Adaptive Immune System

Humoral
1. Antibodies
  1. Functions
    1. Bind very specifically to an antigen
    2. Neutralisaiton
    3. Mark for phagocytosis
    4. Activates complement system
  2. Structure
    1. 5 isotypes: IgA, IgD, IgE, IgG and IgM
    2. IgG most common
      1. Y shaped
      2. 4 polypeptides
      3. Heavy chains help together by covalent intermolecular-disulphide bonds
      4. Heavy chain and light chain held together by covalent intermolecular-disulphide bonds
      5. Antigen binding sites found at teh N-terminus of polypeptides
      6. Variability found in the amino acids of the antigen binding sites
    3. HV = hypervariable
    4. CDR = complementarity determining regions
    5. Epitope = region (small portion) of an antigen that the antibody recognises
  3. Antigens
    1. Antigenicity is the ability to combine with antibodies
    2. Immunogenicity is the ability to induce humoral (or cell mediated) immune response
      1. Foreigness
      2. Molecular size (large molecules are generally more immunogenic than small ones)
      3. Chemical composition
      4. Heterogeneity
2. Generation of antibody diveristy
  1. Can produce billions of different antibodies
    1. Production of variable regions of light and heavy antibody genes by DNA rearrangement
  2. In all cells apart form B-cells immunoglobulin genes are in a form that cannot be expressed
  3. J = Joining, D = Diversity, V = variable
  4. Random recombination of gene segments produces diveristy
    1. Recombine signal sequences (RSSs) flank the 3' of V segment, both sides of D segment and 5' of J segement
    2. Recombination can only occur between RSSs of different types
      1. Ensures correct order of joining
    3. RAG = Recombination activating gene - mediates recombination
  5. Additional diversity is added by recombination enzymes
    1. P-nucleotides generate palindromic sequences at the cut ends of DNA strands
    2. N-nucleotides are added at random to the cut end by terminal deoxynucleotidyl transferase (TfT)
  6. Overview
    1. 1. RAG complex binds to and cleaves recobination signal sequences to yield a DNA hairpin
    2. 2. RAG-mediated cleavage of hairpin generates palindromic P-nucleotides
    3. 3. N-nucleotide additions by TdT
    4. 4. Pairing of strands
    5. 5. Unpaired nucleotides are removed by an exonuclease
    6. 6. These gaps are filled by DNA synthesis and ligation to form coding joint
  7. Naive B-cells use alternative splicing to yield IgM or IgD
  8. Membrane bound immunoglobulins are complexed with other proteins to functional B-cell receptors
  9. Each B-cell has a single antigen specificity
    1. Immunoglobulin gene rearrangement tightly regulated so that only on H and on L chain are expressed
    2. B-cells that don't produce functional immunoglobulin are eliminated from population
3. Development on B-cells
  1. 1. Generation of B cells in bone marrow
  2. 2. Elimination of self reactive B cells in bone marrow
  3. 3. Activation of B cells by foreign antigen in secondary limphoid tissues
  4. 4. Differentiation to antibody-secreting plasma cells and memory cells in the secondary lymphoid tissues
  5. Stages of B-cell development are marked by steps in rearrangement and expression of immunoglobulin genes
  6. Only B-cells that produce functional immunoglobulin can survive
    1. Get a number of chances
    2. 55 billion B-cells per day are lost in the bone marrow because they fail to make functional Ig or are self reactive
  7. Mature naive B-cells compete for access to lymphoid follicles
    1. when mature B-cells leave the bone marrow they circulate between the blood and secondary lymphoid tissues (lymph nodes, spleen)
      1. within these tissues B-cells congregate in primary lymphoid follicles
        Naive B-cells must pause in these follicles in order to receive survival signal s form follicular dendritic cells (a specialised stromal cell)
4. B-cell
  1. Before encountering an antigen, a mature B-cell expresses antibody in a membrane bound form
  2. When a foreign antigen binds to this immunoglobulin, the B-cell is stimulated to proliferate and gives rise to plasma and memory cells
5. B-cells that encounter antigen
  1. Mature naive B-cells encounter specific antigen in secondary lymphoid tissue
    1. Activated by CD4 helper T-cells
    2. These T-cells provide signals that activate the B-cells to proliferate and differentiate further
      1. Some differentiate into plasma cells
      2. Some migrate to primary follicle, change morphology and become secondary lymphoid follicle containing a germinal centre
        Here activated B-cells become large proliferating lymphoblasts called centroblasts
        Centroblasts mature into isotype switched somatically hypermutated non-dividing centrocytes
        Those cells that have the highest affinity for antigen are selected for by affinity maturation
        Cells that survive affinity maturation proliferate and differentiate into plasma cells and memory B cells that persists for a long period of time
Cell mediated
1. T-cell receptor
  1. Always membrane bound
  2. Diversity is generated by gene rearrangmenet
    1. Similar to rearrangement of iG genes
    2. Uses RAG1 and RAG2
    3. Addition of P and N nucleotides
  3. Associates with other proteins
    1. CD proteins (CD3)
2. Antigen processing and presentaiton
  1. T cell receptors can only recognise antigens that are bound to MHC molecules
    1. MHC = Major Histocompatibility Complex
      1. Membrane glycoproteins
      2. Function is to bind antigen and present it to T-cells
      3. MHCI and MHCII have similar 3D structure but formed in different ways
      4. MHC class I
        Bind to CD8
        Peptides are generated in the cytosol by proteasome
        Transported into the ER by transporter associated with antigen processing (TAP)
        Associate with MHCI
        Transported to cell surface
        MHC I molecules cannot leave the ER unless they have bound peptide
        Almost all cells express MHC I molecules
        Erythrocytes lack MHCI, a property that probably allows malarial parasites to persistently infect these cells
      5. MHC class II
        Bind to CD4
        Antigens are taken up by phagocytosis or endocytosis
        Degraded by proteases in lysosome
        Do not bind peptides in the ER
        Bacterial super-antigens
        Bind simutaneously to MHCII and T-cell receptors
        Can stimulate up to 20% of total CD-4 T-cell population
        Results in systemic toxicity and suppression of adaptive immune response
  2. 2 main classes of T-cell
    1. CD4 co-receptor needed for T-cell recognition of MHCII peptides
      1. TH1 cells
        Activate tissue macrophages to take up antigen
        Stimulate B-cells to produce antibody
      2. TH2 cells
        TH2 stimulation of naive B-cells
        During infection contain activated pathogen specific TH2 effector cells
        Mature naive B-cells passing through lymphoid tissue pick up antigen, process it and present it on MHCII
        When B-cell presents antigen recognised by T-cell (TH2), it become trapped
        IFN-gamma can induce expression of MHCII molecules on cells that do not normally produce them
        Presentation of antigen to CD4 T-cells can thus be increased in inflamed tissues
      3. MHCII presents peptides derived from extracellular pathogens (antigens from outside the cell)
    2. CD8 co-receptor needed for T cell recognition of MHCI peptides
      1. Cytotoxic
      2. MHCI responsible for presenting peptides derived from intracellular antigens (antigens produced without own own cytoplasm
  3. Professional APCs (Antigen presenting cells)
    1. MHC class II alert CD4 positive T-cell of infection (extracellular)
      1. Expressed on professional APCs
        Macrophages
        B-cells
        Dendritic cells
    2. Supply co-stimulatory signal to T-cells
      1. Generated by B7 on APC stimulating CD28 on naive T-cells
  4. Macrophages
    1. Phagocytic
    2. Have receptors for bacterial carbohydrate
    3. Inducible B7 expression
  5. Dendritic Cells
    1. Initiate T-cell responses against viruses
    2. Possibly have specialised antigen processing
    3. Immature dendritic cells do not have co-stimulatory acitivity
    4. When they ingest antigens, they migrate to lymph node and become activated
3. T-cell Development
  1. T-cells originate from stem cells in bone marrow
  2. Mature in thymus
    1. Thymus is a primary lymphoid organ as its concern is the production of useful lymphocytes and not with their applications to specific infections
    2. Most active in young
    3. Increases in size up to puberty
  3. Immature CD3-4-8- (double negative)
    1. Become immature CD3+4+8+ (double positive
      1. Mature CD4+8- and CD4-8+
4. T-cell mediated immunity
  1. Activation
    1. Dendritic cells take up bacterial antigens in the skin and then move to a lymphatic vessel
      1. Dendritic cells bearing antigen enter the lymph node, where they settle in the T-cell areas
        T cells that do not encounter specific antigen leave a lymph node through lympatics
        T-cells that encounter specific antigen proliferate and differentiate to effector cells
    2. Naive T cells express the low affinity IL-2 receptor
      1. Activated T-cells express the high affinity IL-2 receptor and secrete IL-2
        Binding of IL-2 to the high affinity receptor sends a signal to the T-cell
        The signal sent from the IL-2 receptor induces T-cell proliferation
    3. Activated CD4 T-cells can differentiate in different ways that favour humoral or cell mediated immune response
    4. Naive CD8 T-cells can be activated in different ways
      1. Generally needs stronger co-stimulatory activity
      2. Dendritic cells
      3. APCs with help of CD4 positive T-cell
  2. Effector T-cells
    1. Can be stimulated by antigen in absence of co-stimulatory signal
    2. Functions are performed by cytokines and cytotoxins
  3. Selective killing
    1. Collision and non-specific adhesion
      1. Specific recognition redistributes cytoskeleton and cytoplasmic components of T-cell
        Release of granules at site of cell contact
  4. Apoptosis
    1. Cytotoxic T-cell (CTL) recognises virus-infected cell
      1. CTL programs target cell to die
  5. Co-operation between B and T-cells occurs that are specific for the same antigen (usually different epitopes)
Responds to challenge with a high degree of specificity
Memory

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