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Immunity against infection and

allergyEvy Sulistyoningrum


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Immunology concept

Immunity against infection

Allergy & hypersensitivity

Outline


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Immunology concepts


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Variety of cells, molecules that performed immune response

Cellular components

Immune cells

Lymphoid tissue or organs

Humoral components Soluble protein: complements, antibody

Physical, mechanical, chemical barriers

Immune system


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All the cellular

elements of the

blood including the

cells of the immune

system arise from

pluripotenthematopoietic cells

in the bone marrow

Cell of the immune system


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Myeloid cells


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Tissue and organs of the immune system


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Response against pathogen infection

4 main tasks:

Immunological recognition Immune effector function

Immune regulation

Immunological memory

Resulted in immunity

Distinguish self vs nonself

Classification

Innate immune response

Adaptive immune response

Immune response


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Innate & adaptive immune response


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Infectious pathogen

Mechanical barriers

Tissue resident cells pathogen

Elimination of pathogen

Inflammatory reaction

Chemokine & cytokine

Complement system Inflammatory cells

Induction adaptive immune response

Interaction between innate & adaptiveimmune response


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Pathogen-resident cell interaction

PAMPS (Pathogen-associated molecular

patterns) PRR (Pattern

recognition receptors)

Activated

macrophage Phagocytosis

Release of cytokine &chemokine

Inflammatory process


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Inflammatory process


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Leucocyte migration to infection site


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APC: Process & presents antigen to lymphocytes insecondary lymphoid organs

T cell activation

B cell activation

ProliferationDifferentiation into effector cell

Cellular mechanism

Humoral mechanism Immunological memory

Adaptive immune response


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Induction of adaptive response

Activation of specializedantigen-presenting cells(APC) is a necessary first

step for induction of

adaptive immunity


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Induction of adaptive response


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Antigen: substances that spesifically bound to lymphocytes

Recognized by:

Antibody/B cell receptor

T cell receptor

Major histocompatibility Complex (MHC)

Antigen recognition


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T cell & B cell activation


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Humoral

Extracellular form of pathogen & its products B cellantibody producing plasma cell

Neutralization

OpsonizationComplement activation

Effector mechanism


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Cellular

Intracellular pathogens

T cell

T cytotoxic/cytolitic : Destroy target cells

T helper: Activate macrophages

Induce formation of cytotoxic T cells

Stimulate B cells to produce antibodies.

Effector mechanism


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Mediated by effector mechanismof innate &adaptive immunity

Immune system responds in distinct andspecialized waysto different type of microbes

Survival and pahogenicity of a microbe influencedby the ability to evade effector mechanism

immune evasion Sometime, tissue injury is caused by host response

to microbe itself

General features


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Single cell prokaryot

Structure: capsule, bacterial cell wall, flagella, pili

Extracellular Replicate outside host cell

Induce inflammationtissue destruction

Produce toxin

Ex: staphylococci, streptococci, E coli, V. Cholerae, C. Tetani,etc

Intracellular

Replicate within cell, even pahagocytes

Ex: M. tuberculosis, M. leprae

Bacteria


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Bacteria


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Innate immunity

Complement activation

Phagocytosis, main effector: neutrophil

Inflammatory response

Adaptive immunity Humoral immunity

Neutralization

Opsonization

Immunity against extracellularbacteria


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Complement activation & effectorphase


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Phagocytes


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Inflammatory response


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Innate immunity

Phagocytes & NK cell

Adaptive immunity

T cell mediated immunitymost effective

Macrophage activation : Th

Cell lysis : Tc

Immunity against intracellularbacteria


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NK cell


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Mechanism of immune evasion ExamplesExtracellular bacteria

Antigenic variation Neisseria gonorrhoeae, E coli

Inhibition of complement activation Many bacteria

Resistance to phagocytosis Pneumonia

Intracellular bacteria

Inhibition of phagolysosome formation Mycobacterium tbc

Inactivation of reactive oxygen &nitrogen species

M. leprae

Disruption of phagosome membrane Listeria monocytogenes

Bacterial immune evasion


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Obligatory intracellular, DNA or RNA genome

Replicate within celldisrupt cell synthesiscell

death Ex: measles, mumps, rubella, chickenpox, hepatitis

Innate immunity

Inhibition of infection by type I IFNs

NK cell killing mechanism Adaptive immunity

Antibody mediated immunity

CTL killing mechanism

Immunity to viruses


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Virus


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Mechanism of immune evasion Examples

Antigenic variation Influenza, rhinovirus, HIV

Inhibition of antigen processing Herpes simplex, CMVProduction of cytokine receptorhomologs

Vaccinia, poxvirus (IL-1,IFN-)CMV (chemokine)

Production of immunosuppresivecytokine

Epstein-Barr virus (IL-10)

Infection of immunocompetentcells

HIV

Viral immune evasion


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Protozoa:

Eukaryot Ex: malaria, amoeba, trypanosoma, leishmania,

toxoplasma Helminths :

Multicellular organism

Extracellular Ectoparacyte:

Ex: dustmite, ticks

Immunity to paracytes


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Parasites


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Innate immunity

Phagocytosis

Eosinophil killing

Complement activation (alternative pathway)

Adaptive immunity Intracellular parasites : Cell mediated immunity

Th1 activate macrophage

Humoral : IgE production & activation of

eosinophils (ADCC)

Immunity to paracytes


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Eosinophilic killing


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Mechanism of immune

evasion

Examples

Antigenic variation TrypanosomesPlasmodium

Resistance to

complements

Schistosomes

Inhibition of host immuneresponse

Filaria, trypanosomes

Antigen shedding Entamoeba

Paracytic immune evasion


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Fungal infection: mycoses

Endemic

Opportunistic

Eukaryot Ex: Candida, histoplasma

Innate immunity

Phagocytes

Adaptive immunity Cell mediated immunity

Immunity to fungi


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Allergy & hypersensitivity


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Hypersensitivity: An immunologic reaction which

produces tissue damage on reexposure to antigen Gel & Coombs classification

Type I (IgE-mediated)

Type II (Fc and complement-mediated)

Type III (Immune complex-mediated) Type IV (Delayed-type hypersensitivity)

Introduction


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Type I Hypersensitivity Diseases

= allergy

Atopy

Mediated by IgE attached to Mast cells. The symptoms resulting from allergic responses are

known as anaphylaxis

Allergic rhinoconjunctivitis (hay fever)

Asthma Eczema (atopic dermatitis)

Acute urticaria

Anaphylaxis shock


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Allergens

Nonparasite antigens that can stimulate a type I hypersensitivityresponse.

Bind to IgE and trigger degranulation of chemical mediators.

Small 15-40,000 MW proteins.

Specific protein components

Often enzymes.

Most allergens promote a Th2 immune.

M h i f ll i


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Mechanisms of allergic response

Sensitization

First exposure to allergens initiates immune response

that generates IgE isotype IgE can attach to Mast cells by FcR receptor,

High affinity IgE receptor found on

mast cells/basophils/activated eosinophils.



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Sensitization

Th2/B cell interactionIL-4IL-4R

CD40B cell activationIgE isotype switch

Busse and Lemanske NEJM Feb 2001. 344:350

h f ll


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Effector Stage of Hypersensitivity

Secondary exposure to allergen

Mast cells are primed with IgE on surface

Allergen binds IgE and cross-links to activate signal

with tyrosine phosphorylation, Ca++ influx,degranulation and release of mediators.


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FceRI Triggers Release of Mediators

Early mediatorscause immediate symptoms

e.g. histamine (preformed in granules)leukotriene C4 and prostaglandin D2

are quickly made 2' mediators

M di t f T I H iti it


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Mediators of Type I HypersensitivityImmediate effects

Primary MediatorsPre-formed mediators in granules

Histamine Constriction of smooth muscles.

Bronchiole constriction = wheezing.

Constriction of intestine = cramps-diarrhea.

Vasodilation with increased fluid into tissues causingincreased swelling or fluid in mucosa.

Activates enzymes for tissue breakdown.

M di t f T I H iti it


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Cytokines TNF-a, IL-1, IL-6.

Chemoattractants for Neutrophils and Eosinophils. Enzymes

tryptase, chymase, cathepsin.

Changes in connective tissue matrix, tissue

breakdown.

Mediators of Type I HypersensitivityImmediateeffects


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Secondarymediators

Mediators formed after activation

Leukotrienes

Prostaglandins Th2 cytokines- IL-4, IL-5, IL-13, GM-CSF


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Treatment for Type I

Drugs.

Non-steroidal anti-inflammatories

Antihistamines block histamine receptors. Steroids

Theophylline OR epinephrine -prolongs or increasescAMP levels in mast cells which inhibits

degranulation.


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Treatment for Type I

Immunotherapy

Desensitization (hyposensitization) Repeated injections of allergen to reduce the IgE on

Mast cells and produce IgG.


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Complement-mediated cytolysis

Antibody-dependent cell-mediated cytotoxicity (ADCC)

Main Ab: IgG

Examples:

Transfusion reactions

Hemolytic disease of the newborn (Rh incompatibility)

Hyperacute graft rejection Drug-induced hemolytic anemia

Drug induced trombocytopenia

TYPE IIAntibody mediated cytotoxicity


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MechanismsOf Drug

Hypersensitivity

TYPE II


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TYPE IIRh factor incompatibility

TYPE III


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TYPE IIIAntigen antibody or immune complexes (IgG

mediated )

Large amount of soluble antigen and antibodies form

immune complexes in blood. Phagocytes failed to eliminate immune complex

deposit in tissues and trigger inflammation mediatedby complement system (C3a, C5a)

Deposited in joints causing local inflammation =arthritis

Deposited in kidneys = glomerulonephritis

Serum sickness

Farmers lung

Type IV Hypersensitivity


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yp yp yDelayed type hypersensitivity

(Th1 cells and macrophages) DTH response:

Allergen contactrecognized by Th1

Th1 cells release cytokines to activate macrophages causinginflammation and tissue damage.

Several hours, fuly developed at 24-48 hours

Continued macrophage activation can cause chronic

inflammation resulting in tissue lesions, scarring, andgranuloma formation.

Stages of Type IV DTH:


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Stages of Type IV DTH:Sensitization stage

Th1 cells recognized DTH antigens are generated by

dendritic cells during the sensitization stage. These Th1 cells can activate macrophages and trigger

inflammatory response.

Stages of Type IV DTH


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Stages of Type IV DTHEffector stage

Secondary contact with DTH.

Th1 memory cells are activated and produce cytokines.

IFN-g, TNF-a, and TNF-b which cause tissue destruction,inflammation.

IL-2 that activates T cells and CTLs.

Chemokines- for macrophage recruitment.

IL-3, GM-CSF for increased monocyte/macrophage

Type IV DTH


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Type IV DTH

Tuberculin test

Contact dermatitis

poison ivy

Small molecules act as haptens and complex with skin proteins

taken up by APCspresented to Th1 cells to get sensitization. During secondary exposure Th1 memory cells become activated to

cause DTH.


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Contact dermatitis


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Granuloma Formation from DTH


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Granuloma Formation from DTHMediated by Chronic Inflammation


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Thank you very much.


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Murphy K, Travers P, Walport M, JanewaysImmunobiology, 7thed

Abbas AK dan Lichtman AH, Pillai S, Cellular & MolecularImmnunology, 6thed

Roitt, IM., Delves, PJ, RoittsEssential Immunology

Burmester, Colour Atlas of Immunology

References

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