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B cells

B cells. Harry W Schroeder Jr MD PhD Division of Developmental and Clinical Immunology Departments of Medicine, Microbiology, and Genetics University of Alabama at Birmingham. Genesis. B cells derive from hematopoietic stem cells Development initiates in bone marrow and fetal liver

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B cells

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  1. B cells Harry W Schroeder Jr MD PhD Division of Developmental and Clinical Immunology Departments of Medicine, Microbiology, and Genetics University of Alabama at Birmingham

  2. Genesis • B cells derive from hematopoietic stem cells • Development initiates in bone marrow and fetal liver • Developing B cells use gene rearrangement to construct their antigen receptor • Immunoglobulin rearrangement is hierarchical • H chains first • L chains second, k before l • Developmental checkpoints are used to test immunoglobulin function

  3. EarlyStages of B cell Development • Immunoglobulin rearrangement • Initial testing of the receptor • Positive selection • Associates with surrogate & conventional light chain • The BCR signals - low level self-reactivity • Negative Selection – unacceptable self-reactivity • Anergy • Elimination • Apoptosis, or • Rescue by Receptor Editing

  4. B cell Development (Human)

  5. Alternative Splicing Yields Secretory or Membrane Ig (BCR)

  6. IgM and IgD via Differential Splicing

  7. B cells in the Bone Marrow

  8. Early Checkpoints

  9. Signal transduction in B cells • Two "domains" • sIg • Iga/Igb • B-cell Receptor – binds antigen • Iga and Igb transduce the signal • Cytoplasmic tails contain immunoreceptor tyrosine-based activation motif (ITAM) • Activate tyrosine kinases (Src family)

  10. Survival in the Periphery • Until the B cell makes a contact with an antigen it can recognize, it must survive in the primary follicle • Follicles contain dendritic cells that release "survival" signals, such as BLyS • There is presumed to be competition between new B cells and naïve B cells for space in the follicle • The mature B cell has a limited time to find its antigen before it dies

  11. BLyS Family Ligands and Receptors Modified from Crowley et al, Semin Immunol 17, 193 (2005)

  12. Modulation of B cell signals • Activation • CD19, CD21, & TAPA-1Complex • CD19, a member of Ig superfamily • CD21 (CR2), a receptor for C3d • CD81 (TAPA-1), a transmembrane protein • ITAM Motifs • Inhibition • CD22 • FcgRII • ITIM Motifs

  13. Initial Activation

  14. Upregulation of B cell signals

  15. Downregulation of B cell signals

  16. Three Types of Mature B cells • B-1 cells • Self-renewing and preferentially produced in the fetus • Spontaneously produce polyreactive Igs • Express CD5, Mac-1 • Marginal Zone B cells • Found in the marginal zone of the spleen • “Pre-activated” • Respond quickly to antigens, e.g. polysaccharides • B-2 cells (‘Conventional’ B cells) • Preferentially produced after birth • Replaced in bone marrow • Typically respond to protein Ag, requiring T cell help

  17. Three Types of Mature B cells

  18. Late Stages of B cell Development • Exposure to antigen in the periphery • Activation • Class switching and somatic hypermutation • Selection for receptor specificity and affinity • Differentiation into plasma or memory B cells

  19. T-Independent Responses • Type 1 – Mitogens (LPS) • Type 2 – Polymeric (polysaccharides, bacterial flagellin)

  20. Rapid Activation of Marginal Zone B cells in Response toStrep. pneumoniae Lopes-Carvalho and Kearney, Immunol Rev197:192 (2004)

  21. T-Dependent Responses

  22. Somatic Hypermutation and Affinity Maturation • Occurs in response to antigen • Primarily occurs in the germinal center • Typically requires T cell help • Mutated antibodies subjected to competition • Increased affinity = Success • Affinity Maturation

  23. Deamination C  U

  24. Somatic Hypermutation

  25. Encounter with an Antigen

  26. Meet a Compatible Helper T cell

  27. Live Life in a Burst of Glory or Grow

  28. Antigen-Driven Differentiation

  29. Antigen-Driven Differentiation

  30. Ontogeny of Immunity

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