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B-cell Development and Activation Chapter 5

B-cell Development and Activation Chapter 5. Self-Test Questions: Sections A, B & C: all (section D covered previously). A LPS a TI-type1 B-cell activator. What are the 2 phases of B-cell development? Antigen-Independent (Maturation) -- mostly in bone marrow

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B-cell Development and Activation Chapter 5

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  1. B-cell Development and Activation Chapter 5 Self-Test Questions: Sections A, B & C: all (section D covered previously) A LPS a TI-type1 B-cell activator

  2. What are the 2 phases of B-cell development? Antigen-Independent (Maturation) -- mostly in bone marrow vs Antigen-dependent (Activation) -- mainly in periphery Antigen-Independent (Maturation) 1) Pro-B stages -- B-cell markers 2) Pre B-stages -- H- an L- chain loci rearrangements 3) Immature B-cell -- functional BCR -- but… “Is it safe”?

  3. How are self-tolerant B-cell selected? Screening on bone marrow stromal cells “2nd chance” -- Receptor editing -- mainly LC -- alternative V segments Survival signals (<10%) or apoptosis

  4. What happens during T-cell dependent B-cell activation? “Td antigens” 1) Antigen crosslinking of antibodies -- antigen engagement -- Igα/Igβsignalling -- up-regulation of CD40 & MHC 2) TH cell engagement -- cell/cell interactions -- MHC presentation -- TCR recognition -- CD40/CD40L coupling 3) Cytokine stimulation -- IL4, IL2, etc. -- class switching to IgG -- memory cell formation Why so complicated?

  5. B-cell activation can occur without T-cell help • “T-independent” B-cell activation • Two types: • Ti type-1– e.g., LPS • -- many are mitogens; • -- bind to TLRs • --can activate polyclonally • without BCR engagement • -- some activate through • binding to BCR & TLR • Yield only… • Predominantly IgM, maybe some IgG • No memory cells • See Table 5-1

  6. T-independent activation cont. • Ti type-2– AGs have repetitive, polymeric structure • -- crosslink Abs • -- e.g. capsule polysaccharides • bacterial flagellin • Yield only… • IgM, maybe some IgG • -- high avidity • No memory cells- ?? • See Table 5-1 Some are important bacterial AGs, but pose problems for vaccine development -- infants do not respond well

  7. Revisiting the lymph node Development of 1O to 2O follicles With germinal centers What happens in GC? -- affinity maturation via “somatic hypermutation” -- memory cells produced -- class switching

  8. How does affinity maturation occur? Key role of AID -- Activation-Induced Cytidine Deaminase -- induced DNA repair Several rounds of selection -- long-lived B-cells 1000 X Increased AG affinity Bind or Die!

  9. How does class switching occur? Alternative RNA processing and . . . IgM and IgD Secreted IgM Gene splicing and switch to: IgG, IgE, and IgA Cytokines influence class switching

  10. The humoral 1O vs 2O responses • What are the key differences? • . . . in lag • . . . in magnitude • . . . in isotypes • How do properties of memory cells account for this? • In peripheral tissues • Other isotypes in BCR • Higher affinity Ab • Greater # of cells against AG • More rapid TH cell stimulation • More rapid class switch

  11. Fc Receptors and antibody effector functions What does “FcγRII” mean? Some example FcR mediated functions

  12. B-cell malignancies can involve different stages of B-cells Types of lymphocyte malignancies Myeloma Leukemia lymphoma Chronic vs acute Clinical Diagnosis 1) Microscopy 2) gel electrophoresis of serum proteins

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