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

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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Your immune system

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Each of your cells has a set of 'identity tags' on itssurface, telling your body that it belongs to you.

Science & Society Picture Library

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The structure of the immune system

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Lymphatic tissue and organs

Tonsils

Lymph nodes

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Lymphatic tissue and organs

Spleen

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Lymphatic tissue and organs

Thymus

LM 10x

Trachea

LymphnodesThymusgland

Fat

Heart

Lobule

Thymiccorpuscle

MedullaCortex

Trabecula

Capsule

Trabecula

Lobule

Thymiccorpuscle

MedullaCortex

Bloodvessels

(a) (b)

(c)

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Lymphatic system and immunity

Valves

Fluid

Heart

Blood capillaries

B and Tcells

B and Tcells

Pre-T cells T cells

Red bone marrow

Small intestineThoracic duct

Arterial circulation Venous circulation

(a) Lymphaticcapillary

Lymphaticvessels (b)

Lymph(e)

Lymphatictrunks and ducts

(d)Lymph node

(filters lymph)(c)

Lactealsabsorb fats

(f)

Chyle(g)

Spleen (filters blood)(h)

Bone(i)

Thymus(j)

All lymphatic tissues(k)

B cellsPre-T cells

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When challenged, the immunsystem has many weapons to choose

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

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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How does your immune system work?

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Immunity• Ability to resist damage from foreign substances as

microorganisms and harmful chemicals

• Categories– Innate or nonspecific resistance

• Mechanical mechanisms: prevent entry or remove microbes. Skin, tears, saliva, mucous membranes, mucus . Considered the acid mantle

• Chemical mediators: promote phagocytosis and inflammation

• Cells: involved in phagocytosis and production of chemicals

– Adaptive or specific immunity• Specificity: ability to recognize a particular substance• Memory: ability to remember previous encounters with a

particular substance and respond rapidly

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Mechanical mechanisms

• Skin, mucous membranes• Tears, saliva, and urine flush out bacteria• Cilia in respiratory tract• Coughing and sneezing

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Complement

Chemicals of innate immunity

•Surface chemicalsLysozymes

•Histamine•Kinins•Complement•Interferon•Prostaglandiner•Leukotriner•Pyrogener

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Interferons are antiviral proteins produced by cells in response to viral infection

• Prevent viral replication (Viruses use the molecular mechanisms of cells to reproduce themselves).

• Interferons produced by infected cell, but cause neighboring cells to produce antiviral proteins, thus act as a paracrine.

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Innate immunity: Cells

• White blood cells: most important cellular components of immune system. Must be able to move into infected tissues and destroy infection

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A white blood cell engulfing disease-causing bacteria

Phagocytes

Chemotaxis: movement toward the source of chemotactic factors (parts of microbes or chemicals act as chemical signals and attract WBCs)Phagocytosis: endocytosis by neutrophils and macrophages.

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Inflammatory response• Tissue injury regardless of type can cause inflammation• Response initiated by chemical mediators that produce

vasodilation, chemotactic attraction, increased vascular permeability. The latter allows fibrinogen and complement to enter tissue. Fibrinogen converted to fibrin, walls off infected area.

• Types– Local: confined to a specific area of the body. Symptoms are

redness, heat, swelling, pain, loss of function– Systemic: occurs in many parts of the body. Same symptoms as

local, but in addition: • Increase in neutrophil numbers released by red bone

marrow• Fever due to production of pyrogens by various kinds of

cells. Improves performance of immune system.• Widespread increased vascular permeability due to

histamines. Large volume of plasma enters interstitial spaces leading to shock

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Adaptive immunity

Involves the ability to a. recognize, b. respond to, c. remember a particular substance

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Adaptive immunity

• Types

– Humoral or Antibody-mediated: B cells

– Cell-mediated: T cells

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Adaptive immunity

• Stimulants– Antigens: large molecules

• Foreign: not produced by body, introduced from outside. – Bacteria, viruses, other microorganisms that cause

disease– Pollen, animal dander, feces of mites, foods, drugs

cause overreaction of immune system called allergic reaction.

• Self-antigens: produced by body. Used as markers to allow adaptive immune response to differentiate self from non-self.

– Response to self tumor antigens helpful– Response to self-antigens resulting in tissue

destruction: auto immune diseases

– Haptens: small molecules, combine with large proteins and producing an adaptive immune response.

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Origin and development of lymphocytes

Stem cell

Pre-B cell

Pre-T cell B cell

Circulation

Thymus

Pre-T cell

T cell

Red bone marrow

Circulation

B cell

T cell

Lymph nodeCirculation

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Activation of Lymphocytes

1. Lymphocytes must be able to recognize the antigen

2. After recognition, lymphocytes must increase in number to effectively destroy antigen

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Activation of lymphocytes: antigenic determinants

major histocompatibility complex(MHC) molecules attached to plasma membranes. Have variable region that can bind to foreign and self antigens.

Differentantigenicdeterminants

Antigen

Antigen-bindingsite

Variable region

Constant region

Cell interior

Plasma membrane

Cell exterior

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Major Histocompatability Complex (MHC)

• Class I. Found on surface of nucleated cells. In concert with antigens that were produced inside the cell from, for example, digested virus particles. Like displaying a flag saying “Kill me!”MHC-restricted: both MHCI and foreign antigen are displayed together

• Class II. Found on surface of antigen-presenting cells. B-cells, macrophages, monocytes and dendritic cells. Display of MHCII with foreign antigen is like “Rally round the flag”, stimulates other immune system cells to respond to the antigen.

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Antigen processing and MHC class I1. Foreign proteins or self-

proteins within the cytosolare broken down intofragments that are antigens.

2. Antigens are transportedinto the rough endoplasmicreticulum.

3. Antigens combine with MHCclass I molecules.

4. The MHC class I/antigencomplex is transported to theGolgi apparatus, packagedinto a vesicle, andtransported to the plasmamembrane.

5. Foreign antigens combinedwith MHC class I moleculesstimulate cell destruction.

6. Self-antigens combined withMHC class I molecules donot stimulate cell destruction.

Self-antigenSelf-antigen

Foreign antigenForeign antigen

Golgi apparatus

Roughendoplasmicreticulum

Roughendoplasmicreticulum

LumenLumenMembraneMembrane

MHC class ImoleculeMHC class Imolecule

Protein

Protein fragments(antigens)

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Antigen processing and MHC class II

5. The displayed MHC class II/antigen complex can stimulate immune cells.

4. The MHC class II/antigen complex is transported to the plasma membrane.

3. The vesicle containing theprocessed antigen fuses withvesicles produced by the Golgi apparatus that contain MHC class II molecules. Theprocessed antigen and the MHCclass II molecule combine.

2. The antigen is broken down into fragments to form processed antigens.

1. The unprocessed extracellularantigen is ingested byendocytosis and is within avesicle.

ProcessedantigenProcessedantigen

MHC class IImoleculeMHC class IImolecule

Vesicle containingprocessedantigen

Unprocessedantigen

Vesicle containingMHC class IImolecules

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MHC class I

MHC class II

Summary: antigen processingAntigens(protein fragments)

MHC class Imolecule

MHC class I/antigen complex

ProteinMembrane Lumen

Roughendoplasmicreticulum

Golgiapparatus

Normally does notstimulate celldestruction

Self-antigen

MHC class Imolecule

Foreign antigen

Stimulates celldestruction

Vesicle containingMHC class IImolecules

Foreignantigen

Vesicle containingprocessedforeign antigens

MHC class IImolecule

Processedforeign antigen

Stimulates immune cells

MHC class II/antigen complex

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To work effectively, most immune cellsneed the cooperation of their comrades

Sometimes immune cells communicate by direct physicalcontact, sometimes by releasing chemical messengers

30From http://nobelprize.org/medicine/educational/immunity/immune-detail.html

Antigen presentation

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Dendritic Cell and T- cell interacting

Dendritic cells (DC) are key antigen presenting cells

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Costimulation First signalMHCclass II molecule

Processedantigen

T-cellreceptor

Macrophage

HelperT cell

Cytokinereceptor

Costimulation by cytokines

MacrophageMHC class II molecule

Costimulation by surface molecules

B7 CD28

HelperT cell

CD4

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Proliferation of LymphocytesCells from original clones must proliferate before antigen can be attacked effectively

1. Proliferation of helper T cells2. Proliferation of cytotoxic T cells3. Proliferation of B cells

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Proliferation of Helper T Cells

Helper T cellcan be stimulated

to divide againHelper T cell can stimulate B cells or effector T cells

Daughterhelper T cell

Daughterhelper T cell

Helper T cellInterleukin-2 receptor

Interleukin-2

Interleukin-1 receptor

Costimulation

Interleukin-1

CD28CD4B7

T-cell receptorProcessed antigen

MHC class II molecule

Antigen Macrophage

Antigenprocessed

Helper T cell

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Proliferation of Cytotoxic T Cells

DaughterT cell

Target Cell CytotoxicT Cell

CD8

MHC class Imolecule

Processedantigen

T-cellreceptor

Interleukin-2

Helper T cell

DaughterT cell

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Cell-mediated immunity

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A strong immune system can kill cancer cells.

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During the killing process, granules in a T-Cell fuse with the cell membrane and release units of the protein PERFORIN. These combineto form pores in the target cell membrane.

Thereafter fluid and salts enter so that the target celleventually bursts.

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Proliferation of B Cells

DaughterB cell

B cell

Antibodies

Unprocessedantigen

B-cellreceptor

MHCclass IImolecule

Processedantigen

T-cellreceptor

Helper T cell

CD4

Interleukins

DaughterB cell

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40From http://nobelprize.org/medicine/educational/immunity/immune-detail.html

Antibody-mediated immunity

41.Mike Clark, Cambridge University

B-cells make antibodies

Antigen-binding sites

Complement-binding site

Site of binding to macrophages, basophils, and mast cells

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Actions of Antibodies

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INNATE IMMUNITY

ADAPTIVE IMMUNITY

Helper T cell can activate a B cell

Direct effectsagainst antigen

Antibody-mediated immunity Cell-mediated immunity

Plasma cell

Antibodies Cytokines

Memory B cell Memory T Cytotoxic T cell

Responsiblefor adaptive immunity

Lysis of cellsexpressing antigen

B cell proliferatesand differentiates.

Cytotoxic T cell proliferates and differentiates.

Helper T cellcan activate acytotoxic T cell

Cytokines and antibodiesenhance inflammationand phagocytosis.

Helper T cell proliferates andsecretes cytokines.

Macrophage

Antigen

Helper T cell

Helper T cell Helper T cell

B cell Cytotoxic T

Mechanicalmechanisms

Neutrophils, macrophages,basophils, and eosinophils

Chemicalmediators

Inflammation and phagocytosiscause destruction of the antigen.

Interferons preventviral infections.

Macrophage presentsprocessed antigen tohelper T cell(see figure 22.17).

INNATE IMMUNITY

ADAPTIVE IMMUNITY

Helper T cell can activate a B cell

Direct effectsagainst antigen

Antibody-mediated immunity Cell-mediated immunity

Plasma cell

Antibodies Cytokines

Memory B cell Memory T Cytotoxic T cell

Responsiblefor adaptive immunity

Lysis of cellsexpressing antigen

B cell proliferatesand differentiates.

Cytotoxic T cell proliferates and differentiates.

Helper T cellcan activate acytotoxic T cell

Cytokines and antibodiesenhance inflammationand phagocytosis.

Helper T cell proliferates andsecretes cytokines.

Macrophage

Antigen

Helper T cell

Helper T cell Helper T cell

B cell Cytotoxic T

Mechanicalmechanisms

Neutrophils, macrophages,basophils, and eosinophils

Chemicalmediators

Inflammation and phagocytosiscause destruction of the antigen.

Interferons preventviral infections.

Macrophage presentsprocessed antigen tohelper T cell(see figure 22.17).

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Ways to acquire adaptive immunity

Acquired adaptiveimmunity

The individual’s own immune systemis the cause of the immunity.

Active immunityImmunity is transferred from anotherperson or an animal.

Passive immunity

Antigens are introducedthrough naturalexposure.

Antigens are deliberately introducedin a vaccine.

Antibodies from the motherare transferred to her childacross the placenta or in milk.

Antibodies produced byanother person or an animal are injected.

ArtificialNaturalArtificialNatural

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

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

•Allergic diseases•Autoimmunity•HIV and immunosuppression

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

Outline..

16

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Allergic diseases

The most common types ofallergic diseases occur whenthe immune system respondsto a false alarm

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Autoimmune diseasesWhen the immune system mistakes self tissues for nonself and mounts an inappropriate attack, the result is an autoimmune disease.

482:1Chronic idiopathic thrombo-

cytopenic purpura

2:1Multiple sclerosis

2:1Myasthenia gravis

3:1Scleroderma

4:1Rheumatoid arthritis

7:1Graves' disease/hyperthyroiditis

8:1Chronic active hepatitis

8:1Mixed connective tissue disease

9:1 Primary biliary cirrhosis

9:1 Antiphospholipid syndrome

9:1 Sjogren's syndrome

9:1 Systemic lupus erythematosus

50:1Hashimoto's disease/hypothyroiditis

Female:Male Ratios in Autoimmune Diseases

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EnvelopeRNA

Capsid

Attachment Maturation

Regulatoryprotein

Structural protein

Reverse transcription

DNA

Uncoating

Penetration

Newgenome

Budding

Assembly

EnvelopeRNA

Capsid

Attachment Maturation

Regulatoryprotein

Structural protein

Reverse transcription

DNA

Uncoating

Penetration

Newgenome

Budding

Assembly

HIV infected cells producemassive amounts of virus

New copies of HIV bud from the surface of an infected Helper T cell

HIV attacks and kills crucial immune system cells

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HIV and Aquired immunodeficiencysyndrome (AIDS)

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HAART, or Highly Active Antiretroviral Therapy, is a combination of three or more drugs that target the HIV virus in different ways.

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

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..

53

Textbook

Seeley, Stephens, Tate: Essentials of Anatomy and Physiology, 6. edition, ISBN:007110805X. Chapter 11 and 14.

and selected websites

CellsAlive.com: Animations and images of human cells.

http://faculty.ccri.edu/kamontgomery/physiology%20outlines.htmPHYSIOLOGY LECTURE OUTLINES

http://nobelprize.org/medicine/educational/immunity/immune-detail.html

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

Torunn Bruland, DMF, IKM, NTNUtorunn.bruland@ntnu.no