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BCR(membrane type) and secretory type Ig

B cells I. Differentiation of B cells in Bone marrow II. BCR and B cell accessory molecules III. The subsets of B cells. I. Differentiation of B cells in Bone marrow 1. process of B cell maturation 2. events in the differentiation of B cells 3. mechanisms of Ig diversity.

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BCR(membrane type) and secretory type Ig

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  1. B cellsI. Differentiation of B cells in Bone marrowII. BCR and B cell accessory moleculesIII. The subsets of B cells

  2. I. Differentiation of B cells in Bone marrow1. process of B cell maturation2. events in the differentiation of B cells3. mechanisms of Ig diversity

  3. I. Differentiation of B cells in Bone marrow1.Process pro-B cell chain pre-B cellsurrogate light chain +  chain immature B cell κ chain or λ chain +  chain (membrane IgM,mIgM) mature B cellmIgM, mIgD

  4. 2. Events in the differentiation of B cells1) Negative selectionimmature B cells : mIgM--self antigen mIgM self antigen apoptosis or anergy surviving to develop mature B cells2) gene rearrangement

  5. It is estimated that in the mouse the bone marrow produces about 5x107 B cells/day but only 5x106 (or about 10%) are actually recruited into the recirculating B-cell pool. This means that 90% of the B cells produced each day die without ever leaving the bone marrow. negative selection Immature B cells that express auto-antibodies against self-antigens are eliminated in the bone marrow.

  6. 2) gene rearrangement(1) germline gene structure of Ig(2)rearrangement of Iggenes (3) characteristics of Ig gene rearrangement

  7. (1)   Germ-line gene structure of BCRH chain: chromosome 14 V region encoding genes: VH (variable gene segments), DH (diversity gene segments), JH (joining gene segments) C region encoding genes:CH (constant gene segments): Cμ , Cδ, Cγ et al. (9)

  8. L chain(-- chromosome 2, -- chromosome 22) V region encoding genes: --V, J -- V, J C region encoding genes: C (1); C(4)

  9. In heavy chains, the V, D and J segments encode the variable domain while the C segment encodes the constant domain. In light chains, the V and J segments encode the variable domain while the C segment encodes the constant domain.

  10. (2) Gene rearrangement of BCRVDJ rearrangement of H chain pro-B cells: D-J V-DJ VDJ DNA transcription pre-B cells: VDJCμ VDJ- Cμ RNAmRNA splicingV-J rearrangement of L chainpre-B cells: V-J VJ DNA immature B cells: VJCVJ-CRNAmRNA

  11. BCR(membrane type) and secretory type Ig

  12. (3) Characteristics of BCR gene rearrangementAllelic exclusion: only one of the two alleles in homologous chromosomes can be expressed.isotypic exclusion:only one of the two types of light chain genes can be expressed.

  13. Allelic exclusion Kuby Figure 5-10 Read Kuby pages 115-117: Allelic Exclusion Ensures a Single Antigenic Specificity

  14. 3. mechanisms of diversity of Ig (BCRor Ab)1). Mutiple germline gene segments2). Combinatorial V(D)J joining3). Junctional flexibility 4). combinatorial assocination of heavy and light chain 5). somatic hypermutation

  15. 1). Mutiple germline gene segmentsThere Are Numerous Germ-Line V, D, and J Gene Segments.

  16. 2). combinatorial V(D)J joining The multiple germ-line gene segments are combined randomly during the rearrangement of BCR genes. human Ig:51VH×27DH ×6JH= 8262 possible combinations

  17. 3). Junctional flexibilityimprecise joiningIn the junction of V-J, V-DJ or D-J, several nucleotides are lost to increase the diversity of the V region encoding gene of L chain or H chain.N-nucleotides addition During the D-J and V to D-J joining process, several nucleotides are inserted to increase the diversity of V region encoding gene of H chain. N-nucleotides insert by TdT(terminal deoxynucleotidyl transferase) without template There is no N-nucleotides insert in L chain.

  18. 4). Combinatorial association of heavy and light chains 5).Somatic hypermutationSomatic hypermutation occurs at a frequency approaching 10-3 per base pair per generation. This rate is at least a hundred thousand-fold higher (hence the name hypermutation) than the spontaneous mutation rate, about 10-8 /bp/generation, in other genes.Somatic hypermutation adds diversityin already-rearranged gene segments

  19. Somatic hypermutation Ag activated B cell proliferate gene mutation in V region encoding genes affinity maturation

  20. II. BCR and accessory molecules of B lymphocytes B cell receptor complex B cell accessory molecules

  21. 1.BCR complexa group of membrane molecules on B cells that can specifically bind to the antigen and pass an activation signal into B cells, consisting of BCR and Ig-Ig  heterodimerBCRmembrane immunoglobulin on B cell, mIg:IgM, IgDIg-Ig , (CD79)ITAMtransduce an activation signal

  22. ITAMAn immunoreceptor tyrosine-based activation motif (ITAM) is a conserved sequence of amino acids (YXX(L/V)X7-11YXX(L/V)) in the cytoplasmic tails of certain cell surface proteins of the immune system. The tyrosine residues within these motifs become phosphorylated following interaction of the receptor molecules with their ligands and transduce an activation signal.ITIMAn immunoreceptor tyrosine-based inhibition motif (ITIM), is a conserved sequence of amino acids (S/I/V/LxYxxI/V/L) in the cytoplasmic tails of many inhibitory receptors of the immune system. After ITIM-possessing inhibitory receptors interact with their ligand, their ITIM motif becomes phosphorylated and tranduce an inhibitory signal.

  23. 2. Co-receptors complex 1) CD19, CD21, CD81, • CD19: • CD21(CR2): receptor of iC3b and C3d

  24. 3.CD40 ---co-stimulatory receptor CD40 on B cell binds to CD40L on activated T cell---pass a costimulatory signal into B cells 4. B7 5. CD45 6. MHC molecules 7. Mitogen receptors 8. Cytokine receptors

  25. B7(CD80,CD86) ------co-stimulator to T cells ligand of CD28

  26. 3.CD40 ---co-stimulatory receptor CD40 on B cell binds to CD40L on activated T cell---pass a costimulatory signal into B cells 4. B7 5. CD45 The cytoplasmic domain of CD45 has an intrinsic phosphatase activity that removes an inhibitory phosphate group on a tyrosine kinase called Lck (in T cells) or Lyn/Fyn/Lck (in B cells) and activates it. 6. MHC molecules 7. Mitogen receptors 8. Cytokine receptors

  27. 6. MHC moleculesMHC-I and MHC-Ⅱ 7. Mitogen receptors Receptors of mitogen:SPA,PWM (pokeweed), LPS8. Cytokine receptors

  28. III. Subset of B cell --------------------------------------------------------------------- Comparison of B1 and B2 cells ------------------------------------------------------------------------------------ B1 B2 CD5 + - location thorax, abdominal cavity lymph organs lamina propria of intestine Recognized Ag TI Ag and auto-Ag TD Ag --------------------------------------------------------------------------------

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