ADVANCED PHYSIOLOGY Instructor Terry Wiseth IMMUNE SYSTEM

ADVANCED PHYSIOLOGY

Instructor Terry Wiseth

IMMUNESYSTEM

2

IMMUNE SYSTEMTwo major categories of immune mechanisms

Nonspecific immunity Specific immunity

3

Nonspecific Immunityincludes mechanisms that resist a variety of

threatening agents or conditionsNonspecific Immunity means that these

immune mechanisms do not act on one or two specific invaders, but rather provide a more general defense by simply acting against any thing recognized as not self

4

Specific Immunityinvolves mechanisms that recognize specific

threatening agents and respond by targeting their activity against these specific agents

These mechanisms often take some time to recognize their targets and react with sufficient force to overcome the threat

5

Cells of Nonspecific Immunity

Natural-Killer (NK) cells Neutrophils Monocytes Macrophages

6

Nonspecific Immunity

Skin and mucous membranesAntimicrobial substancesNatural Killer Cells (NK)PhagocytosisInflammationFever

7


Skin and mucous membranesAntimicrobial substancesNatural Killer Cells (NK)PhagocytosisInflammationFever

8

Skin and Mucous Membranes

Internal environment of the human body is protected by a continuous mechanical barrier formed by the cutaneous membrane (skin) and mucous membranes

9

Skin and Mucous Membranes

Often called the first line of defense Besides forming a protective wall, the skin

and mucous membranes operate various additional immune mechanismsMechanical barriersChemical barriers

10

Mechanical and Chemical Barriers

SebumSebumContains pathogen-inhibiting agents

MucusMucusPathogens may stick and be swept awayViscosity inhibits microbe movements

EnzymesEnzymesMay hydrolyze pathogensLysozymes

11

Mechanical and Chemical Barriers

Hydrochloric acidHydrochloric acidMay destroy pathogens

Sweat, tears, salivaSweat, tears, salivaDilution and washing actionAlso contain enzymes which inhibit

microbial growth

12

Nonspecific ImmunitySkin and mucous membranes

Antimicrobial substancesNatural Killer Cells (NK)PhagocytosisInflammationFever

13

Antimicrobial Substances

2nd line of defenseContained within blood and interstitial fluid

TransferrinsInterferonsComplement

14

Transferrins

Fe++ binding proteins in bloodInhibit microbial growth by binding free Fe++

in blood

Fe++ Transferrin

15

Interferons

Stimulates phagocytosisInhibits viral replication

16

Interferon Cells invaded by viruses may respond

rapidly by synthesizing the protein interferon and releasing it into circulation

Interferon interferes with the ability of viruses to cause disease by preventing the viruses from multiplying in the cell

17

Interferon Interferon is produced within a cell that has

been invaded by a virusVirusVirus Anti viral proteinAnti viral protein

InterferonInterferon

18

Interferon

Intron AIntron AKaposis sarcomaGenital herpesHepatitis B and C

BetaseronBetaseronSlows progression of MS

19

Complement

Is the name given to each of a group of about twenty (20) inactive enzymes in the plasma

activated in a cascade of chemical reactions triggered by either specific or nonspecific mechanisms

20

Complement

Complement or enhance immune, allergic and inflammatory reactions

The complement cascade causes lysis of the foreign cell that triggered it

21

ComplementProteins are given names C1 through C9, B, D, PC3 activation is the key to the complement cascade

22

ComplementC3 activation may occur in two ways

Classical pathwayAlternative pathway

23

Classical PathwayComplexes formed between antibodies and

antigens of microbes

24



25



26

Alternative Pathway

Polysaccharides on microbes can directly trigger C3

27

Complement and Alzheimer’s Disease

Beta-amyloid is a peptide that is the major component of senile plaques within Alzheimer's disease brainsMay trigger an immune response that

significantly contributes to the disease process

28


Beta-amyloid binds very specifically to a protein which is part of the complementary protein group and activates the proteinThere is clear evidence of activated

complement proteins near senile plaques and on damaged neurons in Alzheimer's disease, and it appears that beta-amyloid triggers this response by its binding to complementary proteins

29


Complement proteins are usually released from liver cells but appear to originate in Alzheimer's disease brain from glial cells that surround senile plaquesIt is possible to inhibit the activation of

complement by beta-amyloid without affecting the ability ofcomplement to respondin the rest of the body

30


The results suggest that it may be possible to develop drugs which specifically inhibit complement activation in the Alzheimer's disease brain without causing general immune suppressionThere is increasing evidence that much of

the neuropathology seen in theAlzheimer's disease brainresults from a chronicimmunoinflammatoryreaction to senile plaques

31

Complement

Activated C3 will cascade the complement resulting in:Activation of the inflammatory responseOpsonizationCytolysis

32

Activation of Inflammatory

ResponseArteriole dilationCells release histamine

Increases capillary permeabilityEnhances WBC mobility

Complements act as chemostatic agents attracting other WBC

33

Opsonization

C3 coats the microbes and promotes phagocytosis

34

Opsonization

C3 coats the microbes and promotes phagocytosis

35

CytolysisNumerous complement proteins form a

membrane attack complex (MAC)Punches hole in the microbial membraneMicrobe ruptures

36


Skin and mucous membranesAntimicrobial substances

Natural Killer Cells (NK)PhagocytosisInflammationFever

37

Natural Killer Cells (NK)

3rd line of defensea group of lymphocytes that kill many

types of tumor cells and cells infected by different kinds of viruses

38


Found in the spleen, lymph nodes, red marrowLack antigen receptors

39


Release interferonsRelease perforins which cause cytolysis of

the microbe

40


Attack cells which lack MHC antigensNK cells are decreased in AIDS victims

41


Skin and mucous membranesAntimicrobial substancesNatural Killer Cells (NK)

PhagocytosisInflammationFever

42

Phagocytosis

Is the ingestion and destruction of microorganisms or other small particles by phagocytesNeutrophils (phagocytes)Macrophage (scavenger)

43

Phagocytosis

Macrophages are phagocytic monocytes that have grown to several times their normal size after migrating out of the blood stream

Digestion and killingFuses lysozyme vesicles with engulfed

microbes in cytoplasmRelease defensinsActive against bacteria, fungi, viruses

44

Phagocytosis

Three phases to phagocytosisChemotaxisAdherenceIngestion

45

Chemotaxis

Kinins, microbial productsChemical attraction

46

Adherence

AttachmentOpsonization by complement assists

47

Ingestion

Engulf bacteria or antigen

48

Phagocytosis

Some microbes are ingested but not killedStaphylococcus produce toxins which kill

phagocytesTB multiply within the phagocytesTularemia and brucellosis may lie

dormant for months to years

49

Phagocytes The densest populations of phagocytes

occur in the bone marrow, thymus gland, lymph nodes, and spleen

From these structures, lymphocytes enter the blood and distribute themselves throughout the tissues of the body

50

Phagocytes

After wandering throughout the tissue spaces, they eventually make their way into lymphatic tissues

Lymph flow transports the lymphocytes through a succession of lymph nodes and lymph vessels and empties them into veins

51


Skin and mucous membranesAntimicrobial substancesNatural Killer Cells (NK)Phagocytosis

InflammationFever

52

Inflammatory Response

tissue damage elicits many responses that counteract the injury and promote a return to normal

Bacteria cause tissue damagestriggers the release of mediators from

cells such as mast cells found in connective tissue

53

Inflammation

Response to stress of tissue damageSymptoms include:

Loss of function in injured areaRednessPainHeatSwelling

54

InflammationInflammation helps to restore homeostasisStages of inflammation

1) vasodilation2) phagocyte migration3) tissue repair

55

VasodilationBlood vessels

Become more permeableDilate

56

Vasodilation

Increased blood flow

Allows defensive mediators to leave blood

57

InflammationDefensive mediators

Clot-forming chemicalsAntibodiesPhagocytes

58

InflammationHistamine released by injured cells brings

on vasodilationAlso attract phagocytes

59

Inflammation

Kinines, prostaglandins, leukotrienes and complement promote actions of histamine

Kinins and prostaglandins induce pain associated with inflammation

60

Cytokines

Small protein homonesStimulate or inhibit growth or

differentiation of cellsSecreted by lymphocytes, APC,

fibroblast, endothelial cells, monocytes

61

Cytokine Function

Chemotactic factorsChemotactic factorsattracts macrophages causing hundreds

of then to migrate into the vicinity of the antigen bound, sensitized T-cells

Macrophage activating factorMacrophage activating factorcauses the macrophages to destroy

antigens by phagocytosing them at a rapid rate

LymphotoxinLymphotoxinpowerful poison that acts more directly,

quickly killing any cell it attacks

62

InflammationPus

Collection of dead cells, fluidsAbscess develops when pus cannot drain

awayPimples, boils

63

Inflammation

Phagocytes arrive about 1 hour after inflammationNeutrophils

Arrive firstDie quickly

MonocytesArrive after neutrophilsModify into macrophagesMore powerful and longer lived than

neutrophils

64

Atopic Dermatitis (Eczema)A skin disease characterized by itchy, red,

inflammed portions of the skinScientists have found that people with atopic

dermatitis have a low level of a cytokine (a protein) that is essential to the healthy function of the body's immune system and a high level of other cytokines that lead to allergic reactions

65


Skin and mucous membranesAntimicrobial substancesNatural Killer Cells (NK)PhagocytosisInflammation

Fever

66

FeverAbnormally high body temperatureBacterial toxins trigger release of interleukinInterleukins

Reset body thermostatsIntensify effects of interferons

67

Interleukin

Causes feverStimulates proliferation and activation

of:Helper T-cellsKiller T-cellsB-cells

68

Specific Immune System

The various types of specific immune mechanisms attack specific agents that the body recognizes as "not self"Antigens

Substances that are recognized as foreign and invoke an immune response

69


Two types of specific immune responses are mediated by two different types of cells

The two types of immune responses are:

1) Antibody mediated2) Cell mediated

70


Specific immunity is orchestrated by two different classes of lymphocytes

71

Cells of Specific Immunity

Lymphocytes are formed in red bone marrow and are derived from primitive cells called stem cells

72

Cells of Specific Immunity

Stem cells destined to become lymphocytes follow two developmental paths and differentiate into two major classes of lymphocytesB-lymphocytes or B-cells T-lymphocytes or T-cells

73

B CellsOriginate, mature and develop in bone marrow B-cells do not attack pathogens

Produce antibodies that attack pathogens or direct other cells, such as phagocytes, to attack them

74

B CellsB-cell mechanisms are often classified as

antibody-mediated-immunity (AMI) or humoral immunity

75

T Cells

Originate in bone marrow

Mature and develop in the thymus

76

T CellsProliferate into “killer” T-cells and

“helper” T-cellsAttack pathogens more directly

77

T CellsT-cell immune mechanisms are classified as

cell-mediated-immunity (CMI)

78

TWOTYPES OF SPECIFIC IMMUNE RESPONS

E

79

TWOTWOTYPES OF TYPES OF SPECIFIC SPECIFIC IMMUNE IMMUNE RESPONSRESPONS

EE

80

Antibody Mediated Immunity

Functions in defense against:Dissolved antigensExtracellular pathogens

Bacteria

81

Humoral ResponseAntibody Mediated

82

Humoral ResponseAntibody Mediated

83

Cell Mediated Immunity

Functions in defense against:Intracellular pathogens

Fungi, parasites, virusCancer cellsForeign tissues

84

Cell Mediated Immunity

85

Specific Immune Response

Antibody mediated and Cell mediated immune responses are very complex in how they function

Both responses involve common or similar process and factors

Antigens

Epitopes

MHC

APC

Cytokines

Interleukins

Interferons

Perforins

Antibodies

B-cells

T-cells

86

Antigens

Substances which provoke the immune system

87

Antigens

May consist of:1) Microbes or parts of microbes2) Bacterial toxins3) Allergens

pollen, egg white, etc

88

Antigens

4) Transplanted tissue cells5) Large complex molecules

proteins, glycoproteins, lipoproteins

89

Antigens6) Some smaller substances can act as

antigens if combined with a body proteinEx. Lipid toxin can combine with body protein to form a complex which initiates immune response Poison ivy

Allergic reactions to drugsPenicillin

90

Antigens

7) Allergic reactions to chemicals in the environment

91

Non-antigenicLarge molecules that have simple

repeating units are not antigenic (cellulose, plastics)That is why plastics work as artificial

hearts and joints

92

EpitopesSpecific portions of antigens trigger

immune responsesImmune system capable of recognizing

at least a billion epitopes

93

EpitopesReceptor molecules complementary to

antigen epitopes are located on cell membrane of T-cells and B-cells

94

MHC Antigens Major histocompatibility complex

antigens are found on body cells

95

MHC AntigensUnique to the individualNumber in the thousandsMark body cells as “self”Help T-cells recognize foreign invadersFound on cell membranes

96

MHC –IMarkers of “self”Alert killer T-cells to presence of body

cells that have changed due to viral infection or transformed to cancer cells

97

MHC-IIB-cells, macrophagesMHC-II is combined with ingested

antigens and presented as a complex on the B-cell membrane to T-cells

98

Antigen

If foreign antigen is detected by B-cells and T-cells the immune response is initiatedB-cells can recognize and bind to

antigens in extracellular fluidsT-cells can recognize fragments of

antigen only if presented in association with MHC by antigen presenting cells (APC)

99

Antigen

Epitope binding and presentation of viral epitope

on MHC-1

100

Antigen

T-cell binding to MHC-1 molecule

101

Antigen

T-cell recognition of MHC-2 molecule

102

Antigen

B-cell activated antibody production

103

APC (Macrophages)After macrophages engulf antigen, pieces

of antigen are associated with MHC and subsequently presented as MHC-antigen complex on cell membrane

104

APC

After antigen processing, APC cells migrate to lymphatic tissue and present MHC-antigen complex to T-cells

APC cells located inSkinRespiratoryUrinaryReproductive tractsLymph nodes

105

T-cellsT-cells with correctly shaped receptors that

match the presented MHC-antigen complex trigger:1) Cell-mediated immune response (CMI)2) Antibody-mediated immune response

(AMI)

106

Immune Activation

107

AntibodiesAntibodies are glycoproteins of the family

called immunoglobulins (Igs)

108

AntibodiesEach immunoglobulin molecule consists of

four polypeptide chains joined together by disulfide bonds (S-S)

109

AntibodiesEach polypeptide chain is folded to form

globular regions that are joined together in such a way that the whole molecule is Y-shaped

110

Antibodies

Each of us is thought normally to have millions of different kinds of antibody molecules in our bodies Each of these has its

own uniquely shaped combining sites

Antigen binding sites are in variable regions

111

AntibodiesIt is this structural feature that enables

antibodies to recognize and combine with specific antigens

both of which are crucial first steps in the body's defense against microbes and other foreign cells

112

Functions of Antibodies The function of antibody molecules is to

produce antibody-mediated immunityThis type of immunity is also called

humoral immunity because it occurs within the plasma

113

Antibodies

Antibodies function to:1) Neutralize toxins, viral attachments2) Immobilization of bacteria, flagella, cilia3) Agglutination, clumping of bacteria,

cells4) Activation of complement, classical

pathway5) Enhancing phagocytosis (opsinization)6) Provide fetal newborn immunity

114

Antibody Function

115

Antigen-Antibody Reactions

Antibodies fight disease by distinguishing non-self antigens from self antigens

Recognition occurs when an antigen's epitopes fit into and bind to an antibody molecule's antigen-binding sites

116


The binding forms an antibody-antigen complex that may produce one or more effects It transforms antigens that are toxins into

harmless substancesIt agglutinates antigens that are

molecules on the surface of microorganisms which makes them stick together so phagocytes can engulf them

117


Neutralization of bacteria by antigen-antibody reactions

118

Classes of Antibodies There are five (5) classes of antibodies

identified by letter names as immunoglobulinsMGAED

119

Ig M (Immunoglobulin M)

5-10 % of IgsActivate complement Is the antibody that

immature B cells synthesize and insert into their plasma membranes

Is the predominate class of antibody produced after initial contact with an antigen in the blood

120

Ig G (Immunoglobulin G)

Most abundant circulating antibody

Normally makes up about 75% of the antibodies in the blood

Enhances phagocytosisAble to pass the placenta

from mother to fetusConfers immune

protection to newborn

121

Ig A (Immunoglobulin A)

Constitutes about 15%Major class of antibody present in the

mucous membranes of the body, in saliva, sweat, milk and in tears

122

Ig E (Immunoglobulin E)

Minor in amount (less than 0.1%)Can produce harmful effects such as those

associated with allergies and hypersensitivity

123

Ig D (Immunoglobulin D)

Constitutes less than 1%Activates B-cellsProtects against parasitic worms

124

B-Cells and Antibody-Mediated Immunity

B-cells start their development in the embryonic yolk sac, then the red marrow or fetal liverBy the time a human infant is a few

months old, its pre-B-cells have completed the first stage of development Are then known asinactive B-cells

125


Inactive B-cells synthesize antibody molecules but secrete few if any of them Instead, they insert on the surface of their plasma

membranes perhaps 100,000 antibody moleculesThe combining sites of these surface antibody

molecules are now ready to serve as receptors for a specific antigen if it comes by

126

B-Cell Activation

127


After being released from the bone marrow, inactive B-cells circulate to the lymph nodes, spleen, and other lymphoid structures Occurs when the inactive B-cells become

activated

128


Activation of a B-cell must be initiated by an encounter between an inactive B-cell and its specific antigen

The antigen binds to these antibodies on the B-cell's surface

129


Antigen-antibody binding activates the B-cell triggering a rapid series of mitotic divisions

130


By dividing rapidly, a single B-cell produces a clone mass Some of them become differentiated to form plasma

cellsOthers do not differentiate completely and remain in

lymphatic tissue as memory B-cells

131

Plasma B-CellsPlasma cells synthesize and secrete large

amounts of antibody2000 molecules/sec for 4-5 days or until

plasma cell dies

132

Memory B-Cells

Memory B-cells do not themselves secrete antibodies

if they are later exposed to the antigen that triggered their formationmemory B-cells become

plasma cells and the plasma cells secrete antibodies that can combine with the initiating antigen

133

Memory B-Cells The ultimate function of B-cells is to serve as

ancestors of antibody-secreting plasma cells

134

Humoral Immunit

y

135

Humoral Immunity

136

Humoral Immunity

137

Humoral Immunity

138

Humoral Immunity

139

T-Cells and Cell-Mediated Immunity

T-cells are lymphocytes that have made a detour through the thymus gland before migrating to the lymph nodes and spleen

During their residence in the thymus, pre-T-cells develop into thymocytes

140

T-Cells and Cell-Mediated Immunity

Thymocytes divide up to three times/day and their numbers increase enormously in a relatively short period of time

They leave the thymus and move into the blood and take up residence in lymph nodes and spleennow are known as T-

cells

141

Activation and Function of T-Cells

Each T-cell, like each B-cell, displays unique antigen receptors in its surface membrane

When an antigen (preprocessed and presented by macrophages) encounters a T-cell whose surface receptors fit the antigen's epitopes, the antigen binds to the T-cell's receptors

142


An antigen bound T-Cell activates or sensitizes the T-cell, causing it to divide repeatedly to form a clone of sensitized T-cells

The sensitized T-cells then travel to the site where the antigen originally entered the body

143


There in inflamed tissue, the sensitized T-cells bind to antigens of the same kind that led to their formationT-cells will bind to their

specific antigen only if the antigen is presented by a macrophage

144


The antigen-bound sensitized T-cells then release chemical messengers into the inflamed tissues called cytokines

145

Types of T-cells

Helper T-cellsKiller T-cellsSuppressor T-cellsMemory T-cells

146

Helper T-cellsTH

Cooperate with B-cell to amplify antibody production by plasma cells

Secrete interleukins which stimulates proliferation of T and B cells

147

Helper T-cellsTH

Cooperate with B-cell to amplify antibody production by plasma cells

Secrete interleukins which stimulates proliferation of T and B cells

148

Killer T-CellsTC

Cytotoxic , Killer T-cells

149

Killer T-CellsRecognize foreign antigens presented by:

1) body cells infected by virus2) some tumor cells3) cell of tissue transplant

Requires Helper T-cells to be activatedSensitized T-cells then release lymphotoxin

which kill target cells

150

Suppressor T-CellsTS

Inhibit proliferation of T-cellsDampens immune response

151

Memory T-CellsProgrammed to recognize original invading

antigensAble to initiate a swift reaction on

subsequent infections

152

T-Cell Summary

Animated slide show has 5 seconds between each slide

Slide show is over

153

Types of Specific Immunity

Inherited immunityImmunity to certain diseases develops

before birthAcquired immunity

Exposure to the causative agent is not deliberateNaturalArtificial

154

Natural Acquired ImmunityActive

A child develops measles and acquires an immunity to subsequent infection

PassiveA fetus receives

protection from themother through theplacenta, or an infantreceives protection byway of the mother's milk

155

Artificial Acquired Immunity

Exposure is deliberateActive

Injection of the causative agent, such as vaccination against polio, confers immunity

PassiveInjection of immunoglobulins

(antibodies) that were developed by another individual's immune system

156

Disorders of the Immune System

AIDSChronic Fatigue SyndromeSevere Combined Immunodeficiency (SCID)Allergy Tissue RejectionHodgkin’s DiseaseAutoimmune Disease

LupusMultiple SclerosisMyasthenia GravisGraves Disease

157

AIDS

HIV attack T-cells

158

Chronic Fatigue Syndrome

Extreme fatigueLowered levels of corticotropin releasing

hormone and cortisol

159

Both B-cells and T-cells are missing or inactive

Caused by mutated genesInfusions of red marrow from sibling provide

normal stem cellsDavid “bubble boy”

Severe Combined Immunodeficiency

160

Allergy

Overly reactive to antigen that is tolerated by most others

161

Type I Allergies

AnaphylaxisMost common allergic reactionCells release histamine which causes

bronchiole constrictionBee stingTreated with epinephrine

162

Type II AllergiesCytotoxicCells damaged by lysis

Incompatible transfusion reactions

163

Type III AllergiesImmune complexComplexes of antigen-antibody which are

small and escape phagocytosisAccumulate in blood vessel lining causing

inflammationRheumatoid arthritis, systemic lupus,

glomerulonephritis

164

Type IV Allergies

Delayed type hypersensitivityCarried by macrophages which have been

activated by T-cellsSymptoms occur 12-72 hours after exposure

Skin tests for TB

165

Tissue RejectionImmune system recognizes transplanted

tissues as antigensImmunosuppressive drugs suppress entire

immune systemCyclosporin

Inhibits secretion ofinterleukins by HelperT-cells but does notimpact B-cells

166

Hodgkin’s Disease

Cancer usually arising in lymph nodesConsidered a curable disease

Lymph node Malignant cells

167

Autoimmune Disease

LupusMultiple Sclerosis

Myasthenia Gravis

Grave’s Disease

168

Lupus

Inflammatory, non-contagious disease of connective tissue

Blood vessel damage results in release of chemicals causing inflammation

Skin lesions, rashes

169

Multiple Sclerosisimmune cells mistake myelin as a foreign

invader and attack itthe protective coating on nerve fibers (myelin)

becomes detached and eventually destroyedMS can affect vision, sensation, coordination,

movement and bladder and bowel control

170

Myasthenia GravisDisease affecting the neuromuscular

junction and producing weakness of voluntary muscles

Receptors for acetylcholine at the muscle surface are destroyed

Destroyed Ach

receptors

Healthy Ach

receptors

171

Myasthenia GravisVoluntary muscles of the eyes are

commonly affected

Three different serial pictures to demonstrate fatigue of eyelid muscles as the patient keeps looking up

After a few minutes of rest, the eyelids have returned to near-normal position

172

Grave’s DiseaseAntibodies are produced against certain

proteins on the surface of thyroid cellsStimulating those cells to overproduce

thyroid hormonesResults in an overactive thyroid

173

Grave’s DiseaseThe immune system also attacks the tissue

behind the eyes and the skin of the lower legsTissues behind the eye attract and hold waterWhen this happens, the tissues and muscles

swell, causing the eyeball to move forward in the orbit

EndImmune System

Documents

ADVANCED PHYSIOLOGY Instructor Terry Wiseth IMMUNE SYSTEM