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Stages at which Isotype Switching occurs This will be covered later in the course and is presented here to provide context to understanding isotype switching. It will not to be tested in Exam 1 antigen-independent stem cell pre-B cell immature B cell (IgM +) mature B cell (IgM +, IgD +) antigen-dependent IgM isotype switching IgG IgE IgA Does Isotype Switching occur in one B cell? 1. Activated B cell resides in the Germinal Center -some individuals will mature directly into plasma cells 2. Some B cells in the germinal center divide and undergo hypermutation and/or isotype switching 3. After this stage they cannot divide and the higher affinity ones are selected 4. These cells can mature to plasma cells 5. End result: The B cell makes a different antibody isotype but with the same specificity Exception to the one B-cell: One BCR Dogma One B-cell : Two BCR? One is self-reactive Other is pathogen reactive Why would a B-cell want to express two BCRs of this type? The self-reactive BCR can fill a hole in the B cell repertoire - it might be essential to recognize a pathogen even though it reacts with self. Mechanism of Self-tolerance B-cells with BCR that bind strongly to the constituents of surrounding bone marrow tissue are programmed to die - apoptosis Deficient Slightly Immune overactive Pathogens=0 Response Immune Overactive Pathogens>0 Pathogens=0 Immune Response Response Immune Pathogens>>0 Response Mechanism of Self-tolerance T-cell Receptor • Two Types 1) TCR and TCR T cells TCR and TCR T cells • Antigen Binding site - V and V • Similar to Fab fragment Functions and Properties of T Cells • T cells - Recognize MHC:peptide complex - Diverse Functions A) Stimulate other immune cells B) Cytotoxic - kill infected host cells - Cell:cell interactions • T cells - Dominant T-cell in epithelial tissue (only 1-5% in circulation) - Recognizes more than MHC:peptide - Not well characterized • Antigen-Recognition site = Peptide:MHC Recognition site • Single V region CDR1-3 for each chain • All TCRs on a single T cell are the same • Different T cells express different TCRs • Diversity mechanisms like BCRs Figure 3-3 No Ds in Vgene Occurs in the Thymus DJ first then VDJ in gene rearrangement Figure • -chain locus is within -chain locus 3-8 • Fewer V segments then and • Two D segments can be incorporated Functional T-cell Receptor Complex • Core complex • CD3 complex: , • (zeta) chain • Function of CD3 and : Transport Signal Transduction Invariant Chains Avidity Comparison of B and T cells PROPERTY B CELLS T CELLS Bone Marrow Thymus Pre-antigen Diversity YES YES Post antigen Diversity YES NO Single antigen specificity YES YES Variety Peptide:MHC Secreted form of Receptor Yes No Invariant signaling subunits Yes Yes Initial Development Antigen recognized Immunodeficiency diseases • SCID - severe combined immunodeficiency disease - Many causes but a rare disease - Classified according to lymphocyte profile (T B NK) - Bone Marrow transplant can cure • Omenn syndrome - RAG proteins have reduced activity - Patient is: T+ B- NK+ • CD3 and CD3 deficiency diseases - Mutations in some CD3 genes - Patient is: T+/TCR- B+ NK+ or T- B+ NK+ How do T cells recognize antigens? Antigen Processing Antigen Presentation Antigen Presenting Cell (APC) Professional APC MHC class I communicates with Tc cells MHC class II communicates with TH cells IR to Extracellular Pathogens (CD4-MHC I) 1. Antibodies needed 2. Pathogen recognition/internalization by professional APCs a. B cells b. Macrophages c. Dendritic cells 3. Phagolysosome degrades proteins to peptides 4. Peptides:MHC II complex transported to surface 5. Professional APC contacts CD4 T cells 6. CD4 TH cells secrete cytokines to signal B cell maturation IR to Intracellular Pathogens (CD8-MHC II) 1. Antibodies ineffective 2. Pathogen replicates in the cell and proteins are degraded in the cytoplasm of the cell 3. Peptides are transported into ER and bind MHC I and transported to the surface 4. MHC I expressing cells present to CD8 T cells 5. CD8 T cells (cytotoxic T cell, CTL) kills host cell Figure 3-11 Structures involved in MHC Presentation TCR CD4 and CD8 MHC1 and MHCII T cell Co-Receptors Figure 3-13 part 1 of 2 CD8-MHC I CD4-MHC II Closed Open Figure 3-15 8-10 amino acids 13-25 amino acids Degenerate binding specificity Figure 3-16 Peptide Degradation and Transport Proteosome=Shredder Transporter associated with antigen processing Chaperones Figure 3-19 Prevention of Peptide:MHC II formation in ER CLIP - class II-associated invariant-chain peptide Figure 3-21 part 2 of 3 TCR binds MHC and peptide Sample Exam Question Testing allelic exclusion (inherit alleles for each Ig locus; only one rearranges to produce a heavy or light chain) Which of the following best describes the process of allelic exclusion? a. BOTH alleles of the light chain locus (e.g. lambda) rearrange DNA, but only ONE allele of the heavy chain rearranges DNA b. BOTH alleles of the heavy chain locus rearrange DNA, but only ONE allele of the light chain (e.g. lambda) rearranges DNA c. BOTH alleles of the light chain locus and BOTH alleles of the light heavy chain rearranges DNA d. The primary transcript RNA from BOTH alleles of the light chain and BOTH alleles of the heavy chain is rearranged e. None of the above NOT a Sample Exam Question Testing obscure facts that are probably NOT relevant to your education How many Diversity segments (DH) are present in the Immunoglobulin Heavy chain locus? a. 26 b. 27 c. 3.3 x 106 d. It varies depending on the combinations made with the light chain e. None of the above