Humoral Ir mediated by B cells Chapter 12 Humoral Ir mediated by B cells

Major content Concept Response to TD-Ag Characteristics of primary and secondary Ir Response to TI-Ag Effect of B cell response

体液免疫应答 (humoral immunity) B cells encounter specific Ag, activate ,proliferate and differentiate to plasma cells，produce Abs, eliminate Ags. Ab exist in blood, important effector. * 主要针对细胞外病原体 * TD-Ag和TI-Ag

Classification B cells Respond to TD-Ag （protein) B cells Respond to TI-Ag (Glucose and Glylipid）

B cells response to TD-Ag

B cell antigen receptor complex

BCR direct 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。

B cell and Th cell recognize different epitope on the same Ag 载体效应

BCR recognize Ag and activation of B cell 信号1 * B细胞特异性结合抗原，向B细胞传递抗原刺激信号； * 通过BCR摄取抗原，并将抗原降解为肽段，形成抗原肽-MHC-II类分子复 合物，供抗原特异性Th细胞识别；

B cells response to TD-Ag * B cells recognition to TD Ag * B cells activation, proliferation and differentiation * Primary and secondary response * Effect of B cell response

B cell activation （一）active siganl 1 (Ag) * BCR specific bind epitope on B cell； *co-receptor：CD21/CD19/CD81 bind C3d linked with Ag； * Igα/Igβ：signal transduct； （二） active siganl2 (co-stimulatory molecule) *activation of naive Th：APC（DC) present double siganls and CK to naive CD4+T. develop to effective Th； * B cell present Ag：B cell take in Ag via BCR，process it，formation of peptide-MHC complex，present to Th； * Effective Th combines with B cell specifically：TCR recognize Ag presented by B； *Co-stimulatory sgnal：CD40L(on active T) bind CD40(on B cell)； （三）CKs IL-1/APC、 IL-4/Th promote activation of B cell.

BCR and co-receptor complex 经典途径、替代途径和MBL途径

This slid show us comparison the molecules involved in antigen recognition by T cells and B cells.. Antigen receptor: T cell is TCR and B cell is BCR Recognition: - Antigen recognition of T cell is dual recognition, while antigen recognition by B cell is single recognition. TCR recognizes epitope presented by MHC, so both peptide and self MHC molecule -BCR directly recognizes epitope on tne surface of native antigen. Coreceptor: - For T cell is CD4 and CD8 - For B cell is CD19/CD21/CD81 complex Signal transduction molecules - for T cell is CD3 -for B cell is Ig-alpha and Ig-beta.

Interaction of T and B cells Th细胞和B 细胞间相互作用 Interaction of T and B cells

Bidirectional T cell -B cell interaction

Tow times of recognition CD28 B7.1/2 SIGNAL 2 DC Th Processing SIGNAL 1 naive effector CD28 B7.1/2

Th help B cell activating, proliferating and differentiating

Cytokines promoting B cell activation, proliferation and differentiation B cells are activated by antigen on antigen presenting cells such as macrophages in the presence of IL-4 and IL-1. This cause expression of receptors for IL-2 and other cytokines. IL-2, IL-4 and IL-5 drive cell division. Differentiation into antibody-forming cells is effected by IL-4,5,6,10 and IFN-gamma.

B cells proliferation and differentiation Active B cell express many CKR  receive stimuli of CK from Th  IL-2,IL-4,IL-5 promote B cell proliferation， IL-4,IL-6,IFN-g promote B cell differentiation.

B cell mature in germial center * Somatic hyper-mutation and Ig affinity maturation *Antigenic receptor editing： Ig gene rearrangement occur in auto-reactive B cell, edited BCR point at none-self Ag. *Ab class switch：V region does not change，only C region of H chain change.。

B cells enter into primary follicle 1. Antigen loaded dendritic cells migrate from subcapsular sinus to paracortical area of the lymph node DC B cells (90%) and T cells (10%) migrate to a primary follicle B T B cells enter into primary follicle T 3. T cells proliferate T 2. T cells migrate through HEV and are trapped by antigen on DC B B 4. B cells migrate through HEV - most pass through the paracortex and primary follicle. HEV Some interact with T cells and proliferate to form a primary focus

Cytokines and antibody isotype switch The antibody isotype switch is affected by cytokines. - IFN-gamma promote the switch of the antibody from IgM to IgG2a or IgG3. - IL-4 induces the switch of antibody to IgE or IgG1 -Il-2,4,5 promote IgM production. Flash

B cell mature in germial center * Somatic hypermutation and Ig affinity maturation *Antigenic receptor editing： Ig gene rearrangement occur in autoreactive B cell, edited BCR point at none-self Ag. *Ab class switch：V region does not change，only C region of H chain change.。

B cell primary response toTD-Ag APC take in,process and present Ag B7-CD28 IL-1 TCR recognize peptide/MHCII B/Th interaction CD40/CD40L binding BCR recognize B cell epitope Th develop Signal 2 Signal1 secretIL-2、IL-4、IL-5、IL-6 B cell develop Mature in germinal center PC （early）IgM （die after 2 Wk） Memory B PC （late）IgG （enter lymphocyte re-cycle） （in bone marorw）

Primary and secondary response

（Primary immune response） 初次免疫应答 （Primary immune response） Ir induced by pathogen first invaded human body. Properties： - longer lag phase； - Most class of Ab is IgM ； - Level of Ab is low； - Affinity of Ab is low.

Four phases 潜伏期 对数生长期 平台期 下降期

（secondary immune response） 再次免疫应答 （secondary immune response） The same Ag reenter body, stimulate memory cells to elicit prompt, efficacy and specific response. Properties： - APC (memory B) interact with memory T； - Low amount of Ag for simulation； - Lag phase shorter； - Ab Level higher, Ab duration longer； - Most class of Ab is IgG ，affinity higher。

Primary and secondary humoral immune responses

Memory B cells present antigen to T cell

Raising Ab production and affinity after repetitive immunization

Primary and Secondary Immune Response Ab concentration Total amount of Ab IgG Lag phase Lag phase IgM 10 3 First stimuli of Ag Repetitive stimuli of the same Ag Days

Difference of primary and secondary response Features secondary Ag stimulation Lag phase Ab peak duration Ig Class affinity first second 5-10 days lower shorter IgM low 2-5 days higher longer IgG、IgA high

Effect of B cell response

Neutralization By Antiviral Antibodies

Effector mechanisms against extracellular pathogens (2) OPSONISATION Bacteria in extracellular space Ab + Fc receptor binding Phagocytosis Antibodies can bind the epitopes on pathogen. The Fc regions of antibodies can bind to Fc receptors expressed on phagocytes, then promote the phagocytosis. OPSONISATION

Action of phygosytosis

Complement activation (3) Complement activation

Phagocytosis binding Complement & Fc receptor Opsonisation Effector mechanisms against extracellular pathogens COMPLEMENT Activation Bacteria in plasma Lysis Ab & COMPLEMENT + Phagocytosis binding Complement & Fc receptor Opsonisation Bacteria in plasma bind antibodies to form antigen-antibody complex which can activate complement by classical pathway of complement activation. The activation of complement can leads to the lysis of bacteria by membrane attack complex. The antibodies can use their Fc regions to bind Fc receptors on phagocytes and complement fragments such as C3b can bind to C3bR on phagocytes which promote phagocytosis.

FcgR and Complement Receptors Cooperate To Induce Greater Phagocytosis

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

(4)

(5) IgA against adhesins

(6) Immune damage IgE Antibody Binds To Mast Cells & Basophils To Arm Them For Mediator Release

B cell response to TI Ag

Do not require Th，without immune memory，occur earlier. TI-1Ag activate B cell - At high concentration,TI-1Ag induce activation of many B cells (polyclonal activation) - At low concentration, TI-1Ag induce activation of specific B cell. * TI-2 Ag direct activate mature B1 cell - Repetitive epitopes bind BCR→BCR cross-linkage→produce IgM

Mechanism for TI-Ag activate B cell （A）： TI-1 Ag （B）： TI-2Ag

High Repeatitive epitopes mitogen LPS TI-1 TI-2 SmIg epitope capsule of pneumococcus SmIg High Repeatitive epitopes mitogen R B B2 ① ② Signal Signal Activate Activate B cell activation induced by TI antigen

Thymus dependent Ag(TD—Ag) Thymus independent Ag(TI—Ag) Comparison items Thymus dependent Ag(TD—Ag) Thymus independent Ag(TI—Ag) Th require No require Class of Ir Humoral and cellular Only humoral Class of Ab most are IgG Only IgM Memory reaction Yes Not

Effect of B cell mediated Ir * Neutralization：Neutralize toxin 、virus * Opsonization ：Ag coated with IgG and IgA，promote phygocytosis * Activation of complement：（IgG/IgM）IC，activate classical pathway - CDC - Opsonization * ADCC：NK、M、NC、EC * Mucous defense of secretary IgA * Immune damage: - hypersensitivity and AID - Graft rejection reaction：preformed Ab cause hyper acut reaction - promote tumor growth ：blocking factor，interrupt CTL reorganization to tumor Ag

Review Question Describe the process of B cell response to TD Ag in primary immune response简述B细胞对TD-Ag的初次免疫应答过程。 Compare primary and secondary immune response , describe their significance in application 简述体液免疫应答的一般规律和了 解此规律的意义。 Describe the admission molecules and their functions involved in T-B interaction简述参与T-B细胞相互作用的黏附分子及 其功能。