Kuliah 1. Humoral Effector Mechanism

8/13/2019 Kuliah 1. Humoral Effector Mechanism

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Tonang Dwi Ardyanto

FK UMS Mei 2009


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Plus tumor cells


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The Immune System is the Third Line of

Defense Against Infection


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Figure 1-7Innate (immediate) and

adaptive (late but antigen-specific) immune responses


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Immune cell recognition of pathogensfollowed by destruction


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Infection induces inflammation torecruit more immune cells


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Hematopoiesis

generates immune

cells

Immune cells = Soldiers


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The common myeloid progenitor:most of the cells of the innate immune system:

Macrophagegranulocytes (polymorphonuclear leukocytes)

mast cellsdendritic cells

The lymphoid progenitor:

T cellB cellNK cell


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APC


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h lf b d d


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Figure 1-14

Macrophages engulf bacteria and produceinflammatory cytokines


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Humoral Effector

Mechanism


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Consequences of Antigen-AntibodyBindingAntigen-Antibody Complex: Formed when an antibody

binds to an antigen it recognizes.

Affinity: A measure of binding strength.

1. Agglutination: Antibodies cause antigens (microbes)to clump together. IgM (decavalent) is more effective that IgG (bivalent).

Hemagglutination: Agglutination of red blood cells. Usedto determine ABO blood types and to detect influenza andmeasles viruses.

2. Opsonization: Antigen (microbe) is covered withantibodies that enhances its ingestion and lysis byphagocytic cells.


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Humoral Immunity (Continued)3. Neutralization: IgG inactivates viruses by binding totheir surface and neutralize toxins by blocking theiractive sites.

4. Antibody-dependent cell-mediated cytotoxicity:Used to destroy large organisms (e.g.: worms). Targetorganism is coated with antibodies and bombardedwith chemicals from nonspecific immune cells.

5. Complement Activation: Both IgG and IgM triggerthe complement system which results in cell lysis andinflammation.

C f A ib d Bi di


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Consequences of Antibody Binding

C f A ib d Bi di


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Consequences of Antibody Binding

Eff t F ti f A tib di


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Effector Functions of Antibodies


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Neutralization of Microbes by Antibodies


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Neutralization of Toxins by Antibodies


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Antibody-Dependent Cellular Cytotoxicity (ADCC)

F ti f C l t


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Functions of Complement


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A tib d R Aft E t A ti


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Antibody Response After Exposure to Antigen


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Kuliah ke 2


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Cellular Effector

Mechanism


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Cell Mediated Immunity General responses by CMI, include: Facilitate innate immune response to

bacteriaAnti-viral

Anti-fungal

Anti-tumor Transplantationrejection


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Cell Mediated Immunity Many microbes have developed mechanisms thatenable them to survive and even replicate withinphagocytes, so the innate immunity is unable to

eradicate infections by such microbes. In CMI against phagocytosed microbes, the specificity

of the response is due to T cells but the actualeffector function is mediated by the phagocytes.

T C ll d C ll M di t d


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Types of T cells1. T Helper (TH) Cells: Central role in immune response

Most are CD4+

Recognize antigen on the surface of antigen presenting cells(e.g.: macrophage).

Activate macrophages

Induce formation of cytotoxic T cells

Stimulate B cells to produce antibodies.

T Cells and Cell MediatedImmunity


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Subpopulations of Th Cells

Subpopulations basedon cytokine profiles Th0 Th1

Th2 Differentiation

determined bycytokines Influenced by antigen

IL-4 - Th2 cells IL-12 Th1cells


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Subpopulations of Th Cells

Th1 cell cytokines Activate macrophages

Generation of Tc

Th2 cell cytokines Activate of B cells

Activate granulocytes


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RegulationAntigen

INF-inhibits

proliferation of Th2cells

IL-10 inhibitsproduction of INF-


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Central Role of Helper T Cells


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ANTIGEN RECOGNITION BY NAVE T CELLS IN

ABSENCE OF CO-STIMULATION Nave T cell only activated by professional APC carrying

specific peptide:MHC complex and co-stimulatorymolecule

T cell beomes anergic when it encounters APC carryingspecific peptide:MHC complex without co-stimulatorymolecule

No effect on T cell which encounters APC carrying nospecific peptide:MHC complex but has co-stimulatorymolecule


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TH1 T CELLS AND MACROPHAGE

ACTIVATION Macrophage activation

Enhancement of macrophage function againstintracellular pathogens by TH1 cells

Phagosome fused more efficiently with lysosome

Important with Mycobacteria

Activation of macrophages requires 2 signals providedby TH1 cells

Interferon-gamma

CD40 ligand


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EFFECTOR OPTIONS OF CD8 AND

CD4 T CELLS FOLLOWING ANTIGEN ACTIVATION CD8 committed to becoming cytotoxic effector cells

CD4 T cells can differentiate along two pathways

TH1 or TH2

Mechanisms of differentiation not well understood

Most immune responses involve both TH1 and TH2

CD4 TH1 cells help with cell-mediated immune

response CD4 TH2 cells help with humoral immune response


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TH1 and TH2 The control of TH polarization is through thedendritic cell.

DC1 polarizes TH1 through IL-12

DC2 polarizes TH2 through IL-4 DC1 function appears to be through Toll-like receptors

that bind bacterial DNA motifs (reviewed p 282-283).

DC2 function appears to be though increased levels of

cAMP.

Bacterial antigen presentation to Th1 or


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Figure 1-27Bacterial antigen presentation to Th1 or

Th2 CD4+cells


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TH1

vsTH2


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CD4 T CELL RESPONSE TO

MYCOBACTERIUM LEPRAE Mycobacterium leprae is an intracellular pathogen, agentof leprosy and directs either TH1 or TH2 response

Most effective immune response is mediated by TH1 cells

Immune response mediated by TH1 cells results in Tuberculoid leprosy

Immune response mediated by TH2 cells results in Lepromatous leprosy


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T Cells Only Recognize Antigen Associated


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T Cells Only Recognize Antigen Associated

with MHC Molecules on Cell Surfaces


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Types of T cells (Continued)2. Cytotoxic T (Tc) Cells: Destroy target cells.

Most are CD4 negative (CD4-).

Recognize antigens on the surface of all cells:

Kill host cells that are infected with viruses or bacteria.

Recognize and kill cancer cells. Recognize and destroy transplanted tissue.

Release protein calledperforinwhich forms a pore in targetcell, causing lysis of infected cells.

Undergo apoptosis when stimulating antigen is gone.


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Cytotoxic T cells (CTLs) CTLs are not fully mature when they exit the thymus Have a TCR that recognizes antigen in association with

class I MHC molecules

Cannot kill Called pre-CTL

Must differentiate into fully active CTL


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Generation of CTLs Differentiate in

response to twosignals Specific antigen

associated withclass I MHCmolecules

Cytokines producedby Th1 cells


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Features of CTL KillingAntigen specific

Target cell must bear the same antigen associated withclass I MHC as did the pre-CTL

Requires cell contact

Ensures that nearby cells are not killed

CTLs are capable of killing many targets

CTLs are not injured when they kill a target


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Steps in CTL Killing

Tc cell

1. Tc recognizes antigen on

target cellTarget cell

Tc cell

2. A lethal hit is delivered by

the Tc using agents such asgranzymes or TNF

Target cell

Tc cell

3. The Tc detaches

from the target cellTarget cell

4. Target cell dies

by apoptosis

Target cell


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Mechanisms of CTL Killing Tc kill using a variety of mechanisms Direct cell-cell contact via surface molecules

Indirect signaling via cytokines


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Mechanisms of CTL Killing Fas and TNF-mediated

killing Fas-L induced on CTL

interacting with Fas

receptor on target cell TNF secreted by CTL

interacting with TNFRon target cell


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Mechanisms of CTL Killing Fas and TNF-mediated

killing Binding of ligand results

in tirmerization of thereceptor

Receptors with deathdomains activatecaspases resulting inapoptosis


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Mechanisms of CTL KillingCTL granule-mediated killingGranules containing perforin and

granzymes are released by CTL

Perforin polymerizes and forms channelsin target cell membrane

Granzymes (serine proteases) enterthrough channels and activate caspasesresulting in apoptosis


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Cytotoxic T Cells Lyse Infected Cells


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CTL-Killing


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Viral antigen presentation to CD8+ T cells via MHC class I molecules


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Figure 1-26

CYTOTOXINS AND CYTOKINES OF T


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CYTOTOXINS AND CYTOKINES OF T

CELLS T cells are distinguished by

Cytokines and cytotoxins produced and the effects onimmune response

CD4 T cells produce and act primarily through cytokines Macrophage stimulating (TH1)

B cell activating (TH2)

CD8 T cells produce and act primarily through cytotoxins Perforin and Granzymes


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Relationship Between Cell-Mediated and Humoral Immunity

1. Antibody ProductionT-Dependent Antigens:

Antibody production requires assistance from T helper cells. A macrophage cells ingest antigen and presents it to THcell.

THcell 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

repeating subunits (bacterial capsules).

Weaker immune response than for T-dependent antigens.

Humoral Response to T Dependent Antigens


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Relationship Between Cell-Mediated and HumoralImmunity

2. Antibody Dependent Cell MediatedCytotoxicity Target cell is covered with antibodies, leaving Fc portion

sticking outwards. Natural killer and other nonspecific cells that have

receptors for Fc region are stimulated to kill targetedcells.

Target organism is lysed by substances secreted byattacking cells.

Used to destroy large organisms that cannot bephagocytosed.


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Kuliah 1. Humoral Effector Mechanism