Download doc Immunology Notes From Book

Body Fluids
Physiology: Study of how living organisms work.
Includes the study of individual molecules.

Includes the complex processes that depend on the interplay of many widely separated organs

in the body.
Physiological Genomics: Integration of molecular biology with physiology.
Pathophysiology: Integration of medicine with physiology. Many disease states are also physiology
gone wrong. It is important for pathologists to understand and know physiology to deal with disease.
Cells: Simplest structural units into which a complex multicellular organism can be divided and still
retain the functions characteristic of life.
Certain fundamental activities are common to all cells.

All cells exchange materials with their immediate environment.

200 different types of cells

4 categories of functions:

Muscle

Nerve

Epithelial

Connective

Cell Differentiation: The transformation of an unspecialized cell into a specialized cell.
Muscle cells: Generate the mechanical forces that produce movement.
Surround may tubes in the body. When contracted, they change the diameter of these tubes.

3 categories:

Skeletal

Cardiac

Smooth

Nerve cells: Initiate and conduct electrical signals, often over long distances.
Provide a major way of controlling the activities of other cells.

Epithelial cells: Responsible for the selective secretion and absorption of ions and organic molecules and
for protection.
Located primarily at:

Cover the body or individual organs

Line the walls of carious tubular and hollow structures within the body.

Rest on an extracellular protein layer called the basement membrane.

Form the boundaries between compartments and function as selective barriers regulating the

exchange of molecules.
Cells at the surface of the skin form a barrier that prevents most substances in the external

environment from entering.
Found in glands that form from the invagination of epithelial surfaces.

Connective tissue cells: Connect, anchor and support the structures of the body .
Found in the loose meshwork of cells and fibres underlying most epithelial layers.

Types:

Fat-storing, bone, red blood, white blood

Tissues: Aggregation of specialized cells.
4 types:

Muscle

Nerve

Epithelial

Connective




The immediate environment that surrounds each individual cell in the body is the extracellular
fluid.
Fluid is all between a complex extracellular matrix which is made up of a mixture pf

protein molecules.
The matrix has two main functions:
Allows for cells to attach

Transmits information in the form of chemical messengers to the cells to help regulate

their activities, migration, growth and differentiation.
Consists of collagen fibres and elastin fibres
Collagen constitutes 1/3 of all the body's protein.

They are the communicational links between extracellular chemical messengers and the

cells.
Organs:


Composed of four different types of tissues.
Organized into small, subunits called functional units who perform the organ's function.
Organ system: Collection of organs that perform an overall function
10 organ systems in the body

Refer to page 4 for systems

Extracellular Fluid: The fluid present in blood and in the spaces surrounding cells.
20% of the fluid portion in blood is plasma.

80% is the interstitial fluid.

Plasma exchanges stuff with the interstitial fluid as it flows by so concentrations in both

mediums are virtually the same.
However!! Protein concentration in plasma is much greater than in the interstitial fluid!

Extracellular fluid may be considered as homogeneous though

Intracellular Fluid: The fluid present inside the cells.
Cells regulate their activities by maintaining differences between the two fluids.

Fluids in the body are compartmentalized.
Water

The most important and predominant fluid in the body.


60% of an adult male weighing 70kg.
2/3 is intracellular and 1/3 is extracellular.
Compartmentalization is created by putting barriers around the compartments.
Homeostasis: State of reasonably stable balance between physiological variables.
It is dynamic.

Every organ and organ system contributes in keeping homeostasis.

Everything is interdependent so if 1 system is nonhomeostatic then other system will begin to

fail as well.
Physiology=Homeostatic

Pathophysiology=Lack of homeostasis

It is important to record data over a 24-hour period as many homeostatic systems vary

throughout the day. Ex: Repeated blood measurements. Or a 24 hour cumulative urine sample.
Voluntary behavioural responses are crucial events in homeostasis.

Some homeostatic systems are more important than others so some will be altered to keep the

more important ones constant.
Homeostatic control systems perform regulatory response.
Steady state: System in which a particular variable is not changing however energy is added
continuously to maintain this constancy.
Equilibrium: Variable is not changing but no energy is added.
Set point: The point at which the steady state stops at. For ex: 37C is the set point for the
thermoregulatory system.
Can be reset adaptively. Ex: during a fever, body temperature set point is raised to kill off

pathogens.
Negative feedback system: an increase or decrease in the variable being regulated brings about
responses that tend to move the variable in the opposite direction.
May occur at the organ, cellular or molecular level.

Regulate many enzymatic processes.

Positive feedback system: Accelerates a process.
Less common than negative feedback.

Feedforward regulators: Regulators that anticipate change and act upon it quickly to help the body
achieve homeostasis quicker.
Ex: Faster heartbeat before athletic competitions.

Reflex: Specific involuntary response to a stimuli.
Can be learned or acquired.

Usually associated with a negative feedback system but not necessarily.

Reflex arc: pathway mediating a reflex.
Stimulus: Detectable change in the environment.
Receptor: Detects the environmental change.
Integrating centre: Receives signals from many receptors and outputs instructions.
Sometimes they are the endocrine glands which release hormones to the rest of the body

Afferent pathway: Pathway from receptor to integrating centre.
Effector: Responds to the change.
Muscle and gland are the major effectors of the body.

Efferent pathway: Pathway from integrating centre to effector.
Local homeostatic responses: Initiated by a change in the external or internal environment.
Entire sequence of events occurs only in the area of the stimulus.

Provide individual areas of the body with mechanisms for local self-regulation.

Blood





Composed of formed elements suspended in liquid called plasma
In plasma --> Proteins, nutrients, metabolic wastes
Erythrocytes: Red blood cells
99% of blood cells

Carry oxygen

Leukocytes: White blood cells
Protect against infection and cancer.

Platelets: Cell fragments
Blood-clotting


Hematocrit: Total percentage of red blood cells in blood volume.
Normal hematocrit for women: 42%, men 45%

Plasma volume = Blood volume - Hematocrit



Bulk flow: All blood moving in one direction
Smallest vessels are called capillaries.
Nutrients and wastes diffuse between the blood in the capillaries and the interstitial

fluid.
Between interstitial fluid and cell interior is diffusion and active transport by plasma

membrane.

Two circuits in body:
Pulmonary: Blood from and to lungs

Systemic: Blood from and to rest of body


Arteries carry blood away from heart.
Biggest: Aorta

Veins carry blood to heart.
Biggest: Superior and anterior vena cava.



Microcirculation: System of arterioles, capillaries, venules.

Portal system: Blood passes through two capillary beds before returning to heart.
Water balance
Two sources of water gain:
Water gained from oxidation of organic nutrients (molecules)

Water ingested as liquid and food

Five water loss sites:
Skin

Respiratory passageways

Gastrointestinal tract

Urinary tract

Menstrual flow

Insensible water loss: Continuous water loss from skin and respiratory passageways.
People are unaware and it is involuntary.

No change in body salt and water occurs.

Sweat glands
Secrete electrolytes as well as water

Voluntary and occurs with high work load or high temperatures.

It is a reaction to the relative humidity.

Transport Systems
Diffusion: Movement of molecules from one location to another solely as a result of their random
motion
Flux: Amount of material crossing a surface in a unit of time
Amount of flux depends in on the concentrations

Net-flux : the difference between the two one-way fluxes.
Net amount of material transferred from one location to another.

Depends on a couple of factors

Temperature

Mass of the molecule

Surface area

Medium through which the molecules are moving.



Distance over which molecules diffuse is an important factor in determining the rate.
Diffusion times increase in proportion to the square of the distance over which the molecules
diffuse.

The rate at which diffusion can move molecules within a cell is one of the reasons cells must be
small.

Rate can be measured by monitoring the rate at which its intracellular concentration
approaches diffusion equilibrium

The magnitude of the net flux is directly proportional to the difference in concentration across
the membrane (C0 - Ci), the surface area and the membrane A as well as the permeability
constant.

Permeability constant: Experimentally determined number for a particular type of molecule at a
given temperature.
Greater the Kp, greater the net flux across membrane


Major factor limiting diffusion across a membrane is the hydrophobic interior of its lipid bilayer.
Non-polar molecules have high Kp
Non-polar molecules can dissolve in the non-polar regions of the membrane.

Polar molecules have a much lower solubility in the lipid bilayer.
Increase lipid solubility of substance, increase the solubility, increase the flux.

Oxygen, CO2, fatty acids and steroids are non-polar that diffuse rapidly through membrane.

Ions (Ca, Na, K, Cl)
Integral proteins, each forming a subunit of the walls, form channels that allow ions to pass

through.
Channels are selective for the type of ions that can go through.

Based on channel diameter and on the charged surfaces of the protein subunits that

form the channel walls that electrically attract or repel the ions.
Membrane potential: Different electric charges on both sides of the membrane.
Direction and magnitude of ion fluxes depend on both the electrical and concentration

differences: electrochemical gradient.
Ion channels exist in an open or closed state.
Channel Gating: Process of opening and closing ion channels

Total # of ions that pass through channel depends on how often the channel is open and how

long it stays open.
3 factors that alter channel protein conformation, producing change in the opening frequency or
duration:
1.
Ligand-gated channel: Binding of specific molecules to channel proteins.
2.
Voltage-gated channel: Changes in the membrane potential
3.
Mechanically gated channel: Physically deforming the membrane.
Mediated-Transport:
Integral membrane proteins transport large polar molecules like glucose and amino acids in the

cell. Are called transporters.





# of molecules or ions that are transported are much less than the ion channels.
3 factors influencing flux:
1.
Binding site saturation --> Depends also on solute concentration
2.
# of transporters in membrane
3.
Rate at which the conformational change in transporter occurs.
When binding sites are completely saturated, maximal flux has been reached.
Diffusion flux increases in direct proportion to the increase in extracellular concentration while
in mediated-transport, there is a maximum flux.
Maximal transport flux depends on the rate at which the conformational changes in the
transporters can transfer.
2 types:


Facilitated diffusion:
High concentration to low

Does not require energy

Most important system is the movement of glucose across plasma membrane.

Extracellular glucose concentration is always higher than intracellular glucose

concentration.
Some transporters are influenced by chemical signals such as insulin which increases the

# of glucose transporters in the membrane.
Active transport:
Uses transporter coupled to energy source to go against its electrochemical gradient.

Referred to as pumps

Flux is at max when binding sites are all occupied

2 means of coupling an energy flow to transporters:

1. Direct use of ATP in Primary Active Transport
2. Use of an electrochemical gradient across a membrane in Secondary Active
Transport
Primary Active Transport
Hydrolysis of ATP provides energy

Enzyme (ATPase) catalyzes breakdown of ATP

Phosphorylation of transporter protein changes conformation of transporter and the affinity of

the transporter's solute binding site.
Ex: Sodium, potassium pump.

Other pumps: Calcium ATPase, Hydrogen ATPase, Hydrogen, Potassium ATPase

Try to get calcium concentration inside cell low.

Hydrogen, Potassium pump found in plasma membrane of acid-secreting cells in

stomach and kidneys.
Secondary Active Transport
Use of an electrochemical gradient across plasma membrane as energy source

Move ion and second solute across membrane at same time.

Can be cotransport: Same direction

Can be countertransport: Opposite direction

Usually driven by sodium

Osmosis
Water: polar molecule that diffuses rapidly across most cell membranes.

Through channels formed by proteins called aquaporins

Net diffusion of water across a membrane: Osmosis

Greater the solute concentration, lower the water concentration

Total solute concentration of a solution is known as osmolarity.

Higher osmolarity, lower water concentration

Pressure that must be applied to the solution to prevent the net flow of water into it:

Osmotic pressure
Many solutes are non-penetrating.

85% of the extracellular solute particles are sodium and chloride


Act as non-penetrating solutes because they diffuse in through ion channels and
then are pumped out. So they didn't really move anywhere.
Endocytosis and Exocytosis
Endocytosis: Intracellular, membrane-bound vesicles that enclose a small volume of

extracellular fluid.
Exocytosis: membrane-bound vesicles in cytoplasm fuse with plasma membrane and release

contents to outside of cell.
When the vesicle encloses small volume of extracellular fluid: Fluid endocytosis

When selective molecules bind to specific proteins on the plasma membrane and come in with

fluid: Adsorptive endocytosis.
Pinocytosis: Cell drinking.

Phagocytosis: Cell eating

Only leukocytes carry out phagocytosis

Endocytosis requires energy.

Passage of material is through the formation of vesicles from one organelle and fusion with the

second.
Endosomes: Series of vesicles and tubular elements

Sort, distributes contents of vesicles and its membrane to various locations.

Usually goes from endosomes to lysosomes which contain digestive enzymes that break

down large molecules such as proteins, polysaccharides and nucleic acids
Phagocytosis of bacteria and their destruction by lysosomes is one of the body's main

defence mechanisms versus germs.
Exocytosis has 2 functions:

1.
Provides way to replace portions of plasma membrane and to add new membrane
components
2.
Provides route by which impermeable molecules made by cell can by secreted into the
extracellular fluid.
Travel from Golgi Apparatus to plasma membrane in vesicles from which they can be

released into the extracellular fluid.
Capillary: Thin-walled tube of endothelial cells one layer thick resting on a basement membrane
Capillaries in brain have a second set of cells that surround the basement membrane and affect

the ability of substances to penetrate the capillary wall.
Intercellular cleft: Narrow, water-filled spaces that separate the endothelial tube

Fused-vesicle channels: Endocytotic and exocytotic vesicles fuse

In some tissues and organs, blood enters from vessels called metarterioles.



Contain scattered smooth muscle cells. Surrounded by ring of smooth muscle called
precapillary sphincter.
When contracted, the precapillary sphincter closes entry to capillary completely.
Diffusion Across the Capillary Wall: Exchange of Nutrients and Metabolic End Products


Slow forward movement of blood through the capillaries maximizes the time for substance
exchange across the cap. Wall
3 mechanisms allow substances to move btw the interstitial fluid and blood plasma:
Diffusion

Vesicle transport

Bulk flow

Mediated transport in brain only


Ions and polar molecules are poorly soluble in lipid and must pass through small water-filled
channels in the endothelial lining.
Allows ions and small polar molecules to have high permeabilities.

Channels exist in intercellular cleft.

Fused-vesicle channel penetrate the endothelial cells provide another set of water-filled

channels.
Small amounts of protein can penetrate the endothelial cells by vesicle transport.


Channels have different tightness.
Brain capillaries are tight and have no intercellular clefts.

Liver capillaries which have large intercellular clefts as well as large holes in the plasma

membranes of the endothelial cells so that even protein molecules can pass across them.
Liver functions: Synthesis of plasma proteins, metabolism of substances bound to

plasma proteins.
Membranes
Main function: Act as a selective barrier to the passage of molecules.

Advantage: Can confine products of chemical reactions to specific cell organelles.

Function: Detect chemical messengers arriving at cell surface

Function: Links adjacent cells together by membrane junctions

Function: Anchor cells to the extracellular matrix

Membranes composed of phospholipids (amphipathic)

Fluid mosaic

Contains cholesterol at the polar region of lipid bilayer.

Two types of protein

Integral membrane proteins (also amphipathic)


Transmembrane: Span entire membrane and some form channels for ions or
water. Others help transmit chemical signals across the membrane and help anchor
the extracellular and intracellular protein filaments to the plasma membrane.
Peripheral membrane proteins (Not amphipathic)


Located at membrane surface and bound to polar region of integral proteins.
Influence cell shape and motility

Glycocalyx: Forms a fuzzy sugar-coated layer.




Helps cells identify and interact with each other.
Integrins bind specific proteins in the extracellular matrix and link them to membrane proteins
on adj. cells.
Desmosomes: Region btw 2 cells where the plasma membranes are 20 nm apart and have
accumulated protein at the cytoplasmic surface
Tight-junction: No space in between plasma membranes.
Most epithelial cells are joined by tight-junctions.


Gap junction: Links cytosols of adj cells. 2 to 4 nm of each other.
Forms small protein-lined channels to allows small molecules and ions to pass btw the 2

cells.
Blood
Blood





Composed of formed elements suspended in liquid called plasma
In plasma --> Proteins, nutrients, metabolic wastes
Erythrocytes: Red blood cells
99% of blood cells

Carry oxygen

Leukocytes: White blood cells
Protect against infection and cancer.

Platelets: Cell fragments
Blood-clotting


Hematocrit: Total percentage of red blood cells in blood volume.
Normal hematocrit for women: 42%, men 45%

Plasma volume = Blood volume - Hematocrit



Bulk flow: All blood moving in one direction
Smallest vessels are called capillaries.
Nutrients and wastes diffuse between the blood in the capillaries and the interstitial

fluid.
Between interstitial fluid and cell interior is diffusion and active transport by plasma

membrane.

Two circuits in body:
Pulmonary: Blood from and to lungs

Systemic: Blood from and to rest of body


Arteries carry blood away from heart.
Biggest: Aorta

Veins carry blood to heart.
Biggest: Superior and anterior vena cava.



Microcirculation: System of arterioles, capillaries, venules.

Portal system: Blood passes through two capillary beds before returning to heart.
Capillary: Thin-walled tube of endothelial cells one layer thick resting on a basement membrane
Capillaries in brain have a second set of cells that surround the basement membrane and affect

the ability of substances to penetrate the capillary wall.
Intercellular cleft: Narrow, water-filled spaces that separate the endothelial tube

Fused-vesicle channels: Endocytotic and exocytotic vesicles fuse

In some tissues and organs, blood enters from vessels called metarterioles.

Contain scattered smooth muscle cells. Surrounded by ring of smooth muscle called

precapillary sphincter.
When contracted, the precapillary sphincter closes entry to capillary completely.

Diffusion Across the Capillary Wall: Exchange of Nutrients and Metabolic End Products




Slow forward movement of blood through the capillaries maximizes the time for substance
exchange across the cap. Wall
3 mechanisms allow substances to move btw the interstitial fluid and blood plasma:
Diffusion

Vesicle transport

Bulk flow

Mediated transport in brain only

Ions and polar molecules are poorly soluble in lipid and must pass through small water-filled
channels in the endothelial lining.
Allows ions and small polar molecules to have high permeabilities.

Channels exist in intercellular cleft.

Fused-vesicle channel penetrate the endothelial cells provide another set of water-filled

channels.
Small amounts of protein can penetrate the endothelial cells by vesicle transport.

Channels have different tightness.
Brain capillaries are tight and have no intercellular clefts.

Liver capillaries which have large intercellular clefts as well as large holes in the plasma

membranes of the endothelial cells so that even protein molecules can pass across them.
Liver functions: Synthesis of plasma proteins, metabolism of substances bound to

plasma proteins.
Bulk Flow
Bulk-flow of protein free plasma.

Distribution of extracellular fluid (Plasma and interstitial fluid)

Amount of bulk flow determined by difference btw the capillary blood pressure and the

interstitial fluid hydrostatic pressure.
Also must consider osmotic pressure opposing filtration due to high [protein] in capillary

In bulk flow, small penetrating solutes such as Na, Cl, K (crystalloids) have the same [] in both

fluids.
Plasma proteins (Colloids) are non-penetrating and is very low in interstitial fluid. Hence water

will diffuse to capillary.
Net filtration pressure is determined by 4 factors called Starling forces:

Capillary pressure

Interstitial pressure





Osmotic force due to [plasma protein]
Osmotic force due to [interstitial protein]
Interstitial pressure = approx. 0
Total amount of a substance moving into/out of a capillary due to net bulk flow is minute
compared to diffusion. So, capillary filtration and absorption play no significant role in nutrient
exchange.
Lymphatic System:
Network of small organs and tubes (lymphatic vessels) that lymph flows through.

Lymphatic capillaries: Tubes made of only a single layer of endothelial cells resting on a

basement membrane, but they have large-water-filled channels that are permeable to all the
substances in the interstitial fluid.
Interstitial fluid enters lymph caps by bulk flow.

All lymph goes to 2 large lymphatic ducts that drain into veins near the junction of the jugular

and subclavian veins in the upper chest.
Function: Amount of fluid that filtered out of blood plasma by bulk flow exceeds the daily

uptake by 4L so the 4L of filtered out interstitial fluid is returned to the plasma by the lymphatic
system. Small amounts of protein is also returned to the cardiovascular system.
Edema: Accumulation of a large amount of interstitial fluid (lymph)

Provides pathway by which fat absorbed from gastrointestinal tract reaches the blood.

Smooth muscle in the wall of the lymphatics exerts pumping action by contracting rhythmically.

Smooth muscle responds to stretch, so when there is accumulation, smooth muscle is activated

and starts contracting.
Negative feedback mechanism to prevent edema.

Plasma


Plasma proteins take up most of the plasma solutes by weight.
3 broad groups
Albumins

Globulins

Fibrinogens


Serum: Plasma with no fibrinogen and no blood clotting proteins.
Albumins: Most abundant of the three plasma proteins
Synthesized by liver

Cells do not take up plasma protein, they use plasma amino acids.
Ions contribute much less to the weight of plasma than do the proteins, but they have much higher
molar concentrations.
Blood Cells



Major function of erythrocytes are to carry oxygen taken in by lungs and carbon dioxide
produced by the cells.
Contain a lot of hemoglobin
O2 binds to Fe2+ in hemoglobin molecules.









Average concentration of hemoglobin is 14g/100mL in women and 16g/100mL in men. It is
higher in men because men have testosterone which induces the production of erythropoietin
which stimulates the committed stem cell to become red blood cells.
Erythrocytes have a biconcave disk shape which maximizes the surface to volume ratio.
Erythrocytes' plasma membrane contains specific polysaccharides and proteins that differ from
person to person. This is responsible for the different blood groups.
Erythrocytes are produced in the bone marrow.
Yolk sac --> liver, spleen --> long bones --> Epiphyses of long bones and other.
Reticulocyte: Young erythrocytes that still contain ribosomes that produce hemoglobin.
Gradually stockpile hemoglobin while nucleus and organelles disappear.
Life span: 120 days
Erythrocyte destruction occurs in liver and spleen.
Major breakdown product of hemoglobin is called bilirubin.


Iron: Element to which oxygen binds on a hemoglobin molecule within an erythrocyte.
Low iron: Iron deficiency --> inadequate hemoglobin production

High iron: hemochromatosis

Homeostatic control of iron balance resides primarily in the intestinal epithelium.

Body stores a lot of iron in the liver in a protein called ferritin.

50% of iron is hemoglobin, 25% heme containing proteins and 25% is in liver ferritin.

The iron released from the breakdown of hemoglobin (bilirubin) is bound to a protein

called transferrin which delivers this iron to the bone marrow to be made into new
erythrocytes.
This accounts for 20X the amount the body absorbs and excretes per day.


Folic acid: vitamin found in large amounts in yeast and leafy plants.
Required in the synthesis of thymine.

Essential for DNA formation and for normal cell division.

Fewer erythrocytes are produced when folic acid is deficient.


Vitamin B12: cobalamin
Required for the action of folic acid.

Only found in animal products

Absorption of B12 requires protein intrinsic factor

Lack of this protein results in vitamin B12 deficiency.

Results in erythrocyte deficiency called pernicious anemia


Erythropoiesis: production of red blood cells
Erythropoietin: Hormone that controls erythropoiesis


Acts on the bone marrow to stimulate the proliferation of erythrovyte
progenitor cells and their differentiation into mature erythrocytes.

Secretion rate by kidneys is increased when there is a decreased oxygen delivery
to the kidneys.

Thus, plasma erythropoietin concentration increases, erythrocytes production
increases and the oxygen-carrying capacity of the blood increases.

Anemia: Decrease in the ability of the blood to carry oxygen due to
Decrease in total # of erythrocytes.



Diminished concentration of hemoglobin per erythrocyte
Combination of the above.
Dietary deficiencies of iron, B12 or folic acid
Bone marrow failure due to drugs or cancer
Hemorrhage leading to iron deficiency.
Inadequate secretion of erythropoietin
Excessive destruction of erythrocytes (sickle-cell)

Sickle-cell anemia: Genetic mutation that alters one amino acid in the hemoglobin chain.
Homozygous: Blockage of capillaries with tissue damage and pain. Destruction of the

deformed erythrocytes with consequent anemia.
Persistence of this mutation in humans is due to the fact that heterozygotes are more

resistant to malaria.

Polycythemia: More erythrocytes than normal
Makes flow of blood through blood vessels more difficult.

Leukocytes:
3 types of leukocytes or also called polymorphonuclear granulocytes.
Eosinophils: Take on eosin dye

Basophils: Take on basic dyes

Neutrophils: Little affinity for either dye.

Most abundant kind of leukocyte.

4th kind of leukocyte is the monocyte.
Larger than the granulocyte.

Has horseshoe shaped nucleus.

Has few cytoplasmic granules.

5th kind is the lymphocyte.
Contains little cytoplasm

Has a large nucleus like the monocyte.

Platelets:
Colourless cell fragments that contain numerous granules and are much smaller than

erythrocytes
Produced when megakaryocytes (cytoplasmic portions of large bone marrow cells) break off

and enter circulation.
Regulation of Blood Cell Production

Most of the RBC production occurs in bone marrow.
In children, most bones produce RBCs, however in adulthood, only the chest, the skull

and the epiphysis of the long bones produce erythrocytes.

Pluripotent hematopoietic stem cells: All blood cells are descended from this type of bone
marrow cell.
Undifferentiated cell capable of giving rise to different cells.

1st branching = lymphoid stem cells

2nd branching = myeloid stem cells


Hematopoietic growth factors (HGF) are protein hormones that stimulate the stem cells to
differentiate. Erythropoietin is an HGF.
Physiology of HGF is very complex b/c there are many, HGF are produced by many cells

and HGFs exert other actions in addition to stimulating erythrocyte production.
Inhibit apoptosis of cells

Ex: Erythropoietin is major stimulator but at least 10 other factors contribute.

Erythropoietin is administered in the event that a person has kidney disease and is

unable to produce enough EPO naturally.
Hemostasis: The Prevention of Blood Loss
Hematoma: Accumulation of blood in tissues when a blood vessel has ruptured.

When a blood vessel is injured, it will constrict and slows down the blood in the affected area.

This effect is short-lived except in the capillaries where it is permanent.

The stoppage of bleeding results from 2 mechanisms: Formation of platelet plug and

blood coagulation.
Formation of a Platelet Plug
1.
When endothelial cells are damaged, collagen is exposed. Platelets adhere to the collagen with
the help of a plasma protein called the Von Willebrand factor which is secreted by endothelial
cells and platelets.
i.
vWF makes a bridge between the damaged vessel wall and the platelets.
2.
Binding of platelets to collagen triggers the platelets to release the contents of their secretory
vesicles which contain ADP and serotonin which makes the platelets' surface proteins change
conformation. This is called platelet activation.
3.
Due to these changes, some platelets adhere to old ones in a process called, platelet
aggregation.
i.
This creates a platelet plug.

Adhesion of the platelets causes them to secrete thromboxane A2 which is released into the ECF
and further stimulates platelet aggregation.
Fibrinogen: Plasma protein
Forms bridges between aggregating platelets. The binding sites for fibrinogen on the platelet

plasma membrane are exposed and activated during plasma activation.
Platelets contract as they have high concentrations of actin and myosin.
Causes compression and strengthening of the platelet plug.

Stimulates smooth muscle in damaged vessel to contract.

Adjacent undamaged endothelial cells produce prostacyclin which inhibits platelet aggregation.

Also produce Nitric oxide which is a vasodilator and an inhibitor of platelet adhesion, activation
and aggregation.
Platelet plug is the main mechanism used to seal breaks in vessel walls.
Blood Coagulation: Clot Formation
Transformation of the blood into a solid gel called clot or thrombus.

Composed mainly of protein polymer called fibrin.

Occurs around the original platelet plug and is the main hemostatic defence.

Function: To support and reinforce the platelet plug and to solidify blood that remains in

the wound channel.
Cascade of chemical activations:

Activations consist of splitting a small peptide fragment from the inactive plasma

protein, hence exposing the active site of the enzyme.
Prothrombin is converted to thrombin which causes the plasma protein fibrinogen to

lose several polypeptides. This fibrinogen then binds to each other to form fibrin.
Factor XIII stabilizes the fibrin network.

Thrombin causes a large positive feedback effect in its own production. It also

stimulates platelet activation. This causes platelets to display specific plasma membrane
receptors and display particular phospholipids called platelet factors (PF)
Plasma calcium is required a t various steps and its concentration will never be low

enough to cause clotting defects. Muscle paralysis and cardiac arrhythmias would occur
before.

Essential component of clotting is fibrinogen so clotting can occur in the absence of all cellular
elements except platelets.
2 pathways:
Intrinsic pathway: Named because everything necessary is in the blood.
Extrinsic pathway: Cellular element outside the blood is needed.
 Usual way of initiating clotting.
Hemophilia: Absence of factor VIII
People with liver disease have blood clotting problems because the liver processes or helps the
absorption of vitamin K which is essential in synthesizing blood clotting factors. Liver requires vitamin K
to produce prothrombin and other clotting factors.
Tissue factor --> Factor VII --> VIIa --> Factor X --> Xa --> IX --> Ixa
Anti-clotting systems
Hypercoagulability: Abnormally high risk of clotting.

Tissue factor pathway inhibitor: First anticoagulant mechanism, acts during initiation phase of

clotting. Secreted by endothelial cells.
Prevents tissue factor-factor VIIa to synthesize factor Xa.

This is the reason why the extrinsic factor only generates a little thrombin.


Second anticoagulant: Thrombin
Binds to an endothelial cell receptor call thrombomodulin.

Eliminates all of thrombin's clot-producing effects and causes the bound thrombin to

bind to protein C. This inactivates factors VIIIa and Va.

Third anticoagulant: antithrombin III
Inactivates thrombin when it binds to heparin (substance present on the surface of

endothelial cells)
Prevents spread of a clot by rapidly inactivating clotting factors that are carried away

from the immediate site of the clot by the flowing blood.
Fibrinolytic System
Designed to dissolve a clot after it is formed.

Plasminogen: Plasma proenzyme which is activated into the enzyme plasmin by protein

plasminogen activators.
Plasmin digests fibrin, dissolving the clot.

Tissue plasminogen activator (t-PA): Plasminogen activator that is secreted by endothelial cells.

T-PA binds to fibrin which increases the ability of t-PA to catalyze the generation of plasmin

from plasminogen.
Anti-clotting Drugs
Prevention and treatment of myocardial infarction.

Aspirin inhibits thromboxanes meaning it is a blood thinner.

Oral anticoagulants: drugs that interfere with the action of vitamin K.

Thrombolytic therapy: Plasminogen activators dissolve a clot after it is formed.

Recombinant t-PA, streptokinase: Intravenous administration significantly reduces myocardial

damage
Bat saliva found to be even more effective: Desmodus rotundus salivary plasminogen activator.

Immunology
Immunology: Study of how the body defends itself against foreign matter.
Protects against infection by microbes: viruses, bacteria, fungi and parasites

Isolates or removes non-microbial foreign substances

Destroys cancer cells that arise in the body: Immune surveillance

Classified into two categories:
Nonspecific immune defences:
 Protect against foreign substances or cells without having to recognize them.
Specific immune defences:
 Depend upon specific recognition, by lymphocytes, of the substance or cell to be
attacked.
 An unique attack for that substance or cell to be attacked.
Two categories function together. Example: the non-specific immunity provides instructions
that enables the specific responses to select appropriate targets.
Bacteria: Unicellular organisms that have an outer coating (the cell wall) in addition to a plasma
membrane.
Damage tissues at the sites of replication

Release toxins that enter the blood

Viruses: Nucleic acids surrounded by a protein coat.
Lack enzyme machinery for metabolism.

Immune system: cells that carry out immune defenses collectively.
Diverse collection of cells found in both the blood and lymph.

Leukocytes: Most numerous of the immune system cells.
Include neutrophils, basophils, eosinophils, monocytes and lymphocytes.

Neutrophils, basophils and eosinophils are polymorphonuclear granulocytes.

Plasma cells: Found in tissues in which they differentiate from their parent lymphocytes.
To synthesize and secrete antibodies.

Macrophages: Found in all organs and tissues.
Derived from monocytes that pass through the walls of blood vessels to enter the

tissues.
Function: Engulf particles and microbes

Found in large numbers in the various epithelia in contact with the external

environment
Dendritic cells: Engulf particles and microbes
Mast cells: Found throughout connective tissues, beneath epithelial surfaces of the body.
Made from the differentiation of bone marrow cells.

Not found in the blood.

They have large numbers of vesicles which secrete histamine (chemical messenger)

Lymphocytes:
Are recognition cells and are responsible for identifying threats which start the immune

responses.
Monoytes, neutrophils, macrophages and dendritic cells secrete inflammatory mediators and
undergo phagocytosis. They eat the invaders.
Cytokines: protein messengers that regulate cell division and have functions in specific and nonspecific immune defences.
Produced by a variety of indv. cells.

Their actions occur at the site of cytokine secretion.

Can circulate in the blood to exert hormonal effects on distant organs and tissues

involved in host defenses.
Link the immune system together; they are the chemical communication network. They

are responsible for the cross-talk which is essential for the precise timing of the functions of
the immunes system.


Most cytokines are secreted by more than one type of immune system cell and by
nonimmune cells as well, generating a cascade of cytokine secretion.
Also involved in nonimmunological processes such as bone formation.
Non-specific Immune Defenses
Protect against foreign cells or matter without having to recognize.

Recognize some general property marking the invader.

Most common identity tags are often found in particular classes of carbohydrates or

lipids that are in microbial cell walls.
Specific --> Proteins

Body's 1st line of defence is the barrier offered by surfaces exposed to the external environment.
Skin, tear and salivary glands all produce antimicrobial chemicals which may include

antibodies, enzymes such as lysozyme and lactoferrin (iron-binding protein)
Mucus secreted by epithelial linings also contains antimicrobial chemicals and is sticky.

Thus, particles are stuck and are prevented from entering blood.
Hair in nose, the cough and sneeze reflex and the acid secretion of the stomach also kills

microbes.
Inflammation: Response to infection or injury.
Function: to Destroy or inactivate foreign invaders and prepare tissue repair.

Key player: Phagocytes

Most important phagocytes: Neutrophils, macrophages and dendritic cells.

Occurs in the nonspecific defences caused by the invasion of microbes.

1.
2.
3.
4.
5.
6.
Entry of bacteria into tissues. Injury to tissues causes release of chemicals to initiate a chain
reaction.
Vasodilation of the microcirculation in the infected area. Increased blood flow.
Large increase in protein permeability in the infected area. Filtration of fluid and proteins into
ISF.
Chemotaxis: Leukocytes move from venules into interstitial fluid of infected area.
Destruction of bacteria in the tissue either by phagocytosis or by other processes.
Tissue repair.
Symptoms of tissue injury and inflammation:
Local redness, swelling, heat and pain.

These events are induced by a huge number of chemical mediators.

Any mediator may induce more than 1 event.

2 categories:

Peptides

Substances secreted into the ECF from cells that either already exist in the

infected area or enter it during inflammation.
Some mediators cause microcirculation to dilate and be more permeable to proteins.
Increased blood flow to the inflamed area, increases the delivery of proteins and

leukocytes.
Increased permeability to protein ensures that plasma proteins that participate in

inflammation can get to the interstitial fluid.

However, this causes net filtration of plasma into the ISF and causes the development of
edemas. This is why there is swelling in an inflamed area.
With inflammation, neutrophils move out of blood and through the endothelium into the inflamed
area.
Involves adhesion molecules.

Regulated by messenger molecules (chemoattractants) released by cells in injured area.

1.
2.
Margination: Neutrophil attaches to the endothelial cells by adhesion molecules present on
both cells.
Exposes neutrophil to chemoattractants.

Diapedesis: Neutrophil squeezes through the endothelial wall and into the interstitial fluid.
They then migrate to the site of tissue damage.

Neutrophils get there first but then macrophages get there later.

Multistep chemotaxis provides selectivity and flexibility for the migration of the various

leukocytes.
Once neutrophils and other leukocytes arrive at site of injury, they begin phagocytosing the
invading microbes.
1st step: Contact between the surfaces of the phagocyte and microbe.

interaction of phagocyte receptors with certain carbohydrates or lipids in the microbial

cell walls.
Chemical factors produced by the body can bind the phagocyte tightly to the microbe

and thereby enhance phagocytosis. (Opsonin)
Microbe-containing sac: phagosome

Phagosome encounters lysosome and fuse forming a phagolysosome

Inside, the enzymes produce nitric oxide and hydrogen peroxide which kill the

microbe.

Phagocytes can also release antimicrobial substances into the extracellular fluid.


Final stage of inflammation is tissue repair.
Fibroblasts divide rapidly and being secreting large amounts of collagen.
Interferons: Family of cytokines that nonspecifically inhibit viral replication inside host cells.
When infected, cells produce interferons and secrete then in the ECF. They bind to

plasma membrane receptors on the secreting cell and other cells.
This triggers the synthesis of dozens of different antiviral proteins by the cell which

interfere with viral replication.
Not specific

Lymphocytes:
Essential cells in specific immune defences.

Must recognize the foreign matter to attack.

Antigen: any foreign molecule that can trigger an immune response against itself or the

cell.
Most are proteins or very large polysaccharides





Specific immune response can be divided into 3 stages
encounter and recognition of an antigen by lymphocytes
Lymphocyte activation
Attack launched by the activated lymphocytes and their secretions
Each lymphocyte is specific for just one type of antigen. Its daughter cells are called clones and are
specific for only that one type of antigen.
Binding of antigen to receptor must occur for lymphocyte activation. The original binding of
antigen by a single lymphocyte triggers multiple cycles of cell divisions. (Clonal expansion)
Some leukocytes will be effector lymphocytes while other will be set aside as memory cells.
Activated B cells: differentiate into plasma cells which secrete antibodies.
Antibodies recruit and guide other molecules and cells to attack.

Activated cytotoxic T cells: Directly attack and kill the cells bearing the antigens.
Once immune response is over, the majority of the B cells, plasma cells, helper T cells

and cytotoxic T cells that participated, die by apoptosis.
This prevents the immune response from being excessive and possibly destroying itself.

Memory cells survive

Lymphoid Organs:
Primary: Bone marrow and thymus

Supply the secondary lymphoid organs with mature lymphocytes

Secondary: Lymph nodes, spleen, tonsils, etc.

Lymphocytes get activated here

Thymus: Upper part of chest
Consists of mature lymphocytes that are released into blood that go to secondary

lymphoid organs.
Lymph is the route by which lymphocytes in the lymph nodes encounter the antigens

that activate them.
Lymph nodes contain lymphocytes and macrophages

There is recirculation of lymphocytes. However, in contrast, the polymorphonuclear granulocytes
and monocytes do not recirculate. Once they leave the bloodstream, they remain in the tissue or
die.