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IMMUNOLOGY B cell and humoral immunity Wei Chen, Associate Professor The Institute of Immunology Email: [email protected] http://mypage.zju.edu.cn/566 Password: 8888 Study objective To understand the activation and function of B cells To be aware of the differentiation and maturation of B cells To know the development of B cells To distinguish the subsets and surface markers of B cells. B Lymphocytes (B cells) B cells are an essential component of the adaptive immune system that play a large role in the humoral immune response. The principal functions of B cells are to make antibodies against antigens, perform the role of antigenpresenting cells (APCs) and eventually develop into memory B cells after activation by antigen interaction. The abbreviation "B", in B cell, comes from the bursa of Fabricius in birds, where they mature. In mammals, immature B cells are formed in the bone marrow and resides in LN and spleen. B Lymphocytes (B cells) • B cells distribute in blood, lymphoid organs (lymph node, spleen, tonsil etc.) and mucosa. About 5-15% of the circulating lymphoid pool are B cells • Naive mature B cells exit the bone marrow and migrate into the periphery. If these mature B cells encounter specific antigen, they become activated or tolerized. • Following activation, Ag-specific B cells differentiate into antibody-forming cells (AFC) or memory B cells in the germinal centre. Content Development of B cells B cell surface markers B cell subsets Functions of B cells humoral immunity Content Development of B cells B cell surface markers B cell subsets Functions of B cells humoral immunity Development and migration of B cells (An overview) The phase of B cell development B lineage commitment HSC (hematopoietic stem cell) MPP (lymphoid/myeloid progenitor) ELP (earliest lymphocyte progenitor) (淋巴系髓系多能前体细胞) CLP (common lymphoid progenitor) ETP (early T-lineage progenitor) B cell development related events 1. B cell development dependent on BM stromal cells 2. Transcription factors important for B lineage development 3. B cell development stages characterized by stage‐specific surface markers 4. B cell development is coupled with rearrangement of heavy chain and light chain 5. The role of Ig Heavy Chain and pre‐BCR 6. Immature B cells are tested for autoreactivity before they leave the bone marrow 1. Regulators of Growth of Early B Lineage Cells FLT3-L:induce IL7R IL-7: survival factor for T and B cells CXCL12(SDF-1): Retain precursors in BM Other cell-adhesion molecules VCM-1:binds to integrin VLA-4 SCF: interact with Kit 2. B cell development is coupled with stage‐specific surface markers 3. B cell development is coupled with gene rearrangement Pre-BCR与BCR结构示意图 前B细胞表面表达重链和替代轻链(λ5和Vpre-B),未 成熟B细胞表达完整的重链和轻链 45个VH 23个DH 6个JH The enzymes for gene rearrangement The products of the two genes Rag-1 and Rag-2 (recombination-activating genes) comprise the lymphoid-specific components of the recombinase. Tdt (terminal deoxynucleotidyl transferase) modify the ends of the broken DNA. TdT adds N-nucleotides to the V,D, and J exons, enabling the phenomenon of junctional diversity. Other enzymes: DNA exonuclease, DNA synthetas, DNA ligase. B lineage commitment The results of gene rearrangement Allelic exclusion Isotype exclusion The diversity of BCR Gene rearrangement of BCR Junctional diversity Somatic Hypermutation Affinity maturation in antibody responses Gene rearrangement of TCR and BCR Junctional diversity Somatic Hypermutation 4. Immature B cells are tested for autoreactivity before they leave the bone marrow----Negative Selection 4. Immature B cells are tested for autoreactivity before they leave the bone marrow: Receptor Editing Content Development of B cells B cell surface markers B cell subsets Functions of B cells humoral immunity BCR complex co-receptor CDs related to B cell activation 1. BCR complex • BCR (mIg): VH, VL----Ag binding site mature B cells: mIgM and mIgD. Function: specifically recognizes antigen. • Ig/Ig (CD79a/CD79b): heterodimer cytoplasmic domains contain ITAM. Function: transduce the signals that lead to B cell activation. 2. Co-receptors CD19/CD21/CD81complex CD21=CR2, C3dR, EB virus receptor CD19/CD21/CD81 interactions with complement associated with antigen play a role in antigen-induced B-cell activation. The role of the coreceptor in B cell activation 3. Co-stimulatory molecules (1)CD40 interacts with CD40L (Th cell) (2)CD80(B7.1), CD86(B7.2) Expressed on activated B cells and other APCs (3)ICAM-1 (CD54)、LFA-1(CD11α/CD18): mediate cellcell interaction and co-stimulation Other receptors CD20: function is unclear. It is suspected that it acts as a calcium channel in the cell membrane CD22:Inhibitory receptor with ITIM motif CD32 (FcγRII): Inhibitory receptor Cytokine receptors Complement Receptors Toll-like receptors MHC Content Development of B cells B cell surface markers B cell subsets Functions of B cells humoral immunity Subtype of B cells 1. Conventional B cells (B-2 cells) 2. B-1 cells (expression of CD5) B-2 cells : conventional B cells Recirculating follicular B cells : circulate between LN follicles and blood mIg: IgM, IgD Produce IgG after antigenic stimulation in the presence of T helper cells • B1 cells (CD5+): Many of the first B cells that appear during ontogeny express CD5, a marker originally found on T cells. (express mIgM, no mIgD). They respond well to TI-Ag and may also be involved in the Ag processing and presentation to T cells. Functions 1. produce anti-bacterial IgM against microorganisms; 2. produce polyreactive Ab components; the first line of defence clearance of denatured self 3. produce auto-Ab, thereby participating in the pathogenesis of some autoimmune diseases. Content Development of B cells B cell surface markers B cell subsets Functions of B cells humoral immunity Functions of B cells 1. Production of antibody Abs prevent microorganism from entry into cells and eliminate microorganisms by opsonization causing phagocytosis, complement activation and toxin neutralization. 2. Ag presentation to T cells 3. Immune regulation Secretion of cytokines (TNF, IFN, IL-12) →M, DC, NK, B cell. Co-stimulation of T cells→T cell proliferation. Phases of humoral immune responses Functions of antibodies ADCC Neutralization By Antiviral Antibodies Antibody-mediated opsonization and phagocytosis of microbes Downloaded from: StudentConsult (on 1 June 2006 04:16 PM) © 2005 Elsevier ADCC Complement activation Antigen presentation by B cells to T cells. Mechanisms of Ig heavy chain class switching Content Development of B cells B cell surface markers B cell subsets Functions of B cells humoral immunity 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. • TD‐Ag:T cell‐dependent • TI‐Ag: T cell‐independent The difference between TD-Ag and TI-Ag TD-Ag Most Ags in the nature mainly IgG Cell-mediated immune response Memory T and memory B cells TI-Ag Polysaccharides with repeated epitopes IgM no cell-mediated immunity, no memory requirement for Th cell help. B cell-mediated immune response B cell-mediated humoral immune response 1) Phases Antigen recognition phase proliferation and differentiation phase Effector phase 2) Types • B2→TD-Ag • B1→TI-Ag Phases of humoral immune responses Effector phase B cell-mediated immune Key response point Immune response of B cells to TD-Ag 1. B cells activated by Ag “First signal” a. BCR recognizes B cell epitopes b. Ig/Ig transfer signal c. coreceptors (CD21/CD19/CD81) Antigen receptor-mediated signal transduction in B cells Functional consequences of Ag-mediated B cell activation Key point B cell-mediated immune response 2. Th cell-mediated activation and differentiation of B cells Site: GC (germinal center) Further activation Th cells → CD40L “Second signal” cytokines (IL-2, IFN-γ, IL-4, IL-5, IL-6, IL-13, etc.). Formation of germinal center Affinity maturation Heavy chain class switching p. 292 Ch. 11 The interactions of Th cells and B cells in lymphoid tissues The anatomy of humoral immune responses B cell-mediated immune response Mechanisms of Th cell-mediated activation of B cells The edge of lymphoid follicle Downloaded from: StudentConsult (on 1 June 2006 03:50 PM) © 2005 Elsevier Key point 2. Th cell-mediated activation and differentiation of B cells Site: GC (germinal center) Fully activation Th cells → CD40L “Second signal” cytokines Formation of germinal center Affinity maturation point mutations in the V regions Heavy chain class switching different Ab heavy chain classes Germinal center Function: to generate B cells that produce antibodies with affinity maturation Germinal Center Reaction: Activated B cells give rise to Centroblasts (中心母细胞) - localize in follicle, undergo rapid cell division and turn on machinery that causes somatic mutation in V-regions Centroblasts give rise to Centrocytes (生发中心细胞) - migrate to the FDC-rich region of the Germinal Center - survival is dependent on interaction with FDC-bound Ag and presentation of Ag to Tfh cells - centrocytes that successfully compete to bind antigen (e.g. by having higher affinity BCR) and to receive Tfh cell help are selected and may differentiate into long-lived plasma cells or memory B cells Germinal center p. 294 Ch. 11 Key point 2. Th cell-mediated activation and differentiation of B cells Site: GC (germinal center) Fully activation Th cells → CD40L “Second signal” cytokines Formation of germinal center Affinity maturation point mutations in the V regions Heavy chain class switching different Ab heavy chain classes The anatomy of humoral immune responses 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. Affinity maturation in antibody responses p. 294 Ch. 11 Key point B cell-mediated immune response 2. Th cell-mediated activation and differentiation of B cells Site: GC (germinal center) Fully activation Th cells → CD40L cytokines “Second signal” Formation of germinal center Affinity maturation Heavy chain class switching is initiated by CD40L-mediated signals, and switching to different classes is stimulated by different cytokines Isotype Switching Involves Recombination Between Specific Switch Signals p. 296 Ch. 11 Effector phases of humoral immune responses Effector phase Key point B cell-mediated immune response 3. 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 response 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 B cell-mediated immune response Immune response of B cells to TI-Ag No Th help, Memory? no memory, early effect, IgM * TI-1 (B cell mitogen) activate B cells * TI-2 activate mature B cells directly the repeated epitopes combine with BCR→ BCR cross-linking→produce IgM B cell-mediated immune response (A) TI-1 Ag (B) TI-2 Ag The mechanism of TI-Ag activating B1 cells B cell-mediated immune response General concepts B cell activation: TD-Ag recoginition---First signal Th cell-mediated activation---Second signal Affinity maturation Heavy chain class switching General features of Ab responses in vivo Movies for immune response The Immune Response: http://highered.mcgrawhill.com/sites/0072507470/student_view0/chapter22/animation__the_i mmune_response.html Thank you!