Transcript No Slide Title

Introduction to Cellular Immunology
Dr. Colin R.A. Hewitt
[email protected]
Movie credits:
The movies of cells are used with the permission of
Dr. James A. Sullivan of Cells Alive
http://www.cellsalive.net/
© [email protected] 2000.
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The purpose of this preliminary lecture is to remind
students of the immunology learnt in the second year, and
introduce key concepts that are required for a full
understanding of the later lectures
To use the lecture, click on the projection screen icon
below
, then just click your way through the
presentation.
Don’t forget to try the online multiple choice questions at the end
to find your strengths and weaknesses
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What you should know by the end of this lecture
 The basic terms used in immunology
 The characteristics and interdependence of adaptive and innate immunity
 The names and functions of cells in the immune system
 The structure and function of peripheral lymphoid organs
The purpose of lymphocyte recirculation
 How cells communicate in the immune system and how this is tested
 How the clonal distribution of antigen receptors in the immune system
allows for diverse recognition, self tolerance and memory
 That the compartments invaded by pathogens require different effector
mechanisms of immunity.
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History & impact of immunology on human health
Koch’s
Kohler & Milstein
Postulates Monoclonal Abs
Metchnikoff
Phagocytosis
Müller Jenner
Wright Miller
Bacteria Vaccination
Antisera T cells
Jansen
Microscope
1600
1700
1800
1900
2000
1955
30
Countries with
more than one
smallpox case 15
per month
200 years
WHO announce
after Jenner smallpox eradicated
0
1965
1970
1975
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1980
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Why study immunology now?
Infectious diseases
Mechanisms of pathogenicity
Vaccine development
Diseases caused by a disturbed immune system
ALLERGY: Immune responses to innocuous materials e.g. ASTHMA
AUTOIMMUNITY: Anti-self immunity e.g. MULTIPLE SCLEROSIS
GRAFT REJECTION: Immune responses to TRANSPLANTED TISSUE
IMMUNODEFICIENCY: Defects in immune responses e.g. SCID
Manipulation of immunity to treat disease
IMMUNOSUPPRESSION: Treatment of immune diseases
IMMUNOREGULATION: Immunotherapeutic interventions
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Reminder of basic immunological terms
ANTIGENS (Ag)
are substances recognised by
• ANTIBODIES (Immunoglobulin, Ig, Ab) and
• T LYMPHOCYTES (T CELLS)
Antibodies are made by
B LYMPHOCYTES (B CELLS)
T cells help B cells make antibodies:
T HELPER (Th) cells
T cells kill infected cells
T CYTOTOXIC (CTL)
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Immune responses
Barriers
Invasion
& infection
Innate immunity
+
+
Skin & Mucous membranes
rapidly regenerating surfaces, peristaltic
movement, mucociliary escalator,
vomiting, flow of urine/tears, coughing
Cellular and humoral defences
lysosyme, sebaceous/mucous secretions,
stomach acid, commensal
organisms,complement proteins,
phagocytosis, NK cells
Inflammation
Adaptive immunity
Cellular and humoral defences
Antibodies, cytokines, T helper cells,
cytotoxic T cells
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Adaptive immunity
Immunity established to adapt to infection
• Learnt by experience
• Confers pathogen-specific immunity
• Enhanced by second exposure
• Has memory
• Uses cellular and humoral components
• Is poorly effective without innate immunity
Antibodies reflect infections to which an
individual has been exposed- diagnostic for infection
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Innate immune response
Inbuilt immunity to resist infection
• Present from birth
• Not antigen-specific
• Not enhanced by second exposure
• Has no memory
• Uses cellular and humoral components
• Is poorly effective without adaptive immunity
Also involved in the triggering and amplification of
adaptive immune responses
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Leucocytes
Adaptive and innate immunity depends upon LEUCOCYTES
Innate immunity is mediated largely by GRANULOCYTES
Adaptive immunity mediated by LYMPHOCYTES
The growth, development and activities of granulocytes and
lymphocytes are interconnected and often co-operative.
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Lymphocyte
Adaptive immunity
Macrophage Phagocytosis
Monocyte Ag presentation
Neutrophil
PMN
Cells Of The
Immune System
Common
lymphoid
progenitor
Phagocytic
Anti-bacterial
Eosinophil Anti-parasite
immunity
Basophil
?Protection of
mucosal surfaces?
Mast cell
Protection of
mucosal surfaces
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Pluripotent
haemopoietic
stem cell
Myeloid
progenitor
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Lymphocyte subsets
CLP
T CELLS
B CELLS
Common
lymphoid
precursor
T
Th
Activate B cells
and macrophages
T HELPER CELLS
CTL
Kill virusinfected cells
CYTOTOXIC T
LYMPHOCYTES
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B
PC
Produce antibodies
PLASMA CELLS
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Look for some excellent low power images and electron
micrographs of the cells at the following site:
http://www-medlib.med.utah.edu/WebPath/webpath.html
•Resting Lymphocyte
•Activated Lymphocyte
•Plasma cell
•T and B cells are morphologically identical
Movie:
Cytotoxic T- lymphocyte
killing target
(click on this link)
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Look for some excellent low power images and electron
micrographs of the cells at the following site:
http://www-medlib.med.utah.edu/WebPath/webpath.html
•Erythrocyte (Red blood cell)
•Blood monocyte
•Platelet (thrombocyte)
•Tissue macrophage
Movie:
Human macrophage
ingesting Candida albicans
(click on this link)
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Look for some excellent low power images and electron
micrographs of the cells at the following site:
http://www-medlib.med.utah.edu/WebPath/webpath.html
•Neutrophil
Movie:
Chemotaxis of human neutrophils
(click on this link)
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Look for some excellent low power images and electron
micrographs of the cells at the following site:
http://www-medlib.med.utah.edu/WebPath/webpath.html
•Eosinophil
•Basophil
•Neutrophil
•Lymphocyte
•Monocyte
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Lymphocyte antigen receptors
Until the 1960’s, lymphocytes had no known function.
Lyc
T and B cells are essentially inactive until they
encounter antigen.
T and B cells express ANTIGEN RECEPTORS
B
T
The B cell antigen receptor is a membrane-bound antibody
SURFACE IMMUNOGLOBULIN
The T cell antigen receptor IS NOT membrane bound
antibody but a distinct molecule
T CELL ANTIGEN RECEPTOR
Each antigen receptor binds to a different antigen
Each cell has only one antigen specificity
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Lymphoid organs
Organised tissue in which lymphocytes interact with non lymphoid cells
Sites of maturation & initiation of adaptive immune responses
CENTRAL LYMPHOID ORGANS
PERIPHERAL LYMPHOID ORGANS
Central lymphoid organs:
THYMUS – T cell maturation
BONE MARROW – B cell maturation
Peripheral lymphoid organs:
LYMPH NODES
SPLEEN WHITE PULP
MUCOSAL-ASSOCIATED LYMPHOID TISSUE
T and B cell activation
Antigen trapping
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Lymph node
4. Germinal centre
(site of intense
B cell proliferation)
5. Medullary cords
(Macrophage &
plasma cell area)
3. Secondary
lymphoid follicle
6. Efferent lymphatic
vessel
2. Primary Lymphoid
follicle (B cell area)
Paracortical
(T cell) area
Artery
Vein
1. Afferent lymphatic
vessel. Lymph, cells
& Ag drained from
tissues enters here
Medullary sinus
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Look for an excellent image of a sectioned lymph node at the
following site:
http://www-medlib.med.utah.edu/WebPath/webpath.html
© [email protected] 2000.
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Look for an excellent image of a germinal centre at the following site:
http://www-medlib.med.utah.edu/WebPath/webpath.html
© [email protected] 2000.
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Spleen white pulp
Transverse section
Marginal sinus
B cell corona
Red pulp
Germinal centre
Marginal zone
Periarteriolar lymphocytic
sheath (PALS) – T cell area
Central arteriole
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Look for an excellent image of a sectioned spleen at the following site:
http://www-medlib.med.utah.edu/WebPath/webpath.html
© [email protected] 2000.
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Lymphocyte recirculation
NAIVE LYMPHOCYTES enter
blood, are seeded to the
peripheral lymphoid organs
and recirculate
Cells & antigens from a site of infection
are trapped in draining lymphoid tissue.
Cells proliferate and re-enter the
RECIRCULATING LYMPHOCYTE POOL
to re-seed the peripheral lymphoid organs
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Look for an excellent images of Wuchereria bancrofti and
elephantiasis at the following site:
http://www-medlib.med.utah.edu/WebPath/webpath.html
© [email protected] 2000.
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How immune cells communicate:
SOLUBLE MEDIATORS
Infection
CYTOKINES & CHEMOKINES
Phagocyte
activation
Diverse collection of soluble proteins
made by cells that affect the
behaviour of other cells. The balance
& level of cytokines and chemokines
secreted affects the outcome of the
response
INFLAMMATION
Early events involve endothelial cells and result
in the accumulation of fluid, plasma proteins &
leucocytes.
Later events involve the activation and
maturation of lymphocytes and other
granulocytes.
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Bio-assay of cytokines in vitro
Activation
of M in vitro
Test for effect
on other
cells
Cytokine secretion
Remove cytokine
containing
supernatant
+/Which cytokine?
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Specificity of cytokine bioassays
Test for a characteristic
effect on other cells
e.g. interleukin-1
Induces proliferation in
thymocytes
Include an antibody
that blocks
interleukin-1
+
+ IL-1 absent
- IL-1 present
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How immune cells communicate:
CELL-CELL CONTACT
Peripheral lymphoid tissues trap antigen-containing phagocytic cells
and concentrate cells together to promote cell-cell contact.
Cell-cell contact occurs at many stages of immune responses.
Killing
CTL
Target cell
T
Y
Antigen
presentation
B
T
Ab production
Accessory cell activation
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Cell surface molecules mediate cell-cell contact
Resting cells
Activated cells
Expression and level of expression controls cell-cell adhesion
Activation can induce expression.
Cell adhesion, migration, antigen specificity, antigen presentation,
costimulation, helper function, effector function.
Cell surface molecules influenced by activation include cytokine receptors.
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Bio-assay of cell cell contact requirements in vitro
Physically
separate
cells with permeable
membrane
T
T T
T T
T
Include a blocking
anti-MHC molecule antibody
T
T T
T
+
Due to cytokine
or cell-cell contact?
T
T
-
-
Not due to a cytokine
MHC molecules important
Which cell surface molecule?
+
MHC molecules not important
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Clonal nature of the adaptive immune response
Each lymphocyte expresses a single antigen
receptor specificity.
There are millions of lymphocytes in the body, and thus millions of
different antigen receptors.
Each naive lymphocyte bearing a unique receptor is the progenitor
of a genetically identical CLONE of daughter cells.
PROBLEM: The CLONAL DISTRIBUTION of antigen receptors
means that lymphocytes of a particular specificity will be too
infrequent to mount an effective response.
A process akin to natural selection, CLONAL SELECTION raises
the clonal frequency of cells with a particular antigen specificity
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Clonal selection theory:
MacFarlane Burnet 1957
Each lymphocyte bears a single type of receptor of unique specificity.
Antigen interaction leads to lymphocyte activation.
Daughter cells bear identical antigen specificity to the parent cell.
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Clonal selection induces proliferation
and increases effector cell frequency
No. of
cells with
useful
specificity
Threshold of
protective effector
function
No. of cell divisions
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Clonal nature of adaptive immune response
allows for removal of harmful cells
!!!!Cells specific for self antigen!!!!
Opportunity to remove harmful
specificity at an early stage of
development
IMMUNOLOGICAL TOLERANCE
Antigen receptors recognising self antigens can be individually purged
from the antigen receptor REPERTOIRE before clonal expansion
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Clonal nature of adaptive immune response
allows for immunological memory
2° response
to antigen A
Antibody
titre
1° response
to antigen B
1° response
to antigen A
4
8
12
A
16
20
64 68
72 Days
A B
Lymphocyte
proliferation
to Ag A
Lymphocyte
apoptosis
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Lymphocyte
proliferation
to Ag B
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Immune effector mechanisms against
extracellular pathogens & toxins
NEUTRALISATION
`
`
Y
`
Adhesion to
host cells blocked
Toxin release
blocked
Prevents
invasion
Prevents
toxicity
`
Y
NEUTRALISING ANTIBODIES
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Effector mechanisms against
extracellular pathogens
OPSONISATION
Bacteria in extracellular space
+
Ab
OPSONISATION
Fc receptor
binding
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Phagocytosis
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Effector mechanisms against
extracellular pathogens
COMPLEMENT
Bacteria in plasma
Lysis
+
Ab &
COMPLEMENT
Opsonisation
Complement &
Fc receptor
binding
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Phagocytosis
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Effector mechanisms against
intracellular pathogens
CYTOXICITY
CTL
CTL
CTL
Viral infection
Lethal hit
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Target cell
death
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Effector mechanisms against
intracellular bacteria
MACROPHAGE ACTIVATION
Inflammatory
T cell
Cytokines
Th
Resting Macrophage
Th
Activated macrophage
Activation of killing mechanisms
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Summary:
 Reminder of 2nd year immunology
 Characteristics and components of adaptive and innate immunity
 Peripheral lymphoid organs & lymphocyte recirculation
 Intercellular communication by cytokines and cell-cell contact
 Clonal selection: Ag recognition, self tolerance and memory
 Effector mechanisms
NOW TRY THE MULTIPLE CHOICE QUESTIONS
(click on this link)
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