Humoral Immune response Jianzhong Chen, Ph.D. Institute of Immunology, ZJU

B cell-mediated humoral immune response Humoral immunity is mediated by antibodies and is the arm of the adaptive immune response that functions to neutralize and eliminate extracellular microbes and microbial toxins. It is more important than cellular immunity in defending against microbes with capsules rich in polysaccharides and lipids, and against polysaccharide and lipid toxins.

Phases and types of humoral immune responses Antigen recognition phase Activation, proliferation and differentiation phase Effector phase 2) Types Response to TD-Ag Response to TI-Ag * 主要针对细胞外病原体 * TD-Ag和TI-Ag

Phases of humoral immune responses Effector phase Phases of humoral immune responses

2. Response to TD-Ag

a. BCR directly recognizes B cell epitopes 1) B cells recognize TD-Ag a. BCR directly recognizes B cell epitopes b. Ig/Ig transfer the first signal c. Effect of coreceptors (CD21/CD19/CD81) d. Signalling pathways

BCR directly recognize B cell epitope 复习B表位和T表位 BCR直接识别B表位，为单识别，不受MHC的限制性。 BCR directly recognize B cell epitope

The role of coreceptor (CD19/CD21/CD81) in B cell activation

BCR complex-mediated signal transduction in B cells

Functional consequences of Ig-mediated B cell activation: Increase in expression of costimulators (such as B7) Increase in expression of CKRs Decrease in their expression of receptors for chemokines produced in lymphoid folicles

2) Role of Th cells in humoral immune response to TD-Ag For a protein Ag to stimulate Ab response, B cells and Th cells specific for that Ag must come together in lymphoid organs and interact in a way that stimulates B cell proliferation and differentiation.

a. Activation and migration of helper T cells Th cells that have been activated to differentiate into effector cells interact with antigen-stimulated B cells at the edges of lymphoid follicles in the peripheral lymphoid organs.

The interactions of Th cells and B cells in lymphoid tissues.

b. Presentation of Ags by B cells to Th cells B cells that bind protein Ags by their BCR endocytose these Ags, process them in endosomal vesicles, display MHC II-peptides for recognition of Th cells. B cells and Th cells recognize different epitopes of the same protein Ag.

Ag presentation by B cells to Th cells

c. Mechanisms of Th cell-mediated activation of B cells Th cells that recognize Ag presented by B cells activated B cell by expressing CD40L and by secreting cytokines (IL-2, IFN-, IL-4, IL-5, IL-6, IL-13, etc.).

Mechanisms of Th cell-mediated activation of B cells Downloaded from: StudentConsult (on 1 June 2006 03:50 PM) © 2005 Elsevier

d. Th cells stimulate B cells to produce Abs of different heavy chain classes (isotypes) Heavy chain class switching is initiated by CD40L-mediated signals, and switching to different classes is stimulated by different cytokines.

Ig heavy chain class (isotype) switching

e. Affinity maturation in Ab responses Affinity maturation is the process by which the affinity of Abs produced in response to a protein Ag increases with prolonged and repeated exposure to that Ag. The increase in affinity is due to point mutations in the V regions, and particularly in the Ag-binding HVR, of the Abs produced. Affinity maturation occurs in the germinal centers of lymphoid follicles.

Selection of high affinity B cells in germinal centers Downloaded from: StudentConsult (on 1 June 2006 03:50 PM) © 2005 Elsevier

The anatomy of humoral immune responses

A fraction of the activated B cells, which are often the progeny of class-switched high-affinity B cells, do not differentiate into Ab secretors but instead become memory B cells.

3. Immune response of B cells to TI-Ag No Th help，no memory, early effect * TI-1 (B cell mitogen) activate B cells - high dose TI-1Ag polyclonally activates B cells - low dose TI-1Ag specifically activate B cells * TI-2 activate mature B cells directly -the repeated epitopes combine with BCR→ BCR cross-linking→produce IgM

The mechanism of TI-Ag activating B1 cells The immune response followed by primary antigenic challenge. (A) TI-1 Ag (B) TI-2 Ag The mechanism of TI-Ag activating B1 cells

4. General features of Ab responses in vivo Primary immune response - longer latent phase; - smaller peak response (lower Ab titer); - remaining in the serum at detectable levels for much shorter periods; - lower average affinity; - usually IgM;

Secondary immune response (The immune response followed by secondary antigenic challenge) - shorter latent phase; - bigger peak response (higher Ab titer); - remaining in the serum at detectable levels for much longer periods; - higher average affinity; - usually IgG.

Features of primary and secondary antibody responses

5. Functions of antibodies Neutralization of microbes and toxins Opsonization ADCC and other FcR-dependent functions Activation of complement lysis of microbes opsonization of microbes with C fragments (C3b) inflammation: C3a, C5a chemoattract neutrophils

The effector functions of antibodies (1)

The effector functions of antibodies (2) Downloaded from: StudentConsult (on 1 June 2006 04:16 PM) © 2005 Elsevier

Neutralization By Antiviral Antibodies

Antibody-mediated opsonization and phagocytosis of microbes Downloaded from: StudentConsult (on 1 June 2006 04:16 PM) © 2005 Elsevier

Antibody-mediated opsonization and phagocytosis of microbes Downloaded from: StudentConsult (on 1 June 2006 04:16 PM) © 2005 Elsevier

ADCC

Effector cells of ADCC ADCC can be mediated by NK cells, macrophages, neutrophils and eosinophils.

Complement activation

immunopathology IgE Antibody Binds To Mast Cells & Basophils To Arm Them For Mediator Release