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B-Cell Generation, Activation, and Differentiation

B-Cell Generation, Activation, and Differentiation. B-Cell Maturation B-Cell Activation and Proliferation The Humoral Response In Vivo Sites for Induction of Humoral Responses Germinal Centers and Antigen-Induced B-Cell Differentiation Regulation of the Immune Effector Response.

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B-Cell Generation, Activation, and Differentiation

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  1. B-Cell Generation, Activation, and Differentiation B-Cell Maturation B-Cell Activation and Proliferation The Humoral Response In Vivo Sites for Induction of Humoral Responses Germinal Centers and Antigen-Induced B-Cell Differentiation Regulation of the Immune Effector Response

  2. Naïve B cells are short-lived Class switch Affinity maturation Ab 10% Chap. 11 Chap. 11 Chap. 5 Chap. 11

  3. Committed Lymphocyte Progenitor Adhesion molecules

  4. Progenitor B cells Proliferative signal

  5. Precursor B cells Proliferation and development

  6. Rearrangement of Immunoglobulin Genes during B cell Development

  7. The pre-B cell receptor complex: Membrane heavy chain  associates with surrogate light chain (Vpre-B and a C-like sequence, 5). This associates with the Ig-/Ig- heterodimer. Signaling complex

  8. Fig. 5-17

  9. B-1 B cells • “Innate-like” subset of B cells. • Appear during fetal life and express IgM but little IgD and display CD5. Are also found in peritoneum. • Originates from stem cell in bone marrow, but also from proliferation of B-1 cells outside the BM. • Responds poorly to protein antigen, but strongly to carbohydrate antigens. • Antibodies produced are of low affinity.

  10. Self-reactive B cells are eliminated in bone marrow (BM). • BM produces 5 x 107 B cells/day, but only 5 x 106 B cells/day or 10% actually enter the circulation. • Some of this loss is due to negative selection and elimination or clonal deletion of immature B cells expressing autoantibodies to self-antigens.

  11. Experiment by D.A. Nemazee and K. Burki (1989) demonstrated negative selection of B cells DNA encoding IgM specific for H-2Kk, a class I MHC molecule Mice were H-2d or H-2d/k

  12. Endogenous H-2k and H-2d class I MHC molecules are present on bone marrow stromal cells of transgenic mice. • Transgenic B cells will express anti-MHC Kk IgM antibodies.

  13. Total IgM anti-Kk IgM ** ** 61.6% of IgM antibody Membrane IgM

  14. “There is negative selection against any immature B cell expressing auto-antibodies on their membranes because these antibodies react with self-antigens present on stromal cells, leading to crosslinking and death of the B immature B cells.”

  15. Tiegs and Nemazee (1993) demonstrated that self-reactive B cells can be rescued by expressing an “edited” light-chain gene. • Found that a few mature B cells in the H-2d/k transgenic mouse expressed the transgene encoded  chain but a different light chain. B cell maturation is arrested

  16. B cell activation • Depending on antigen, B-cell activation proceeds by two different routes. • Thymus-dependent (TD) antigens require direct contact with TH cells to activate B cells. • Thymus-independent (TI) antigens can activate B-cells in the absence of TH cells.

  17. Thymus independent (TI) antigens are divided into two types, 1 and 2, and activate B cells by different mechanisms • Most TI-1 antigens are polyclonal B-cell activators, or mitogens, for example, LPS. • TI-2 antigens work by crosslinking the mIg receptor. • TI-2 are different from TI-1 in three ways. • Are not B-cell mitogens. • Activate only mature B cells and inactivate immature B cells. • Cytokines from TH cells are required for proliferation and class switching.

  18. Progression Competence Signals G0

  19. Transition of lymphocytes from G0 into S (cell cycle), requires two steps - competence and progression. Competence requires signal 1 and signal 2. Progression requires interaction with cytokines and other ligands with receptors on the B cell membrane Competence Signals Signal 1 Signal 2

  20. Signal 1 => Antigen binding the B cell receptor (BCR) associated with Ig/Ig heterodimer. Signal 2 => Interaction between CD40 on the B cell and CD40L on the activated helper T cell.

  21. Lyn BCR

  22. Lyn BCR

  23. Similar to T cell receptor signaling

  24. 4 2 1 5 3 • Compartmentalization. • Activation by receptor-mediated PTKs. • Assembly of signaling complex. • Recruitment of other signaling pathways. • Changes in gene expression. 7 8 9

  25. CD22 (resting B cells) delivers a negative signal. Amplification

  26. Effects of co-receptors on BCR signals. • Without coreceptors, more molecules of IgM need to be engaged for B-cell activation. • Mice immunized with a C3d-antigen fusion protein developed a stronger immune response. • CD19 knockout mice had greatly diminished responses to most antigens.

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