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Chapter 14 B Lymphocytes

Chapter 14 B Lymphocytes. Contents. B cell receptor and B cell complex B cell accessory molecules B cell subpopulations Functions of B cells B cell maturation BCR diversity and TCR diversity. I. B cell antigen receptor and B cell receptor complex. BCR BCR complex

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Chapter 14 B Lymphocytes

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  1. Chapter 14B Lymphocytes

  2. Contents • B cell receptor and B cell complex • B cell accessory molecules • B cell subpopulations • Functions of B cells • B cell maturation • BCR diversity and TCR diversity

  3. I.B cell antigen receptor and B cell receptor complex • BCR • BCR complex • Function: Recognize antigen

  4. 1. B cell receptor----BCR • Membrane immunoglobulin (mIg) on B cells: mIgM, mIgD • Recognize and bind antigen specifically

  5. 2. BCR complex • BCR and Ig - Ig  (heterodimer) Ig (CD79a) , Ig (CD79b) • Participate in BCR formation • ITAM------bind to tyrosine kinase • Transmit activating signal

  6. II. Accessory membrane molecules on B cells • CD19, CD21(CR2), CD81(TAPA-1) ----B cell co-receptor complex • CD21(CR2): receptor of C3dg,C3d and iC3b ----Enhance the binding of BCR and antigen ----Pass activating signal to CD19 ----EB virus receptor • CD19: Transmit activating signal into B cell

  7. 2. CD40----co-stimulatory receptor • CD40 on B cell binds to CD40L on activated T cell • Transmit an important co-stimulatory signal to B cells • Upregulate expression of B7 on B cells • Participate in class switching of antibody

  8. 3. Co-stimulatory molecule: B7 B7-1 (CD80) and B7-2 (CD86) Expressed on B cells or other APC B7-CD28: activation signal B7-CTLA-4: inhibitory signal 4. MHC molecules Class Ⅰ,Ⅱ MHC molecules

  9. 5. Mitogen receptor SPA, LPS PWM 6. Cytokine receptor IL-4R, IL-5R, IL-6R 7.Fc receptor(CD32---FcRII-b) ------Related to immunological regulation

  10. III. B cell subpopulations According to expression of CD5 or not • B1 cell (CD5+) • B2 cell (CD5-)

  11. Comparison of B1 and B2 cells B1 B2 Development early late BCR mIgM mIgM and mIgD CD5 + - Reproduction self-renewing from pre-B cell in BM Recognized Ag TI-Ag and auto-Ag TD-Ag Ab type IgM >IgG IgG >IgM Ab avidity low high Second IR - + Function innate immunity adaptive immunity

  12. IV. Functions of B cells • Produce the antibody----HI • Present antigen----APC • Participate in immunological regulation: secrete various cytokines, FcRII-b

  13. The comparison of main membrane molecules between T and B cells

  14. SectionⅡ Development and differentiation of B cells • Differentiation of B cells in Bone marrow • Differentiation of B cells in peripheral lymphoid tissue (B cell mediate immune response, HI)

  15. μ

  16. Differentiation of B cells in Bone marrow----Ag independent • Hematopoietic stem cells • Lymphoid progenitor • Pro-B cells( chain rearrangement) • Pre-B cell( chain+ surrogate light chain ) • Immature B(mIgM,  chain +κchain orλchain) • Mature B(mIgM, mIgD) • Functional B repertoire

  17. Negative selection of B cells inbone marrow

  18. 2. Differentiation of B cells in peripheral lymphoid tissue----Ag dependant • Virgin B/naïve B cell most die • Plasma cell Ab • Memory B cell secondary immune response

  19. 3.Events in the differentiation of B cells:Gene rearrangement of IgNegative selectionImmature B cells : mIgM--self antigen mIgM -- self antigen apoptosis or anergy surviving to develop mature B cells

  20. Questions? • Why can TCR or BCR recognize so many Ag in nature? • Why does IgM produce earlier than others? • How does Ig produce BCR and Ab? • How can B produce different type of Igs? • ---------------?

  21. PartⅢ BCR diversity and TCR diversity • BCR diversity • TCR diversity

  22. SectionⅠ BCR diversity • Gene structure of Ig • Gene rearrangement of Ig • Characteristics of Ig gene expression • Mechanism of Ig diversity

  23. 1. Germ line gene structure of Ig (human) H chain:14 chromosomeV region encoding genes:VH (variable gene segments) – 65 DH (diversity gene segments) – 27 JH (joining gene segments) – 6 Leader sequence—signal peptide C region encoding genes:CH (constant gene segments): Cμ, Cδ, Cγ et al.(11)

  24. L chain(--2 chromosome, --22 chromosome)V region encoding genes: --V, J– 40, 5 -- V, J– 30, 4Leader sequence—signal peptideC region encoding genes:C (1); C(4)

  25. 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.

  26. (a)  Chain (22 chromosome)) V JC JC JC JC (2 chromosome)

  27. 2. Gene rearrangement of IgV-D-J rearrangement of H chain pro-B cells: D-J V-DJ VDJ DNA pre-B cells: VDJCμ VDJ- Cμ RNAmRNA V-J rearrangement of L chainpre-B cells: V  -J  V  J  DNA immature B cells: V  J CV  J  -CRNAmRNA transcription splicing

  28. C C C3 C 1 C1 C2 C4 C C2 C C C3 C1 C1 C2 C4 C C2 C C C3 C1 C1 C2 C4 C C2 C C C C 

  29. The expression of BCRIntranuclear:DNA rearrangement: ------- V region encoding gene (VDJ or VJ) Transcription and splicing -------leader sequence + V region encoding gene + C region encoding gene (L gene-V gene –C gene)Extranuclear:Translation -------- nascent peptide L-V-CEndoplasmic reticulum:assembly--------H chain and L chain (IgM or IgD)transportation------BCR (membrane Ig, mIg)

  30. 3. Characteristics of Ig gene expression ① recombination enzyme: RAG (recombination activating gene) TdT (terminal deoxynucleotidyl transferase) other DNA enzymes

  31. ② Allelic exclusion and isotype exclusionAllelic exclusion:only one of the two alleles in homologous chromosomes can be expressed. Isotype exclusion:only one of the two types of light chain genes can be expressed(:=65:35).

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

  33. ③ Isotype switching ( class switching ) Ag activated B cells proliferate VDJ is switched to recombine with another C region encoding gene IgM IgD, IgG, IgA, IgESwitching region

  34. ④ Membrane type (BCR) and Secretory type Ig (Ab)

  35. 4. Mechanism of Ig diversity ① Combinatorial diversity human Ig: 65VH×27DH ×6JH=10530V 40V ×5J =200V 30V ×4J  =120V

  36. C C C3 C 1 C1 C2 C4 C C2 C C C3 C1 C1 C2 C4 C C2 C C C3 C1 C1 C2 C4 C C2 C C C C 

  37. ② Junctional diversity • CDR3 lies in V-DJ or D-J junctions • Lose or insert of several nucleotides will increase the diversity of CDR3. • N-nucleotides insert by TdT without template • There is no N-nucleotides insert in L chain

  38. ③ Somatic hypermutation Ag activated B cells proliferate gene mutation in V region encoding genes affinity maturationmature B cells which finished V gene rearrangement

  39. SectionⅡ Gene structure and rearrangement of TCR • Gene structure of TCRαβ α chain (14 chromosome): V, J, C β chain (7 chromosome): V, D, J, C

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