© [email protected] 2000. [email protected] Slide 1/43 Introduction to Cellular Immunology Dr. Colin R.A. Hewitt [email protected] Movie credits: The movies of.

© [email protected] 2000. Slide 1/43

Introduction to Cellular Immunology

Dr. Colin R.A. [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/


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


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.

What you should know by the end of this lecture


History & impact of immunology on human health

200 yearsafter Jenner

WHO announcesmallpox eradicated

1965 1970 1975 1980

Countries withmore than onesmallpox case

per month

30

15

0

1700 19001800 2000

Jenner Vaccination

1600

JansenMicroscope

Müller Bacteria

Koch’sPostulatesMetchnikoff

Phagocytosis

WrightAntisera

Kohler & MilsteinMonoclonal Abs

1955

MillerT cells


Why study immunology now?

Infectious diseases

Mechanisms of pathogenicityVaccine development

Diseases caused by a disturbed immune system

ALLERGY: Immune responses to innocuous materials e.g. ASTHMAAUTOIMMUNITY: Anti-self immunity e.g. MULTIPLE SCLEROSIS

GRAFT REJECTION: Immune responses to TRANSPLANTED TISSUEIMMUNODEFICIENCY: Defects in immune responses e.g. SCID

Manipulation of immunity to treat disease

IMMUNOSUPPRESSION: Treatment of immune diseasesIMMUNOREGULATION: Immunotherapeutic interventions


ANTIGENS (Ag)are substances recognised by

• ANTIBODIES (Immunoglobulin, Ig, Ab) and

• T LYMPHOCYTES (T CELLS)

Antibodies are made byB LYMPHOCYTES (B CELLS)

T cells help B cells make antibodies:T HELPER (Th) cells

T cells kill infected cellsT CYTOTOXIC (CTL)

Reminder of basic immunological terms


Immune responses

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

Invasion& infection

Barriers

Innate immunity

Adaptive immunity

+

+

Inflammation

Cellular and humoral defences

Antibodies, cytokines, T helper cells,

cytotoxic T cells


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


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


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.


Cells Of TheImmune System

Pluripotenthaemopoietic

stem cell

Commonlymphoidprogenitor

Myeloidprogenitor

MacrophageMonocyte

NeutrophilPMN

Eosinophil

Basophil

Mast cell

Phagocytosis Ag presentation

PhagocyticAnti-bacterial

Anti-parasiteimmunity

?Protection ofmucosal surfaces?

Protection ofmucosal surfaces

Lymphocyte Adaptive immunity


Lymphocyte subsets

Activate B cellsand macrophagesT HELPER CELLS

Th

Kill virus-infected cells

CYTOTOXIC TLYMPHOCYTES

CTL

Produce antibodiesPLASMA CELLS

PC

T B

T CELLS B CELLS

CLP

Commonlymphoidprecursor


•Resting Lymphocyte•Activated Lymphocyte•Plasma cell•T and B cells are morphologically identical

http://www-medlib.med.utah.edu/WebPath/webpath.html

Look for some excellent low power images and electron micrographs of the cells at the following site:

Movie:Cytotoxic T- lymphocyte

killing target(click on this link)




Movie:Human macrophage

ingesting Candida albicans(click on this link)

•Erythrocyte (Red blood cell)

•Blood monocyte

•Platelet (thrombocyte)

•Tissue macrophage


•Neutrophil



Movie:Chemotaxis of human neutrophils

(click on this link)



•Eosinophil

•Basophil

•Neutrophil

•Lymphocyte

•Monocyte




Lymphocyte antigen receptors

Until the 1960’s, lymphocytes had no known function.

T and B cells are essentially inactive until theyencounter antigen.

T and B cells express ANTIGEN RECEPTORS

Lyc

Each antigen receptor binds to a different antigenEach cell has only one antigen specificity

BThe B cell antigen receptor is a membrane-bound antibody

SURFACE IMMUNOGLOBULIN

TThe T cell antigen receptor IS NOT membrane bound antibody but a distinct molecule

T CELL ANTIGEN RECEPTOR


Lymphoid organs

Peripheral lymphoid organs:LYMPH NODES

SPLEEN WHITE PULPMUCOSAL-ASSOCIATED LYMPHOID TISSUE

T and B cell activationAntigen trapping

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


Paracortical(T cell) area

5. Medullary cords (Macrophage & plasma cell area)

Medullary sinus

6. Efferent lymphatic vessel

Artery

Vein

4. Germinal centre (site of intense B cell proliferation)

3. Secondary lymphoid follicle

2. Primary Lymphoid follicle (B cell area)

1. Afferent lymphatic vessel. Lymph, cells & Ag drained from tissues enters here

Lymph node



Look for an excellent image of a sectioned lymph node at the following site:



Look for an excellent image of a germinal centre at the following site:


Red pulp

Marginal zone

Marginal sinus

B cell corona

Germinal centre

Periarteriolar lymphocyticsheath (PALS) – T cell area

Central arteriole

Spleen white pulpTransverse section



Look for an excellent image of a sectioned spleen at the following site:


Lymphocyte recirculation

NAIVE LYMPHOCYTES enterblood, are seeded to the

peripheral lymphoid organsand recirculate

Cells & antigens from a site of infectionare trapped in draining lymphoid tissue.

Cells proliferate and re-enter the RECIRCULATING LYMPHOCYTE POOLto re-seed the peripheral lymphoid organs



Look for an excellent images of Wuchereria bancrofti and elephantiasis at the following site:


Infection

Phagocyteactivation

How immune cells communicate: SOLUBLE MEDIATORS

CYTOKINES & CHEMOKINESDiverse 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

responseINFLAMMATION

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.


Activationof M in vitro

+/-

Cytokine secretion

Remove cytokine containing

supernatant

Test for effecton other

cells

Bio-assay of cytokines in vitro

Which cytokine?


Specificity of cytokine bioassays

Include an antibody that blocks

interleukin-1

Test for a characteristiceffect on other cells

e.g. interleukin-1Induces proliferation in

thymocytes

- IL-1 present+ IL-1 absent+


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.

T

CTL

T

BY

Ab productionAccessory cell activation

Antigenpresentation

Target cell

Killing


Cell surface molecules mediate cell-cell contact

Expression and level of expression controls cell-cell adhesionActivation can induce expression.

Cell adhesion, migration, antigen specificity, antigen presentation,costimulation, helper function, effector function.

Cell surface molecules influenced by activation include cytokine receptors.

Resting cells Activated cells


-Not due to a cytokine

Which cell surface molecule?

T

Bio-assay of cell cell contact requirements in vitro

T

Include a blockinganti-MHC molecule antibody

-MHC molecules important

T

Physicallyseparate

cells with permeablemembrane

+Due to cytokine

or cell-cell contact?

T

TTT

T

T T

TT

+MHC molecules not important


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


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.


Clonal selection induces proliferationand increases effector cell frequency

No. of cell divisions

No. ofcells with

usefulspecificity

Threshold ofprotective effectorfunction


Antigen receptors recognising self antigens can be individually purged from the antigen receptor REPERTOIRE before clonal expansion

!!!!Cells specific for self antigen!!!!

Opportunity to remove harmful specificity at an early stage of

developmentIMMUNOLOGICAL TOLERANCE

Clonal nature of adaptive immune responseallows for removal of harmful cells


Clonal nature of adaptive immune responseallows for immunological memory

Lymphocyteapoptosis

Lymphocyteproliferationto Ag A

1° responseto antigen A

A A B

1° responseto antigen B

Lymphocyteproliferationto Ag B

4 16128 20 64 68 72

Antibodytitre

Days

2° responseto antigen A


Y`

`

Immune effector mechanisms against extracellular pathogens & toxins

NEUTRALISATION

Y ``

Y` `

Y` `

Toxin releaseblocked

Preventstoxicity

NEUTRALISING ANTIBODIES

Adhesion tohost cells blocked

Preventsinvasion


Effector mechanisms against extracellular pathogens

OPSONISATION

OPSONISATION Phagocytosis

Bacteria in extracellular space

Ab

+

bindingFc receptor


Effector mechanisms against extracellular pathogens

COMPLEMENTBacteria in plasma

Ab & COMPLEMENT

+

PhagocytosisOpsonisation

binding

Complement &Fc receptor

Lysis


CTL

Effector mechanisms against intracellular pathogens

CYTOXICITY

Viral infection

CTL

Lethal hit

Target celldeath

CTL


Effector mechanisms against intracellular bacteria

MACROPHAGE ACTIVATION

InflammatoryT cell Th

Resting Macrophage

Cytokines

Th

Activated macrophage

Activation of killing mechanisms


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)

© [email protected] 2000. [email protected] Slide 1/43 Introduction to Cellular Immunology Dr. Colin R.A. Hewitt [email protected] Movie credits: The movies of.

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