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B CELL DEVELOPMENT AND ACTIVATION • In healthy people, there are mature B cells with the capacity to make antibodies to virtually any antigen. • Bone marrow is the primary lymphoid organ in which B cell development occurs. • Bone marrow is the primary lymphoid organ in which B cell development occurs. • Following initial development in bone marrow, mature B cells migrate to various secondary lymphoid tissues, including lymph nodes, spleen, gut-associated lymphoid tissue and blood. • There, mature B cells can interact with antigen, become activated, and further differentiate into antibodysecreting cells • B and T cells undergo distinct differentiation pathways. • B cells are generated in the bone marrow, with mature B cells, which are ready to respond to antigen, then exiting and migrating to lymph nodes and spleen. • The development of B cells, starting from hematopoietic stem cells and ending with cells that produce antibodies, can be divided into four phases: Phase 1 – development of B cells in bone marrow • This first phase of B cell development is the generation of B cells in bone marrow. • There, stem cells develop into pro-B cells, then pre-B cells, and finally mature B cells, which exit the bone marrow and migrate to secondary lymphoid organs. • This phase of B cell development is not driven by contact with antigen: antigen independent. • The DNA rearrangements that result in a functional cellsurface immunoglobulin molecule occur during this phase. Phase 1 – development of B cells in bone marrow: _____________________________________ • Stem cells have both their H-chain and L-chain genes in germline, un-rearranged configuration • The earliest cell that has made the commitment to the B cell lineage is the pro-B cell: pro-B cells have begun to rearrange their H-chain gene. • Once a B lineage cell expresses cell surface H-chain (m) it is defined as a pre-B cell. • However, the early pre-B cell receptor is not the final form of surface immunoglobulin: H-chain + surrogate light chain (molecule that mimics L-chain) • Further DNA rearrangements result in the formation of a functional L-chain, then IgM (H-chain + L-chain) is expressed on the cell surface. • When a cell has productive rearrangements of both H- and Lchains) it becomes an immature B cell: • These surface IgM-positive cells are ready to leave the bone marrow, go to secondary lymphoid organs, and interact with antigen. • This first phase of B cell development in bone marrow is dependent on association with stromal cells. • Stromal cells are non-lymphoid cells that provide an appropriate microenvironment for B cell development. • Bone marrow stromal cells produce both cell surface-stimulatory molecules, as well as growth factors and cytokines, which help drive B cell development. • For a B cell to survive this phase of development, it must have productive rearrangements of both H-chain and L-chain. • Failure to do this results in cell death - cells that have unproductive rearrangements (such as rearrangements that are not in a correct reading frame) are eliminated. • A given B cell can undergo repeated rearrangements. • The rearrangements that result in functional H- and L-chains occur in a specific order: • Expression of a functional B cell receptor protein on the cell surface stops further rearrangement of the gene encoding that product: Phase 2 – elimination of self-reactive cells • Once B cells have reached the stage of immature B cells, they are able to interact with antigen – they express a functional cell surface receptor for antigen, and have the potential to be stimulated to become antibody-secreting cells. • Since the DNA rearrangements that result in functional H-chain and L-chain are not antigen-driven, a fraction of immature B cells will have a BCR that, by chance, reacts with some component of self - self antigen reactive cells • These immature B cells are removed by clonal deletion, either in the bone marrow, or shortly after leaving the bone marrow. • Encounter with self-antigen results in apoptosis (death), or anergy (unresponsiveness) • B cells that survive this step express surface IgD as well as IgM: mature B cells • How do these immature B cells know that the antigen that they’re binding is a self Ag? They don’t: – B cells are more susceptible to anergy at this stage in development – They become anergic if they don’t receive a co-stimulatory signal: • Therefore, signaling via the BCR alone is not sufficient to activate the B cell • Second signals (co-stimulatory signals) are necessary for activation. Phase 2 – elimination of self-reactive B cells, generation of mature IgM+, IgD+ cells: Phase 3 – activation of B cells on contact with antigen • Following the generation of a functional B cell receptor for Ag, and the removal of selfreactive cells, mature Agresponsive B cells (IgM+, IgD+) emigrate from bone marrow. • These mature B cells go to secondary lymphoid organs. • In the lymph node, B cells gather in primary lymphoid follicles, where they receive viability-promoting signals, interacting with follicular dendritic cells, and wait for antigen • B cells enter lymph nodes via high endothelial venules (HEV) to reach these primary follicles. • B cells can recirculate out via the lymphatic circulation, and back into blood. • B cells can interact with an antigen that is bound to the surface of follicular dendritic cells in the lymph nodes. • These cells trap and concentrate antigen, maximizing the interaction of antigen with B cells • Antigen-specific B cells are detained in the T cell-areas, where they interact with antigen, and with antigen-specific activated helper T cells. Stimulated antigen-specific B cells then proliferate and differentiate, eventually forming plasma cells and germinal centers: • Binding of antigen to the B cell’s antigen receptor results in an initial activation signal (first signal) if there is receptor cross-linking. • Cross-linking of the B cell receptor results in a cascade of intracellular signals, which results in the induction of specific gene expression leading to cellular proliferation and differentiation. • However, signaling via the BCR alone is not sufficient to activate the B cell - • Second signals (co-stimulatory signals) are necessary for activation. activation signal activation signal Laâbi, Y. and A. Strasser. Science 289:883, 2000 Phase 4 – differentiation to antibody-secreting cells • Some of the progeny of these antigen-activated B cells differentiate into plasma cells, which are antibody-secreting cells. • Plasma cells: – terminally-differentiated cells – derived from activated B cells or memory cells – loaded with endoplasmic reticulum – devoted to protein (antibody) synthesis – no longer express surface immunoglobulin or MHC class II – no longer responsive to antigen contact – live for several weeks – migrate away from the site of initial contact with helper T cells, either to the medullary cords of the lymph nodes or to the bone marrow • Other antigen activated B cells give rise to germinal centers (GC), zones of proliferating activated B cells: • These germinal centers (GC) contains: – proliferating (D - centroblasts) B cells – differentiating (L - centrocytes) B cells • Germinal centers are where isotype switching and somatic hypermutation occur. • Somatic hypermutation: – rapid mutation (hypermutation) of immunoglobulin genes – results in antigen-binding affinity that is higher, or lower, than its original binding affinity – selection by antigen results in the generation of BCR with increased affinity for antigen • Only those B cells that have enhanced their antigen receptor’s binding affinity survive. • This selection process involves competition for both antigen and for helper T cells. • Antigen is trapped on the surface of follicular dendritic cells in the form of immune complexes (antigen + antibody complexes). • B cells that bind to Ag with high affinity live, others die by apoptosis. • Centrocytes interact with T cells by presenting processed antigen to them via their MHC class II molecules. • Centrocytes that receive co-signaling (via CD40, MHC class II and cytokines), as well as signaling via their antigen receptor survive • Centrocytes that do not bind antigen and T cells with sufficient affinity die by apoptosis. • These germinal centers (GC) contains: – proliferating (D - centroblasts) B cells – differentiating (L - centrocytes) B cells • Isotype switching - change in the type of H-chain that is used by a given B cell, also occurs in germinal centers: • Isotype switching involves DNA rearrangements - replacement of one H-chain class gene with another • Isotype switching also occurs in germinal centers • Isotype switching is guided by the pattern of cytokines that are produced by helper T cells: • These somatically mutated and isotype switched B cells can then continue to differentiate into memory cells or plasma cells, producing: – IgG or other switched isotypes – much higher affinity Ab, due to somatic hypermutation increasing the antigen binding affinity Together, these processes result in a 1-2 log increase in the number of antigen-specific B cells (clonal selection and expansion), an increase in antibody binding affinity for antigen (somatic hypermutation), and the expression of new Ig subclasses (Ig isotype switching): • Other germinal center B cells develop into memory B cells: – quiescent – Increased in frequency following primary responses – long-lived – posses high-affinity, isotype-switched antigen receptors – form a pool of cells ready to mount a rapid secondary antibody response, on subsequent exposure to antigen • The combined result of somatic hypermutation, isotype switching, and the generation of memory cells, is the creation of a pool of cells that can respond rapidly and vigorously to subsequent contact with antigen, with high-affinity, IgG and IgA antibodies. B cell cancers mirror these different stages of B cell development