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Blood and Immunity

MFEL1010 2006, Torunn Bruland, IKM, DMF, NTNUTorunn.bruland@ntnu.no

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I:•Functions of the blood•The components of the blood•Blood clotting•Blood groups•Diagnostic blood test

II:•The immune system•The immune responses•Disorders of the immune system

•Allergic disease•Autoimmunity•HIV and immunosuppression

Blood and Immunity MFEL1010 2006, Torunn Bruland, IKM, DMF, NTNU

Outline..

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Functions of Blood

1. Transport– of gases, nutrients and waste products; e.g. oxygen– of processed molecules; e.g., precursor of vitamin D from

skin to liver then kidneys– of regulatory molecules; e.g., hormones

2. Regulation– of pH and osmosis (normal pH of most body tissues

between 7.35 and 7.45)– Maintenance of body temperature; e.g., warm blood

shunted to the interior of the body3. Protection

– against foreign substances; e.g., antibodies– Clot formation

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Composition of the Blood-formed elements

Red Blood Cells (erythrocytes)

White Blood Cells (leukocytes)• granulocytes• agranulocytes

Platelets (thrombocytes)

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Composition of the Blood-plasma

a. fluid: water, ions, hormones

b. proteins (most made in liver)1. Albumin 56%2. Globulins 38%3. Fibrinogen 4%

Sex hormone-bindingglobulin

Antibody(immunglobulin)

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Composition of Blood

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Production of formed elements

• Hematopoiesis or hemopoiesis: Process of blood cell production

• Stem cells: All formed elements derived from single population– Proerythroblasts: Develop into red blood cells– Myeloblasts: Develop into basophils,

neutrophils, eosinophils– Lymphoblasts: Develop into lymphocytes– Monoblasts: Develop into monocytes– Megakaryoblasts: Develop into platelets

-blast bud, germ

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Stem cell (hemocytoblast)

Proerythroblast Myeloblast Lymphoblast Monoblast Megakaryoblast

Earlyerythroblast

Progranulocyte

Intermediateerythroblast

Basophilicmyelocyte

Eosinophilicmyelocyte

Neutrophilicmyelocyte

Lateerythroblast

Reticulocyte

Red blood cell

Nucleusextruded

Basophil

Megakaryocyte

Megakaryocyte breakup

Platelets

MonocyteLymphocyteEosinophil Neutrophil

Granulocytes AgranulocytesWhite blood cells

Basophilicband cell

Eosinophilicband cell

Neutrophilicband cell

Hematopoiesis

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Red blood cells (RBCs)

• Components– 1/3 Hemoglobin– 2/3 Lipids, ATP,

carbonic anhydrase

Red bloodcell

White bloodcell

Platelet

Top view Side view

2.0 µm

7.5 µm

SEM 2600x

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RBC function: Transport• Oxygen from lungs to tissues:

– 98.5% attached to hemoglobin; – 1.5% dissolved in plasma

• Carbon dioxide from tissues to lungs. – 7% dissolved in plasma– 23% in combination with

hemoglobin– 70% transported as bicarbonate

ions produced as a result of combination of H2O and CO2because of enzyme carbonic anhydrase found within RBCs

Left shift: increased Hb-O2 affinityRhight shift: decreased Hb-O2 affinity

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Hemoglobin

• Types of hemoglobin– Embryonic and fetal: have greater attraction for oxygen than

adult. Fetal production stops after birth.– Adult

• Oxyhemoglobin: transporting oxygen• Dexoyhemoglobin• Carbaminohemoglobin: transporting carbon dioxide

CH2CH2COOH

b2

a2

Hemoglobin

b1

Heme

a1

CH2CH2COOH

CH2=CH

CH3

CH3

CH2=CH

CH3CH3

FeN N

N

N

Heme

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Erythropoiesis

• RBCs last 120 days in circulation (enucleated)• Production of red blood cells

– Stem cells → proerythroblasts → early erythroblasts →intermediate erythroblasts → late erythroblasts →reticulocytes

• Erythropoietin: hormone stimulates RBC production; produced by kidneys in response to low blood O2 levels.

Increasedred blood cell

production

Red blood cells

Red bonemarrowIncreased

erythropoietin

Decreasedblood

oxygen

Kidney

Increasedblood

oxygen

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Aged, abnormal, ordamaged red blood cells

MacrophageHemoglobin 120 days in

general circulationHeme Globin

BiliverdinIron

BilirubinAminoacids Red blood cells

ErythropoiesisIron +transferrin

Free bilirubin

LiverSpleen

Conjugatedbilirubin

Bile

Intestine

Bilirubinderivatives

Kidney

Storage

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2

4 3

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Hemoglobin breakdown

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The globin chains of hemoglobin are broken down to individual amino acids (pink arrow) and are metabolized or used to build new proteins.

Aged, abnormal, or damaged red blood cellsMacrophageHemoglobin

120 days in general circulationGlobinAminoacids Red blood cells

Erythropoiesis

Liver

IntestineKidney

Spleen

Hemoglobin breakdown I

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Aged, abnormal, or damaged red blood cellsMacrophageHemoglobin

120 days in general circulationHemeBiliverdin

IronBilirubin Red blood cells

Erythropoiesis

Iron is released from the heme of hemoglobin. The heme is converted into biliverdin, which is converted into bilirubin.

IntestineKidney

Liver Spleen

Hemoglobin breakdown II

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Aged, abnormal, or damaged red blood cellsMacrophageHemoglobin

120 days in general circulationIron

Red blood cells

ErythropoiesisIron +transferrin

Storage

Iron is transported in combination with transferrin in the blood to various tissues for storage or transported to the red bone marrow and used in the production of new hemoglobin (green arrows).

Intestine Kidney

Liver Spleen

Hemoglobin breakdown III

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Aged, abnormal, or damaged red blood cellsMacrophageHemoglobin

120 days in general circulation

Red blood cells

ErythropoiesisFree bilirubin

Free bilirubin (blue arrow) is transported in the blood to the liver.

IntestineKidney

Liver Spleen

Hemoglobin breakdown IV

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Aged, abnormal, or damaged red blood cellsMacrophageHemoglobin

120 days in general circulation

Red blood cells

Erythropoiesis

ConjugatedbilirubinBile

IntestineKidney

Most conjugated bilirubin is excreted as part of the bile; some is transported in the blood to the kidneys and excreted in the urine.

Liver Spleen

Hemoglobin breakdown V

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Aged, abnormal, or damaged red blood cellsMacrophageHemoglobin

120 days in general circulation

Red blood cells

Erythropoiesis

Spleen

IntestineBilirubinderivatives

Kidney

Bilirubin derivatives contribute to the color of feces or are reabsorbed from the intestine into the blood and excreted from the kidneys in the urine.

Liver

Hemoglobin breakdown VI

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Normal red blood cells vs. Sickle Cell

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Sickle Cell Hemoglobin

GUG CAC CUG ACU CCU GAG GAG AAGval his leu thr pro glu glu lys1 2 3 4 5 6 7 8

GUG CAC CUG ACU CCU GUG GAG AAGval his leu thr pro val glu lys1 2 3 4 5 6 7 8

Mutation (in DNA)

Normal mRNA

Normal protein

Mutant mRNA

Mutant protein

Glutamate (glu), a negatively charged amino acid, is replaced by valine (val), which has no charge.

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Sickle Cell HemoglobinSignificant change in structure caused by the single mutation

Glutamate 6

Valine 6

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Sickle Cell AnemiaGenetic Disease

Heterozygous individuals – carriersHomozygous individuals – diseased

SCA Results from Defective HemoglobinHemoglobins stick togetherRed blood cells damaged

Complications from low oxygen supply to tissuesPain, organ damage, strokes, increased infections, etc.

Incidence highest among Africans and IndiansHeterozygotes protected from Malaria

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White Blood Cells

• Protect body against microorganisms and remove dead cells and debris

• Movements– Ameboid: pseudopods– Diapedesis: cells become thin, elongate and

move either between or through endothelial cells of capillaries

– Chemotaxis: attraction to and movement toward foreign materials or damaged cells. Accumulation of dead white cells and bacteria is pus.

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•Basophils: least common. Leave circulation and migrate through tissues, play a role in both inflammatory response and allergic reactions. Produce histamine and heparin.

•Eosinophils. Leave circulation and enter tissues during inflammatory response. Prevalent in allergic reactions. Destroy inflammatory chemicals like histamine. Release chemicals that help destroy tapeworms, flukes, pinworms, and hookworms.

•Neutrophils: after leaving bone marrow, stay in circulation 10-12 hours then move into other tissues. Become motile, phagocytize bacteria, antigen-antibody complexes and other foreign matter. Secrete lysozyme. Last 1-2 days.

Granulocytes

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•Lymphocytes: produced in red bone marrow but then migrate to lymphatic tissues and proliferate. Responsible for antibody production. Studied extensively with the immune system.

•Monocytes: remain in circulation for 3 days, leave circulation and become macrophages. Phagocytic cells. Can break down antigens and present them to lymphocytes for recognition.

Agranulocytes

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Platelets

• Cell fragments pinched off from megakaryocytes in red bone marrow

• Surface glycoproteins and proteins allow adhesion to other molecules; i.e., collagen

• Important in preventing blood loss– Platelet plugs– Promoting formation

and contraction of clots

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Platelets

Typical spiny spheric shape ofactivated platelets

Typical smooth discoid shape ofresting platelets

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I:•Functions of the blood•The components of the blood•Blood clotting•Blood groups•Diagnostic blood test

II:•The immune system•The immune responses•Disorders of the immune system

•Allergic disease•Autoimmunity•HIV and immunosuppression

Blood and Immunity MFEL1010 2006, Torunn Bruland, IKM, DMF, NTNU

Outline..

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The Clotting Process:

http://www.mhhe.com/biosci/esp/2002_general/Esp/folder_structure/tr/m1/s7/trm1s7_3.htm

Blood clotting

Hemostasis stages:

1) vascular spasm

2) platelet plug formation

3) Coagulation or clot formation

Arrest of bleedingEvents preventing excessive blood loss

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Platelet plug formation

ADP

Thromboxane

Platelet

Granules

von Willebrand factor

Collagen

Plateletplug

Smoothmusclecell

Bloodvesselwall

EndothelialcellFibrinogen

receptor

Fibrinogen

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Coagulation • Stages– Activation of prothrombinase– Conversion of prothrombin to

thrombin– Conversion of fibrinogen to

fibrin

• Coagulation factors. – Proteins found in plasma. – Circulate in inactive state until

tissues are injured. – Damaged tissues and platelets

produce chemicals that begin activation of the factors.

• Pathways– Extrinsic– Intrinsic

• Result: blood clot. A network of threadlike fibrin fibers, trapped blood cells, platelets and fluid

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Clot formation Intrinsic clotting pathwayExtrinsic clotting pathway

Stage 1

Stage 2

Stage 3

Tissuedamage

Thromboplastin

Thromboplastin/factor VII complex

Activatedfactor X

Prothrombinase

ThrombinProthrombin

Fibrinogen Fibrin

Fibrinclot

Activatedfactor XIII Factor XIII

Factor V, plateletphospholipids, Ca2+

Factor VIIIplatelet phospholipids, Ca2+

Factor VII

Ca2+

Ca2+

Factor X

Factor IXActivatedfactor IX

Activatedfactor XI

Activatedfactor XII

Contact with collagen ofdamaged blood vessel

Factor XII

Factor XI

Ca2+

1122

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Extrinsic clotting pathway• Begins with chemicals outside of blood

• Stage 1– Damaged tissues release tissue factor (TF; factor III)– When Ca2+ is present, forms complex with factor VII,

activating factor X– Prothrombinase is formed

• Stage 2: – prothrombinase converts prothrombin into thrombin

• Stage 3– Thrombin converts fibrinogen to fibrin– Thrombin activates factor XIII, which stabilizes clot

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Intrinsic clotting pathway

• Begins with chemicals that are part of the blood

• Stage 1– In damaged blood vessels, factor XII comes in contact with

exposed collagen, activating factor XII– Stimulates factor XI, activates factor IX– Activated factor IX joins with factor VIII, platelet phospholipids

and Ca2+ to activate factor X– Prothrombinase is formed

• Stages 2 and 3 progress to clot formation– Stage 2:

• prothrombinase converts prothrombin into thrombin

– Stage 3• Thrombin converts fibrinogen to fibrin• Thrombin activates factor XIII, which stabilizes clot

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Control of clot formation

• Anticoagulants: prevent coagulation factors from initiating clot formation.

• Coagulation occurs when coagulation factor concentration exceeds a given threshold. At site of injury, threshold is exceeded.

• Anticoagulants– Antithrombin: produced by liver, slowly inactivates

thrombin– Heparin: produced by basophils and endothelial cells.

Increases effectiveness of antithrombin– Prostacyclin: prostaglandin derivate from endothelial

cells. Causes vasodilation and inhibits release of coagulating factors from platelets

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Fibrinolysis

• Clot dissolved by activity of plasmin, an enzyme which hydrolyzes fibrin

Thrombin,factor XII, t-PA, urokinase,lysosomal enzymes

Plasminogen Plasmin

ClotdissolutionFibrin

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I:•Functions of the blood•The components of the blood•Blood clotting•Blood groups•Diagnostic blood test

II:•The immune system•The immune responses•Disorders of the immune system

•Allergic disease•Autoimmunity•HIV and immunosuppression

Blood and Immunity MFEL1010 2006, Torunn Bruland, IKM, DMF, NTNU

Outline..

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Blood Grouping

• Transfusion: transfer of blood or blood components from one individual to another

• Infusion: introduction of fluid other than blood

• Determined by antigens (agglutinogens) on surface of RBCs

• Antibodies (agglutinins) can bind to RBC antigens, resulting in agglutination (clumping) or hemolysis(rupture) of RBCs

• Groups: ABO and Rh

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ABO Blood Groups

Red blood cells

Plasma

Antigen A Antigen B Antigen A and B Neither antigen A nor B

Anti-B antibody Anti-A antibody Neither Anti-A norAnti-B antibodies

Anti-A and Anti-Bantibodies

Type A Type B Type AB Type O

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Agglutination reaction

Type A blood of donor Anti-B antibodyin type A bloodof recipient Antigen and

antibody donot match

No agglutination

Anti-A antibodyin type B bloodof recipient

Antigen andantibodymatch

Agglutination

Type A blood of donor

+

+

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Transfusion

• Type A blood has anti-B antibodies• Type B blood has anti-A antibodies

• Suggested that these antibodies are present because of exposure to A and B antigens on bacteria and food

• Donor: gives blood. Recipient: receives blood• Type O as “universal donor”.

– Can actually cause transfusion reactions because of antibodies in O blood plasma

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Rh Blood Group

• First studied in rhesus monkeys

• Types– Rh positive: Have these antigens present on

surface of RBCs

– Rh negative: Do not have these antigens present

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Erythroblastosis Fetalis•Rh positive fetus, Rh negative mother.Late in pregnancy, Rh antigens of fetus cross placenta (through a tear in placenta or during delivery); mother creates antiRhantibodies (primary response)

•Second Rh positive pregnancy might initiate secondary response and hemolytic disease of the newborn (HDN)

•Injection of RhoGAM. Contains antibodies against Rh antigens. Antibodies attach to any fetal RBCs and they are destroyed.

Maternal circulation

MaternalRh-negativered blood cellFetal Rh-positivered blood cell in thematernal circulation

Maternal circulation

Maternal Rh-negativered blood cell

Anti-Rh antibodies

Fetal Rh-positivered blood cell

Maternal circulation

Maternal anti-Rhantibodies cross the placenta

Agglutination offetal Rh-positivered blood cells leads to HDN

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I:•Functions of the blood•The components of the blood•Blood clotting•Blood groups•Diagnostic blood test

II:•The immune system•The immune responses•Disorders of the immune system

•Allergic disease•Autoimmunity•HIV and immunosuppression

Blood and Immunity MFEL1010 2006, Torunn Bruland, IKM, DMF, NTNU

Outline..

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Diagnostic Blood Tests• Type and Crossmatch: determination of ABO and Rh

blood types. Red cells tested against antibodies

• Complete Blood Count– Red Blood Count: number of RBCs/ microliter of

blood– Hemoglobin Measurement: grams of

hemoglobin/100 mL of blood. For a male, 14-18, female 12-16 g/100 mL

– Hematocrit Measurement: percent of blood that is RBCs

– White Blood Cell Count: 5,000-10,000 /microliter of blood

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HematocritCentrifuge blood in the hematocrit tube

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90

80

70

60

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10

0

Plasma

Male Female

Red blood cells

Hematocrit tube

Withdrawblood intohematocrittube

White blood cellsand platelets formthe buffy coat

Hem

atoc

rit

scal

e

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• Differential White Blood Count: determines percentage of each of the five types of WBC– Neutrophils: 60-70%– Lymphocytes: 20-30%– Monocytes: 2-8%– Eosinophils: 1-4%– Basophils: 0.5-1%

• Clotting– Platelet Count: 250,000- 400,000/microliter– Prothrombin Time Measurement: measures how long

it takes for blood to start clotting. 9-12 seconds. To test, thromboplastin is added to whole plasma

• Blood Chemistry: composition of materials dissolved or suspended in the plasma. Used to assess functioning of many body systems

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I:•Functions of the blood•The components of the blood•Blood clotting•Blood groups•Diagnostic blood test

II:•The immune system•The immune responses•Disorders of the immune system

•Allergic disease•Autoimmunity•HIV and immunosuppression

Blood and Immunity MFEL1010 2006, Torunn Bruland, IKM, DMF, NTNU

Outline..

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