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Immunology- Exam 2 (Antibodies (Structure (Isotypes (IgG (80% of the blood…

- - - - Encounter Antigens
        
        Stimulated B cell gives rise to antibody-secreting plasma cells
  - - - Constant region
        
        Determine antibody class
      - Variable region
        
        Determine region specificity
        
        Hypervariable region- Antigen Specificity
        
        Framework position- Provides general antibody shape
    - - Held together via through disulfide bonds
      - Constant regions
        
        Kappa
        
        Lambda
      - Variable region
        
        Determines binding specificity
    - - IgG
        
        80% of the blood serum antibodies
        
        Can easily enter tissue
      - IgM
        
        Mostly in blood
        
        Great for activating the complement
      - IgE
        
        Tightly bound to basophils and mast cells
        
        Parasites and Allergies
      - IgD
        
        Activates basophils in respiratory tract
        
        Largely unknown
      - IgA
        
        Found in tissues and secreted onto mucosal surfaces
    - - Amino acids in variable region that distinguish antibodies
    - - Ex. - Allergies
    - - "Stem"
    - - Allows for flexibility within the antibody structure
  - - - Derived from a single B cell & identical
      - Drugs
        
        Humira
      - ELISA
        
        Pregnancy test
        
        Rapid Strep test
        
        Direct ELISA
        
        Tests for the specific antigen
        
        Indirect ELISA
        
        Tests for antibodies to a pathogen
      - Flow Cytometry
        
        Each antibody binds one specific cell type
        
        Each antibody has a different colored fluorescent tag
      - Hybridomas- Fuse normal B cell to tumor B cell to continually produce antibody
        
        Inject mouse with antigen
        
        Harvest B cells from the spleen
        
        Fuse normal B cells to B cell tumors
        
        Select for the best hybridoma producing antibody
        
        Issues
        
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    - - Derived from multiple B cells & diverse
- - - - Lobules
      - Cortex
      - Cortico-medullary junction
      - Medulla
  - - - No T cell markers
      - Become double-negative thymocytes
    - - do NOT express CD4 or CD8
    - - If b gene recombines first, then both CD4 and CD8 are expressed
        
        a:b TCR T cell receptors
        
        Double-positive thymocyte
      - If g:d recombine first, then no CD4 or CD8 are made and the cell commits to the g:d lineage
        
        g:d TCR T cells
      - If neither goes recombine, the cell undergoes apoptosis
  - - - If TCR binds, T cell continues development
      - If TCR does NOT bind at first, only recombines the a chain to try to bind
        
        If still failing after 3-4 days, apoptosis
    - - Whichever receptor (CD4 or CD8) binds to the APC, that receptor get made by the cell
  - - - Transcription factor in the thymus epithelial cells that allow expression of tissue-specific proteins from other organs
  - - - Regulatory T cells that suppress CD4 T cells that bind self-antigens on the same cell as Treg
      - Have CD25 surface protein, along with CD4
- - - - Only 50% survive Phase 1
    - - Productive Rearrangements
      - Non-productive Rearrangements
    - - Early Pro B-Cell
        
        Late Pro-B Cell
        
        Pre-B Cell
        
        Immature B Cell
        
        Cell-Surface IgM antibodies, but remain in the bone marrow
        
        Rearrange k gene on first and second chromosome
        
        Rearrange λ gene on first or second chromosome
        
        Still fail, apoptosis
        
        Express IgM
        
        Express IgM
        
        V-DJ rearrangement on first chromosomes
        
        If fail, try second chromosome
        
        Still fail, apoptosis
        
        Surrogate Light Chain
        
        VpreB
        
        Similar to light chain variable region
        
        λ5
        
        Similar to light chain constant region
        
        If the heavy chain can form pre-B cell receptor with surrogate light chain, then cell changes to a pre-B cell
        
        H-chain gene rearrangement
        
        D-J rearrangement on both chromosomes
  - - - RAG proteins are activated and Receptor Editing occurs
        
        Rearranging the light chain genes again
        
        If successful, the B cell leaves the bone marrow
        
        If an immature B cell binds soluble self-antigen...
        
        Anergy occurs, meaning the B cell is inactive
        
        To become anergic, the B cell activates alternative splicing to make mostly IgD instead of IgM
        
        If fail, the B cell undergoes apoptosis
  - - - Lymph Nodes
        
        CCL21
        
        Chemokine secreted by lymph node cortex cells attracts immature B cells
        
        CCR7
        
        B cell receptor that recognizes and binds CCL21
        
        B cell enters the lymph nodes through the HEV
        
        Primary Lymphoid Follicles
        
        Region of lymph node where immature B cells migrate
        
        Follicular Dendritic Cells
        
        CXCL13
        
        Chemokine secreted by FDCs attract B cells to primary lymphoid follicles
        
        BAFF
        
        Cytokine binding to B cell BAFF receptor stimulates B cell maturation
        
        Mature, naïve B cells re-enter blood and express more IgD than IgM
  - - - Effector cells
        
        Secrete copious amounts of antibody
        
        No cell surface immunoglobulins
      - Memory B cells
      - B Cell Cancers
        
        Proto-Oncogenes
        
        Genes involved in cell growth that, when activated, increase the risk of cancer
        
        Tumor suppressor genes
        
        Genes, when deleted, increase the chance of cancer
- - - - For intracellular pathogens
        
        Viruses
      - Found on most cell types including professional APCs
      - Recognized by cytotoxic T cells
      - CD8 co-receptor is necessary for TCR binding to MHC Class I
      - Antigen Processing for MHC Class I
        
        MHC Class I protein is partly folded in ER
        
        IFN-y interferon is released by NK cells to signal cells to express immunoproteasome
        
        Immunoproteasome cleaves intracellular pathogen proteins into short peptides
        
        Pathogen peptides are transported to the ER
        
        Antigen peptide binds to MHC class I in ER & allows MHC class I to finish folding
        
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      - Structure
        
        a chain
        
        Binds peptide antigen
        
        b2-microglobin chain
        
        Provides structure
      - 3-6 copies of a gene from each parent
      - Only one copy of b2-microglobin from each parent
    - - Extracellular Pathogens
      - Found only on Professional APCs
      - Recognized by helper T cells
      - CD4 co-receptor is necessary
      - Antigen Processing for MHC Class II
        
        Invariant Chain protein binds MHC Class II in ER and keeps MHC Class II inactive
        
        MHC Class II in vesicle cuts invariant chain to free MHC Class II for binding
        
        Phagocytosis of extracellular pathogen
        
        pH drop in phagolysosome activates proteases to cut pathogen proteins into short peptides
        
        Vesicle with MHC Class II combines with vesicle containing pathogen peptides
        
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      - Structure
        
        Both a and b chains bind to peptide antigen
      - 3-5 copies of a gene from each parent
      - 3-8 copies of b gene from each parent
    - - Human Leukocyte Antigens (HLA)
        
        No direct DNA recombination
        
        Stable with normal inheritance patterns
        
        HLA Complex
        
        Region of human chromosome 6 containing genes encoding for MHC proteins
        
        Halotype
        
        Combination of isotopes and allotypes
        
        Organ matches
      - Gene Family
        
        Multiple copies of a gene inherited from one parent
      - Gene Polymorphism
        
        Alleles within a population
      - MHC Restriction
        
        T cell binding is specific for the peptide antigen and also the isotype of the MHC
      - Peptide-binding Motif
        
        Portion of the MHC that determines what kind of peptide antigen can be bound by MHC
        
        Some MHC molecules are better at presenting antigens from a certain pathogen than other MHC molecules
    - - MHC Isotypes
        
        MHC proteins encoded by different genes
      - MHC Allotypes
        
        Proteins encoded by different alleles of same gene
- - - - IgH
        
        Encodes for the heavy chain
        
        4 Major Regions
        
        V,D,J, and C
      - Igκ
        
        Encodes for the light chain k
        
        3 Major Regions
        
        V,J, and C
      - Igλ
        
        Encodes for the light chain λ
      - Each gene is found in a non-functional form in germline cells
      - Ig genes are functional ONLY IN B cells
    - - Specific DNA sequences that guide RAG-1 and RAG-2
    - - RAG Complex cleaves the heptamer RSSs from the D and J segments, forming two DNA hairpins
        
        RAG Complex opens hairpins by nicking one strand of the DNA, generating palindromic P-nucleotides
        
        N-nucleotide additions by TdT
        
        Pairing of strands
        
        Unpaired nucleotides are removed by an exonuclease
        
        Gaps are filled by DNA synthesis and ligation to form coding joint
        
        Exonucleases remove single bases
        
        TdT- Adds single bases
    - - Naive B cells express the immunoglobin gene products as cell-surface receptors
        
        Naive B cells can either express IgM or IgD, based on alternative splicing of IgH mRNA
        
        B CELL ACTIVATION via Antigen Binding
        
        Somatic Hypermutation
        
        Genes are purposefully mutated in the variable region
        
        Activation-induced cytidine deaminase (AID)
        
        Changes single nucleotides within variable region during somatic hypermutation
        
        AID converts cytosine to uracil
        
        DNA Repair enzymes convert uracil to A, C, T, or G.
        
        Class Switching
        
        DNA is recombined to make different isotypes (classes) of the constant region
        
        Antigen-binding region remains the same
        
        AID & UNG
        
        AID- Marks S regions for UNG
        
        UNG- Takes out bases marked by AID
        
        IgH region is changed at the DNA level
        
        Occurs after B cell bind to antigen (Activation)
        
        Cytokines determine what isotope is selected
        
        Common Variable Immunodeficiency (CVID)
        
        Low or no class switch of antibodies
        
        One of the most common immune disorders
        
        Cause is unknown, weak genetic links