Immunology BE433 Lecture 9 Humoral Immunity PDF

Immunology BE433 Prof Christine Loscher Lecture 9 Humoral Immunity How do B cells see antigen? • Antigen recognition molecules are immunoglobulins (Ig) • Proteins produced by B cell with single specificity • Membrane bound Ig on the cell surface acts as the cells receptor for antigen – B cell rece...

Immunology BE433 Prof Christine Loscher Lecture 9 Humoral Immunity How do B cells see antigen? • Antigen recognition molecules are immunoglobulins (Ig) • Proteins produced by B cell with single specificity • Membrane bound Ig on the cell surface acts as the cells receptor for antigen – B cell receptor (BCR) • Ig of same specificity is secreted by activated B cells (plasma cells) – main effector function of B cells • Ig binds pathogens or their toxic products in the extracellular spaces Figure 3-1 part 3 of 3 • Difference between Abs is in the variable region • Hypervariable regions determine the specificity – complementarity-determining regions (CDR) • Amino acid side chains in almost all of the hypervariable regions make contact with the antigen • Rest of Ab provides framework to support interaction • Ab against intact proteins usually bind the surface but sometimes bind fragments • Those raised against peptide fragments can sometimes detect the whole protein Humoral Immune Response • Extracellular spaces are protected by humoral immunity • Many bacteria multiply in the extracellular spaces • Most intracellular pathogens spread by moving from cell to cell through extracellular fluids • Requires Th2 cells • Antibodies contribute to immunity in 3 ways Activation of B cells by T helper cells • The BCR has 2 roles in B cell activation • 1. The antigen receptor transmits a signal inside the cell when it binds antigen • 2. The BCR delivers the antigen to intracellular sites for degradation and binding to MHC2 • This peptide:MHC molecule is recognised by antigen-specific armed T helper cells. • This stimulates them to produce proteins and causes them to proliferate and differentiate into antibody-secreting cells • [many microbial molecules can induce antibody production in the absence of T helper cells] Armed helper T cells activate B cells that recognise the same antigen – linked recognition • The epitope/peptide recognised by armed T cells must be linked to that recognised by the B cells – don’t need to recognise identical epitopes/proteins • Needs to be physically associated • Activation of B cell depends on its ability to concentrate the appropriate peptide on its surface MHC2 molecules • Linked recognition important for self tolerance and development of vaccines T helper cells secrete molecules to activate B cells • Recognition of peptide:MHC2 complex on B cells triggers armed T helper cells to synthesise both cell-bound and secreted effector molecules • CD40 ligand on T cells binds CD40 on B cells • This ligation helps to drive the resting B cell into the cell cycle and increases expression of co-stim molecules – B7 family • IL-4 secreted by T cell and induces B cell proliferation • Other molecules include CD30, 41BB • After proliferation B cells differentiate into plasma cells – IL-5 and IL-6 from T cells important here Isotype switching • Antibodies are versatile effector molecules • The specificity of antibody is determined by the antigen binding site – 2 variable V domains • The effector action determined by the isotype of its heavychain C region • The DNA rearrangements that underlie isotype switching and confer functional diversity on the humoral immune response are directed by cytokines – especially those produced by CD4 T cells • All naïve B cells express cell-surface IgM and IgD. Most abundant isotype in plasma is IgG – much of the antibody in plasma is produced by B cells that have undergone isotype switching • Predominance of IgG is due to its longer lifetime • Early response – IgM and little IgD • Later – IgG and IgA • CD40-CD40L required for this Antibody types • Antibodies of different isotype operate in distinct places and have distinct effector functions • IgM produced first - rapid – tend to have low affinity – found in blood and lymphs • IgG, IgA, IgE produced later. • IgG – principal isotype in blood and extracellular fluid • IgA – in secretions (intestine/respiratory) • IgE – low levels in blood/extracellular fluid – binds receptors on mast cells – triggers them to produce powerful chemical mediators that induce coughing, sneezing and vomiting IgG and IgA can neutralize bacterial toxins • Some bacteria cause disease by releasing toxins – damage or disrupt function of host cells • To exert its effect this toxin must interact specifically with a molecule that serves as a receptor on the surface of target cell • Antibodies bind to the receptor binding site on toxins block binding of toxin to target cell – neutralize toxin • IgG can diffuse easily and have high affinity – principal neutralizing antibody • IgA neutralize toxins at mucosal/secretory surfaces in body IgG and IgA can inhibit the infectivity of viruses Antibodies can block adherence of bacteria to host cells Antibody:antigen complexes activate the classical complement pathway by binding C1q Destruction of antibody-coated pathogens via Fc receptors • Binding of antibodies to pathogens can protect against infection but does not solve the problem of how to remove the pathogen/products from the body • And some pathogens cannot be neutralised by Ab and need to be linked to other effector mechanisms • Activation of accessory effector cells bearing Fc receptors – bind Fc portion of Ab • These receptors facilitate the phagocytosis of neutralised pathogens by macrophages, DC and neutrophils • Other non-phagocytic cells – NK, mast cells, basophils are triggered to release stored mediators when Fc receptors are engaged • Different cell types bear Fc receptors for antibodies of different isotypes – the isotyope of Ab will determine which cell will be activated to respond • Antibodies can also bind to infected cells expressing pathogen proteins on it’s surface • These can be killed by natural killer (NK) cells – antibody-dependent cell-mediated cytotoxicity (ADCC)