医学免疫学课件：B cells and humoral immunity 2014

1、IMMUNOLOGY,B cell and humoral immunity,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 a

2、n 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 antigen-presenting cells (APCs) and eventually develop into memory B cells after activation by an

3、tigen 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 cells distribute in blood, lymphoid organs (lymph node, spleen, tonsil etc.) and mucosa. About 5

4、-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

5、) or memory B cells in the germinal centre.,B Lymphocytes (B cells),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 mi

6、gration 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

7、,1. B cell development dependent on BM stromal cells 2. Transcription factors important for B lineage development 3. B cell development stages characterized by stagespecific surface markers 4. B cell development is coupled with rearrangement of heavy chain and light chain 5. The role of Ig Heavy Cha

8、in and preBCR 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 V

9、LA-4 SCF: interact with Kit,2. B cell development is coupled with stagespecific 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（5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

10、 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

11、 exonuclease, DNA synthetas, DNA ligase.,B lineage commitment,The results of gene rearrangement,Allelic exclusion Isotype exclusion,Gene rearrangement of BCR Junctional diversity Somatic Hypermutation Affinity maturation in antibody responses,The diversity of BCR,Gene rearrangement of TCR and BCR,Ju

12、nctional 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

13、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.

14、Function: transduce the signals that lead to B cell activation.,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.,2. Co-receptors,The role of the coreceptor in B cell activatio

15、n,(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（CD11/CD18)： mediate cell-cell interaction and co-stimulation,3. Co-stimulatory molecules,Other receptors,CD20: function is unclear. It is suspected that it acts as

16、a calcium channel in the cell membrane CD22：Inhibitory receptor with ITIM motif CD32 (FcRII)： 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 ce

17、lls,Conventional B cells (B-2 cells) 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

18、 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 the first line of defence against microorganism

19、s; 2. produce polyreactive Ab clearance of denatured self components; 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. Producti

20、on 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-stimulat

21、ion of T cellsT cell proliferation.,Phases of humoral immune responses,Functions of antibodies,ADCC,Neutralization By Antiviral Antibodies,Downloaded from: StudentConsult (on 1 June 2006 04:16 PM), 2005 Elsevier,Antibody-mediated opsonization and phagocytosis of microbes,ADCC,Complement activation,A

22、ntigen 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 cellmediated humoralimmune response,Humoral immunity is mediated by antibodies and is the arm of the ad

23、aptive 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. TDAg：T celldependent TIAg： T cellindependent,TD-Ag Most Ags in th

24、e 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.,The difference between TD-Ag and TI-Ag,B cell-mediated humoral immune response,1) Phases Antigen recogniti

25、on phase proliferation and differentiation phase Effector phase 2) Types B2TD-Ag B1TI-Ag,B cell-mediated immune response,Phases of humoral immune responses,Effector phase,“First signal” a. BCR recognizes B cell epitopes b. Ig/Ig transfer signal c. coreceptors (CD21/CD19/CD81),Key point,1. B cells ac

26、tivated by Ag,Immune response of B cells to TD-Ag,B cell-mediated immune response,Antigen receptor-mediated signal transduction in B cells,Functional consequences of Ag-mediated B cell activation,2. Th cell-mediated activation and differentiation of B cells,Further activation Th cells CD40L cytokine

27、s (IL-2, IFN-, IL-4, IL-5, IL-6, IL-13, etc.). Formation of germinal center Affinity maturation Heavy chain class switching,Key point,“Second signal”,Site: GC (germinal center),B cell-mediated immune response,Ch. 11,p. 292,The interactions of Th cells and B cells in lymphoid tissues,The anatomy of h

28、umoral immune responses,Downloaded from: StudentConsult (on 1 June 2006 03:50 PM), 2005 Elsevier,Mechanisms of Th cell-mediated activation of B cells,B cell-mediated immune response,The edge of lymphoid follicle,Fully activation Th cells CD40L cytokines Formation of germinal center Affinity maturati

29、on point mutations in the V regions Heavy chain class switching different Ab heavy chain classes,Key point,“Second signal”,Site: GC (germinal center),2. Th cell-mediated activation and differentiation of B cells,Germinal center,Function: to generate B cells that produce antibodies with affinity matu

30、ration 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 Cen

31、ter - 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

32、,Germinal center,Ch. 11,p. 294,Fully activation Th cells CD40L cytokines Formation of germinal center Affinity maturation point mutations in the V regions Heavy chain class switching different Ab heavy chain classes,Key point,“Second signal”,Site: GC (germinal center),2. Th cell-mediated activation

33、and differentiation of B cells,The anatomy of humoral immune 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,

34、 and particularly in the Ag-binding HVR, of the Abs produced. Affinity maturation occurs in the germinal centers of lymphoid follicles.,Affinity maturation in Ab responses,Affinity maturation in antibody responses,Ch. 11,p. 294,Fully activation Th cells CD40L cytokines Formation of germinal center A

35、ffinity maturation Heavy chain class switching is initiated by CD40L-mediated signals, and switching to different classes is stimulated by different cytokines,Key point,“Second signal”,Site: GC (germinal center),2. Th cell-mediated activation and differentiation of B cells,B cell-mediated immune response,Isotype Switching Involves Recombination Between Specific Switch Signals,Ch. 11,p. 296,Effector phases of humoral immune responses,Effector phase,3. General features of Ab responses in vivo,Key point,Primary immune response- longer latent