B cell mediated immune response

(Humoral immunity)

Humoral immunity(HI) or antibody mediated

immunity

The total immunological reaction that B cells recognize

antigen, then activate, proliferate, differentiate into

plasma cells and produce Ab.

Contents

Part Immune response of to TD-AgⅠ

Part Immune response to TI-AgⅡ

Part Rules of humoral immunityⅢ

Part Immune response to TD-AgⅠPart Immune response to TD-AgⅠ

Characteristics• Most native Ag• Protein, large molecules• Need Th cells participation• Produce several types of antibodies:• Produce immune memory

B cells can recognise native antigens directly

YY Y Y YYY

B

Proliferation and antibody production

Cross-linking of surface membrane Ig

Y

B

Y

B Y

B

Y

B

Y

B Y

B

Y

BYY

B

Th

1. B cells recognize antigen

• BCRs directly recognize the epitope on the surface of Ag

• No APC , no MHC restriction

• Capture Ag by BCR, present Ag signal to Th cells

Antigen presentation on B cells

2. B cells activation, proliferation and 2. B cells activation, proliferation and differentiationdifferentiation

(1) B cell activation: dual signals

• First signal: antigen signal BCR-- determinant on the surface

of Ag Igα/Igβtransduct the first signal CD19/CD21/CD81 (co-receptor)

binds to C3d on Ag

•Second signal: co-stimulatory signal The CD40 on B cells binds to CD40L on activated Th cells

Ch. 11

Mechanisms of helper T cell–mediated B cell

activation.

Interaction between Th cells and B cells

B cells act on Th cells:• B cells(APC) present Ag to Th cells.• B cells provide B7 for Th cells.

Th cells act on B cells:• B cells present peptide-class MHC complex Ⅱ

and provide B7 for T cells, Th cells are activated and express CD40L

• Activated Th cells provide co-stimulatory molecule for B cells: CD40L- CD40.

• Activated Th cells secrete Cks（ IL-4、 IL-5、 IL-6、 IL-10、 IL-13） which help B cells proliferate and differentiate.

Interaction between Th cells and B cells

The ligation of BCR

Cross-link of the receptors

PLCγ activation Ras & Rac activation

DAG generation IP3 generation MAP kinase cascade

PKC activation Ca2+ release

Canonical NF-κB NFAT AP-1

IL-4R ,IL-5R Gene expression

(2) B cells proliferation and differentiation------help of Th cells

• Activated B cells express receptors of cytokines such as IL-4R, IL-5R.

• Activated Th2 cells secrete cytokines such as IL-4, IL-5 to enhance proliferation and differentiation of B cells.

Where is the humoral response actually induced?

Ch. 11

(no antigen-driven processes are taking place)

Spleen, lymph nodes, Peyer’s patches,appendix, tonsils, and MALT

Antigen entersnode in afferent

lymphatic

Y

Y

Y

Y

Y

YY

Y

Y

Y

Y

Y

Y

Y

YY

Y

YB cells leave blood & enter lymph node via

high endothelial venulesB cellsproliferate

rapidly

GERMINAL CENTERStructure of

Intense proliferation

Germinal centerreleases B cellsthat differentiateinto plasma cells

Germinal Center ResponseGerminal Center Response

The germinal center reaction in a lymph node.

Events in germinal Center

• During proliferation and differentiation, Somatic hypermutation of B cells induces affinity maturation of Ab.

• Some B cells differentiate to the plasma cells which produce IgM.

• Some B cells have an isotype switch to produce other types of Ig.

• Production of memory B cells.

Affinity maturation

As a humoral immune response

develops, activated B cells that produce

antibodies that bind to antigens with

increasing affinity progressively dominate

the response; this process is called

affinity maturation.

Affinity maturation

Control of Affinity & Affinity Maturation

Five B cell antigenreceptors - all specificfor , but withdifferent affinitiesdue to somatichypermutationof Ig genes in the germinal center B B B B B

Only this cell, that has a high affinity for antigen can express CD40.Only this cell can receive signal 2

Only this cell is rescued from apoptosis i.e. clonally selected

The cells with lower affinity receptors die of apoptosis by neglect

Mechanism of somatic hypermutation

in Germinal Center

Red boxes - somatic mutations; CDR, complementarity determining regions

Rearranged V-region gene segments are further diversified by somatic hypermutation

This leads to antibodies with increased affinity for the inducing antigen

• The first antibodies produced in a humoral immune response are IgM, but activated B cells subsequently undergo isotype switchingisotype switching or or class switchingclass switching to secrete antibodies of different isotypes: IgG, IgA, and IgE. Isotype switching does not affect antibody specificity significantly.

isotype switchingisotype switching

Isotype Switching Under the Influence of HelperT Cell-Derived Cytokines

Mechanism of Class switch

At the H chain locus, the constant region gene segments are arranged next to each other.

CD40/CD40L

Phases of the Humoral Immune Response toT-Dependent Antigen

Memory B cells

Part II Immune response of B cell to TI-AgPart II Immune response of B cell to TI-Ag

Characteristics of TI-Ag:

Repeat B cell epitope

No T cells participation

Only humoral immunityNo immune memory

TI-Ag

Most TI antigens are polyvalent and induce maximal Crosslinking of membrane Ig on B cells, without a Need for T cell help.

TI-Ag fall into two categories:

TI-1

TI-2

TI-1 antigen: also named B cell mitogen

1. Contains B cell mitogen and repeated B epitopes

2. Can induce immature and mature B cell-mediate immune response

3. In high concentrations, can induce polyclonal B-cell activation

4. In lower concentrations, only the BCR-binding TI-1 antigens can activate B cells

5. Not able to induce Ig class switch, antibody affinity maturation and memory B cells

TI-I response

TLR4

BCR

TLR4

BCR

TLR4 TLR4 TLR4

BCR BCR BCR

High concentration of LPS (B cell mitogen)

Polyclonal activation of B cells No affinity maturation or memory.

Low concentration of LPS

TLR4

LPSbacteria

Antibodies specific for antigen

TI-2 antigen

1. Only contains multitude repeated B-cell epitopes

2. Merely induces mature B cell-mediated immune response

3. Unresponses or hyporesponsive to infantile B cells

4. Activates the B-1 cells

YYYY

Y

YYYY

YYYYY

Y

YYYYY

IgM

YYYYY

MatureB-1

Non-bone marrow derived B-1 cells are directly stimulated by antigens

containing multivalent epitopes.

No T cells are necessary

Induces the expression of natural antibodies specific for TI-2 antigens

TI-2 AntigenTI-2 response

YYImmatureB-1 Cell

TI-2 Antigen

Why are babies unresponsive to TI-2 antigens?

Hence babies do not respond to TI-2 antigens.

Babies are, therefore susceptible to pathogens with multivalent antigens such as those on pneumococcus

In babies:All B-1 cells are immature

TDependentAntigens

TI-1Antigens

TI-2Antigens

Induce responses in babies Yes YesInduce responses in athymics No Yes YesPrime T cells Yes No NoPolyclonally activate B cells No Yes NoRequire repeating epitopes No No Yes

T Dependent & Independent Antigens

No

T Dependent: Activate B-1 and B-2 B cells

TI-1: Activate B-1 and B-2 B cells

TI-2: Activate only B-1 B cells

PartPartΙΙΙΙΙΙ Rules of humoral immunity Rules of humoral immunity

1. Primary response

2. Secondary response

Phases of the Humoral Immune Response

Primary and Secondary humoral Responses

In a primary immune response, naïve B cells are stimulated by antigen, become activated, and differentiate into antibody-secreting cells that produce antibodies specific for the eliciting antigen. A secondary immune response is elicited when the same antigen stimulates memory B cells, leading to production of greater quantities of specific antibody than are produced in the primary response. Note that the characteristics of secondary antibody responses summarized in the table are typical of T-dependent antibody responses to protein antigens.

Antibody Functions:

NeutralizationNeutralization

Activate complement systemActivate complement system

ADCC — NK, macrophage, neutrophilADCC — NK, macrophage, neutrophil

Opsonization — macrophage Opsonization — macrophage

Functions of Antibodies