Chapter 6 (slides 21-38) (Immuno)
Self-reactive Immature B Cells Are Altered, Eliminated, Or Inactivated By Contact With Self-antigens
*A B cell first expresses IgM on its surface as an immature B cell *Mature B cell involves emigration from the bone marrow and the use of alternative splicing of H-chain mRNA to place IgD with IgM on the cell surface *Quality control mechanisms prevent the maturation of B cells whose receptors bind normal components of the human body - called self-antigens (protein, carbohydrates, lipids found on the surface of human cells. Soluble antigen are also tested before the B-cell leaves the bone marrow)
Comparison Of The Properties Of B-1 Cells And B-2 Cells
*B-1 cells develop in the omentum and in the liver in the fetus *Produced by the bone marrow for only a short period around birth *Pool of self-renewing B-1 cells established that do not require bone marrow for survival *The limited diversity and low affinity of the antibodies made by B-1 cells suggest these are components of a simpler, less adaptive immune response
Population Dynamics Of B Cells
*B-cell population = continually changing and heterogeneous population -Different states of development and differentiation -Immature B cells produced --> bone marrow have Igs specific for the entire range of molecules found in biological systems -B cells with receptors that bind to self-antigen present in the bone marrow =Eliminated by clonal deletion or inactivated -Passage through lymphoid follicles is essential for sustaining mature, naïve B cells in the peripheral circulation =No follicle visit --> die (typically less than a week) =Follicle visit --> unless stimulated by specific-Ag --> die (mature B cell --> live for weeks) =Proliferation, differentiate --> memory B cells
Final Maturation of B-cells
*B-cells interact with Follicular dendritic cells to receive their final signal to fully mature and survive. *Now called naïve B-cells (mature) *Immature B-cells that fail to enter the follicle will die.
Selection After Affinity Maturation
*Cells that survive the selection process after affinity maturation undergo further proliferation and migrate from the germinal center to other sites in the secondary lymphoid tissues or bone marrow *Selected B cells differentiate into plasma cells secreting high affinity, isotype-switched antibody *As immune response subsides, germinal center B cells develop into memory B cells capable of making high affinity antibody when re-exposed to the same antigen (basis of secondary immune response)
The Circulation Route Of B Cells Through A Lymph Node
*From the bone marrow, an immature B cell will migrate via the blood to the secondary lymphoid organs, directed by cytokines *B cells enter the cortex of the lymph node through the wall of specialized high endothelial venules (HEV), also directed by cytokines
Binding To self-Ag In The Bone Marrow Can Lead To The Deletion Or Inactivation Of Immature B Cells
*Immature B cells that do not encounter a self-antigen leave the bone marrow and enter the peripheral circulation expressing both IgM and IgD on their surface *When immature B cells express receptors that recognize common cell-surface components (multivalent self-antigens) of human cells: -They are deleted from the repertoire by the induction of apoptosis -Immature B cells that bind soluble self-antigens (monovalent self-antigens) are rendered unresponsive or anergic to the antigen =As a consequence express low levels of IgM at the cell surface and can enter the peripheral circulation where they express IgD but remain anergic
Architecture of the Lymph Node
*In LN, there are discrete sites for B cells and T cells. *Effector B cells; plasma cells -secrete antibodies. *Expansion occurs in lymphoid follicles. *As lymphocyte development proceeds, follicle shape changes - germinal center.
Many B-cell Tumors Carry Chromosomal Translocations That Join Immunoglobulin Genes To Genes Regulating Cell Growth
*Normal process as B cells cut, splice and mutate their Ig genes can cause mutations that produce a tumor cell *In B-cell tumors disruption of regulated growth is associated with aberrant Ig-gene rearrangement -Joining an Ig gene to a gene (involved in the control of cellular growth on a different chromosome) - translocation -Proto-oncogenes, genes that cause cancer when their function or expression is perturbed =Viral genes responsible for transformation = oncogenes and it was sometime before it was know they had evolved from cellular genes that control cell growth, division and differentiation
B Cells Bearing CD5 Express A Distinctive Repertoire Of Receptors
*Not all B cells conform to the developmental pathway -Subset of human B cells =Arise early in embryonic development =Expresses CD5 - Cell surface glycoprotein marker for the human T-cell lineage *Minority subset of B cells (b-1-cells) precedes that of the majority subset (b-2-cells) *B-1-cells -Little or no IgD on surface -Distinctive repertoire of Ag receptors -Know as CD5 B cells (CD5 is not essential for their function) -Dominant B cells in pleural and peritoneal cavities -5% of B cells in humans -Arises from a stem cell most active in prenatal period
Chromosomal Rearrangements In Burkitt's Lymphoma
*Parts of chromosome 8 and chromosome14 have been exchanged -The sites of breakage and rejoining are in the proto-oncogene MYC on chr8 and the Ig H-chain gene on chr14 or the or light chains genes on chr2 or chr22 -MYC is normally involved in regulating cell division. Abnormal expression as a result of translocation causes increased growth -Another translocation frequently found is the fusion of an Ig gene to the proto-oncogene BCL-2 *Translocations probably occur during the first attempt to rearrange a heavy-chain gene -This would have counted as an unproductive rearrangement and the other gene would then be rearranged -In cases where the 2nd rearrangement is also unproductive, the cell dies and thus cannot give rise to a tumor
Replacement Of L-chains By Receptor Editing Can Rescue Some Self-reactive B Cells By Changing Their Ag Specificity (cont.)
*Receptor editing -If this new receptor is not self-reactive the cell is "rescued' and continues normal development much like a cell that had never reacted with self -If the cell remains self-reactive, it may be rescued by another cycle of rearrangement but if it continues to react strongly with self it will undergo apoptosis and be deleted from the repertoire
Encounter With Antigen Leads To The Differentiation Of Activated B Cells Into Plasma Cells And Memory B Cells
*Secondary lymphoid tissue are the sites where mature, naïve B cells encounter specific antigen *Antigen-specific B cells stay in the T-cell areas, and are activated by Ag-specific, CD4 helper T cells -T cells provide signals that activate the B cells to proliferate and differentiate -In lymph nodes and spleen some of the activated B cells immediately proliferate and differentiate into plasma B cells and secrete antibody (lower affinity) -Other activated B cells migrate to a primary follicle that matures into a secondary follicle containing a germinal center
A Summary Of The First Two Main Phases Of B-cell Development
*Stages in B-cell development *Stem cell in bone marrow --> mature, naïve B cell -Location of B cells at different stages -State of the Ig H- and L-chain genes -Form of Ig expressed at each stage *Recall: B-2 cells
A Summary Of The Last Two Main Phases Of B-cell Development (cont.)
*Stages in B-cell development from the activated mature B cell terminally differentiated plasma cell *Plasma cells can differentiate directly from activated B cells, from isotype switched, somatically hypermutated centrocytes or from memory B cells
Ig H-chain Gene Rearrangements Use The VH Gene Segments Closest To The D Gene Segments
*TdT is not expressed in early prenatal period, therefore H-chain gene of B-1 cells lack N nucleotides and their VDJ junctions are less diverse *Ab secreted by B-1 cells to be low affinity, but each binds to many different antigens (polyspecificity) -Abs made against bacterial polysaccharides & carbohydrate Ags but little against protein Ags *Postnatal B-1 cells use more diverse repertoire of V gene segments, and have abundant N nucleotides -With time, B-1 cells no longer produced by the bone marrow -Adult population of B-1 cells is maintained by the division of existing B-1 cells at site in peripheral circulation =Self-renewal dependent on the cytokine IL-10
Replacement Of L-chains By Receptor Editing Can Rescue Some Self-reactive B Cells By Changing Their Ag Specificity
*When a developing B cell produces surface IgM that are strongly cross-link by multivalent self-antigens (MHC complex molecule on cell surfaces) the B cell undergoes developmental arrest -The amount of IgM on the surface is reduced and the RAG genes are not turned off -Continued synthesis of RAG proteins allow the cell to continue L-chain gene rearrangement -Usually leads to a new productive rearrangement and expression of a new L-chain which combines with the previous H-chain to form a new receptor (receptor editing)
