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 Stages at which Isotype Switching occurs

antigen-independent stem cell pre-B cellimmature B cell (IgM +) mature B cell (IgM , IgD +) IgG IgA IgE IgM antigen-dependent isotype switching

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

One B-cell : Two BCR? Exception to the one B-cell: One BCR Dogma 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 Immune Response Pathogens=0 Deficient Immune Response Pathogens>>0 Overactive Immune Response Pathogens=0 Slightly overactive Immune Response Pathogens>0

Mechanism of Self-tolerance

Two Types 1) TCR  and TCR   T cells  TCR  and TCR   T cells Antigen Binding site - V  and V  Similar to Fab fragment T-cell Receptor

 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 Functions and Properties of T Cells

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 V  gene DJ first then VDJ in  gene rearrangement Occurs in the Thymus

Figure 3-8  -chain locus is within  -chain locus 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

PROPERTYB CELLST CELLS Initial DevelopmentBone MarrowThymus Pre-antigen Diversity YES Post antigen Diversity YESNO Single antigen specificity YES Antigen recognizedVarietyPeptide:MHC Secreted form of Receptor YesNo Invariant signaling subunits Yes Comparison of B and T cells

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+ Immunodeficiency diseases

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 T H 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 T H 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 ICD4-MHC II

Figure 3-15 ClosedOpen 8-10 amino acids amino acids Degenerate binding specificity

Figure 3-16

Proteosome=Shredder Transporter associated with antigen processing Peptide Degradation and Transport

Chaperones

Figure 3-19

CLIP - class II-associated invariant-chain peptide Prevention of Peptide:MHC II formation in ER

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 (D H ) are present in the Immunoglobulin Heavy chain locus? a. 26 b. 27 c. 3.3 x 10 6 d. It varies depending on the combinations made with the light chain e. None of the above