Immunology Exam 4

• 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).

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.

That is where they proliferate and go through the affinity maturation process.

It forms a germinal center where it proliferates and then differentiates into a plasma cell.

• 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.

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.

• 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.

CD8 or CD4 depends on the selecting MHC molecule. MHC 1 molecules recruit CD8 T cells and MHC 2 molecules recruuit CD4 T cells.

It must be able to form a self-peptide:self-MHC complex (autoreactive).

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.

Dendritic cells and macrophages with MHC molecules on their surfaces.

2 heavy and 4 light.

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.

• 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.

Bone marrow stromal cells nurture the developing B cells. They interact thru adhesin:ligand interactions & stromal cells provide growth factors.

• 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

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.

• Nonproductive rearrangements occur most often during the addition of N and P nucleotides.
• 50%

Allelic exclusion at the immunoglobulin loci results in B cells with Ag receptors of a single specificity. High avidity.

• 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)

• 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)

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.

• 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)

• 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.

Cells with autoreactive receptors in the bone marrow are given a chance to modify their BCR. Keeps RAG complex going.

Ig is A) Expressed on surface B) But not auto-reactive

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.

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)

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)

Enable secondary IR which is rapid & with higher levels of high affinity IgG

Found in medullary cord of LN, red pulp of spleen, lamina propria of gut & bone marrow