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Describe what clonal deletion of B cells is, where it occurs and what/who eliminates the self-reactive B cell?
- The elimination of immature lymphocytes that bind to self antigens, the main mechanism that produces self tolerance.
- Note that these self-reactive receptors are specific for multi-valent self-Ags borne on cells in the bone marrow. Occurs in the bone marrow (apoptosis)or the periphery (anergy).
Compare clonal deletion to anergy. (Fig. 6.18 & 6.19)
Clonal deletion is the death of a self reactive B cell by apoptosis in the bone marrow, anergy refers to T or B cells that can not respond to their specific antigen.
Why is it important for a naive B cell to pass through a secondary lymphoid follicle?
That is where they proliferate and go through the affinity maturation process.
What happens if a naive B cell encounters its antigen in a lymph node? (Fig. 6.20 & 6.21)
It forms a germinal center where it proliferates and then differentiates into a plasma cell.
Compare and contrast a B cell, a plasma cell and a memory B cell. (Section 6-15)
- B cell:dedicated to making immunoglobulins and antibodies.
- Memory B: long lived, antigen specific B cell produced from activated B cells during primary response.
- Plasma cell:terminally differentiated B cell that only produces antibodies for a specific antigen, surface immunoglobulin is no longer expressed.
Describe the role the thymus plays in T cell development. Why is a 70 year person whose thymus has atrophied still able to mount an immune response to a pathogen?
T cells develop in the thymus. T cells are long living and self renewing so an atrophied thymus does not affect the T cell response.
Describe positive selection of T cells, where it occurs and what/who eliminates the T cell that is not chosen? Which cell of the thymus is instrumental in this process?
- T cells with a TCR that binds a self MHC on thymic cortical epithelial cells are signaled to survive and go through negative selection.
- T cels with TCRs that do not bind the self MHC molecules die by apoptosis.
What sets a double positive T cell on the path to becoming a CD8 or CD 4 T cell (i.e. single positive)? (Sections 7-8 and 7-10, Figures 7.16 and 7.17)
CD8 or CD4 depends on the selecting MHC molecule. MHC 1 molecules recruit CD8 T cells and MHC 2 molecules recruuit CD4 T cells.
For a cell to be allowed to survive positive selection, what must it be able to do?
It must be able to form a self-peptide:self-MHC complex (autoreactive).
What is the purpose of negative selection of a T cell? Where does it occur and who/what eliminates the self-reactive T cell? (Section 7-11 and fig. 7.18)
To eliminate cells with TCRs that bind too tightly to self MHC. This occurs in the thymus. When a T cell binds too tightly to an MHC mloecule on a DC or macrophage it is signaled to die by apoptosis.
What cell(s) play an instrumental role in negative selection?
Dendritic cells and macrophages with MHC molecules on their surfaces.
How many loci are present for heavy and light chains of immunglobulins?
2 heavy and 4 light.
What are B-1 cells?
They develop in early embryonic life and produce antibodies that bind bacterial polysaccharides, but are polyspecific, of low affinity and generally of the IgM isotype.
What are the phases of a B-cells life according to figure 6.1?
- Phase 1: Repertoire assembly; generation of diverse, clonally expressed B-cell receptors in bone marrow.
- Phase 2: Negative selection; alteration, elimination and inactivation of BCRs that are autoreactive.
- Phase 3: Positive selection; promotion to maturity of fraction of immature B cells in secondary lymph.
- Phase 4: Searching for infection; circulation between lymph, blood and secondary lymph.
- Phase 5: Finding infection; activation and clonal expansion of B cells by Ag in sencondary lymph.
- Phase 6: Attacking infection Differntation to plasma cells or memory B.
What is the importance of the bone marrow stroma for B cell development? (6-3 a)
Bone marrow stromal cells nurture the developing B cells. They interact thru adhesin:ligand interactions & stromal cells provide growth factors.
What are the two main checkpoints for B cell development in the bone marrow? What is the fate of developing B cells with functional and nonfunctional H and L chains?
- 1) Checking the capacity of H chain to make functional pre-B cell receptors. Yes: move on No: apoptosis
- 2) Checking the cells ability to make L chains that bind to H chain and make a functional BCR. Yes: become immature B cell. No: apoptosis
What is terminal deoxynucleotidyl transferase? What would be the consequence if it were expressed throughout small pre-B-cell development? (6-5)
TdT is the enzyme that adds N nucleotides at the junctions of rearranging gene segments in heavy chains. If it were constantly expressed light chain rearrangement would never begin.
When are nonproductive rearrangements most common in B cell development? What percentage of B cells are eliminated because of this?
- Nonproductive rearrangements occur most often during the addition of N and P nucleotides.
What is the importance of allelic exclusion in B cell development?
Allelic exclusion at the immunoglobulin loci results in B cells with Ag receptors of a single specificity. High avidity.
Bruton's x-linked agamma-globulinemia(page 170)
- Lack BtK gene: Bruton's tyrosine kinase which is needed for signal transduction & B cell development -- no circulating Ab as B cells are blocked at pre-B cell level ( Fig. 6.12 )
- Recurrent infections from pyogenic bacteria.
- RX: antibiotics and regular infusions of pooled immunoglobulin from healthy donors
due in part to translocations of segments of chromosome 8 & 14 so that Ig gene is joined to genes involved in cell growth . (Note that there are other changes needed)
What is the order of gene rearrangemants that leads to the production of cell surface immunoglobulins?
- 1) D-J (H chain) on both chroms: Early pro-B cell
- 2) V-DJ (H chain) on one chrom, repeat on 2nd chrom if unsuccessful: Late pro-B
- 3) Rearrange k (L chain) gene on 1st chrom, repeat on 2nd chrom if unsucccessful then lambda gene: Immature B cell (either u/k or u/l)
Explain the difference between central & peripheral tolerance (section 7-12).
Central tolerance refers to negative selection in the thymus while peripheral tolerance occurs in the peripheral circulation if an autoreactive T cell eludes negative selection.
What is the role of regulatory T cells in peripheral tolerance?
- Regulatory T cells prevent prloiferation of autoreactive helper T cells to a self antigen on the same antigen presenting cell.
- (Section 7-13 & figure 7.19)
What are the stages of T cell development?
- Stage 1: DN CD3- thymocytes undergo proliferation and differentation to Dp thymocytes. Subcapsular zone.
- Stage 2: DP CD3+ thymocytes undergo positive selection. Thymic Cortex.
- Stage 3: DP CD3+ thymocytes undergo negative selection. Throughout cortex, cortico-medullary junction.
- Stage 4: Mature, self-restricted, self-tolerant, SP, CD4 and CD8 T cells enter circulation.
What is receptor editing?
Cells with autoreactive receptors in the bone marrow are given a chance to modify their BCR. Keeps RAG complex going.
What are two factors for successful B cell development?
Ig is A) Expressed on surface B) But not auto-reactive
When is an autoreactive B cell NOT eliminated by clonal deletion? What happens to it?
If a B cell has a BCR reactive to monovalent self-AG ( often soluble proteins), then it will not be eliminated in the bone marrow as if Fig 6.18. Instead, when it reaches the periphery, it becomes anergic.
What is anergy in a B cell?
An anergic B cell makes both IgM & IgD internally, but IgM is not allowed onto the cell's surface. Even if its IgDs bind Ag, this is not enough to activate the B cell. They only survive 1-5 days in the periphery ( other mature B cells have a half life of ~40 days)
What happens if a B cell is stimulated in the T cell zone?
Some travel to medullary region of LN and become plasma cells. Some migrate to secondary follicle (contains Germinal center) & undergo affinity maturation then migrate out of LN (plasma cells or memory B cells)
What happens when a memory B cell is activated by it's antigen?
Enable secondary IR which is rapid & with higher levels of high affinity IgG
Where are plasma cells found?
Found in medullary cord of LN, red pulp of spleen, lamina propria of gut & bone marrow