Tonang Dwi Ardyanto FK UMS Mei 2009

Plus tumor cells

The Immune System is the Third Line of Defense Against Infection

Figure 1-7

Innate (immediate) and adaptive (late but antigen-specific) immune responses

Immune cell recognition of pathogens followed by destruction

Infection induces inflammation to recruit more immune cells

Hematopoiesis generates immune cells

Immune cells = Soldiers

The common myeloid progenitor:

most of the cells of the innate immune system:

Macrophage granulocytes (polymorphonuclear leukocytes) mast cells dendritic cells

The lymphoid progenitor: T cell B cell NK cell

APC

Figure 1-14

Macrophages engulf bacteria and produce inflammatory cytokines

Humoral Effector Mechanism

Consequences of Antigen-Antibody Binding

Antigen-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. Used to determine ABO blood types and to detect influenza and measles viruses.

2. Opsonization: Antigen (microbe) is covered with antibodies that enhances its ingestion and lysis by phagocytic cells.

Humoral Immunity (Continued)

3. Neutralization: IgG inactivates viruses by binding to their surface and neutralize toxins by blocking their active sites. 4. Antibody-dependent cell-mediated cytotoxicity: Used to destroy large organisms (e.g.: worms). Target organism is coated with antibodies and bombarded with chemicals from nonspecific immune cells. 5. Complement Activation: Both IgG and IgM trigger the complement system which results in cell lysis and inflammation.

Consequences of Antibody Binding

Consequences of Antibody Binding

Effector Functions of Antibodies

Neutralization of Microbes by Antibodies

Neutralization of Toxins by Antibodies

Antibody-Dependent Cellular Cytotoxicity (ADCC)

Functions of Complement

Antibody Response After Exposure to Antigen

Kuliah ke 2

Cellular Effector Mechanism

Cell Mediated Immunity

General responses by CMI, include:

Facilitate innate immune response to bacteria Anti-viral Anti-fungal Anti-tumor Transplantation rejection

Cell Mediated Immunity

Many microbes have developed mechanisms that

enable them to survive and even replicate within phagocytes, 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 actual effector function is mediated by the phagocytes.

T Cells and Cell Mediated Immunity

Types of T cells
1. 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.

Subpopulations of Th Cells
Subpopulations based

on cytokine profiles
Th0 Th1 Th2

Differentiation determined by cytokines

Influenced by antigen IL-4 - Th2 cells IL-12 Th1cells

Subpopulations of Th Cells
Th1 cell cytokines
Activate macrophages Generation of Tc

Th2 cell cytokines

Activate of B cells Activate granulocytes

 Regulation
Antigen INF- inhibits

proliferation of Th2 cells IL-10 inhibits production of INF-

Central Role of Helper T Cells

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-stimulatory molecule

T cell beomes anergic when it encounters APC carrying

specific peptide:MHC complex without co-stimulatory molecule

No effect on T cell which encounters APC carrying no

specific peptide:MHC complex but has co-stimulatory molecule

TH1 T CELLS AND MACROPHAGE ACTIVATION

Macrophage activation Enhancement of macrophage function against intracellular pathogens by TH1 cells Phagosome fused more efficiently with lysosome Important with Mycobacteria
Activation of macrophages requires 2 signals provided

by TH1 cells
Interferon-gamma CD40 ligand

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

TH1 and TH2

The control of TH polarization is through the

dendritic 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 + cells Th2 CD4 Figure 1-27

TH1 vs TH2

CD4 T CELL RESPONSE TO MYCOBACTERIUM LEPRAE

Mycobacterium leprae is an intracellular pathogen, agent

of 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

T Cells Only Recognize Antigen Associated with MHC Molecules on Cell Surfaces

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 called perforin which forms a pore in target cell, causing lysis of infected cells. Undergo apoptosis when stimulating antigen is gone.

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

Generation of CTLs
Differentiate in

response to two signals

Specific antigen

associated with class I MHC molecules Cytokines produced by Th1 cells

Features of CTL Killing

Antigen specific Target cell must bear the same antigen associated with class 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

Steps in CTL Killing

Tc cell
Target cell

1. Tc recognizes antigen on target cell

Tc cell

Target cell

2. A lethal hit is delivered by the Tc using agents such as granzymes or TNF 3. The Tc detaches from the target cell

Tc cell

Target cell

Target cell

4. Target cell dies by apoptosis

Mechanisms of CTL Killing

Tc kill using a variety of mechanisms Direct cell-cell contact via surface molecules Indirect signaling via cytokines

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 TNFR on target cell

Mechanisms of CTL Killing Fas and TNF-mediated

killing
Binding of ligand results

in tirmerization of the receptor Receptors with death domains activate caspases resulting in apoptosis

Mechanisms of CTL Killing

CTL granule-mediated killing
Granules containing perforin and

granzymes are released by CTL Perforin polymerizes and forms channels in target cell membrane Granzymes (serine proteases) enter through channels and activate caspases resulting in apoptosis

Cytotoxic T Cells Lyse Infected Cells

CTL-Killing

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

Figure 1-26

CYTOTOXINS AND CYTOKINES OF T CELLS

T cells are distinguished by
Cytokines and cytotoxins produced and the effects on

immune 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

Relationship Between Cell-Mediated and Humoral Immunity

1. Antibody Production
T-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

repeating subunits (bacterial capsules). Weaker immune response than for T-dependent antigens.

Humoral Response to T Dependent Antigens

Relationship Between Cell-Mediated and Humoral Immunity

2. Antibody Dependent Cell Mediated Cytotoxicity

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 targeted cells. Target organism is lysed by substances secreted by attacking cells. Used to destroy large organisms that cannot be phagocytosed.

Destruction of Large Parasites by ADCC