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THE IMMUNE SYSTEM

Presented by: DongJae Ryoo (2014)

INTRODUCTION
Immune System a functional system of the body

The Immune system


= an elaborate, multi-level network of defences cells, proteins and chemicals

Host Defences:
= keep pathogenic microbes & foreign materials from penetrating body
nonspecific ~ specific

innate (inborn) ~ acquired

Other functions of the immune system:


monitor changes to our own cells
clean up damaged tissue & assist with repair
have memory of previous threats
Figure 14-1. Craft et al. Understanding Pathophysiology 2011

OVERVIEW OF IMMUNE SYSTEM


Overview Main topics of immune system
PART 1: the Innate Defences
PART 2: the Interactions Between Innate and Specific Defences
PART 3: Humoral Immunity (Specific Defences)
PART 4: Cell-mediated Immunity (Specific Defences)

OVERVIEW OF IMMUNE SYSTEM


Immune System the major components of the host defence
Immune System

Reinforce & enhance


Innate
(non-specific)

Adaptive
(specific)

preventing entry of pathogens (barriers)

prevent establishment of invaded pathogens (tissue defences)

Responsible for communicating to specific defences (2nd line)

Chemical barriers

constantly present
skin & mucosal membranes

to trigger specific defences

to target the right thing

2nd line of defence

1st line of defence

Physical barriers

Communicates

Inflammatory
response

3rd line of defence

Phagocytosis

Cells/proteins in tissues
active when barriers are penetrated

Humoral
(B lymphocyte)

Cell-mediated
(T lymphocyte)

Take longer to exert effects


Usually in response to the first infection
Specific & aggressive

OVERVIEW OF IMMUNE SYSTEM


Learning Objectives

Figure 14.1 Cowan MK 2012

I. BARRIERS: THE FIRST LINE

THE FIRST LINE OF DEFENCE


Barriers block invasion at the portal of entry

Barriers
= Non-specific; limits access to the internal tissues of body
external body membranes skin & mucous membranes

both are epithelial tissues


very general in action (non-specific)

Figure 14-1. Craft et al. Understanding Pathophysiology 2011

SKIN
Skin thick, tough, impervious & waterproof

Skin

Subcutaneous

Dermis

Epidermis

= the largest organ in the body; consists of multiple layers


separates inner bodies from external threats
outer layers constantly sloughing off
sweat acidic, also has flushing effect

(helps remove microbes)


sebum bactericidal secretion

Keratin:
= packed in the top layer of cells,
a protective & waterproofing protein
Figure 1-4. Hansen , Netters Clinical Anatomy 2009

MUCOUS MEMBRANES
Mucosa provide barrier protection, without keratised layer

Mucous membranes
= external lining of the digestive, respi, urinary & reproductive tracts + eyes

Mucus

continuous flow of mucus in one direction flushing action


Upper respiratory tract mucociliary escalator
http://www.vetmed.vt.edu/education/curriculum/vm8054/labs/Lab25/IMAGES/TRE%20COMPOSITE.jpg

MUCOUS MEMBRANES
Mucociliary escalator ciliated epithelium of the upper respiratory tract
Mucociliary escalator
= consists of (a) goblet cell & (b) ciliated cell
escalate particle-bound mucus up to mouth
expel it by either coughing out or swallowing

(a) Goblet cell:


= produce mucus which traps microbes
(b) Ciliated cell:
= propel particle-trapped mucus towards exterior

Goblet cell

http://www.nhlbi.nih.gov/health/health-topics/topics/pcd/causes.html

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MUCOUS MEMBRANES
Other mechanisms prevent microbes from penetrating sterile body spaces

Nonspecific chemical defences


= offered by the skin & mucous membranes

Mechanisms

Description & Examples

Acids

HCl & pepsin secreted from stomach mucosa


Protect stomach from infection & toxins

Antimicrobial
proteins

Always present in epithelial mucosal cells


Help maintain sterile environments of tracts
For example, lactoferrin & B-defensin

Antimicrobial
enzymes

Lysosome in saliva & lacrimal fluid


Hydrolyses peptidoglycan in bacterial cell wall
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QUIZ #1
[Learning Objective 1] the innate defences

Which of the following is present in respiratory tract and


prevents entry of particles into lower respiratory tracts?
A. goblet cell
B. mucociliary escalator
C. ciliated cell

D. lactoferrin

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II. INNATE: THE SECOND LINE

THE SECOND LINE OF DEFENCE


Innate means internal defence; consists of cells & proteins within tissues

Innate defences (aka natural, native or non-specific immunity)


= activated when tissues are penetrated; to inhibit establishment of microbes

Main components:

Healthy immune system:

Inflammation

Surveillance

Antimicrobial proteins

Recognition of foreign material

Phagocytes

Destruction of foreign materials

Fever
Natural killer cells

Figure 14.4 Cowan MK 2012

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THE SECOND LINE OF DEFENCE


Innate means internal defence; consists of cells & proteins within tissues

Innate defences (aka natural, native or non-specific immunity)


= activated when tissues are penetrated; to inhibit establishment of microbes

Main components:

Healthy immune system:

Inflammation

Surveillance

Antimicrobial proteins

Recognition of foreign material

Phagocytes

Destruction of foreign materials

Fever
Natural killer cells

Figure 14.4 Cowan MK 2012

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INFLAMMATION
Innate non-specific, primary immune response to tissue injury & infection
Roles of Inflammation:

Injurious agents

Limit the spread of damage/infection

damage/disrupt

Remove cell debris (+ pathogens)

FIRST LINE OF
DEFENCE
(skin, mucosa)

Set injured tissue for repair

results in

Inflammatory response:

Injured tissue

= brings immune cells, fluid, clotting proteins


local
systemic e.g. infection in blood

Injurious agents
(microbes,
chemical)

Necrotic cells &


tissues

Destroyed/
Neutralised

Cleaned
(removed)

SECOND LINE OF
DEFENCE
(Acute Inflammation)

Injured tissue is
READY for healing
Modified from DongJae 2014

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QUIZ #2
Acute Inflammation Five Cardinal Signs

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INFLAMMATION
Cardinal signs heat, redness, swelling, pain (+ loss of function)

Figure 13-3. Craft et al. Understanding Pathophysiology 2011

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ACUTE INFLAMMATION
Inflammatory response details of three main processes
Acute Inflammation

Vasodilation

vascular
permeability
vol. blood to site
blood flow (local)
# inflamm cells
& chemicals

Local warmth

Local redness

Pain
Swelling (local)

= due to stimulation of nociceptors by:


Prostaglandins
Kinins
Bacterial toxins
Mechanical pressure exudate + vasodilation

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ACUTE INFLAMMATION
Inflammatory response details of three main processes

Allergen

Antigen Presentation

Figure 13-2. Craft et al. Understanding Pathophysiology 2011

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QUIZ #3
[Learning Objective 1] the innate defences

Which of the following is not a function of the inflammatory


response?
A. prevents the spread of the injurious agent to nearby tissue
B. replaces injured tissues with connective tissue
C. disposes of cellular debris and pathogens

D. sets the stage for repair processes

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PHAGOCYTES
Phagocytes present in tissues & bloodstream

Phagocytes (eating cell)


= cells that carry out phagocytic engulfment, killing & recognition

More than just eating foreign materials:


Recognise common danger signs
Remove debris/damaged-cells

Prepare injured tissue for repair


Communicate with specific defence cells
Attract other immune cells (by chemokines)

Macrophage
Figure 14.17 Cowan MK 2012 22

PHAGOCYTES
Phagocytes present in tissues & bloodstream

Phagocytes (eating cell)


= cells that carry out phagocytic engulfment, killing & recognition
Fixed in a tissue
Kuppfer cells (Macrophages) in the liver
Alveolar macrophages in lungs
Microglia in the brain
Free in the bloodstream
Attracted to injured site by chemical signals
(chemotaxis)
Monocytes/Macrophages
Dendrocytes
Neutrophils
Macrophage
Figure 14.17 Cowan MK 2012 23

PHAGOCYTOSIS
Phagocytosis
1)

Adhesion of pathogens/debris

2)

Engulfment

3)

Phagosome containing microbe

4)

Phagolysosome formation

5)

Killing & destruction of microbe

6)

Release of digested material

Antigen presentation:
= fragments specific to pathogen are

presented on surfaces for


specific defences
Figure 14.17 Cowan MK 2012

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QUIZ #4
[Learning Objective 1] the innate defences

When pathogens break through the first line of defences, which of the
following events is/are likely to occur?

A. 2, 7, 5, 6, 3, 1, 4
B. 7, 2, 5, 3, 6, 1, 4

C. 2, 7, 4, 3, 6, 1, 5
D. 7, 2, 4, 6, 3, 1, 5
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INNATE DEFENCE ACTIVATION


OF SPECIFIC DEFENCES

ACTIVATION OF SPECIFIC DEFENCES


Specific Defences activated by non-specific defences (the second line)

Role of specific defences


= Non-specific alone may not prevent establishment & spread of infection

Innate-Specific Communication:
A.

Release of cytokines

B.

Antigen presentation

Most immune response:


= requires the encounter between
A

antigens & WBCs

Figure 14.18 Cowan MK 2012

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ANTIGEN
Antigen a foreign substance that provokes an immune response

Antigen, perceived as foreign


= all substances from other humans, animals etc are potential antigenic

In most immune reactions:


= the antigen must be processed
& formally presented to lymphocytes

by antigen-presenting cells (APCs).


Antigen presentation:
= involves marker proteins, called
major histocompatibility complex (MHC)
Figure 15.7 Cowan MK 2012

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MHC PROTEINS
Major Histocompability Complex (MHC) marker proteins

MHC markers
= the flags molecules for inspection of the body

Class I MHC:
self-antigens
appear on almost all body cells

Class II MHC:
found on APCs
involved in presenting antigen to T cells

Figure 15.2 Cowan MK 2012

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ACTIVATION OF SPECIFIC DEFENCES


Antigen Presentation activated by non-specific defences (the second line)
Antigen presenting cells:
Macrophages
Dendritic cells (in skin & tissues)

B lymphocytes

Antigen presentation:
1)

Phagocytosis

2)

Process, then display on MHC II

3)

Helper T cells recognise antigen

4)

Specific immune response

Figure 15.9 Cowan MK 2012

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QUIZ #5
[Learning Objective 1] the innate defences

Phagocytes
A. alert the specific defences to a foreign threat using MHC II
B. are antigen presenting cells
C. alert the specific defences to a foreign threat using MHC I
D. Both A and B are correct

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III. SPECIFIC: THE THIRD LINE

ADAPTIVE IMMUNE SYSTEM


Overview Specific immune response to a particular antigen

Main cell types of adaptive immunity


= (a) B & T lymphocytes, and (b) antigen presenting cells (APCs)

specific & systemic

takes longer to mount effect


amplifies inflammatory response

Functions of adaptive immunity:


Identifies & responds to specific antigens
attacks identified molecules
Figure 14.4 Cowan MK 2012

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ADAPTIVE IMMUNE SYSTEM


Overview two branches of adaptive immunity (the third line)

Most B cells require


stimulation from T cells

CD4

Helper T cells:
Communication with APCs

Assist humoral activities


Help activate CD8

B lymphocyte:
focus on exogenous threats
produce antibodies

CD8

Cytotoxic T lymphocyte:
focus on infected host cells
Endogenous: viral/cancerous

Modified from Figure 15.1 Cowan MK 2012

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LYMPHOCYTE DEVELOPMENT
Origin of Immunological Diversity B & T lymphocytes

Lymphocyte development
= immature lymphocytes produced in bone marrow
Differentiation:
B cells in Bone marrow

T cells in Thymus

Migration:
= both immunocompetent B & T cells
migrate to lymphoid tissues
Activation:

= once activated, migrate to


blood/lymph for its action
Figure 15.4 Cowan MK 2012

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LYMPHOCYTE DEVELOPMENT
Second Stage in Details enables recognition of numerous antigens
Each lymphocyte:

= possess a receptor unique to an antigen


receptors made from a set of genes
genes rearrange randomly

Lymphocyte selection:
those w/ non-self receptors mature
those w/ self receptors are destroyed

Immunocompetent lymphocytes:
= mature lymphocytes that react to
only foreign, NOT to self!
Figure 15.5 Cowan MK 2012

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LYMPATHIC SYSTEM
a network of lymphatic vessels, lymphoid tissues & organs

Effective immune responsiveness


= requires communication of the activities between fluid compartments

During inflammation:
= excess tissue fluid & phagocytes drained
by lymphatic vessels (lymphatics)
Lymphatics, also important for:
Non-specific & specific cell communication
Surveillance of body fluids

Modified from Figure 12.7 Moore, KL, Dalley, AF & Agur, AMR 2014, Clinically Oriented Anatomy, 7th edn

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LYMPHOID TISSUE
Lymphatic tissue largely composed of reticular connective tissue
Lymphoid tissue, consists of:
Lymphoid macrophages

Dendritic cells
lymphocytes
Reticular cells
Reticular fibres (stoma)

Reticuloendotheliar system:

= provides a fibrous support


network enmeshing each cell

Figure 14.6 Cowan MK 2012;


https://s3.amazonaws.com/classconnection/619/flashcards/6041619/png/lymph_node_sem-149077986716CE4F1D6.png

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LYMPH NODE
Lymph node the principal lymphoid organs in body; cluster along lymphatics
Structure:
= consists of many afferent & fewer efferent
lymphatics (Afferent > Efferent)
slow fluid flows through lymph nodes
important for surveillance of lymph (fluid)
also allows filtering of lymph

Site of communication:
= between non-specific cells (APCs) &
specific cells (B & T lymphocytes)

Activation by antigen = swelling of lymph node!


Modified from Figure 12.7 Moore, KL, Dalley, AF & Agur, AMR 2014, Clinically Oriented Anatomy, 7th edn

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SPLEEN
Spleen blood-rich organ, responsible for blood screening
Immune-related roles:
Spleen

Immune surveillance (resident macrophage)


Initiate specific immune cell proliferation
Serve as a filter for blood (NOT lymph)
Site of lymphocyte proliferation (B & T)

Other roles:
Pancreas

Destruction of old/damaged RBCs & platelets


Recycling iron & globin
Storage of platelets

Figure 4-23 Hansen, JT 2009, Netter;s Clinical Anatomy, 2nd edn

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THYMUS
Thymus the site of T cell maturation (No surveillance function)
Essential during childhood
Less important from adolescence ~

T cell maturation:
Immature T cell differentiate
Self-reacting T cells are destroyed

Blood-thymus barrier:
= prevents entry of blood-borne agents,

and hence, premature activation of T cells

Figure 14.8 Cowan MK 2012

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QUIZ #6
[Learning Objective 1] the innate defences

Which of the following is the main function of spleen in


immune system?
A. provides a site for lymphocyte proliferation
B. removal of old, damaged, defective blood cells & platelets
C. immune surveillance of blood & response to antigens

D. storage of blood platelets

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QUIZ #7
[Learning Objective 1] the innate defences

Lymphocytes that develop immunocompetence in the


thymus are:
A. natural Killer cell
B. B lymphocytes
C. T lymphocytes

D. macrophages

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QUIZ #8
[Learning Objective 1] the innate defences

The site of communication between non-specific and


specific defence cells is:
A. lymph node
B. thymus
C. skin

D. bone marrow

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III. SPECIFIC: HUMORAL IMMUNITY

HUMORAL IMMUNITY
Humoral provided by antibodies which are secrete by B cells

Humoral, liquid
= antibodies circulate throughout body & act separately to B cells

Antibody proteins that are capable of binding to antigen


Each B cell produces only one kind of antibody
Antigen have several different antigenic determinants
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HUMORAL IMMUNITY RESPONSE


Humoral provided by antibodies which are secrete by B cells

Activation of B lymphocyte
= activated by either (a) helper T cell or (b) antigen directly
I

Cytokines

In lymph nodes specific Helper T cell recognise the antigen on APC


Cytokines released after recognition of specific antigen
Modified from Figure 15.1 Cowan MK 2012

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HUMORAL IMMUNITY RESPONSE


Humoral provided by antibodies which are secrete by B cells
II

Activation of B cell & Selection:


TCD4 release cytokines
Cytokines trigger clonal selection

Alternative pathway:
1)

Specific B cell

phagocytises microbe
2)

Present it to specific TCD4

3)

TCD4 checks it with another APC

4)

Release cytokines

Modified from Figure 15.10 Cowan MK 2012

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HUMORAL IMMUNITY RESPONSE


Humoral provided by antibodies which are secrete by B cells
III

B clone proliferation:
Transforms into blast cells
Blast cells proliferate

A large clonal population formed

B clone differentiation:
Differentiate into plasma cells
Undifferentiated cells become

memory cells

Modified from Figure 15.10 Cowan MK 2012

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HUMORAL IMMUNITY RESPONSE


Humoral provided by antibodies which are secrete by B cells
III

Plasma cells (effector B cells):


mature cells
secrete antibody

short lifespan (4~5 days)

Memory B cells:
undifferentiated
long lifespan (year ~ entire)
produce immediate 2nd response

Modified from Figure 15.10 Cowan MK 2012

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ANTIBODY
Antibody form antigen-antibody complex; have several different functions

Figure 21.14 Marieb 2004

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ANTIBODY CLASS
Antibody also known as immunoglobulin (Ig)

IgG normal memory antibody; most abundant in plasma


IgA normal memory antibody in secretions (saliva, sweat, mucus etc...)
IgM normal early antibody in infection; circulate in blood plasma
IgD antigen receptor of B cells (always bound)
IgE antibody for parasites; involved in allergy

Table 15.2 Cowan MK 2012

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SECONDARY RESPONSE
Humoral responses to a specific antigen over time

Figure 15.14 Cowan MK 2012

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HUMORAL IMMUNE RESPONSE


Summary primary & secondary responses

Lag period the time required for clonal selection & differentiation
Memory cells sensitised to the specific antigen
Antibody titre concentration of antibody in blood

Antibody titre rises steeply much higher (than during primary response)
Antibody circulates longer time (than during primary response)
Modified from Figure 15.14 Cowan MK 2012

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QUIZ #9
[Learning Objective 1] the innate defences

The primary humoral immune response has a lag period


about 3-6 days because:
A. antigen challenge is a slow process
B. only a few B cells are specific for the antigen
C. antigen has to penetrate the first line of defence

D. Both A and C are correct

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QUIZ #10
[Learning Objective 1] the innate defences

Which of the following correctly match the following


antibody types with their characteristics?
A. IgG most abundant antibody found in plasma
B. IgM found in body secretions such as milk, saliva & sweat
C. IgE levels greatly reduced during severe allergic response

D. IgA first class released by plasma cells & is indicative of a

current infection

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III. SPECIFIC: CELL-MEDIATED


(http://www.cell.com/cell/issue?pii=S0092-8674%2814%29X0022-X; Hussain et al. 2014, p. 600, p. 601)

CELL-MEDIATED IMMUNITY
Cell-mediated reliant upon cytotoxic T cells (CD8) to directly kill target

Cell-mediated immunity is important


= as humoral provides only partial immunity & for only external threats

Targets:
Virus-infected host cells
Intracellular-bacteria-infected host cells
Parasite-infected
Cancer cells
Introduced foreign cells (blood transfusions or organ transplants)

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CELL-MEDIATED RESPONSE
Cell-mediated activation of T cells

Activation of T lymphocyte
= activated by the APCs with antigens from dead cancer/infected cells
Processed antigen
MHC-II receptor

APC

APC
Tumour-specific T-cell
receptor (TCR)

MHC-II
Cytokine

Antigen
TCR
TH cell

Helper T cell

Modified from Figure 15.9 Cowan MK 2012


http://www.nature.com/nrc/journal/v13/n5/fig_tab/nrc3498_F4.html

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CELL-MEDIATED RESPONSE
Cell-mediated differentiation of T cells into subsets

Clonal selection & differentiation


= activated T cells transform in preparation for mitotic divisions
CD4 cells = Cytotoxic T cells
CD8 cells = Helper T cells

cytokines
Activated B cell

Memory CD4

cytokines
CD4
stimulate
cytokines

macrophages
promote
inflammation

CD8

Memory CD8

Activated CD8

Directly kill target

Infected host cell

Modified from Figure 15.15 Cowan MK 2012

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CELL-MEDIATED RESPONSE
Overall scheme T-cell activation & differentiation

Summary of cell-mediated immune response


= APCs present antigen to T cells bearing either CD4 or CD8 markers

stimulate
Macrophages

TH subset

Dead host cells

promote

(infected/cancerous)
CD4

phagocytised by:

Inflammation

TH subset

(MHC II)

Clone formation
(in thymus)

amplify
B lymphocytes

TH subset

Memory CD4
APC

Cytokine activate
Memory CD8

CD8

Clone formation

(MHC I)

(in thymus)

directly kill
Activated CD8

Target host cells

(w/ TCR specific to target MHC I)

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QUIZ #11
[Learning Objective 1] the innate defences

The role of the helper T cell is critical for the specific


defences because:
A. it is responsible for killing cancerous cells
B. it is responsible for confirming the presence of a threat
C. it provides go signal for the appropriate specific response

D. both B and C are correct

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QUIZ #12
[Learning Objective 1] the innate defences

Which of the following statements is incorrect?


A. clonal expansion & differentiation of T cells occur in thymus
B. cytotoxic T cells are only activated by helper T cells
C. memory T cells are also formed during clonal expansion
D. both B and C

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IMMUNE SYSTEM
Summary innate & specific immunity
: stimulate
: primary exposure
: secondary exposure

Plasma cells

Modified from http://academic.brooklyn.cuny.edu/biology/bio4fv/page/aviruses/immuneresponse.jpg

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REFERENCE LIST
All copyrights are reserved. No copyright infringement intended
Cowan, MK 2012, Microbiology: A Systems Approah, 3rd edn, McGraw-Hill, New York.
Hansen, JT 2009, Netter's Clinical Anatomy, 2nd edn, Saunders, Philadelphia.

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