Lecture 1 Week 3: B Cells

Lecture 1 Week 3: B Cells

1. Lymphocytes

   • Highly diverse antigen receptors (immune repertoire)
   • Diversity is achieved by rearrangement of the genes coding for the BCR

2. Variable and constant regions

   • Heavy chain
     • Variable region comprised of the protein segments encoded by variable, diversity and joining genes
   • Light Chain
     • Variable region comprised of variable and joining gene products

3. Recombination is driven by RAG up-regulation

   • Recombination of Ig genes is controlled by the recombination-activating genes, RAG-1 and RAG-2
   • RAG enzymes catalyze the formation of stem-and-loop structures in the Ig DNA that brings together distant exons
   • Enzymes cleave off the loop, and the gap in the DNA is filled by nucleotides under the direction of terminal deoxyribonucleotidyl transferase
   • Random nucleotides can be added that are not encoded by germline DNA but contribute further to diversity of Ig

4. Steps in recombination

   • Synapsis: portions of the chromosome made available for recombination
   • Cleavage: Double-strand breaks generated
   • End processing: addition or removal of bases result in greater diversity generation (junctional diversity)
   • Joining: coding ends are brought together and ligated

5. Central tolerance

   • Immature B cells in bone marrow express IgM
   • Cells with BCRs that bind self antigens with high affinity can be
     • Deleted by induction of apoptosis (clonal deletion)
     • Induced to enter state of anergy
     • Replace the light chain (receptor editing)

6. BCR cross-linking and signalling

   • Cross-linking mediates phosphorylation by Src kinases of tyrosine motifs of Iga Beta
   • Provides a docking site for tyrosine kinase Syk, resulting in signalling cascades of
     • PLC gamma
     • PKC
     • ERK, JNK, MAP
   • Activation drives transcription of various genes important for promoting B cell survival

7. Role of complement in enhancing B cell response to antigen binding

   • Binding of antigen-bound C3d to the complement receptor CD21 (CR2) enhances weak Ig signalling effects
   • Phosphorylation of tyrosine resides on CD21 and CD19 activate signal transduction pathways

8. Result of B cell activation

   • Clonal expansion
   • Co-stimulation receptors: Primes for T cell help
   • Increased expression of cytokine receptors: primes for T cell help
   • Activation drives transcription of various genes important for promoting B cell survival

9. Production of secreted antibody by plasma cells

   • Cognate B and T cell activation (B cell presentation to T cells)
   • Activated B cell interacts with activated T cell

10. Cognate B cell-T cell activation

    • B cell internalises antigen combines with MHC Class II molecule
    • Presents antigen/MHC complex on surface
    • Interacts with activated T helper (CD4+)
    • Co-stimulatory signals required (Two hit)
    • Results in Ig isotype switch and Ig receptor affinity maturation

11. Affinity maturation: Refining the Ab response

    • During clonal expansion in germinal centres
    • Complementary determining regions (CDRs) have high rate of mutations
    • Results in B cell progeny displaying surface of Ig of varying affinity for the antigen

12. Affinity maturation

    • B cell activation - antigen binding and T helper interactions
    • Somatic mutation generates B Cells with Igs of varying affinity for antigen
    • B cells bind to follicular dendritic cells displaying antigen
    • High affinity Ig receptors promote B cell survival - increased affinity of Ig response over time

13. B memory cells provide a fast, high affinity secondary Ab response

    • B memory cells have class switched (i.e. IgG or IgE) surface Ig receptors of high affinity (i.e. somatic mutation)