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TODAY

TODAY. B CELL DEVELOPMENT. STAGES OF B CELL DEVELOPMENT. 1. B Cells develop from pluripotent stem cells in the bone marrow. 1. 2. The stem cell develops into a mature IgM+ B cell. 2. GENERATIVE LYMPHOID ORGANS. PERIPHERAL LYMPHOID ORGANS.

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TODAY

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  1. TODAY B CELL DEVELOPMENT

  2. STAGES OF B CELL DEVELOPMENT 1. B Cells develop from pluripotent stem cells in the bone marrow. 1 2. The stem cell develops into a mature IgM+ B cell. 2 GENERATIVE LYMPHOID ORGANS PERIPHERAL LYMPHOID ORGANS

  3. B Lymphocytes are predicted to generate approximately 1 X 1011 distinct antigen receptors. However, the human genome only contains about 35,000 distinct genes. How does such a limited genome enable the generation of an almost infinite number of antigen receptors?

  4. Answer: Diversity is generated through somatic recombination of gene segments that code for the variable regions of the receptors.

  5. Exon 1 Promoter Exon 2 Genomic DNA Transcription Primary Transcript Splicing mRNA Translation Protein Going from DNA (gene) to protein: the usual way.

  6. The Light chain loci displays a similar organization to the Heavy chain locus, except that it lacks any D gene segments. There are two light chain loci - k and l. THE GERMLINE ORGANIZATION OF ANTIGEN RECEPTOR GENE LOCI. The Ig Heavy chain locus contains up to a few hundred variable (V) region genes. The variable region gene segments are followed by diversity (D) and joining (J) gene segments.

  7. 1. V, D and J gene segments are arranged in tandem. 2. In a single lymphocyte clone, one D gene segment randomly recombines with one J gene segment. 3. A V gene segment then recombines with the D-J segment, generating a recombined V-D-J gene. 4. The new gene is then transcribed. 5. The V-D-J gene segment is spliced to the first C region RNA (m Chain) 6. The resulting mRNA is translated to generate a unique IgM heavy chain. GENERATING DIVERSITY BY V(D)J SOMATIC RECOMBINATION

  8. V D J constant V D J constant VDJ recombination #1 VDJ recombination #2 variable constant variable constant VARIABLE REGION 1. Each recombination generates a unique variable region - unique antigen specificity. 2. In contrast, the constant region does not change - conserved effector function.

  9. SOURCES OF DIVERSITY

  10. STAGES OF B CELL DEVELOPMENT 1. B Cells develop from pluripotent stem cells in the bone marrow. 1 2. The stem cell develops into a mature IgM+ B cell. 2 3 3. The mature, naïve B cells circulates through the peripheral lymphoid organs. GENERATIVE LYMPHOID ORGANS PERIPHERAL LYMPHOID ORGANS

  11. STAGES OF B CELL DEVELOPMENT 1. B Cells develop from pluripotent stem cells in the bone marrow. 1 2. The stem cell develops into a mature IgM+ B cell. 2 3 3. The mature, naïve B cells circulates through the peripheral lymphoid organs. 4 4. B cells that fail to encounter antigen die through apoptosis. GENERATIVE LYMPHOID ORGANS PERIPHERAL LYMPHOID ORGANS

  12. STAGES OF B CELL DEVELOPMENT 5 5. B cells that encounter antigen are activated. PERIPHERAL LYMPHOID ORGANS

  13. STAGES OF B CELL ACTIVATION 1. Naïve B cell encounters antigen. 2. Helper T cells stimulate B cells.

  14. PRESENTATION OF ANTIGENS TO T HELPER CELLS BY B CELLS 1. The naïve B cell receptor binds its cognate antigen. 2. The receptor triggers endocytosis of the antigen. 3. Antigen is processed and presented on a Class II MHC molecules. (B cell acts as classical APC) 4. B cell stimulates T cell activation.

  15. HELPER T CELL ACTIVATION OF B CELLS 1. B Cells process and present antigens to helper T cells. 3. The combination of CD40 (physical contact) and cytokines activates B cells. 2. T cells commence production of molecules that activate B cells (CD40, cytokines). 4. T helper cell signals induce B cell activation (proliferation and differentiation).

  16. STAGES OF B CELL ACTIVATION 1. Naïve B cell encounters antigen. 2. Helper T cells stimulate B cells. 3. Activated B cells begin clonal expansion.

  17. CLONAL EXPANSION Each B and T cell encodes a unique BCR or TCR with a unique specificity. When a BCR or TCR encounters its cognate antigen the B cell or T cell is stimulated to undergo multiple rounds of cell division, thereby expanding. Each daughter is identical to the parent cell, i.e. a clone.

  18. STAGES OF B CELL ACTIVATION 1. Naïve B cell encounters antigen. 2. Helper T cells stimulate B cells. 3. Activated B cells begin clonal expansion. 4. Some B cells differentiate into antibody secreting plasma cells.

  19. STAGES OF B CELL ACTIVATION 1. Naïve B cell encounters antigen. 2. Helper T cells stimulate B cells. 3. Activated B cells begin clonal expansion. 4. Some B cells differentiate into antibody secreting plasma cells. 5. Others become memory cells.

  20. MEMORY LYMPHOCYTES Some active lymphocytes differentiate into memory lymphocytes. Memory Lymphocyte Active Lymphocyte MEMORY LYMPHOCYTES: Produced from naïve lymphocytes as a result of antigen exposure. Persist for years in a quiescent state. Rapidly reactivated by repeat exposure to antigen and mediate faster, more potent immune responses.

  21. Secondary Versus Primary Antibody Responses. FASTER STRONGER MORE SPECIFIC THE SECONDARY RESPONSE IS…….

  22. STAGES OF B CELL ACTIVATION 1. Naïve B cell encounters antigen. 2. Helper T cells stimulate B cells. 3. Activated B cells begin clonal expansion. 4. Some B cells differentiate into antibody secreting plasma cells. 6. Others switch class to produce a new Ig Isotype. 5. Others become memory cells.

  23. CLASS SWITCHING All mature B cells start out making IgM m d g a e V IgM mRNA IgM A clone of B cells is not committed to make a single Ig isotype forever.

  24. CLASS SWITCHING m d g a e V g a e V B cell activation triggers rearrangements at the Ig locus d m Exposed DNA ends are joined together DNA encoding some constant regions is deleted IgG End result: New class of Ig A clone of B cells is not committed to make a single Ig isotype forever.

  25. CLASS SWITCHING - AFFINITY UNCHANGED Class switching does not affect the variable region. A clone of B cells is not committed to make a single Ig isotype forever. m d g a e V g a e V IgM mRNA IgG mRNA IgG IgM The Antibody retains Antigen specificity throughout.

  26. CLASS SWITCHING Ag BCR 1. Mature B lymphocyte express IgM as BCR Ag BCR IgM Ag IgG BCR Class switching explains why IgM is not seen upon re-exposure to antigen. 2. Lymphocyte is activated by antigen and starts to secrete IgM 3. Activation induces class switching, so that repeat exposures induce IgG, IgA or IgE.

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