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Immunology Week 5 (Antibodies and Ig Genes (Variability (Recombination…

- - - - Genes for Ab are on different chromosomes
      - Genes have coding and noncoding segments
        
        Light chain: V, J, and C gene segments
        
        Heavy chains: V, D, J, and C gene segments
        
        Rearranged to form functional gene
        
        Light chains: VJ segments
        
        Heavy chains: VDJ segments
      - Pick the genes we want, alter the DNA, and create a transcript from that DNA
        
        C regions removed in selection, D regions present only in heavy chain
        
        Heavy chain: D and J regions joined by V
        
        Ab that's ready to circulate has two different constant regions/two different classes that are separated after transcription of the mRNA produced from the rejigged DNA
        
        Light Chain: VJ joining starts it off b/s there is no D segment
    - - Recombination Signal Sequences (RSS)
        
        Flank V, D, and J segments
        
        one-turn RSS always joins with two-turn RSS to ensure proper V(D)J combination
        
        Provide instructions
        
        physical turn in the DNA
      - Recombinase enzymes recognize RSS - physical bending of the strand so that sequences are closer together
      - 2.RAG1 and RAG2 cleave DNA b/w gene segments and RSS. RAG1 is more important, RAG2 is mostly a stabilizer
      - Large protein complex join RSS to form signal joint and cleave the hairpin left by RAG1/2
      - Additional nucleotides added (TdT) and segments are ligated (DSBR)
    - - Junctional flexibility (variation in the trimming, addition, and joining between gene segments)
      - Somatic hypermutation
      - Combinations of the V(D)J
      - Combination of light and heavy chains
      - Number of gene segments in species
  - - - different classes of antibodies with same antigen specificity
- - - - Site of maturation (Ag independent) starting with progenitors to...
        
        Precursor B cell (has pre-B cell receptor) to...
        
        Immature B cell (fully functional B cell receptor)
        
        Negative selection [90%]
        
        Selected against for self-reactive BCRs (rendered anergic/lack normal immune response capabilities)
        
        Receptor Editing
        
        Deletion via apoptosis
        
        Step 3: IgM receptor expressed, Ready to leave bone marrow
        
        Step 2: finalization of heavy chain, light chain rearrangement, Pre-B-cell receptor expressed (Includes signals to slow and stop rearrangement. Receptor is there and signalling)
        
        Step 1: Heavy chain recombination, Ig-alpha and Ig-beta (≠ T cell Igs) production, CD19 expression (CD19 important in later activation and regulation)
      - Holds progenitors
        
        Undergo DJ H chain, VDJ H chain recombination, clonal expansion
      - Stromal cells
        
        Provide mircoenvironment through
        
        CAM interaction
        
        Signalling to induce expression of cytokine receptors
        
        Cytokine secretion
        
        Multistep ... Regulation control
    - - Site of Activation and Differentiation
      - Antigen dependent
      - Mature B cell has co-expression only at this stage
        
        mIgM
        
        mIgD
      - Naive B cell in periphery
    - - Surface molecule present tells us which stage the cell is at
        
        Adhesion molecules
        
        Surface Receptors for chemokines and cytokines
        
        Antigens
      - Transcription factors determine which genes are expressed at each step
      - Resulting signal induces various processes
        
        Proliferation
        
        Differentiation
        
        Movement
    - - Leaves as an immature B cell (non-functional, Ag binding = death or anergy)
  - - - B cells Lack AIRE, DN/DP transition, no positive selection, no MHC molecules
  - - - Signal 1 via cross linkage of mIg
        
        3 Ag presentation (MHC ll)
        
        2 Internalization of Ag
      - 4 Signal 2 via interaction with Th cell: CD40/CD40L (ligand) binding sets off signal
      - 5 B cell binds cytokines released from Th cell
        
        Differentiation into plasma cells and memory cells
        
        Activated B cell proliferates
    - - Molecules with repeating epitopes
      - Bacterial wall products
      - Occurs when we need a response faster than a TD response
    - - Survival signal (w/o recognition they will die when they leave the BM)
      - Ag interaction via Abs
        
        Ig = antibody
        
        Two heavy chains
        
        Two light chains
        
        Held together by intra-/interchain disulfide covalent bonds
        
        Both chains have constant and light regions (constant regions resemble T cell constant regions)
    - - Signalling induced by clustering of Ags and receptors
      - Clustering, phosphorylation, docking due to Ig-a/Ig-b
        
        BCRs cross-link
        
        Sarcoma kinase (Src) phosphorylates ITAMs and creates Syk docking sites so they can dock
        
        Once Syk is phosphrylated it docks, is activated, and initiates a protein signalling pathway
    - - B cell Co-receptor - intensifies activation by associating with mIg and sends signals via CD19 [upregulate]
      - CD22 - negative regulator that dephosphorylates BCR [downregulate]
  - - - ZAP70
      - Syk
    - - TCR+ CD3
      - mIg + Ig-alpha/Ig-beta
    - - B7 & CD28/CTLA4
      - B cell receptor (CD19) and CD22