Introduction to The Immune System - kauDr. Mohamed Farouk Elshal Immunity • Immunity – The ability of the body to fight infection and/or foreign invaders by producing antibodies

Dr. Mohamed Farouk Elshal

Introduction to The ImmuneSystem

• Mohamed Farouk Elshal, Ph.D.Bldg.: 71 / Room:2008;[email protected]

References:1. Abbas, A, K. et.al, Cellular and MolecularImmunology, 6th ed., 20072. Male D., J. Brostoff, D. B Roth, and I. RoittImmunology, 7th ed., 2006.

mailto:[email protected]


Keys toward Learning Immunology

• Lectures => Deliver the key concepts ofImmunology.

• Workbook => Apply the knowledge fromImmunology to the solution of clinicalproblems.

• Textbook reading => Help learn thedetails and build up comprehensiveknowledge of immunology


Evaluation

For the Immunology Section:

• Examination => 70 %

• Attendance & Class performance=> 30%


What isImmunity?


Immunity• Immunity

– The ability of the body to fight infection and/or foreign invaders byproducing antibodies or killing infected cells.

• Immune System– The system in the body responsible for maintaining homeostasis

by recognizing harmful from nonharmful organisms and producesan appropriate response.


Foreign Invaders• Called Pathogens

– Viruses, bacteria or other living thingthat causes disease/immune response.

• Antigens– Toxins that pathogens produce that

cause harm to an organism.– A molecule which elicits a specific

immune response when introduced intoan animal.

More specifically, antigenic (immunogenic)substances are:

– Generally large molecules (>10,000daltons in molecular weight),

– Structurally complex (proteins areusually very antigenic),

– Accessible (the immune system must beable to contact the molecule), and

– Foreign (not recognizable as "self").


Epitopes: Antigen Regions that Interact withAntibodies


Components of Human Immune System



CELLS OF THE IMMUNE RESPONSE

Cells:Blood - White Blood Cells in particular.

1. B-cells2. T-cells [Helper T-cells (TH), Suppressor T-cells

(TS), Cytotoxic T-cells (CTL) ]3. Accessory cells [Macrophages, Dendritic cells,

Polymorphonuclear cells (PMNs)]4. Killer cells [NK cells, K cells]5. Mast cells



Lymphoid Tissues:• Thymus Gland – Produces T

Lymphocytes• Bone Marrow – Produces B

Lymphocytes• Lymph nodes• Spleen


LYMPHOID TISSUES


LYMPHOID TISSUES


How does the body fightinfection/foreign invaders?

• Administration of antitoxin (passive)• Vaccination (active)

Artificially acquired

• Placental transfer of antibody(passive)

• Recovery from disease (active)

Specific (acquired) Naturallyacquired

• Intact skin• Mucous membranes• Phagocytic cells• Enzymes in secretions• Cytokines (Interferon)

Nonspecific (innate)

ExamplesTypes of Immunity


How does the body fightinfection/foreign invaders?

The Body’s THREE lines of DefenseFirst Line of Defense – The Skin

• Provides Physical and Chemical barriers• Physical – hard to penetrate, made of indigestible keratin• Chemical – tears, sweat


Second Line of Defense –Nonspecific Immune Response

These are defenses the body uses no matter what the invadermay be. These defenses include:– Phagocytosis – done by Macrophages– Natural Cell Killers– Inflammation - caused by release of Histamine from leukocytes– Fever – caused by histamines. The fever (high temp) kills invaders by

denaturing their proteins.

Macrophage: A phagocytic cell found in the liver, spleen, brain and lungs. Travels

to all areas of the body to find and eat pathogens.


This is a specific response to a specificpathogen/antigen.

• The response involves the creation of Antibodies.

Third Line of Defense –Specific Immune Response


Innate Immunity


Innate immunity

Innate immunity is the older host defense system:- Existed in both Invertebrates & Vertebrates- Provides the initial defense against infections- Activates and shapes adaptive immune responses


Inflammation

=>A hallmark of innate immunity=>Local accumulation of immune cells & molecules

against microbes=>Function to eliminate infections but often cause

tissue damage & disease



Epithelial barriers prevent theentry of microbes


Movements of phagocytic cells

• Ameboid movement.Phagocytic cellsmigrate in and out ofblood vessels andthroughout thetissues.

• The process ofcellular emigrationfrom capillaries iscalled diapedesis.



Phagocytosis during innate immunity

Stages in phagocytosisA. Phagocyte detects chemicals released by a foreign

intruder (e.g. bacteria)

B. Phagocyte moves up the concentration gradienttowards the intruder

C.The phagocyte adheres to the foreign cell and engulfs itin a vacuole by an infolding of the cell membrane.

D.Lysosomes (organelles which are rich in digestiveenzymes & found in the phagocytes cytoplasm) fusewith the vacuole & release their contents into it leadingto killing the bacterium by the enzymes, and thebreakdown products are absorbed by the phagocyte.






Adaptive Immunity


Adaptive Immunity

Immunity that an organism develops duringlifetime.– Not genetically determined.– May be acquired naturally or artificially.

• Development of immunity to measles inresponse to infection or vaccination.


Naturally Acquired Immunity

I. Obtained in the course of daily life.A. Naturally Acquired Active Immunity:– Antigens or pathogens enter body naturally.– Body generates an immune response to

antigens.– Immunity may be lifelong (chickenpox or

mumps) or temporary (influenza or intestinalinfections).


Naturally Acquired Immunity (Continued)

I. Obtained in the course of daily life.B. Naturally Acquired Passive Immunity:– Antibodies pass from mother to fetus via

placenta or breast feeding (colostrum).– No immune response to antigens.– Immunity is usually short-lived (weeks to

months).– Protection until child’s immune system

develops.


Artificially Acquired Immunity

II. Obtained by receiving a vaccine or immuneserum.1. Active Immunity:– Antigens are introduced in vaccines

(immunization).– Body generates an immune response to antigens.– Immunity can be lifelong (oral polio vaccine) or

temporary (tetanus toxoid).


Vaccination (also called Immunization)

• The scientific view of immunity => EdwardJenner (1796)

• Observation => Milkmaids generally get Nosmallpox

• Hypothesis => Pus from vaccinia (cowpox)• => Protect milkmaids from smallpox• Test => Inoculate materials from cowpox pus• => Protect a young boy from smallpox• (Protective immunity)


Edward Jenner

Eradication of smallpox


Vaccines for common infectious diseases

Still no effective vaccines for many infectious microbes,ex. HCV, HIV, …..etc


Artificially Acquired Immunity (Continued)

II. Obtained by receiving a vaccine or immuneserum.2. Passive Immunity:– Preformed antibodies (antiserum) are introduced

into body by injection.• Snake antivenom injection from horses or rabbits.

– Immunity is short lived (half life three weeks).– Host immune system does not respond to

antigens.


– Serum: Fluid that remains after blood has clotted and cellshave been removed.

– Antiserum: Serum containing antibodies to a specificantigen(s). Obtained from injecting an animal (horse, rabbit,goat) with antigen (snake venom, botulism or diphtheriatoxin).

– Serology: The study of reactions between antibodies andantigens.

– Gamma Globulins: Fraction of serum that contains most ofthe antibodies.

– Serum Sickness: Disease caused by multiple injections ofantiserum. Immune response to foreign proteins. Maycause fever, kidney problems, and joint pain. Rare today.

Artificially Acquired Immunity (Continued)


Active vs. Passive immunityActive immunity => A host response to a microbe (Ag)

=> specific and long-term immune defense (memory)Passive immunity => Adoptive transfer of Ab or lymphocytes

specific for a microbe (or Ag)=> specific, instant but transient immune defense


Interaction between innate and& adaptive immunity

1. Innate immunity=> Ag presentation

(by infected cells)

2. Adaptive immunity=> Ag recognition

(by T & B lymphocytes)


Innate vs Adaptive immunity


Epitopes: Antigen Regions that Interact withAntibodies


Innate vs Adaptive immunity


Features of Adaptive immunity


Types of adaptiveimmunity

1. Humoral immunity=> Molecules in body fluid,

ex. Antibody (Ab)=> Key player => B cells=> Target extracellular

microbes & toxins

2. Cell-mediated immunity=> Key player => T cells =>

regulate other immunecells

=> Target intracellularmicrobes, ex. viruses,bacteria

For innate immunity, it also includes Humoral & Cellularcomponents for immune defense


Cellular Immunity .vs. AntibodyImmunity

• Carried out by T-Cells• Infected cells are killed by

Cytotoxic T –Cells.

• Carried out by B-cells• Antibodies are

produced anddumped into bloodstream.

• Antibodies bind toantigens anddeactivate them.

Cellular Immunity Antibody or Humoral Immunity


Humoral Immunity


Adaptive Humoral (Antibody-Mediated) Immunity

I. Humoral (Antibody-Mediated) Immunity– Involves production of antibodies against foreign antigens.

– Antibodies are produced by a subset of lymphocytes called Bcells.

– B cells that are stimulated will actively secrete antibodies andare called plasma cells.

– Antibodies are found in extracellular fluids (blood plasma, lymph,mucus, etc.) and the surface of B cells.

– Defense against bacteria, bacterial toxins, and viruses thatcirculate freely in body fluids, before they enter cells.

– Also cause certain reactions against transplanted tissue.


How Do B Cells Produce Antibodies?

B cells develop from stem cells in the bonemarrow of adults (liver of fetuses).– After maturation B cells migrate to lymphoid organs

(lymph node or spleen).– Clonal Selection: When a B cell encounters an

antigen it recognizes, it is stimulated and divides intomany clones called plasma cells, which activelysecrete antibodies.

– Each B cell produces antibodies that will recognizeonly one antigenic determinant.


Clonal Selection ofB Cells is Caused

by AntigenicStimulation


Clonal Selection– Clonal Selection: B cells (and T cells) that

encounter stimulating antigen will proliferateinto a large group of cells.

– Why don’t we produce antibodies againstour own antigens? We have developedtolerance to them.

– Clonal Deletion: B and T cells that reactagainst self antigens appear to be destroyedduring fetal development. Process is poorlyunderstood.

Humoral Immunity (Continued)


Apoptosis– Programmed cell death (“Falling away”).– Human body makes 100 million lymphocytes every

day. If an equivalent number doesn’t die, willdevelop leukemia.

– B cells that do not encounter stimulating antigenwill self-destruct and send signals to phagocytes todispose of their remains.

– Many virus infected cells will undergo apoptosis, tohelp prevent spread of the infection.



Most are proteins or large polysaccharides from a foreignorganism.– Microbes: Capsules, cell walls, toxins, viral capsids,

flagella, etc.– Nonmicrobes: Pollen, egg white , red blood cell surface

molecules, serum proteins, and surface molecules fromtransplanted tissue.

Lipids and nucleic acids are only antigenic when combinedwith proteins or polysaccharides.Molecular weight of 10,000 or higher.– Hapten: Small foreign molecule that is not antigenic. Must be

coupled to a carrier molecule to be antigenic. Once antibodiesare formed they will recognize hapten.

Antigens


Epitope:Small part of an antigen that interacts with anantibody.Any given antigen may have several epitopes.Each epitope is recognized by a differentantibody.

Antigens


Epitopes: Antigen Regions that Interactwith Antibodies


Antibodies• Y-shaped protein

molecule.• Made up of variable and

constant regions.• Made up of Heavy and

Light chains.• Produced by B-

Lymphocytes• Function: Recognize

antigens, bind to anddeactivate them.– Note: Variable region

recognizes the anitgens.


One virus or microbe may have several antigenicdeterminant sites, to which different antibodies maybind.Each antibody has at least two identical sites that bindantigen: Antigen binding sites.Valence of an antibody: Number of antigen bindingsites. Most are bivalent.Affinity: A measure of binding strength.Belong to a group of serum proteins calledimmunoglobulins (Igs).There are five classes of antibodies: IgD, IgM, IgG, IgA,and IgE

Antibodies


IgM – pentamer released by plasma cells during theprimary immune response

IgA – dimer that helps prevent attachment ofpathogens to epithelial cell surfaces

IgG – monomer that is the most abundant anddiverse antibody in primary and secondaryresponse; crosses the placenta and conferspassive immunity

IgE – monomer that binds to mast cells andbasophils, causing histamine release whenactivated

IgD – monomer attached to the surface of B cells,important in B cell activation

Classes of Antibodies


• Antibodies themselves do not destroy antigen;they inactivate and tag it for destruction

• All antibodies form an antigen-antibody(immune) complex

• Defensive mechanisms used by antibodiesare:

1. neutralization,2. agglutination,3. precipitation, and4. complement fixation

Antibody mechanisms of action


1. Agglutination: Antibodiescause antigens (microbes) toclump together.• Enhances phagocytosis• Reduces number of infectious

units to be dealt with• IgM (decavalent) is more

effective than IgG (bivalent).• Hemagglutination:

Agglutination of red blood cells.Used to determine ABO bloodtypes and to detect influenzaand measles viruses.

Consequences of Antigen-Antibody Binding


2. Opsonization: Antigen(microbe) is coveredwith antibodies thatenhances its ingestionand lysis by phagocyticcells.

3. Neutralization: IgGinactivates viruses bybinding to their surfaceand neutralize toxins byblocking their activesites.

Consequences of Antigen-Antibody Binding


4. Antibody-dependentcell-mediatedcytotoxicity (ADCC):– Used to destroy large

organisms (e.g.: worms).– Target organism is coated

with antibodies andbombarded withchemicals fromnonspecific immune cells.



5. ComplementActivation: Both IgGand IgM trigger thecomplement systemwhich results in cell lysisand inflammation.




6. Disruption of cell bycomplement/reactiveprotein attractsphagocytic and otherdefensive immunesystem cells



• Antibody Titer: The amount of antibody inthe serum.

• Pattern of Antibody Levels During InfectionPrimary Response:

– After initial exposure to antigen, no antibodiesare found in serum for several days.

– A gradual increase in titer, first of IgM and thenof IgG is observed.

– Most B cells become plasma cells, but some Bcells become long living memory cells.

– Gradual decline of antibodies follows.

Immunological Memory


Secondary Response:– Subsequent exposure to the same antigen

displays a faster and more intense antibodyresponse.

– Increased antibody response is due to theexistence of memory cells, which rapidlyproduce plasma cells upon antigenstimulation.

Immunological Memory (Continued)


Antibody Response After Exposure to Antigen


Cellular Immunity


Specific Immune ResponseII. Cell Mediated Immunity

– Involves specialized set of lymphocytes calledT cells that recognize foreign antigens on thesurface of cells, organisms, or tissues:• Helper T cells• Cytotoxic T cells

– T cells regulate proliferation and activity ofother cells of the immune system: B cells,macrophages, neutrophils, etc.


• T cells recognize and respond only toprocessed fragments of antigen displayedon the surface of body cells (exogenousantigens)

• T cells are also recognize and targetintracellular antigens like:– Cells infected with viruses, bacteria, or

intracellular parasites– Abnormal or cancerous cells– Cells of infused or transplanted foreign tissue

Importance of Cellular Response


Cell Mediated Immunity

• Requires constant presence of antigen to remain effective.

• Unlike humoral immunity, cell mediated immunity is nottransferred to the fetus.

• Cytokines: Chemical messengers of immune cells.– Over 100 have been identified.

– Stimulate and/or regulate immune responses.• Interleukins: Communication between WBCs.

• Interferons: Protect against viral infections.

• Chemokines: Attract WBCs to infected areas.


• Immunocompetent T cells are activatedwhen the V regions of their surfacereceptors bind to a recognized antigen

• T cells must simultaneously recognize:– Nonself (the antigen)– Self (a MHC protein of a body cell)

Antigen Recognition and MHCRestriction


• The Major Histocompatibility Complex (MHC) isa set of molecules displayed on cell surfacesthat are responsible for lymphocyte recognitionand "antigen presentation".

• The MHC molecules control the immuneresponse through recognition of "self" and "non-self" and, consequently, serve as targets intransplantation rejection.

MAJOR HISTOCOMPATIBILITYCOMPLEX


• The Class I and Class II MHC moleculesbelong to a group of molecules known asthe Immunoglobulin Supergene Family,which includes immunoglobulins

• Both types of MHC proteins are importantto T cell activation

MAJOR HISTOCOMPATIBILITYCOMPLEX


• Class I MHC proteins– Always recognized by CD8 cytotoxic T cells

(CTL)– Display peptides from endogenous antigens

• Endogenous antigens are:– Degraded by proteases and enter the

endoplasmic reticulum– Loaded onto class I MHC molecules– Displayed on the cell surface in association

with a class I MHC molecule

Class I MHC Proteins


• Class II MHC proteins are found only onmature B cells, some T cells, and antigen-presenting cells

• Loaded Class II MHC molecules thenmigrate to the cell membrane and displayantigenic peptide for recognition by CD4 Thelper cells (Th-cells).

Class II MHC Proteins


MHC Proteins and antigen recognition


T Cells Only Recognize Antigen Associated withMHC Molecules on Cell Surfaces


Cell Mediated Immunity

• Immune responsive cells can be dividedinto five groups based on the presence ofspecific surface components and functioninto:

1. lymphocytes (B-cells, and T-cells).2. Accessory cells (Macrophages and other antigen-

presenting cells),3. Killer cells (NK and K cells), and4. Mast cells.


B-lymphocytesSurface components• Surface immunoglobulin (Ag recognition)• Immunoglobulin Fc receptor• Class II Major Histocompatability Complex

(MHC) molecule (Ag presentation)Function• Direct antigen recognition• Differentiation into antibody-producing plasma

cells• Antigen presentation within Class II MHC


T-lymphocytes

Surface components• CD3 moleculeFunction• T-cell receptor (TCR, Ag recognition)• Involved in both humoral and cell-

mediated responses


– T cells are key cellular component of immunity.– T cells have an antigen receptor that recognizes

and reacts to a specific antigen (T cell receptor).– T cell receptor only recognize antigens combined

with major histocompatability (MHC) proteins onthe surface of cells.

• MHC Class I: Found on all cells.• MHC Class II: Found on phagocytes.

– Clonal selection increases number of T cells.

T-lymphocytes



Major Types of T CellsHelper T-cells (TH)

Surface components• CD4 moleculeFunction• Recognizes antigen presented within

Class II MHC• Promotes differentiation of B-cells and

cytotoxic T-cells• Activates macrophages• Stimulate B cells to produce antibodies.


Central Role of Helper T Cells


Suppressor T-cells (TS)

Surface components• CD8 moleculeFunction• Downregulates the activities of other cells


Cytotoxic T-cells (CTL)

Surface components• CD8 moleculeFunction• Recognizes antigen presented within Class I

MHC• Release protein called perforin which forms a

pore in target cell, causing lysis of infected cells.• Undergo apoptosis when stimulating antigen is

gone.


Cytotoxic T Cells Lyse Infected Cells


Types of T cells (Continued)

• Delayed Hypersensitivity T (TD) Cells:Mostly T helper and a few cytotoxic T cellsthat are involved in some allergic reactions(poison ivy) and rejection of transplantedtissue.

• T Suppressor (Ts) Cells: May shut downimmune response.


Nonspecific Cellular Components

Natural Killer (NK) Cells:– Lymphocytes that destroy virus infected and tumor

cells.– Not specific. Don’t require antigen stimulation.– Not phagocytic, but must contact cell in order to lyse

it.• Surface components

– Variable• Function

– Direct cell killing– Kills variety of target cells (e.g. tumor cells, virus-

infected cells, transplanted cells)



Polymorphonuclear cells (PMNs)• Surface components

– Immunoglobulin Fc receptor– Complement component C3b receptor

• Function– Bind Fc portion of immunoglobulin (enhances

phagocytosis)– Bind complement component C3b (enhances

phagocytosis)



Macrophages• Surface components

– Variable– Immunoglobulin Fc receptor– Complement component C3b receptor– Class II MHC molecule

• Function– Bind Fc portion of immunoglobulin (enhances phagocytosis)– Bind complement component C3b (enhances phagocytosis)– Antigen presentation within Class II MHC– Secrete IL-1 (macrokine) promoting T-cell differentiation and

proliferation– Can be "activated" by T-cell lymphokines



Dendritic cells• Surface components

– Class II MHC molecule• Function

– Antigen presentation within Class II MHC



Mast cells• Surface components

– High affinity IgE Fc receptors• Function

– Bind IgE and initiate allergic responses byrelease of histamine


1. Antibody ProductionT-Dependent Antigens:

– Antibody production requires assistance from T helper cells.

– A macrophage cells ingest antigen and presents it to TH cell.

– TH cell stimulates B cells specific for antigen to become plasma cells.

– Antigens are mainly proteins on viruses, bacteria, foreign red blood cells,and hapten-carrier molecules.

T-Independent Antigens:– Antibody production does not require assistance from T cells.

– Antigens are mainly polysaccharides or lipopolysaccharides with repeatingsubunits (bacterial capsules).

– Weaker immune response than for T-dependent antigens.

Relationship Between Cell-Mediatedand Humoral Immunity


Humoral Response to T DependentAntigens


The Pathway of Specific ImmuneResponse

Pathogens

Pathogens eaten by Macrophage

Displays portion of Pathogenon surface

Helper-T cell recognizesPathogen

Step 1

Step 2

Step 3


Activates B- CellActivates Cytotoxic

T- Cell

Memory B-CellMemory T-Cell

Kills Infected CellsAntibodies


Immune Response Explained1. Antigen infects cells.2. Macrophage ingests antigen and displays portion on its surface.3. Helper T- Cell recognizes antigen on the surface of the

macrophage and becomes active.4. Active Helper T-Cell activates Cytotoxic T-Cells and B-Cells.5. Cytotoxic T-Cells divide into Active Cytotoxic T-cells and Memory

T – Cells.6. Active Cytotoxic T-Cells kill infected cells.7. At the same time, B-Cells divide into Plasma Cells and Memory

B- Cells.8. Plasma cells produce antibodies that deactivate pathogen.9. Memory T and Memory B cells remain in the body to speed up the

response if the same antigen reappears.10. Supressor T-Cells stop the immune response when all antigens

have been destroyed.


Immune Response Summary

Antigen

Macrophage

Helper T - Cell

Active Cytotoxic T-Cell Active B - Cell

Kills Infected Cells Memory T- Cell Plasma Cell Memory B-Cell

Antibodies

Deactivates Antigens

Displays copy of antigenon surface of cell

Cellular Immunity Antibody Immunity


Overview of the Immune Response


Primary .vs. Secondary ImmuneResponse

• Primary Immune Response– This is a response to an invader the First time the

invader infects the body.• No measurable immune response for first few days.• Next 10 – 15 days antibody production grows steadily

• Secondary Immune Response– A more rapid response to an invader the 2nd time it

invades the body.• Antibody production increases dramatically and in a much

shorter time period..


Primary .vs. Secondary ImmuneResponse


SUMMARY

1. Protective immunity against microbes is mediated by theearly response of innate immunity and the later response ofadaptive immunity.

2. Innate immune responses are initiated by recognition ofcommon microbial structures by- Provide the first line of host defense- Activate and regulate the adaptive immunity

3. Adaptive immune responses are initiated by recognition offoreign antigens by specific lymphocytes.- Provide more potent, specific (Ag), & broad protection- Develop immune memory for next exposure- Feedback regulate innate immunity


Failure of the immune system

Ineffective response-Immunodeficiency

Overactive response-Hypersensitivity

Auto-reactive response-Autoimmunity


Autoimmune Disease

• Autoimmune diseases are diseases where the immunesystem begins to attack itself.– Ex:

• Rheumatoid Arthritis – crippling disease of thejoints.

• Lupus – disease of blood and organs.• Multiple Sclerosis – disease of nervous system

• Cause(s): unknown• Cures/Treatments: No known cures. Usually treated

with drugs.


AllergiesAllergy

- An exaggerated response by the immune system to an allergen.

Allergen: a normally harmless substance that causes an allergicreaction.ex: dust, pollen, mould, food, insect stings

Types of Allergic reactionsThere are two types of allergic reactions.

a. Immediate – occurs within seconds and normally lasts for about30 mins.b. Delayed – takes longer to react and can last for a much longertime.


What happens during an allergicreaction?

• During an allergic reaction antibodies cause histamines to bereleased from certain cells.

Histamines cause:a. Swelling of tissuesb. Release of fluids (runny noses and eyes)c. muscle spasms (some cases)

Anaphylaxis or anaphylactic shock:This is the sudden and severe allergic reaction to a substance thatcan cause death.

Treatments for Allergies1.Avoidance of material – especially food.2.Epinephrine – “epi – pen”3.Antihistamines -- benadryl

Introduction to The Immune System - kauDr. Mohamed Farouk Elshal Immunity • Immunity – The ability of the body to fight infection and/or foreign invaders by producing antibodies

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