Chapter 11. Immune response (1)Chapter 11. Immune response (1)

I. IntroductionI. Introduction

II. Antibody-mediated Humoral II. Antibody-mediated Humoral ImmunityImmunity

I. IntroductionI. Introduction

1. Concept of Immune Response1. Concept of Immune Response

2. Types of Immune Response2. Types of Immune Response

3. Process of Immune Response3. Process of Immune Response

1. Immune response

The immune system of body is able to The immune system of body is able to recognize subtle chemical differences that recognize subtle chemical differences that distinguish one foreign pathogen from another. At distinguish one foreign pathogen from another. At the same time, the system is able to discriminate the same time, the system is able to discriminate between foreign molecules and the body’s own between foreign molecules and the body’s own cells and proteins. Once a foreign organism is cells and proteins. Once a foreign organism is recognized, the immune system eliminate or recognized, the immune system eliminate or neutralize the organism, finally.neutralize the organism, finally.

2. Types of Immune Response2. Types of Immune Response

AutoimmunityAutoimmunity

selection Immune “Self”Ag Autoimmune Tolerance selection Immune “Self”Ag Autoimmune ToleranceAg system:Ag system: activation “non-self”Ag HI / CMI activation “non-self”Ag HI / CMI Immune Tolerance Immune Tolerance Hypersensitivity Reaction Hypersensitivity Reaction

II. Antibody-mediated Humoral ImmunityII. Antibody-mediated Humoral Immunity

concept of HI concept of HI ，， simple process of HIsimple process of HI

1. Common rule of Ab production 1. Common rule of Ab production

2. Interaction between immune cells in2. Interaction between immune cells in

process of producing Ab process of producing Ab

3. Immune Memory 3. Immune Memory

4. Effect of Humoral Immunity 4. Effect of Humoral Immunity

Humoral ImmunityHumoral Immunity ，， HIHI

Humoral immunity is mediated by antiHumoral immunity is mediated by antibodies of various different classes; which Abodies of various different classes; which Ab are produced by cells of the B cell lineage b are produced by cells of the B cell lineage in response to stimulation by Ag.in response to stimulation by Ag.

Simple process of HI:

11 、、 TD—Ag APC TH BL2TD—Ag APC TH BL2

THmTHm BLmBLm

22 、、 TI—Ag BL1 Mature B cellTI—Ag BL1 Mature B cell

Plasma cellsPlasma cells

Ab Ab HIHI

1.Common rule of Ab production

a. The regularity of Ig production in phylogenic ea. The regularity of Ig production in phylogenic evolution and development,and ontogenesis.volution and development,and ontogenesis.

b. The regularity of Ab production in the primary b. The regularity of Ab production in the primary and secondary responseand secondary response 。。

Secondary Immune Response

When the immunized individual after a primary contact with antigen is injected by a second injection of the same antigen, production of antibody becomes apparent, this response is called the secondary response.

Primary IR Secondary IR

Antigen The first contact of an A second injection of the individual with an Ag same Aglatent period long (1W ， 2-3W) short (1-3day) slow of Ab productionAb Conc. low in serum high in serum Maintain Time short,decrease quickly longertype of Ig IgM IgGAffinity lower higherpresent of Ag M, DC B cell

Concentration of IgConcentration of Ig

IgIgMIgG

10day 3day

Latent period

Primary stimulation of AgPrimary stimulation of Ag Secondary stimulation of AgSecondary stimulation of Ag

2. Interaction between immune cells2. Interaction between immune cells in the process of producing Ab in the process of producing Ab

TD—Ag responseTD—Ag responsea. Interaction between Ma. Interaction between M and Th cells and Th cells

* M* M presented Ag *Interaction between cells presented Ag *Interaction between cells

b. Interaction between Th cell and B cellsb. Interaction between Th cell and B cells

* B cell presented Ag * Interaction between* B cell presented Ag * Interaction between cellscells

c. Interaction between Mc. Interaction between M and B cells and B cells

TI—Ag responseTI—Ag response

B cell : response of TI—AgB cell : response of TI—Ag

• Ags are ingested, processed, presented Ags are ingested, processed, presented by M by M (primary response)(primary response)

IngestionIngestion ：： endocytosis, passive adhesionendocytosis, passive adhesion 。。 ProcessingProcessing ：： lysosomal enzymes condense anlysosomal enzymes condense an

d degrade d degrade Ag,Ag,and combine to self-MHCII moland combine to self-MHCII molecules.ecules.

PresentationPresentation ：： These complexes of peptide aThese complexes of peptide and MHC molecules are transported to the surnd MHC molecules are transported to the surface of the cell where they are recognized by tface of the cell where they are recognized by the T-cell receptor. he T-cell receptor.

Exogenous AgExogenous Ag

endosome

Transportation

combination

degradation

expression

endocytosis

APC

CD4

TCRTCR

MHCII

transcription

DNA

mRNA

Virus （ endogenous Ag ）

translationPr

degradation CD8CTL

MHCI

Target cell

TCR

• Interaction between MInteraction between M and Th cells and Th cells （（ primary responseprimary response ）） Double signal hypothesis of Th cell activation Double signal hypothesis of Th cell activation ：：The first signal The first signal ：： Th: TCR/CD3——APC: Ag-MHCII complexes Th: TCR/CD3——APC: Ag-MHCII complexes

at the same time, TH: CD4——APC: The at the same time, TH: CD4——APC: The 2,2,2 domain of MHCII2 domain of MHCII

The second signal The second signal ：： APC: B7/BB1APC: B7/BB1 （（ CMCM ）——）—— TH: CD28TH: CD28 （（ CMRCMR ））

TH secreted IL-2 and expressed IL-2RTH secreted IL-2 and expressed IL-2R

Finally cells divide, clones proliferation, and produce a kind of CK.Finally cells divide, clones proliferation, and produce a kind of CK.

ICAM-1 LFA-1

APC(CMs)

MHC-IIAg

B7/BB1

VLA-4VCAM-1

CD2CD58

Cell activation,（ CK ）cell differentiation and clone proliferation

TH(CMRs)

TCR

CD3

CD4

CD28CTLA4

Signal 1

Signal 2

IL-2

IL-2R

Interaction between APC and Th cellInteraction between APC and Th cell

MHC-Ag

APC

TCR/CD3

B7/BB1

CD28

TH

Signal 1 Signal 2

IL-2 production clone proliferation

APC

TH

Signal 1 Signal 2

not IL-2 production clone anergy

inactivation

Suppressive immune response Suppressive immune response ：： Hypersensitivity DiseaseHypersensitivity Disease Autoimmunity DiseaseAutoimmunity Disease Graft rejection responsesGraft rejection responses

Anti-B7AbCTLA4 IgAnti-CD28

Interdiction of co-stimulatory signals

THAPC MHC TCR

Ag

CD28

B7

Enhancing immune responseEnhancing immune response ：： Tumor immunity treatmentTumor immunity treatment

B7

Transfection B7gene

CTLMHC TCR

Ag

CD28

Tumor cellsignal1

signal2

CTLMHC TCR

Ag

CD28

Tumor cellsignal1

signal2

CTL activatedKiller tumor cell

CTL activatedKiller tumor cell

• Interaction between Th and B cellsInteraction between Th and B cells （（ secondary responsesecondary response ））

Th cell activationTh cell activation ： ： Double signal hypothesis Double signal hypothesis Signal 1Signal 1 ：： Th: TCR/CD3——B cell: Ag-MHCII complexesTh: TCR/CD3——B cell: Ag-MHCII complexes

Th: CD4——B cell: Th: CD4——B cell: The The 2,2,2 domain of MHCII2 domain of MHCII

Signal 2Signal 2 ：： Th: CD28 molecule ——B cell: B7 molecule.Th: CD28 molecule ——B cell: B7 molecule.

B cell activationB cell activation ： ： Double signal hypothesis Double signal hypothesis Signal 1Signal 1 ：： B cell: BCR--AgB cell: BCR--Ag ，， IgIg,Ig,Ig transfer activation signal transfer activation signal 11

Signal 2 ： B cell: CD40——Th: CD40LB cell: CD40——Th: CD40L

Th and B cell inducing signal of activation each otherTh and B cell inducing signal of activation each other ，， Th produced IL-4,5,Th produced IL-4,5,6.6.

B cell is helped at Th cell, finally B cell proliferated and differentiatedB cell is helped at Th cell, finally B cell proliferated and differentiated

turn into the plasma cells of producing a kink of Igs.turn into the plasma cells of producing a kink of Igs.

CD3

singal

B cell activation

B cell

Ag

SIg

12

Signal 1

T cell

B7 CD28

ICAM-1 LFA-1

CD3

TCR

CD4

MHC-II

CD40LCD40

LFA-1 ICAM-1

Signal 2Signal 2

Th activationCK

Ag process

present

Interaction between B cell and T cellInteraction between B cell and T cell

CKR

Ag

Bm

B B

B B

PC

IgM IgG

IgA IgE

Bm Bm

Bm Bm

Activate Th

Activate B

IL-2 ， 4 ， 5 ， 6IL-1

process

present

process

present

proliferation

ingestion

ingestion

MHC-II

MHC-II

TCR

TCR

M M

differentiation

c. Interaction between M and B cells

signalsignal

B cell B cell

I type: TI—Ag is

polyclonal stimulator II type: multiple repeat-lined antigenic determinant makes receptor linkage

TI-Ag response

3. Immune Memory-Secondary response

CharacteristicCharacteristic : :

a. Immune memory cellsa. Immune memory cells

b. Class switching of Igb. Class switching of Ig

c. Affinity Maturation of Abc. Affinity Maturation of Ab

CharacteristicCharacteristic ：： * Immune memory cells: THm Bm

* Involved in Humoral immunity and

cell-mediated immunty.

* Ab conc. increases ， class switching of Ab ， and affinity maturation of Ab

4. Effect of Humoral Immunity

Neutralization of AbNeutralization of Ab Opsonization of AbOpsonization of Ab Complement dependent cell-mediated cComplement dependent cell-mediated c

ytotoxicity,CDCytotoxicity,CDC Antibody dependent cell-mediated cytoAntibody dependent cell-mediated cyto

toxicity,ADCCtoxicity,ADCC Immune regulation of AbImmune regulation of Ab

Opsonization of Ab

Bacteria Anti-bacteria Ab M

FcrR

Boost up lick up action

Target cell

M , NK

Dissolution of target cell

IgG

Surface AgFcrR

Antibody-dependent cell-mediated cytotoxicity, ADCC

Chapter12. Chapter12. Immune response (2)Immune response (2)

I. Introduction I. Introduction

II. CD4 T-mediated immunityII. CD4 T-mediated immunity

III.CD8 T-mediated immunityIII.CD8 T-mediated immunity

I. Introduction

1. Concept, Simple process1. Concept, Simple process

2. Major functions of CMI2. Major functions of CMI

Simple process:Simple process:

TD-Ag Immune system

secondary

TDTH

Tc

CK

Cytotocixity

2. Major Functions of CMI

Delayed Type Hypersensitivity, DTHDelayed Type Hypersensitivity, DTH Intracellular Anti-infection Intracellular Anti-infection Anti-tumor Anti-tumor Transplantation rejection reactionTransplantation rejection reaction Graft Versus Host Reaction, GVHRGraft Versus Host Reaction, GVHR Autoimmunity diseasesAutoimmunity diseases

II. CD4 T-mediated immunity

1. Activation of CD4 T cells1. Activation of CD4 T cells

2. Formation of DTH inflammation2. Formation of DTH inflammation * CK production * Function of M* CK production * Function of M

• Activation of CD4 T cells

Double signal hypothesis of CD4 T cell activation Double signal hypothesis of CD4 T cell activation ：：The first signal The first signal ：： Th: TCR/CD3——APC: Ag-MHCII complexes Th: TCR/CD3——APC: Ag-MHCII complexes

at the same time, TH: CD4——APC: The at the same time, TH: CD4——APC: The 2,2,2 domain of MHCII2 domain of MHCII

The second signal The second signal ：： APC: B7/BB1APC: B7/BB1 （（ CMCM ）——）—— TH: CD28TH: CD28 （（ CMRCMR ））

TH secreted IL-2 and expressed IL-2RTH secreted IL-2 and expressed IL-2R

Finally cells divide, clones proliferation, and produce a kind of CK.Finally cells divide, clones proliferation, and produce a kind of CK.

IL-2RIL-2R APC(CMs)

TH(CMRs)

CD28CTLA4 CD3

TCR

CD4ICAM-1 LFA-1

MHC-II Ag

B7/BB1

VLA-4VCAM-1

CD2CD58

Signal1

Signal 2

IL-2

IL-2R

Cell activation,（ CK ）cell differentiation and clone proliferation

APC T

APC T

APC T

T

T

T

T

IL-2

IFNr

TNF

T

M

rest

M

activation

CK of DTH reaction

III.CD8 T-mediated immunity

1. Activation ofCD8 T cells1. Activation ofCD8 T cells

2. Mechanisms of Tc killing 2. Mechanisms of Tc killing target cellstarget cells

a. a. PerforinPerforin

b. b. GranzymesGranzymes

c. c. TNF associated proteinsTNF associated proteins

• Activation of CD8 T cells

Double signal hypothesis of CD8 T cell activation Double signal hypothesis of CD8 T cell activation ：：The first signal The first signal ：： Tc: TCR/CD3——Target cell: Ag-MHC-I complexes Tc: TCR/CD3——Target cell: Ag-MHC-I complexes

at the same time, Tc: CD4——Target cell: The at the same time, Tc: CD4——Target cell: The 3 domain of MHC-I3 domain of MHC-I

The second signal The second signal ：： Target cell: B7/BB1Target cell: B7/BB1 （（ CMCM ）——）—— Tc: CD28Tc: CD28 （（ CMRCMR ））

Tc secreted IL-2 and expressed IL-2RTc secreted IL-2 and expressed IL-2R

Finally cells divide, clones proliferation, and secrete effect molecules.Finally cells divide, clones proliferation, and secrete effect molecules.

Interaction between target cell and TcInteraction between target cell and Tc

ICAM-1 LFA-1

Target cell

(CMs)

MHC-IAg

CD2CD58 Tc(CMRs)

TCR

CD3

B7/BB1 CTLA4

Signal 1

Signal 2

IL-2R

CD8

Cell activation,differentiation , clone proliferation and

secreted effect molecules.

IL-2

Ag recognitionAg recognition

Tc activationTc activation

Tc killed target cellTc killed target cell

Tc unbindTc unbind Target cell diedTarget cell died

TH1

Effector Tc

Rest Tc

Target cell

APC

MHCI

MHCII

IL-2 ， IL-6 ， IFN

TCR

death

Target cell