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Physical Characteristics of Blood
• Thicker (more viscous) than water and flows more slowly than
water
• Temperature of 100.4 degrees F
• pH 7.4 (7.35-7.45)
• 8 % of total body weight
• Blood volume
– 5 to 6 liters in average male
– 4 to 5 liters in average female
– hormonal negative feedback systems maintain constant blood volume and
osmotic pressure
Components of Blood
• Hematocrit
– 55% plasma
– 45% cells
• 99% RBCs
• < 1% WBCs
and platelets
Blood components
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55% plasma: 7 to 8% dissolved substances (sugars, amino acids,
lipids & vitamins), ions, dissolved gases, hormones
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ions are involved in membrane excitability, determination of fluid pH
and osmotic pressure
most of the proteins in plasma are plasma proteins: provide a role in
balancing osmotic pressure and water flow between the blood and
extracellular fluid/tissues
loss of plasma proteins from blood – increases osmotic pressure in
blood and results in water flow out of blood into tissues – swelling
do not exit the blood due to their size – creates a protein gradient
between blood and interstitial fluid
partially responsible for the plasma’s capacity to buffer pH
most common plasma proteins: albumin, globulins, clotting proteins
(fibrinogen)
• albumins – most abundant
• globulins – three classes
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alpha, beta and gamma
• fibrinogen – cleaved by thrombin to produce a very stick
mass of fibers made of fibrin
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participate in clot formation
Blood: Cellular elements
• 45% of blood is the cellular elements or formed elements
• 99% of this is erythrocytes or RBCs
– formed by differentiation of hematopoietic stem cells (HSCs) in the red bone
marrow of long bones and pelvis – makes about 2 million per second!
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immature RBCs = reticulocytes
still possess a nucleus and organelles
lack mitochondria and cannot use the oxygen they transport for ATP synthesis
maturation of the reticulocyte causes loss of nucleus and organelles and the filling of
the RBC with close to 250 million Hb molecules
• also contain crucial erythrocytic enzymes
– 1. glycolytic enzymes
– 2. carbonic anhydrase – converts the soluble form of CO2 (HCO3 in carbonic acid) into
CO2 gas at the lungs and CO2 gas into HCO3 at the tissues
– most numerous cell type in the body – 4 to 6 million per ul blood
– flat, biconcave discs
• provides a larger surface area for diffusion of oxygen across their membrane
• thinness of the membrane allows rapid diffusion
• very flexible membrane that allows their deformation for travel through thin
capillaries
Hematopoiesis
Erythrocytes: Red Blood cells & their
development
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hemoglobin
pigment – naturally colored that is red due to its iron content
combines with
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oxygen
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carbon dioxide
the acidic portion of carbonic acid
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four, highly folded protein chains
2. heme component
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binds to Hb in the lungs where it vasodilates pulmonary arterioles to ensure efficient transport of
oxygenated blood from the lungs back to the heart
composed of a:
1. globin portion
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occupies the oxygen binding sites
nitric oxide
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oxidation of CA occurs at the tissue level
carbon monoxide
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binding sites
four molecules of iron-based heme bound to each globin protein chain
each heme can bind one oxygen – total binding capacity of 4 oxygen molecules per Hb
Erythropoiesis
• produced first by the yolk sac
• then from myeloid stem cells in the red bone marrow
• controlled at the level of the kidneys by the secretion of erythropoietin (EPO)
– increased differentiation of the myeloid stem cell
– release of mature RBCs or, if needed, the release of reticulocytes
– synthetic EPO – can now be made in the lab
• used to boost RBC production during chemotherapy, diminishes the need for transfusions
• role in blood-doping
Feedback Control of RBC Production
• Tissue hypoxia (cells not getting
enough O2)
– high altitude since air has less O2
– anemia
• RBC production falls below RBC
destruction
– circulatory problems
• Kidney response to hypoxia
– release erythropoietin
– speeds up development of
proerythroblasts into reticulocytes
RBC life-span and recycling
– RBC lives only about 120 days – destroyed by macrophages in the liver, bone marrow and
spleen
– most RBCs are destroyed in the spleen – small vessels tend to lyze the fragile RBCs as they
travel through this organ
– 1. liver/spleen/bone marrow degrades the hemoglobin to its globin component and heme
– 2. heme is degraded into free iron and biliverdin – Fe released into the blood
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transported in blood attached to transferrin protein (4&5)
stored in liver, muscle or spleen (6)
attached to ferritin or hemosiderin protein
sent to the bone marrow for hemoglobin synthesis (7&8)
– 9. biliverdin is converted into bilirubin in the liver (11) which travels to the small intestine in
the bile where it is converted into a series of compounds – end up expelled in urine as urobilin
(13) or in the feces as stercobilin (14)
Hematocrit
• Percentage of blood occupied by cells – since
RBCs are 99% of these cells, hematocrit is a
measurement of RBC count
– female normal range
• 38 - 46% (average of 42%)
– male normal range
• 40 - 54% (average of 46%)
• testosterone
Polycythemia
– too many RBCs (hematocrit over 65%)
– dehydration, tissue hypoxia, blood doping in athletes
– primary polycthemia
• caused by a tumor-like condition of the bone marrow
• overproduction of RBCs through increased differentiation of the myeloid stem
cell
• too many RBCs can increase the viscosity of the blood and result in dramatic
decreases in blood pressure as frictional forces in the vessels increase – increases
the workload of the heart
• increased viscosity also slows the velocity of blood flow - reduce oxygen
delivery to tissues
– secondary polycthemia
• appropriate EPO-induce adaptive mechanism to improve the blood’s oxygen
carrying capacity
• occurs at high altitudes or in people with chronic lung diseases
Anemia
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Symptoms
– oxygen-carrying capacity of blood is reduced
– fatigue, cold intolerance & paleness
• lack of O2 for ATP & heat production
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Types of anemia
– iron-deficiency = lack of absorption or loss of iron
• type of nutritional anemia
• failure to take in essential raw ingredients not made by the body
– pernicious = lack of intrinsic factor for vitamin B12 absorption from the digestive tract
• B12 is essential for normal RBC formation and maturation
• binding of B12 to intrinsic factor allows its absorption
• intrinsic factor – synthesized by the small intestine
– hemorrhagic = loss of RBCs due to bleeding (ulcer)
– hemolytic = defects in cell membranes cause rupture
• rupture of too many RBCs by external factors such as malaria (normal RBCs) or genetic disorders like
sickle cell anemia (defective RBCs)
– thalassemia = hereditary deficiency of hemoglobin
– aplastic = destruction of bone marrow (radiation/toxins)
• failure of the bone marrow to produce enough RBCs
• may selectively destroy the ability to produce RBCs only
• but may also destroy the myeloid stem cells – affect WBCs and platelets
Sickle-cell Anemia (SCA)
• Genetic defect in hemoglobin molecule (Hb-S)
that changes 2 amino acids in the globin protein
– at low very O2 levels, RBC becomes deformed by
changes in hemoglobin molecule within the RBC
• sickle-shaped cells do not pass through capillaries well
and get stuck = causing occlusions and decreased
blood flow to organs
• also rupture easily = causing anemia & clots
• Found among populations in malaria belt
– Mediterranean Europe, sub-Saharan Africa & Asia
• Person with only one sickle cell gene
– increased resistance to malaria because RBC
membranes leak K+ & lowered levels of K+ kill the
parasite infecting the red blood cells
Blood disorders
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http://members.aol.com/Sheffbp/products/bludphys.htm (Simulation of anemia
diagnosis)
http://www.udel.edu/Biology/Wags/histopage/colorpage/ch/ch.htm
(Hematopoiesis)
http://www.bloodline.net (Hematology education and news)
http://www.thrombosis.net/lframes/intro.htm (Introduction to thrombosis)
http://www.vh.org/adult/patient/cancercenter/blooddisorders/index.html
(Blood disorders)
http://www.bmtnews.org (Blood and Marrow Transplant Information
Network)
http://www.psbc.org/hematology (Introduction to hematology)
http://www.pediatrics.emory.edu/ (Sickle cell anemia)
http://www.bloodjournal.org (Journal of the American Society of Hematology)
http://medir.ohsu.edu/cliniweb/C15/C15.378.html (Blood protein disorders)
Blood Groups and Blood Types
• RBC surfaces are marked by genetically
determined glycoproteins & glycolipids
– agglutinogens or isoantigens
– distinguishes at least 24 different blood groups
• ABO, Rh, Lewis, Kell, Kidd and Duffy systems
RH blood groups
• Antigen was discovered in blood of Rhesus monkey
• People with Rh agglutinogens on RBC surface are
Rh+. Normal plasma contains no anti-Rh antibodies
• Antibodies develop only in Rh- blood type & only
with exposure to the antigen
– transfusion of positive blood
– during a pregnancy with a positive blood type fetus
• Transfusion reaction upon 2nd exposure to the
antigen results in hemolysis of the RBCs in the
donated blood
Hemolytic Disease of Newborn
• Rh negative mom and Rh+ fetus will have mixing of blood at birth
• Mom's body creates Rh antibodies unless she receives a RhoGam shot
soon after first delivery, miscarriage or abortion
– RhoGam binds to loose fetal blood and removes it from body before she reacts
• In 2nd child, hemolytic disease of the newborn may develop causing
hemolysis of the fetal RBCs
Thrombocytes: Platelets & clotting
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Disc-shaped, 2 - 4 micron cell fragment with no nucleus
– not whole cells!
– do have organelles and cytosolic enzymes for generating energy from glucose
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Normal platelet count is 150,000-400,000/drop of blood
Platelets form in bone marrow by following steps:
– myeloid stem cells to megakaryocyte-colony forming cells to megakaryoblast to
megakaryocytes whose cell fragments form platelets
– one megakaryocyte forms 1000 platelets
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Short life span (5 to 9 days in bloodstream)
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formed in bone marrow
few days in circulating blood
aged ones removed by fixed macrophages in liver and spleen
30% of platelets are stored in the spleen – in blood-filled spaces since platelets do
not leave the blood
Platelet Plug Formation
• hemostasis = arrest of bleeding from a broken vessel
– 3 steps:
– 1) vascular spasm – constriction of smooth muscle layer in damaged vessel
• intrinsic response triggered by physical damage
– 2) platelet plug formation
– 3) blood clotting
• Platelets store chemicals in granules needed for platelet plug formation
– platelets do not stick to the smooth endothelium
– damage to the endothelial lining exposes collagen fibers to the platelet – results
in their activation and adhesion to the collagen fibers to form a plug
– alpha granules
• clotting factors –clot formation
• platelet-derived growth factor – repair of damaged vessel wall
– dense granules
• ADP, ATP, Ca+2, serotonin, fibrin-stabilizing factor, & enzymes that produce
thromboxane A2
– thromboxane – chemotactic factor for other platelets – platelet aggregation
– ADP causes circulating platelets to become sticky – adhere to the first layer of aggregating
platelets – results in the secretion of more ADP by the incoming platelets
– release of serotonin, epinephrine and thromboxane act as vasoconstrictors to reinforce the
initial vascular spasm
– aspirin – inhibits COX enzyme which inhibits the production of thromboxane A2
Platelet Plug formation
Steps in the process:
(1) platelet adhesion & activation – by
collagen interaction
(2) platelet release reaction – from their
storage granules
-Release thromboxane A2 & ADP arrival and activation of other platelets
-Serotonin & thromboxane A2 are also
vasoconstrictors decreasing blood flow
through the injured vessel
(3) platelet aggregation – self-perpetuating
-inhibited at a specific level by the release
of inhibiting factors by the adjacent
normal endothelium
-actin-myosin interactions contract within
the aggregating platelets – strengthens the
plug
-plug becomes reinforced through the
formation of sticky fibrin strands
Blood Clotting
– in a test tube gel separates into liquid (serum) and a clot of insoluble fibers
(fibrin) in which the cells are trapped
– in the body the clot stabilizes the weaker platelet plug and initiates healing
– ultimate step is conversion of fibrinogen (soluble plasma protein) into
insoluble fibrin
• Substances required for clotting are Ca+2, clotting factors and
plasma proteins from the liver and substances released by
platelets or damaged tissues
• Clotting is a cascade of reactions in which each clotting factor
activates the next in a fixed sequence resulting in the formation
of fibrin threads
– prothrombinase & Ca+2 convert prothrombin into thrombin
– thrombin converts fibrinogen into fibrin threads
Overview of the Clotting Cascade
-may be triggered through two possible
paths
1. extrinsic pathway
2. intrinsic pathway
-either path leads to activation of the
final pathway in which thrombin
cleaves fibrinogen to form fibrin
Extrinsic Pathway
• short-cut to clot formation
• requires contact with tissue factors
produced externally from the blood
• damaged tissues produce and release
Tissue Factor or thromboplastin
into bloodstream
• In the presence of Ca+2, clotting
factor X becomes activated and
combines with clotting factor V to
form prothrombinase
• Prothrombinase forms in seconds
Intrinsic Pathway
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drives clotting in damaged vessels and also induces
clotting in blood samples in test tubes
Activation of this pathways occurs either when:
– endothelium is damaged & platelets come in contact
with collagen of blood vessel wall – initiates plug
formation by activated platelets
– OR platelets themselves become damaged & release
phospholipids which activate incoming platelets
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Requires several minutes for reaction to occur –
occurs concurrently with platelet plug formation and
the extrinsic pathway
Substances involved: Ca+2 and clotting factors XII,
X and V
first factor – Factor XII (Hageman factor)
activated by contact with exposed collagen or glass
surfaces
activated Factor XII requires calcium – which then
combines with Factor V to produce prothrombinase
Final Common Pathway
• activated prothrombinase and Ca+2
– catalyze the conversion of prothrombin to
thrombin
• Thrombin
– in the presence of Ca+2 converts soluble
fibrinogen to insoluble fibrin threads
– activates fibrin stabilizing factor – clotting
factor XIII
• stabilizes the forming fibrin mesh
– positive feedback effects of thrombin
• accelerates formation of prothrombinase
• activates platelets to release phospholipids which
acts to activate more Factor X and therefore
produces more thrombin (positive feedback)
• also acts to promote platelet aggregation
Clotting: A summary
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Platelet
aggregation
Clot Retraction & Blood Vessel Repair
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Fibroblasts & endothelial cells repair the blood
vessel
– Formation of PDGF
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release of the fibrinolytic enzyme plasmin
dissolves the clot
– plasmin – plasma protein present in the blood
as inactive plasminogen
– activated by Factor XII
– plasminogen becomes trapped in the forming
clot, becomes activated to plasmin and
slowly dissolves the clot as the tissue repairs
itself
Role of Vitamin K in Clotting
• Normal clotting requires adequate vitamin K
– fat soluble vitamin absorbed if lipids are present
– absorption slowed if bile release is insufficient
• Required for synthesis of 4 clotting factors by the
hepatocytes
– factors II (prothrombin), VII, IX and X
• Produced by bacteria in large intestine
• anti-coagulants called the coumarin drugs (heparin and
warfarin) act by competing with vitamin K in the liver
– inhibits the formation of the vitamin K-dependent clotting factors
Clotting Disorders: Hemophilia
• Inherited deficiency of clotting factors
– bleeding spontaneously or after minor trauma
– subcutaneous & intramuscular hemorrhaging
– nosebleeds, blood in urine, articular bleeding & pain
• Hemophilia A lacks factor VIII (males only)
– most common
– over 150 point mutations in the DNA identified
– factor VIII acts as a cofactor for the activation of factor X
• Hemophilia B lacks factor IX (males only)
– less common
– over 300 mutations in the DNA identified
• Hemophilia C (males & females)
– less severe because alternate clotting activators exist
• Treatment is transfusions of fresh plasma or concentrates of the missing clotting
factor
Clotting Disorders
• If clotting occurs in an unbroken vessel is called a thrombosis
– clots can form in undamaged vessels if the body’s clotting and anti-clotting
mechanisms are not kept balanced and in check
– inappropriate clot attached to a vessel wall = thrombus
– freely floating clot = embolus
– thrombosis can result from several factors
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1. roughening of the endothelial lining during arterosclerotic plaque formation
2. slow moving blood
3. unbalanced fibrin-plasmin production
4. widespread release of thromboplastin by tissues
• Disseminated Intravascular Clotting :
– Life threatening paradoxical presence of blood clotting and bleeding at
the same time throughout the whole body
– so many clotting factors are removed by widespread clotting that too
few remain to permit normal clotting
– Associated with infections, hypoxia, low blood flow rates, trauma,
hypotension & hemolysis
– Clots cause ischemia and necrosis leading to multisystem organ failure
Immunity
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Immunity: ability of the body to defend itself from infectious agents, foreign cells,
cancer cells
immune system has two functional divisions
innate immune system
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non-specific immunity
cell-mediated and humoral (secreted) mediated
chemical and physical barriers
chemical: complement and inflammation
no memory
all forms of life
adaptive immune system
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pathogen and antigen specific response
cell-mediated and humoral mediated
chemical barriers
memory results
only jawed vertebrates
1) Non-specific defenses: Innate immunity
A)Mechanical barriers: first line of defense
- Skin and mucus membranes lining the respiratory tract, digestive & reproductive
systems
e.g. ciliated epithelium of respiratory system - coated with mucus, coughed out
B) Chemical barriers (humoral mediated defense): first line of defense
-acidic pH of the stomach interior
-E.coli within the small intestine
-gastric enzymes in gastric juice
-high salt in perspiration kills some bacteria
C) Fever: second line of defense
-secretion of pyrogen by lymphocytes - raises body temp
-rise in body temp enhances the phagocytic activity of immune cells
D) Inflammation & complement: second line of defense
E) Phagocytosis by phagocytic cells (cell-mediated defense)
-dendritic cells, macrophages, neutrophils
-cells of the innate system: WBCs with the exclusion of the T and B lymphocytes
Complement
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group of about 20 proteins who control
inflammation
several of these proteins are called acute
phase proteins (serum proteins that
dramatically increase upon infection)
complement proteins interact with many
components of both the innate and
adaptive immune systems
similar to a blood clotting system – one
complement protein activates another which
activated another etc…..
functions
– 1. attraction of phagocytes upon activation
of the pathway – chemotaxis
– 2. coating of foreign cells with complement
– recognition of the foreign particle by the
incoming phagocytes
– 3. intrinsic ability to coat bacteria
(opsonization) and lead to their lysis
Inflammation:
1) injury to tissue
2) release of histamine and kinins (pain) by damaged cells – along with prostaglandins
3) histamine - dilation of capillaries & increased blood flow
-histamine causes the gaps between endothelial cells to widen to allow the
passage of larger molecules – immune cells and complement proteins
4) delivery of proteins (e.g .clotting, immune cells), increase of fluid in damaged area,
reddening of skin – swelling/edema
5) migration of neutrophils and monocytes/macrophages (WBCs) via
capillaries - phagocytosis of foreign particles
6) clotting response by blood - cascade/positive feedback - to minimize blood loss
7) macrophages release Colony stimulating factors - differentiation of more WBCs
by the bone marrow and increased distribution systemically
8) production and release of lymphocytes from lymph nodes - travel to infection
site
-anti-inflammatories (ibuprofen, aspirin, cortisones) can be administered to combact
chronic or persistent inflammation
-act against chemicals produced by WBCs and prostaglandins made by
damaged cells
-anti-histamines - block the binding of histamine to receptors
WBCs
• cells of the lymphoid lineage
– T and B lymphocytes
• cells of the myeloid lineage
– phagocytes and other cells
-Leukocytes are 1% of the total cellular elements
- found in the Buffy coat together with the platelets:
-granular and agranular classification
-neutrophils: phagocytic properties
-release lysozymes which destroy/digest bacteria
-release defensin proteins that act like antibiotics & poke holes in
bacterial cell walls destroying them
-release strong oxidants (bleach-like, strong chemicals ) that destroy
bacteria
- releases cytokines that attract other neutrophils
-eosinophils: parasitic defense cells
-also involved in the allergic response
-release histaminase
slows down inflammation caused by
basophils
-basophils: heparin, histamine & serotonin
-heighten the inflammatory response and account for
hypersensitivity (allergic) reaction
-monocytes: enter various tissues and
differentiate into phagocytic macrophages
-lymphocytes: T and B cells
Leukocytes: White
Blood cells & the
Immune system
WBC Physiology
• Less numerous than RBCs
– 5000 to 10,000 cells per drop of blood
– 1 WBC for every 700 RBC
• Leukocytosis is a high white blood cell count
– microbes, strenuous exercise, anesthesia or surgery
• Leukopenia is low white blood cell count
– radiation, shock or chemotherapy
• Only 2% of total WBC population is in circulating
blood at any given time
– rest is in lymphatic fluid, skin, lungs, lymph nodes &
spleen
Lymphatic & Immune System
Lymphatic system: system of lymphatic vessels and organs
-multiple functions
1. defense against disease – lymph flows through lymph nodes
-the lymph is filtered by the nodes and microorganisms are
destroyed
2. transport of absorbed fat
3. return of filtered proteins – return of plasma proteins that
have leaked from capillaries
-larger lymphatic vessels are similar to blood vessels - presence of valves
-lymphatic vessels - for the transport of lymph
-lymph: filtrate produced in tissues and NOT reabsorbed by the
CV system
-lymphatic capillaries join to form lymphatic
vessels
-lymphatic vessels join to form:
1) thoracic duct
2) lymphatic duct
- Right side head, arm & chest empty into lymphatic
duct and rest of body empties into thoracic duct
-then dumped directly into left & right subclavian veins
-lymphatic system is ONE WAY
(from tissues to heart)
Lymphatic organs:
1) lymph nodes: found at certain points along the lymphatic system
-for the cleaning of lymph
-capsule surrounding an outer cortex and inner medulla
-cortex contains immune cells = lymphocytes (fight pathogens)
-medulla contains immune cells = macrophages (clean lymph)
2) tonsils: lymphatic tissue located in the pharynx (adenoids) or oral cavity (palatine tonsils)
-defense against pathogens ingested through food and drink
3) spleen: upper left region of the abdomen
-cleanses the blood
-capsule, white and red pulp
-white pulp contains lymphocytes
-red pulp contains red blood cells & macrophages
4) bone marrow (red): adult - within the spongy bone of the epiphyses, pelvis, skull, clavicle, sternum
-site of origin for all blood cells (RBCs, WBCs)
-derived from hematopoietic stem cells (hematopoiesis)
-also the site of origin for all mesodermal cells (bone, muscle, cartilage, fat…..)
-derived from mesenchymal stem cells
5) thymus gland: located below the trachea, on top of the heart
-divided into lobules
-larger in children
-production of T lymphocytes
-production of hormones - thymosin - stimulates the lymphocytes located in other tissues
Cells of Innate and Adaptive
Immunity: Phagocytes
• one of the first cells to arrive upon inflammation
• Two major kinds: monocytes/macrophages and
polymorphonuclear granulocytes (neutrophils)
• attracted through the process of chemotaxis (soluble
chemicals that attract cells)
• need a method of recognizing the foreign antigen – use
antibodies/immunoglobulins (macrophages)
• or can use non-specific attachment to microorganisms
(neutrophils)
• Phagocytosis enhanced if the microorganism has been
coated with complement protein
Cells of Innate and Adaptive Immunity: Neutrophils
(Polymorphonuclear Granulocytes)
• are over 90% of the circulating granulocytes
• Nuclei = 2 to 5 lobes connected by thin strands
– older cells have more lobes
– young cells called band cells because of horseshoe shaped nucleus (band)
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Fine, pale lilac practically invisible granules
Diameter is 10-12 microns
Fastest response of all WBC to bacteria
Direct actions against bacteria
– release lysozymes which destroy/digest bacteria
– release defensin proteins that act like antibiotics & poke holes in bacterial cell
walls destroying them
– release strong oxidants (bleach-like, strong chemicals ) that destroy bacteria
Cells of Innate and Adaptive
Immunity: Monocyte (Agranulocyte)
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two main functions
– 1. “professional” phagocytic macrophages – derived from monocytes
– 2. antigen-presenting cells
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Nucleus is kidney or horse-shoe shaped
Largest WBC in circulating blood
– does not remain in blood long before migrating to the tissues
– differentiate into macrophages
– form the reticuloendothelial system (RES)
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Destroy microbes and clean up dead tissue following an infection
fixed group found in specific tissues
Or as “wandering cells” gathers at sites of infection
express an Fc receptor on their surface – important for recognizing the foreign microorganism
Diameter is 12 - 20 microns
Cytoplasm is a foamy blue-gray
3 to 8% of circulating WBCs – form a circulating pool of monocytes
Take longer to get to site of infection, but arrive in larger numbers
Cells of Innate and Adaptive Immunity:
Eosinophils (Granulocyte)
• Nucleus with 2 or 3 lobes connected by a thin strand
• Large, uniform-sized granules stain orange-red with acidic
dyes
– do not obscure the nucleus
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Diameter is 10 to 12 microns
2 to 4% of circulating WBCs
Leave capillaries to enter tissue fluid
Release histaminase
– slows down inflammation caused by basophils
• Attack parasitic worms
• Phagocytize antibody-antigen complexes
Cells of Innate and Adaptive
Immunity: Basophils (Granulocyte)
• Large, dark purple, variable-sized granules stain with basic
dyes
– obscure the nucleus
• Irregular, s-shaped, bilobed nuclei
• Diameter is 8 to 10 microns
• Less than 1% of circulating WBCs
• Involved in inflammatory and allergy reactions
• Leave capillaries & enter connective tissue as mast cells
• Release heparin, histamine & serotonin
– heighten the inflammatory response and account for hypersensitivity
(allergic) reaction
Cells of Adaptive Immunity:
Lymphocytes (Agranulocyte)
• Dark, oval to round nucleus
• Cytoplasm sky blue in color
– amount varies from rim of blue to normal amount
• Small cells 6 - 9 microns in diameter
• Large cells 10 - 14 microns in diameter
– increase in number during viral infections
• 20 to 25% of circulating WBCs
• produced in the primary lymphoid tissues – thymus and adult bone marrow
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B cells
– destroy bacteria and their toxins
– turn into plasma cells that produces antibodies
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T cells
– attack viruses, fungi, transplanted organs, cancer cells & some bacteria
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Natural killer cells = sometimes classified as large granular lymphocytes
– attack many different microbes & some tumor cells
– destroy foreign invaders by direct attack
– kill by binding directly to the target = cytotoxicity
2) Specific Defenses (Cell-mediated Immunity)
Antigens:
-before birth, the body takes an “inventory” of all self proteins = antigens
-lymphocytes develop receptors that allow them to distinguish between self and
foreign
-non-self antigens combine with T and B cell receptors and stimulate an immune
reaction
T Cell-mediated immunity:/Cell-mediated immunity
-T = thymus derived
-respond to antigens by cell-cell contact - attach to foreign cells directly
-antigens are processed before interacting with T cells
-antigen-presenting cells (B cells, macrophages)
Antigen Presenting Cell (APC)
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Foreign antigen in body fluid is phagocytized by APC
– macrophage, B cell, dendritic cell (communicates with the B cell in the lymph node and spleen)
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Antigen is digested and fragments are bound to MHC-II molecules stuck into antigen
presenting cell membrane
APC migrates to lymphatic tissue to find T cells
found primarily in skin, lymph nodes, spleen and the thymus
typical APC – Langerhans cell in the skin
– migrate out of the skin
– enter into the lymph node where they interdigitate with the T lymphocytes
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APC displays the foreign antigen to the
T cell
this requires cell-cell contact between
the APC and T cell in order to activate
the T cell
both T helper and cytotoxic T cells can
be activated by an APC
interaction between the MHC complex
with the Ag and a complex of proteins
on the T cell called the T cell receptor
TCR = multiple proteins associated
with a co-receptor (CD4 for a T helper
or CD8 for a cytotoxic T cells)
- Activated T cells synthesize specific soluble chemicals called cytokines
-also “decide” to become either helper or cytotoxic T cells
-if the foreign Ag is bacterial = T helper
-if the foreign Ag is viral = T cytotoxic
-T cells secrete chemicals called cytokines - enhance other cell responses to antigens
-cytokine = secreted signaling molecules
-cytokines made by lymphocytes may be called lymphokines
e.g. interleukins, interferons
-interleukins - over 23 made by various WBCs
-several made by T cells
-play various roles in activating the many components of the immune system
-interferons: play a role in viral infections
-released by virally-infected cells or by activated T cells in response to
the infection
-three types of IFNs are made naturally by T cells – alpha, beta and gamma IFN
-also made synthetically
T cell types
• 1. Cytotoxic T cells (Tc cells) destroy virally infected cells and tumor cells
– also implicated in transplant rejection.
– are also known as CD8+ T cells, since they express the CD8 glycoprotein at their
surface.
– secrete perforin which punches holes in the foreign membrane
• 2. Helper T cells, (Th cells) participate in bacterial infections
– need to be activated by an APC
– once activated - divide rapidly (clonal expansion) and secrete small proteins
called cytokines that regulate or "help" the immune response.
– also called CD4+ T cells
– are a target of HIV infection - virus infects the cell by using the CD4 protein to
gain entry. The loss of Th cells .
• 3. Memory T cells - T cells that persist long-term after an infection has
resolved.
– quickly expand to large numbers of effector T cells upon re-exposure to their
cognate antigen,
– provide the immune system with "memory" against past infections.
– comprise two subtypes: central memory T cells (TCM cells) and effector
memory T cells (TEM cells).
– may be either CD4+ or CD8+.
•
•
4) Regulatory T cells (Treg cells), formerly known as suppressor T cells
5) Natural Killer T cells (NKT cells) – also called natural killer (NK) cells
Interactions
among the
cells of the
immune
system
Activated T
TH
B Cell-mediated immunity/Antibody mediated immunity (Humoral
Immunity)
-antibody producing cells – B cells
-activated by interacting with an antigen that fits with the B cell’s specific receptors
(B cell receptor or immunoglobulin)
-activation is helped by T helper cells - releases cytokines that induce the B cell to
proliferate - clonal expansion
-activated B cell differentiates into a plasma cell - secretes antibodies specific to the
bound antigen and therefore similar in structure to the antigen receptor on the B cell
surface
Antibodies
• Antibodies = Immunoglobulins
• B cells produce a polyclonal response - several
types of antibodies against one type of foreign
particle
• comprised of 4 chains of amino acids linked by
pairs of sulfur atoms (disulfide bonds)
• two light chains, two heavy chains
• each light and heavy chain is comprised of
constant regions that do not change
significantly from antibody class to class
• each light and heavy chain also has a variable
region that recognizes a specific antigen
• also called an antigen-binding site
• heavy chain defines the class of antibody along
with isoforms (subtypes) within that class
Antibody types: 5 major types
1) IgG = immunoglobulin G
-plasma and tissue fluids
-effective against bacteria, viruses and toxins
-activates the complement system
2) IgA - exocrine gland secretions
e.g. breast milk, tears, nasal discharge, gastric juices
3) IgM - blood plasma
-develops in response to contact with certain antigens in foods and bacteria
-also activates complement
4) IgE - exocrine secretions with IgA
-associated with the allergic response
5) IgD - surfaces of most B cells
-activation of B cells
Antibodies
• immunoglobulins
• flexible adaptor for helping cells without inherent
recognition systems to recognize microorganisms
• when activated, the B cell produces soluble
antibodies that recognizes a specific microbe via
its variable region
• these antibodies can act as an adaptor to link a
microorganism to an immune cell
• however, the antibody also binds onto
phagocytic cells at the other end of the antibody
(via the constant region of the heavy chain)
• OR also can act to activate the complement
system which coats microorganisms – aids in
recognition by phagocytic cells
B cell types
•
1) Plasma B cells (also known as plasma cells)
– large B cells that have been exposed to antigen
– produce and secrete large amounts of antibodies
•
2) Memory B cells - formed from activated B cell
– activation requires interaction with between the B cell and an antigen encountered
during the primary immune response.
– are able to live for a long time
– respond quickly following a second exposure to the same antigen.
•
3) B-1 cells - B cells that express CD5
– thought to mediate B cell-B cell interaction
– express IgM on their surface in greater quantities than IgG
– have a preference for binding other immunoglobulins, self antigens and common
bacterial polysaccharides.
– present in low numbers in the lymph nodes and spleen
– found predominantly in the peritoneal and pleural cavities.
•
4) B-2 cells are the conventional B cells most texts refer to.
B cell activation
•
requires binding of a foreign antigen to
the antibody displayed on the surface of
the B cell
– antigen is internalized and processed into
fragments which are displayed in
association with the MHC-II complex =
APC
•
the membrane bound antibody is called a
B cell receptor (BCR)
– the BCR recognizes the unprocessed form
of an antigen
– the TCR recognizes a processed form of
the antigen
•
•
interaction of the B cell displaying the
antigen activates the T helper cell
interaction leads to the differentiation of
the B cells into a plasma cell and
production of soluble antibodies
– activated T cells secrete lymphokines
which stimulates the differentiation of the
B cell
B cell activation
• Scenario #1: B cells acts as an APC
– Internalizes the foreign invader and displays Ag
– Both B and T cell are activated
– If bacterial antigen – B cell makes Abs to bacteria and T
cell becomes a T helper
– If viral antigen – B cell makes Abs to virus and T cell
becomes a cytotoxic T cell
• Scenario #2: naïve B cell
– Naïve B cell activated through binding with activated T
helper cell
• Scenario #3: B cell receptor activation
– B cell binds foreign Ag via its BCR (IgD/IgM complex)
– Stimulates differentiation into plasma cells
Immune Responses
Primary response: when B or T cells become activated after an intial exposure
-release of IgM then IgG by plasma cells into the lymph
-several weeks
-several B and T cells become dormant but persist in the lymph = memory cells
-if an identical antigen is encountered - clonal expansion and an immediate response
called a Secondary response
-lasts years
Immunity Types
1) Passive - when an individual is given prepared antibodies to combat a disease
-temporary because the Ig’s are not produced by the individual
-passed from mother to child in breast milk
-usually given as a gamma globulin injection (blood serum) from a
person who have recovered from an infection
2) Active - develops after exposure to an antigen
-also can be induced through exposure to small amounts of the pathogen
Immunization = administration of a vaccine
-vaccine = contains small amounts of an antigen to which the
immune system responds
-antigens are treated so that they are no longer virulent (i.e.
no longer replicates or no longer viable)
-today - bacteria can be engineered to mass produce specific
proteins from a pathogen
e.g. Hepatitis B vaccines
-active immunity depends on the presence of memory T and B cells
-long lasting - although booster shots may be required
e.g. Diptheria, tetanus, pertussis - age 4 to 6 years, tetanus boosters at 11 and 14 years
and older
e.g. Polio - age 2, 4 and 6 months, 4 to 6 years, no booster
e.g. measles, mumps, rubella - 12 to 15 months, 4 to 6 years, booster at 11-12 years
Allergies
-type I hypersensitivity
-hypersensitivities to substances such as pollen, dander, or other substances
that normally do no damage to others
-these antigens = allergens
1. Immediate response: Immediate hypersensitivity
-within seconds of contact
-cold-like symptoms or increased swelling and redness at area of contact
-caused by release of IgE antibodies
-IgE antibody release is a local event – occurs at the site of the allergen’s entrance
into the body
e.g. mucosal surfaces and lymph nodes
-IgE antibodies are produced by B cells
-IgE binds to the cell surface of mast cells in tissues and basophils in the blood
-via the Fc receptor
-allergen-IgE interaction causes release of histamine
-severe reaction = anaphylatic shock
e.g. bee sting - first exposure results in high sensitivity
-second exposure can be fatal due to massive histamine release,
resulting in increased vessel permeability and a drastic drop in
blood pressure
-allergy shots - build up of IgG which will react with the allergen before
the allergens can interact with IgE
Mast cell
•
•
often indistinguishable from the basophil
expel their granule contents via exocytosis
– release of histamine is triggered by the crosslinking of IgE
antibodies on the cell surface to the microorganism
– but also can be triggered by crosslinking by lectin (high
doses in strawberries)
– can also be directly activated by synthetic compounds like
codeine and morphine
– following exocytosis – there is the production of new
compounds derived from arachidonic acid (prostaglandins
and leukotrienes)
•
two types
– 1. connective tissue mast cells
• located around the blood vessels is most connective tissues
– 2. mucosal mast cells
• dependent on T cells for proliferation
• highest in concentration in the mucosa of the lung and gut
-also a role for the T helper cell in allergies in regulating IgE production
-presentation of an Ag to a T helper cell results in the production of a IgE binding factor (IgEBF)
-this factor potentiates the production of IgE by the B cell and the production of IgE memory
cells
-IgE production can be limited by a class of T cell = T suppressor cells
-Ts cells produce a factor which limits the activation of B cells and production of IgE
Allergies
• 2. Delayed response:
•
-initiated by memory T cells
•
-regulated by cytokines secreted by T
cells
•
e.g. tuberculosis skin test - positive =
red and hardened at injection site
•
e.g. contact dermatitis - poison ivy,
jewelry, cosmetics