine release or killing
    - 2 types of Tregs (NTregs - natural derived in thymus - nonspecific, ITregs - induced - antigen specific inhibition)

B. Myeloid Derived suppressor cells

  • granulocyte or monocytes like
  • ARGINASE; inhibit T cell response
  • Arginin is important for T cell function so arginase reduces arginine
  • Release TGF beta
92
Q

Identify the T cell subsets

  1. Precursor cell, before antigen exposure
  2. CD4 helper, CD8 killer or CD4 suppressor or Treg
  3. Generated at the end of the adaptive response, at the point where the pathogen is cleared
    **3 types
    2 of them circulate in blood and lymph
    1 do not circulated
A
  1. Naive T cells; never seen antigen
  2. Effector T cells; deliver lethal hit (no costimulation required?)
  3. Memory T cell; get turned on quick on subsequent exposure (express IL 2 receptors and divide)
    A. Central memory cells ; can circulate in blood and lymph
    B. Effector memory cells ; can circulate in blood and lymph
    C. Resident memory cells ; DO NOT circulate
93
Q

What is responsible for this?

  • increased expression of CD40 and TNF receptors
  • secrete increased amounts of TNF alpha
  • increased production of NO, O2- superoxide, B7, MHC class II
A

Activated macrophages

**Autocrine stimulus synergized with gamma interferon secreted by Th1 cells to increase antimicrobial activity

94
Q

Identify 4 functions of antibody

A
  1. Neutralization of foreign cells and toxins
  2. Facilitate phagocytosis (opsonization)
  3. Scaffold for complement activation
  4. ADCC (antibody dependent cellular cytotoxicity)
    - antibodies bind to Fc receptor found on NK, macrophages or neutrophils and some cases eosinophils, mast cell and basophils
95
Q

Where does induction of humoral immunity occur

  1. Pathogens in MALT
  2. Pathogens in blood
  3. Pathogens in tissue

*4. What is result of inducing humoral immunity

**what way can you different B cell from T cell

A
  1. MALT - primary follicles become germinal centers. B and T cells interact resulting in antibody production
  2. Blood - white pulp of spleen - germinal centers form
  3. Tissues - draining lymph node, cortical region, germinal center

4*. B cell precursor- plasma cells secreting antibody

**as antibody response continue - AFFINITY MATURATION occurs along with isotype switching (T cell don’t do affinity maturation)

96
Q

Identify 2 types of antibody response

  1. Dont require interaction with T cell or APC. Secrete antibody like IgM - directed against polysaccharide found on bacteria
  2. must interact with antigen specific Tfh helper T cell

**majority of antibody is?

A
  1. T- independent (B1) - innate (inflammation)
    - B1 make natural antibody
    - found in peritoneum
  2. T-dependent (B2) - adaptive - plasma cell - memory cell
    - B2 make most of antibody

**majority of antibody is made by B2 cells

B2 cells Require help from Tfh cells to make majority of antibody (IgM, IgG, IgA, IgE)
◦ Helper T cell (TCR) bind to B cell. Bcell is an APCs which will internalize/process/present antigen. T cell make cytokines and will signal the Bcell and then make the antibodies
◦ CD40 on B cell, CD40L on Tfh cell

MS 2 POD (7 decks)

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