Adaptive Immune System

Adaptive Immune System

1. Humoral

   • Antibodies
     • Functions
       • Bind very specifically to an antigen
       • Neutralisaiton
       • Mark for phagocytosis
       • Activates complement system
     • Structure
       • 5 isotypes: IgA, IgD, IgE, IgG and IgM
       • IgG most common
         • Y shaped
         • 4 polypeptides
         • Heavy chains help together by covalent intermolecular-disulphide bonds
         • Heavy chain and light chain held together by covalent intermolecular-disulphide bonds
         • Antigen binding sites found at teh N-terminus of polypeptides
         • Variability found in the amino acids of the antigen binding sites
       • HV = hypervariable
       • CDR = complementarity determining regions
       • Epitope = region (small portion) of an antigen that the antibody recognises
     • Antigens
       • Antigenicity is the ability to combine with antibodies
       • Immunogenicity is the ability to induce humoral (or cell mediated) immune response
         • Foreigness
         • Molecular size (large molecules are generally more immunogenic than small ones)
         • Chemical composition
         • Heterogeneity
   • Generation of antibody diveristy
     • Can produce billions of different antibodies
       • Production of variable regions of light and heavy antibody genes by DNA rearrangement
     • In all cells apart form B-cells immunoglobulin genes are in a form that cannot be expressed
     • J = Joining, D = Diversity, V = variable
     • Random recombination of gene segments produces diveristy
       • Recombine signal sequences (RSSs) flank the 3' of V segment, both sides of D segment and 5' of J segement
       • Recombination can only occur between RSSs of different types
         • Ensures correct order of joining
       • RAG = Recombination activating gene - mediates recombination
     • Additional diversity is added by recombination enzymes
       • P-nucleotides generate palindromic sequences at the cut ends of DNA strands
       • N-nucleotides are added at random to the cut end by terminal deoxynucleotidyl transferase (TfT)
     • Overview
       • 1. RAG complex binds to and cleaves recobination signal sequences to yield a DNA hairpin
       • 2. RAG-mediated cleavage of hairpin generates palindromic P-nucleotides
       • 3. N-nucleotide additions by TdT
       • 4. Pairing of strands
       • 5. Unpaired nucleotides are removed by an exonuclease
       • 6. These gaps are filled by DNA synthesis and ligation to form coding joint
     • Naive B-cells use alternative splicing to yield IgM or IgD
     • Membrane bound immunoglobulins are complexed with other proteins to functional B-cell receptors
     • Each B-cell has a single antigen specificity
       • Immunoglobulin gene rearrangement tightly regulated so that only on H and on L chain are expressed
       • B-cells that don't produce functional immunoglobulin are eliminated from population
   • Development on B-cells
     • 1. Generation of B cells in bone marrow
     • 2. Elimination of self reactive B cells in bone marrow
     • 3. Activation of B cells by foreign antigen in secondary limphoid tissues
     • 4. Differentiation to antibody-secreting plasma cells and memory cells in the secondary lymphoid tissues
     • Stages of B-cell development are marked by steps in rearrangement and expression of immunoglobulin genes
     • Only B-cells that produce functional immunoglobulin can survive
       • Get a number of chances
       • 55 billion B-cells per day are lost in the bone marrow because they fail to make functional Ig or are self reactive
     • Mature naive B-cells compete for access to lymphoid follicles
       • when mature B-cells leave the bone marrow they circulate between the blood and secondary lymphoid tissues (lymph nodes, spleen)
         • 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)
   • B-cell
     • Before encountering an antigen, a mature B-cell expresses antibody in a membrane bound form
     • When a foreign antigen binds to this immunoglobulin, the B-cell is stimulated to proliferate and gives rise to plasma and memory cells
   • B-cells that encounter antigen
     • Mature naive B-cells encounter specific antigen in secondary lymphoid tissue
       • Activated by CD4 helper T-cells
       • These T-cells provide signals that activate the B-cells to proliferate and differentiate further
         • Some differentiate into plasma cells
         • 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

2. Cell mediated

   • T-cell receptor
     • Always membrane bound
     • Diversity is generated by gene rearrangmenet
       • Similar to rearrangement of iG genes
       • Uses RAG1 and RAG2
       • Addition of P and N nucleotides
     • Associates with other proteins
       • CD proteins (CD3)
   • Antigen processing and presentaiton
     • T cell receptors can only recognise antigens that are bound to MHC molecules
       • MHC = Major Histocompatibility Complex
         • Membrane glycoproteins
         • Function is to bind antigen and present it to T-cells
         • MHCI and MHCII have similar 3D structure but formed in different ways
         • 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
         • 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 main classes of T-cell
       • CD4 co-receptor needed for T-cell recognition of MHCII peptides
         • TH1 cells
           • Activate tissue macrophages to take up antigen
           • Stimulate B-cells to produce antibody
         • 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
         • MHCII presents peptides derived from extracellular pathogens (antigens from outside the cell)
       • CD8 co-receptor needed for T cell recognition of MHCI peptides
         • Cytotoxic
         • MHCI responsible for presenting peptides derived from intracellular antigens (antigens produced without own own cytoplasm
     • Professional APCs (Antigen presenting cells)
       • MHC class II alert CD4 positive T-cell of infection (extracellular)
         • Expressed on professional APCs
           • Macrophages
           • B-cells
           • Dendritic cells
       • Supply co-stimulatory signal to T-cells
         • Generated by B7 on APC stimulating CD28 on naive T-cells
     • Macrophages
       • Phagocytic
       • Have receptors for bacterial carbohydrate
       • Inducible B7 expression
     • Dendritic Cells
       • Initiate T-cell responses against viruses
       • Possibly have specialised antigen processing
       • Immature dendritic cells do not have co-stimulatory acitivity
       • When they ingest antigens, they migrate to lymph node and become activated
   • T-cell Development
     • T-cells originate from stem cells in bone marrow
     • Mature in thymus
       • Thymus is a primary lymphoid organ as its concern is the production of useful lymphocytes and not with their applications to specific infections
       • Most active in young
       • Increases in size up to puberty
     • Immature CD3-4-8- (double negative)
       • Become immature CD3+4+8+ (double positive
         • Mature CD4+8- and CD4-8+
   • T-cell mediated immunity
     • Activation
       • Dendritic cells take up bacterial antigens in the skin and then move to a lymphatic vessel
         • 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
       • Naive T cells express the low affinity IL-2 receptor
         • 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
       • Activated CD4 T-cells can differentiate in different ways that favour humoral or cell mediated immune response
       • Naive CD8 T-cells can be activated in different ways
         • Generally needs stronger co-stimulatory activity
         • Dendritic cells
         • APCs with help of CD4 positive T-cell
     • Effector T-cells
       • Can be stimulated by antigen in absence of co-stimulatory signal
       • Functions are performed by cytokines and cytotoxins
     • Selective killing
       • Collision and non-specific adhesion
         • Specific recognition redistributes cytoskeleton and cytoplasmic components of T-cell
           • Release of granules at site of cell contact
     • Apoptosis
       • Cytotoxic T-cell (CTL) recognises virus-infected cell
         • CTL programs target cell to die
     • Co-operation between B and T-cells occurs that are specific for the same antigen (usually different epitopes)

3. Responds to challenge with a high degree of specificity

4. Memory