Transcript to find the lecture notes for lecture 13 Immunity click here

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
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
Components of Blood
• Hematocrit
– 55% plasma
– 45% cells
• 99% RBCs
• < 1% WBCs
and platelets
•
55% plasma: 7 to 8% dissolved substances (sugars, amino
acids, lipids & vitamins), ions, dissolved gases, hormones
– 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 – decreases osmotic
pressure in blood and results in water flow out of blood into
tissues – swelling
– dispersed as colloid in the blood
– do not exit the blood due to their size – creates a protein
gradient between blood and interstitial fluid
– most common plasma proteins: albumin, globulins, clotting
proteins (fibrinogen)
• albumins – most abundant
–
–
–
contribute to most of the osmotic colloidal pressure
non-specifically bind many substances to help transport them through
the blood
these substances are generally poorly soluble in water
» e.g. bilirubin, bile salts, penicillin
• globulins – three classes
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–
–
–
–
alpha, beta and gamma
some alpha and beta globulins bind substances for transport
» e.g. thyroid hormone, cholesterol
also involved in clotting
many inactive substances are alpha globulins
» e.g. angiotensinogen (precursor to angiotensin)
gamma globulins = immunoglobulins
• fibrinogen – cleaved by thrombin to produce a very stick mass of
fibers made of fibrin
–
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!
•
•
•
•
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 – cells cannot use the O2 they are carrying for energy production
» since they lack mitocondria
» for energy they rely on glycolysis and the enzymes of this pathway exclusively
– 2. carbonic anhydrase – converts the soluble form of CO2 (HCO3 in carbonic acid) 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
Erythrocytes: Red Blood cells & their
development
•
•
•
hemoglobin
pigment – naturally colored that is red due to its iron content
combines with
–
oxygen
•
–
–
carbon dioxide
the acidic portion of carbonic acid
•
•
•
–
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
•
–
occupies the oxygen binding sites
nitric oxide
•
–
–
oxidation of CA occurs at the tissue level
combination of carbon dioxide with water
combination with Hb buffers the pH effects of CA
carbon monoxide
•
–
binding sites
four, highly folded protein chains
2. heme component
• 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
• generally Hb is 98% saturated with oxygen in the capillaries and 60-70% saturated in the tissues
at sea level
• -saturation level can be affected by temperature (increase temp, decrease saturation)
• saturation level can be affected by atmospheric pressure (decrease pressure, decrease saturation)
•
**acclimatization
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 the liver and spleen
converts into 700 miles of vessels travelled per RBC before it is destroyed
as it ages the plasma membrane becomes very fragile and prone to rupture
most RBCs are destroyed in the spleen – small vessels tend to lyze the fragile RBCs as they
travel through this organ
– can also be degraded in the bone marrow and liver by macrophages
– 1. liver/spleen/bone marrow degrades the hemoglobin to its globin component and heme
• amino acid components of globin are reused for protein synthesis (3)
– 2. heme is degraded into free iron and biliverdin – Fe released into the blood
•
•
•
•
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)
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
•
Symptoms
– oxygen-carrying capacity of blood is reduced
– fatigue, cold intolerance & paleness
• lack of O2 for ATP & heat production
•
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 gastric mucosa
– 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
ABO Blood Groups
• Based on 2 glycolipid isoantigens called A and B
found on the surface of RBCs
–
–
–
–
display only antigen A -- blood type A
display only antigen B -- blood type B
display both antigens A & B -- blood type AB
display neither antigen -- blood type O
• Plasma contains isoantibodies or agglutinins to the
A or B antigens not found in your blood
– anti-A antibody reacts with antigen A
– anti-B antibody reacts with antigen B
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
•
Disc-shaped, 2 - 4 micron cell fragment with no nucleus
– not whole cells!
– do have organelles and cytosolic enzymes for generating energy from glucose
•
•
Normal platelet count is 150,000-400,000/drop of blood
Other blood cell counts
– 5 million red & 5-10,000 white blood cells
•
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
•
Short life span (5 to 9 days in bloodstream)
–
–
–
–
formed in bone marrow
few days in circulating blood
aged ones removed by fixed macrophages in liver and spleen
numbers can be increased through the secretion of thrombopoietin (liver) which
increases megakaryocyte development in the bone marrow and stimulates the
formation of platelets
– 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 – release of paracrine factors from the
damaged endothelium
– 2) platelet plug formation
– 3) blood clotting
• Platelets store a lot of 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 – initiates the next phase of hemostasis – clot formation
• platelet-derived growth factor
– cause proliferation of vascular endothelial cells, smooth muscle & fibroblasts to repair
damaged vessels
– 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 – by collagen interaction
(2) platelet release reaction – from their
storage granules
-Platelets activated by adhesion
-Extend projections to make contact with
each other
-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 (prostacyclin and
NO) – limits to plug to the area of damage
-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, enzymes synthesized
by liver cells (clotting factors and plasma proteins) and
substances released by platelets or damaged tissues
– thrombin – released by damaged cells, catalyzes the conversion of
fibrinogen to fibrin
– 12 clotting factors involved
• 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 thrombin
Common Pathway
• activated prothrombinase and Ca+2
– catalyze the conversion of prothrombin to
thrombin
• Thrombin
– activated factor X (Xa) and thrombin are called
serine proteases
– in the presence of Ca+2 converts soluble
fibrinogen to insoluble fibrin threads
– activates fibrin stabilizing 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
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
•
•
•
drives clotting in damaged vessels and also induces
clotting in blood samples in test tubes
all elements for this pathway are present in the blood
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
•
•
•
•
•
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
Clotting: A summary
12
Platelet
aggregation
•
release of the fibrinolytic enzyme plasmin
dissolves the clot
– plasmin – plasma protein present in the blood as
inactive plasminogen
– plasminogen becomes trapped in the forming clot,
becomes activated to plasmin and slowly dissolves
the clot as the tissue repairs itself
– white blood cells then phagocytose the remaining
parts of the clot as it dissolves
– plasmin also functions to prevent clots from
forming when not needed
• small levels of fibrin are constantly being formed in
the blood plasma – yet no clot forms
– fibrin is quickly degraded by tissue-type
plasminogen activator (tPA) that is secreted by
tissues
• helps convert plasminogen into plasmin
– tPA- along with a similar protease (uPA) - is also
released during induced clot formation upon the
formation of fibrin – together with factor X, these
proteases activate plasminogen
– synthetic tPA is now being used as a clot-busting
drug to prevent damage to heart muscle by
occlusions of coronary arteries
– excess levels of activated plasmin circulating
freely in the blood are prevented by the formation
of plasminogen activator inhibitors (PAIs)
Clot Remodelling
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
•
•
group of about 20 proteins who control
inflammation
several of these proteins are called acute
phase proteins (serum proteins that
dramatically increase upon infection
– e.g. C reactive protein
•
•
•
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
3) histamine - dilation of capillaries & increased blood flow
-histamine causes the gaps between endothelial cells to widen to allow the
passage of larger molecules into the blood – immune cells and complement proteins
-however – it can allow for leakage of plasma proteins out into tissues = swelling/edema
4) migration of neutrophils and monocytes/macrophages (WBCs) via capillaries
- phagocytosis of foreign particles
5) delivery of proteins to damaged area (e.g. clotting factors) – platelet plug response
6) clotting response by blood - cascade/positive feedback
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
-anti-histamines - block the binding of histamine to receptors
Inflammation
• several levels of interaction with the
inflammatory system
• called the plasma enzyme system
– 1. complement – for destruction of
microorganisms and induction of histamine
release by mast cells
• increased vasodilation
– 2. clotting system – by production of Factor
XII
– 3. kinin system – for production of pain,
increased vascular permeability and
vasodilation
– 4. fibrinolytic system – activated by the
kinin system
• production of activated plasmin
• ensured eventual destruction of clot over
time
• also activated Factor XII
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
-enters lymphatic capillaries from the tissues
-low pressure system - moves by
muscular contraction and breathing
-capillaries join to form lymphatic
vessels
-vessels join to form:
1) thoracic duct
2) lymphatic duct
- Right side head, arm & chest empty into right 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
-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
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: Neutrophils
(Polymorphonuclear Granulocytes)
• Polymorphonuclear Granulocytes or Leukocytes
• PNGs are about 60 to 70% of circulating WBCs and are also found in
extravascular sites
• neutrophils 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)
•
•
•
•
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)
•
•
also called the mononuclear phagocytic system
two main functions
– 1. “professional” phagocytic macrophages – derived from monocytes
– 2. antigen-presenting cells
•
•
Nucleus is kidney or horse-shoe shaped
Form the reticuloendothelial (RES) system
– differentiate into macrophages
• Destroy microbes and clean up dead tissue following an infection
• fixed group found in specific tissues
–
–
alveolar macrophages in lungs
kupffer cells in liver
• wandering group gathers at sites of infection
• possess numerous lysosomes with acid hydrolases and peroxidase for killing microorganisms
• 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: Phagocytes
• one of the first cells to arrive upon inflammation
• two kinds: monocytes and polymorphonuclear
granulocytes (neutrophils)
• attracted through the process of chemotaxis (soluble
chemicals that attract cells)
• macrophages, neutrophils, dendritic cells
• need a method of recognizing the foreign antigen – use
antibodies/immunoglobulins
• allows non-specific attachment to microorganisms
• enhanced if the microorganism has been coated with
complement protein – by the C3b protein
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
• Diameter is 10 to 12 microns
• 2 to 4% of circulating WBCsLeave 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
•
B cells
– destroy bacteria and their toxins
– turn into plasma cells that produces antibodies
•
T cells
– attack viruses, fungi, transplanted organs, cancer cells & some bacteria
•
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
Differential WBC Count
• Detection of changes in numbers of circulating
WBCs (percentages of each type)
– indicates infection, poisoning, leukemia, chemotherapy,
parasites or allergy reaction
• Normal WBC counts
–
–
–
–
–
neutrophils 60-70% (up if bacterial infection)
lymphocyte 20-25% (up if viral infection)
monocytes 3 -- 8 % (up if fungal/viral infection)
eosinophil 2 -- 4 % (up if parasite or allergy reaction)
basophil <1% (up if allergy reaction or hypothyroid)
Leukemia
• Acute leukemia
– uncontrolled production of immature leukocytes
– crowding out of normal red bone marrow cells by
production of immature WBC
– prevents production of RBC & platelets
• Chronic leukemia
– accumulation of mature WBC in bloodstream because
they do not die
– classified by type of WBC that is predominant--monocytic, lymphocytic.
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)
•
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)
•
•
•
•
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
•
•
•
•
•
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
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)
activation of the T cell now causes a
fraction of them to synthesize specific
soluble chemicals called cytokines
•
•
•
in addition to making cytokines – some T cell
specialize
if stimulated by a bacterial Ag – T cell becomes a Y
helper
if stimulated by viral Ag – becomes a cytotoxic T
cell
-T cells secrete chemicals called cytokines
-cytokine = secreted signaling molecules
-enhance other cell responses to antigens
e.g. interleukins, interferons
-interleukins
-play a role in immune cell development and activation
e.g. B and T cell proliferation
-play a role in allergic response
-play a role in chemotaxis
- interferons
-play a role in viral infections, produced early in viral infections
-released by virally-infected cells or by activated T cells in response to
the infection
-induce a state of antiviral resistance to uninfected cells
-three types of IFNs are made naturally by T cells – alpha, beta and gamma IFN
-also made synthetically
-inhibit proliferation of viruses and tumor cells within normal cells
-alpha-interferon used to treat Kaposi’s sarcoma, genital herpes,
hepatitis B and C & some leukemias
-beta-interferon and gamma-interferon used to treat multiple sclerosis
T cell types
•
1. Cytotoxic T cells (Tc cells) destroy virally infected cells and tumor cells
–
–
–
•
2. Helper T cells, (Th cells) participate in bacterial infections
–
–
–
–
•
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
–
–
•
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.
–
–
–
–
•
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
are crucial for the maintenance of immunological tolerance.
major role is to shut down T cell mediated immunity towards the end of an immune reaction and to suppress auto-reactive T
cells that escaped the process of negative selection in the thymus.
5) Natural Killer T cells (NKT cells) – also called natural killer (NK) cells
–
–
–
are a special kind of lymphocyte that bridges the adaptive immune system with the innate immune system
activated not through an interaction between the APC and the T cell via MHC-TCR interactions BUT through an interaction
between the APC expressing a molecule called CD1d
Once activated - perform functions ascribed to both Th and Tc cells (i.e. cytokine production and release of cytolytic/cell
killing molecules).
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
• binds the microorganism via the variable regions
• however, the antibody also binds onto phagocytic
cells at the other end of the antibody (via the
constant region of the heavy chain)
– interact with a receptor on the phagocyte = Fc
receptor
• OR also can act to activate the complement system
which coats microorganisms – aids in recognition
by phagocytic cells
Antibody actions
1) direct attack on antigens - combine with antigens and cause them
to agglutinate or clump
-easier to phagocytose
-or neutralizes the toxic portions of an antigen by binding
-or causes antigens to precipitate and become insoluble
2) activation of complement
3) stimulates changes in local environment making spread of antigens difficult
B cell activation
• antigen is internalized by B cell
and processed into fragments
which are displayed in
association with the MHC-II
complex = B cells acts as an
APC
• 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
• but the T cell is also activated!!
• B cells can also be activated by binding
foreign antigens via a membrane bound
antibody is called a B cell receptor (BCR)
– the BCR recognizes the unprocessed form of an
antigen
– composed of IgD and IgA complexes
– typical human B cell has 50,000 to 100,000
BCRs on its surface
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.
Interactions
among the
cells of the
immune
system
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
– granules fuse before 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
– granule exocytosis requires the influx of calcium
– 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 (IgE-BF)
-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