浙江大学医学免疫学经典课件免疫9、13-B细胞.ppt
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1、Lie Wang (汪洌),浙江省杭州市浙江大学紫金港校区 医学院科研楼A810-814 医学院免疫学研究所,B lymphocytes and Humoral Immune Response,The discovery of B cell immunity,1954 - Bruce Glick, Ohio State University Studies on the function of the bursa of Fabricius, a lymphoid organ in the cloacal region of the chicken,Bursa was later found t
2、o be the organ in which antibody producing cells developed antibody producing cells were thereafter called B cells Mammals do not have a bursa of Fabricius,Origin of B cells and organ of B cell maturation,After birth, development continues in the bone marrow,B cell development starts in the foetal l
3、iver,B cell development in the bone marrow,Bone Marrow provides a MATURATION & DIFFERENTIATION MICROENVIRONMENT for B cell development,Bone marrow stromal cells nurture developing B cells,Types of cytokines and cell-cell contacts needed at each stage of differentiation are different,Bone marrow stro
4、mal cell,Maturing B cells,B,B,Stromal cell,B lineage commitment,HSC (hematopoietic stem cell) MPP (淋巴系髓系多能前体细胞) ELP (earliest lymphocyte progenitor) ETP (early T-lineage progenitor) CLP (common lymphoid progenitor),HSC,Development and migration of B cells (An overview),Stages of differentiation in t
5、he bone marrow are defined by Ig gene rearrangement,B CELL STAGE IgH GENE CONFIGURATION,Stem cell,Early pro-B,Late pro-B,Large pre-B,Germline,DH to JH,VH to DHJH,VHDHJH,Ig light chain gene has not yet rearranged,B cell receptor,Transiently expressed when VHDHJH CHm is productively rearranged,Pre-,B
6、cell development is coupled with rearrangement of heavy-chain,B cell development is coupled with rearrangement of heavy-chain,B cell development is coupled with rearrangement of heavy-chain,B cell development is coupled with rearrangement of heavy-chain,B cell development is coupled with rearrangeme
7、nt of heavy-chain,B cell development is coupled with rearrangement of heavy-chain,Splicing of IgM and IgD RNA,Two types of mRNA can be made simultaneously in the cell by differential usage of alternative polyadenylation sites and splicing of the RNA,B cell development is coupled with rearrangement o
8、f heavy-chain,6000 heavy chains combined with 320 light chains 1.9X106 Abs,Ligation of the pre-B cell receptor,1. Ensures only one specificty of Ab expressed per cell,2. Triggers entry into cell cycle,ALLELIC EXCLUSION Expression of a gene on one chromosome prevents expression of the allele on the s
9、econd chromosome,1. Suppresses further H chain rearrangement,2. Expands only the pre-B cells with in frame VHDHJH joins,Evidence for allelic exclusion,Allotypes can be identified by staining B cell surface Ig with antibodies,AND,ALLOTYPE- polymorphism in the C region of Ig one allotype inherited fro
10、m each parent,Suppression of H chain rearrangement by pre-B cell receptor prevents expression of two specificities of antibody per cell (Refer back to Dreyer & Bennet hypothesis in Molecular Genetics of Immunoglobulins lecture topic),Suppression of H chain gene rearrangement ensures only one specifi
11、city of Ab expressed per cell.,Allelic exclusion prevents unwanted responses,One Ag receptor per cell,IF there were two Ag receptors per cell,Prevents induction of unwanted responses by pathogens,Allelic exclusion is needed for efficient clonal selection,All daughter cells must express the same Ig s
12、pecificity otherwise the efficiency of the response would be compromised,Suppression of H chain gene rearrangement helps prevent the emergence of new daughter specificities during proliferation after clonal selection,Antibody,Allelic exclusion is needed to prevent holes in the repertoire,Exclusion o
13、f anti-brain B cells i.e. self tolerance,Anti-brain Ig AND anti-S. aureus Ig,Anti-brain Ig,anti S.aureus B cells will be excluded leaving a “hole in the repertoire”,BUT,1. Suppresses further H chain rearrangement,Ligation of the pre-B cell receptor,1. Ensures only one specificity of Ab expressed per
14、 cell,2. Triggers entry into cell cycle,2. Expands only the pre-B cells with in frame VHDHJH joins,Ligation of the pre-B cell receptor triggers entry into the cell cycle,Many large pre-B cells with identical pre-B receptors,Small pre-B cell No antigen receptor at cell surface Unable to sense Ag envi
15、ronment !May be self-reactive!,Immature B cell Cell surface Ig expressed Able to sense Ag environment Can now be checked for self-reactivity,Acquisition of antigen specificity creates a need to check for recognition of self antigens,Physical removal from the repertoire DELETION Paralysis of function
16、 ANERGY Alteration of specificity RECEPTOR EDITING,B cell self tolerance: clonal deletion,Immature B cell recognises MULTIVALENT self Ag,Clonal deletion by apoptosis,Y,B cell self tolerance: anergy,Y,Y,Y,Anergic B cell,IgD normal IgM low,Immature B cell recognises soluble self Ag No cross-linking,Ig
17、M,IgD,IgD,IgD,Receptor editing,A rearrangement encoding a self specific receptor can be replaced,V,V,V,V,V,V,V,Y,Y,Y,Y,Y,Y,Mature B cell exported to the periphery,Y,Y,B cell self tolerance: export of self tolerant B cells,Immature B cell doesnt recognise any self Ag,B-cell surface markers,1. BCR com
18、plex,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.,Antigen receptor-mediated signal transduction in B cells
19、,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 activation,(1)CD40 interacts with CD40L (Th cell) (2)CD80(B7.1), CD86(B7
20、.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,CD20: function is unclear. It is suspected that it acts as a calcium channel in the cell membrane CD22:Inhibitory receptor with ITIM motif
21、 CD32 (FcRII): Inhibitory receptor Cytokine receptors Complement Receptors Toll-like receptors MHC,4. Other receptors,3. Subtype of B cells,Conventional B cells (B-2 cells) B-1 cells (expression of CD5),Two B cell lineages,B2 B cells,IgM - no other isotypes,B1 B cells Primitive B cells found in pleu
22、ra and peritoneum,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
23、 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 microorganisms; 2. produce polyreactive Ab clearance of denatu
24、red self components; 3. produce auto-Ab, thereby participating in the pathogenesis of some autoimmune diseases.,Comparison of B-1 and B-2 B cell properties,Property B-1 cells B-2 cells N regions Few Extensive V region repertoire Restricted Diverse Location Peritoneum/pleura Everywhere Renewal Self r
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