ANTIBODY-ANTIGEN REACTIONS

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  Basics
  
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    Interaction is non-covalent: H-bonding, electrostatic, Van Der Waals, hydrophobic
    
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    Better fit  tighter bonding
    
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    Interaction is reversible
    
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      Mass action: K = [Ab—Ag]/[Ab][Ag]
      
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  Types of antigen-Ig reactions
  
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    Agglutination: antigen particle plus specific Ig  aggregation of particle
    
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    Precipitation: soluble antigen plus specific Ig  insoluble lattice formation
    
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    Complement activation: antigen in solution/on cell plus specific IgG or IgM  complement inactivation
    
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    Cytolysis: cell plus anti-cell Ig plus complement  lysis of cell
    
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    Opsonization: antigenic particle plus Ig plus complement  enhanced phag
    
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    Neutralization: toxins/viruses/hormones plus specific Ig  inactivation
    
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  Antigens
  
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    Microbes have lots of surface molecules each with many antigenic determinants
    
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      Some elicit stronger responses than others (based on health, age, genetics)
      
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    Haptens (e.g. Penicillin): small molecules that can’t elicit Ig response unless attached to larger molecules (carriers)
    
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  Cross-reactivity
  
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    Similar/identical antigenic determinant on multiple molecules or cells (shared epitope)
    
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    Cross-reactive antigen may not bind to Ig quite as well
    
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    E.g. people have Ig’s to blood type antigens other than their own bc they’re similar to carb antigens on some microbes
    
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    May explain natural/innate Ig’s to a variety of molecules
    
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    Autoimmune (e.g. group A strep infection  rheumatic fever; strep antigens similar to heart muscle)
    
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  Precipitation: antigenic particles initially soluble
  
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    Anti-hapten Ig plus hapten  soluble complex
    
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    Anti-hapten Ig plus protein with many haptens attached  insoluble complex
    
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    Lattice formation: if protein has several hapten determinants, Ig can bind to more than one antigen (hapten) at a time
    
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      Leads to precipitation
      
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      Adding hapten to anti-hapten Ig before adding hapten-protein conjugate inhibits precipitation
      
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    Level of precipitation
    
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      Antibody excess zone: lattice doesn’t develop, soluble
      
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      Equivalence zone: maximum precipitation; no antigen or Ig detected in supernatant
      
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      Antigen excess zone: lattice doesn’t develop, soluble
      
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    Protein antigens don’t usually have repeating sequences  1 determinant of a particular kind per protein antigen
    
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      So, there are usually multiple Ig’s formed for each protein antigen (specific to its diff determinants)
      
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      So, lattice formation doesn’t occur for most soluble proteins (unless it has repeats)
      
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  Agglutination: linking insoluble antigenic particles
  
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    Interaction of surface antigens on insoluble particles (e.g. cells) with antigen-specific Ig
    
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    Need much less Ig than for precipitation
    
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      Clinical uses:
      
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        Blood type
        
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        If bacteria is present in blood
        
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    IgM is more efficient at it than IgG bc it has 10 binding sites
    
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    Sometimes Ig binding to cell doesn’t cause agglutination
    
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      Use second Ig reactive to first Ig
      
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      Coombs test
      
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        Identifying patients with hemolytic anemia
        
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        Use Ig reactive to human Ig  causes agglutination of RBCs if human Ig is bound to RBCs
        
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        Or indirectly: add patient serum to cells and then add mouse or rabbit anti-human Ig to detect circulating Ig reactive to cell surface Ig
        
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    Results in bigger circle on plates
    
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  Monoclonal antibodies
  
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    Making monoclonal antibodies (mAbs)
    
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      Fuse immortal cell (myeloma tumor cell) with specific Ig-producing B cell from immunized animal/human  hybridoma cell
      
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      Hybridoma cell is immortal and makes specific mAbs
      
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      Used for clinical applications
      
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    Fv libraries to make mAbs
    
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      Get mRNA for Vh and Vl regions from lots of B cells
      
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      Use the mRNA to make cDNA for each H chain V region and randomly join it with cDNA for each L chain V region  produces genes with lots of diff antigen combining sites (Fv regions)
      
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      Clone the Fv’s into cells  source for specific mAbs
      
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  Antigen-Antibody assays used clinically
  
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    Background
    
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      Antigen on cell can be detected via labeled Ig
      
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        Radioisotopes, fluorescein, enzymes
        
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    Radioimmunoassay (RIA)
    
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      Measure serum level of Ig to a specific antigen
      
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      Add antigen to wells  wash  add test Ig  wash  detect with radiolabeled ligand that binds to Ig
      
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    Enzyme-linked immunoabsorbent assays (ELISA)
    
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      Like RIA, but ligand is coupled to enzyme (e.g. peroxidase)
      
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      Bind ligand to test Ig  wash  detect by adding substrate that reacts with enzyme  color
      
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    RadioAllergoSorbent Test (RAST)
    
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      Like RIA, but measures antigen-specific IgE with radiolabeled anti-IgE
      
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    Antigen detection
    
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      Competitive assay: Ig on plate  add test antigen (serum) and labeled antigen  test antigen will out-compete labeled if it’s present
      
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      Two-site capture assay (more common): capturing Ig on plate  add test antigen (serum)  binds to capturing Ig  add labeled Ig  binds to other site on test antigen
      
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    ELISPOT: for cells that produce cytokines
    
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      Cytokine-specific Ig on plate  add activated T cells  T cells secrete cytokines  cytokines bind to Ig  add second cytokine-specific Ig that’s labeled with enzyme  colored precipitate
      
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    Mistakes during antigen detection
    
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      Caused by heterophillic Ig (HA) – anti-animal human Ig
      
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      False positives: HA bridges test Ig and labeled Ig via Fc or Fb regions
      
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      False negatives:
      
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        Anti-idiotype HA steric hindrance: HA blocks test-Ig binding sites by binding to Fab
        
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        Anti-isotype HA steric hindrance: HA blocks test-Ig binding sites by binding to Fc
        
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        Antigen binding HA steric hindrance: HA binds to antigen so it can’t bind to test Ig
        
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    Flow cytometry
    
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      Bind labeled Ig to cells in suspension  run through flow cytometer  cytometer measures fluorescence of each cell
      
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      If labeled Ig cells are run through fluorescence-activated cells sorter (FACS), cells get separated into diff tubes based on their brightness
      
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      Use to test for cancer types with blood cancer
      
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    Immunohistochemistry (IHC)
    
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      Detect antigens on histological specimens
      
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      Bind labeled Ig to tissue section  wash  detect expression via fluorescence or enzymes
      
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      Advantage: detect antigen within complex tissue
      
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        Counterstain all/adjacent cells and tissues to get location of antigen
        
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      Use to test for cancer types with solid tumors
      
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  What to know
  
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    Understand the basic nature of antigen-antibody reactions
    
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    Know the difference between a hapten and an immunogen
    
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    Understand cross-reactivity and the consequences of it
    
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    Know requirements for lattice formation and precipitation
    
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    Know what a Coombs test is
    
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    Know what monoclonal antibodies are and their uses
    
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    Be familiar with the basic concepts involved in antigen-antibody assays, including RIA, RAST, ELISA, and flow cytometry
    

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  Immune system must monitor for pathogens inside and outside cells
  
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    Outside: bacteria, protozoa, worms, fungi
    
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    Inside: viruses, bacteria, protozoa, tumors
    
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    Monitor outside via Ig
    
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    Hard to get at the inside ones  small pieces of proteins inside cells (peptides) are presented on surface via MHC
    
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    MHC-peptide complex scanned by TcR
    
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    If TcR binds MHC-peptide complex AND gets costimulatory signals, T cell responds  proliferation, cytokine production, differentiation
    
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  MHC Class I pathway: presentation to CD8 T cells (CTL) – kill virus-infected cells ----
  
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    Occurs in all nucleated cells
    
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    Proteosome: protein complex that degrades defective cellular proteins in cytoplasm for reuse
    
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      During immune response, proteosome changes shape better  makes peptides that have better fit with MHC I
      
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    Transporters associated with antigen processing (TAP): Brings peptides into ER
    
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    In the ER: peptides associate with MHC I exported to cell surface
    
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    Cell surface: MHC-peptide complex recognized by CD8 T cells
    
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  MHC Class II pathway: present to CD4 helper T cells – interact with DC, macro, B cell
  
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    Occurs in antigen presenting cells (APC) – macrophage, B cell, dendritic cell
    
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    APC phagocytoses extracellular proteins
    
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      Macrophage and DC take up lots of antigens via nonspecific receptors
      
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      B cell takes up specific antigen via specific Ig  B cell activation
      
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    Endocytic/lysosomal vesicles: pathogen proteins broken into peptides
    
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    MHC II fuses with endocytic vesicle and gets loaded with peptide
    
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      MHC II is assembled in ER but doesn’t take up peptides there (MHC I does)
      
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      Invariant chain blocks binding pocket of MHC II when in ER
      
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      Invariant chain degraded in endosome, leaving CLIP peptide
      
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      HLA-DM removes CLIP, so MHC II can bind to peptides in endosome
      
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    MHC-peptide complex goes to cell surface  recognition by CD4
    
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      TcR binds to specific MHCII (recognizes antigen)
      
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      CD4 binds to invariant region of MHC II
      
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  Features of MHCs
  
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    One peptide displayed at a time  each T cell responds to single MHC-peptide
    
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    Peptides acquired during MHC complex assembly intracellularly (endosome for MHC II, ER for MHC I)
    
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    Low affinity, broad specificity  different peptides can bind to the same MHC
    
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    Slow off-rate  peptide displayed long enough to get specific T cell
    
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    Stable expression requires peptide  empty MHCs recycled
    
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    MHCs only bind peptides  MHC-restricted T cells only respond to protein antigens (not carb, lipid, na!)
    
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  Cross-presentation
  
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    Costimulation is only provided well by APCs (especially DCs)
    
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    So, CD8 cells need a way to respond to virus-infected cells, which don’t provide costimulation
    
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    DCs ingest virus-infected cells and present viral peptide on MHC I
    
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      = cross-presentation
      
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      antigens move from endosome to cytoplasm!
      
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      Then they follow MHC I pathway and are presented to CD8
      
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      They’re also present to CD4 via MHC II like usual
      
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  MHC molecules and peptide binding
  
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    MHC’s have polymorphic peptide binding domains
    
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    Peptides that bind are 9-12 aa
    
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      Have anchor residues (Y) which bind to MHC
      
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    Diff MHC’s bind to diff peptides from same antigen bc they have diff aa’s
    
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    MHC must be able to bind to peptides of an antigen to have T cell response to that antigen
    
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  MHC structure
  
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    MHC I and II genes linked on chromosome 6
    
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    MHC I
    
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      HLA- A, B, C genes
      
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      10-70 alleles for each
      
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      Complex: MHC I alpha chain, beta-2-microglobulin, peptide
      
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        CD8 binds to alpha 3 domain
        
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    MHC II
    
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      HLA- DR, DQ, DP genes
      
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      7-70 alleles for each
      
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      Complex: MHC II alpha chain, MHC II beta chain, peptide
      
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        Alpha and beta are polymorphic, mostly in alpha 1 and beta 1 domains, which interact with TcR
        
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        CD4 binds to beta 2 domain
        
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    Codominant expression; complete set of genes inherited from each parent  increases diversity of MHC
    
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    Polymorphic genes  diff individuals present and respond to diff microbial peptides
    

Examples:

1. influenza virus

2. mycobacterium tuberculosis

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  Tissue distribution of MHC I and II antigens
  
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    B cells, DC, macrophages express lots of MHC II  proficient at presenting to CD4 T cells
    
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    All nucleated cells express MHC I  proficient at presenting to CD8 T cells
    
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  Non-classical MHC molecules
  
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    HLA-G
    
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      MHC I
      
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      Nonpolymorphic, no HLA-A, B, or C
      
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      In extravillous trophoectoderm (fetal tissue contacting maternal circulation)
      
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      May prevent maternal immune response (T and NK cells) against paternal antigens in the fetus
      
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    CD1d
    
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      Nonpolymorphic
      
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      Not encoded in MHC region
      
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      On B cells, DC, and some non-APCs
      
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      Presents non-peptide antigens (lipid and glycolipid) to T cells
      
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      Restricts T cell response to foreign microbial antigens
      
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  Uptake and presentation of foreign antigens (MHC II, or MHC I via cross-presentation)
  
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    Immature DCs take in foreign antigens at epithelium/CT
    
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    DCs get signals that there’s a pathogen
    
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      Pathogen-associated molecular signals (lipopolysaccharide, double stranded RNA)
      
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      Inflammatory cytokines
      
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    DCs migrate to lymph nodes via lymphatics to present to T lymphocytes
    
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      Migrate to T cell areas using cytokine gradients
      
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      DCs mature and upregulate expression of costimulatory molecules  activate antigen-specific T cells by presenting antigen and giving costimulation
      
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    Antigens that enter blood stream can be captured by APCs in spleen
    
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  What to know
  
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    Understand MHC class I pathway
    
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    Understand MHC class II pathway
    
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    Know the fundamental differences in the Class I and II MHC processing pathways, and with which subsets of T cells they interact.
    
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    Know the general properties of class I and class II MHC molecules
    
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    Know the restrictions for peptide binding to MHC molecules.
    
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    Know the significance of MHC gene polymorphisms
    
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    Understand the role of dendritic cells in antigen presentation to naïve T cells
    

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  Combatting intracellular infections is primary role of T lymphocyte
  
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    Microbes in phagosome can resist proteolysis
    
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    Viruses in cytoplasm
    
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  T lymphocytes
  
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    Scan for intracellular pathogens via TcR
    
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    TcR recognizes antigenic peptides on MHC
    
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    Once recognized, T cells become effectors  attack, recruit other cells, increase killing efficiency
    
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    CD8 cells (CTL)
    
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    CD4 cells (Th)
    
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      Can differentiate to effectors, secrete cytokines
      
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      Target of AIDS virus
      
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    Induce adaptive immune response and immunological memory
    
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  Antigen recognition
  
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    DO NOT recognize native antigen
    
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      Recognize peptides from antigens (bacteria, virus) on MHC
      
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    TcR --------------------------------------------------------------------------------
    
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      Alpha and beta chains created from gene recombination
      
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      Each T cell expresses TcR with diff sequence that recognizes unique peptide-MHC complex
      
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      Rearrangement/expression in thymus during T cell devel.
      
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      TcR complex
      
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        TcR: unique alpha and beta for each MHC-peptide
        
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        CD3 proteins: activate signaling pathways in T cell; identical on all T cells
        

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  Coreceptors needed for T cell activation
  
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    CD4: binds to MHC II invariant residues in beta 2 domain
    
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    CD8: binds to MHC I invariant residues in alpha 3 domain
    
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  Immunological synapse
  
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    Naïve T cells circulate through nodes and spleen looking for APCs with MHC-peptide that matches their TcRs
    
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    T cell stimulation requires:
    
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      TcR binding to MHC-peptide
      
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      CD4/8 coreceptor activation
      
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      CD3 signal conduction
      
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      Adhesion molecule (integrin) engagement
      
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        ICAM-1 on T cell, LFA-1 on APC
        
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        Surround TcR-MHC proteins and hold cells together
        
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          = immunological synapse
          
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        Chemokines and antigen-TcR binding make integrins become high-affinity  strong adhesion between cells  T cell response
        
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      Costimulation (see below)
      
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  Costimulation
  
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    Activates specific pathways, ESSENTIAL for naïve T cell activation
    
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    CD80 (aka B7): on APCs, binds to CD28 on T cells
    
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    CD86: on APCs
    
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    Expression on APC increases in response to microbe  signal 2
    
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    Only on DC, mac, B cell  ONLY THES PROFESSIONAL APCs can activate naïve T cells!!
    
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    Two-signal model to prevent response to self antigens
    
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      Signal 1: TcR binds to MHC-peptide
      
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        If CD8 T cell only gets signal 1  tolerance (T cell is unresponsive/inactived – anergy)
        
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      Signal 2: CD28 binds to costimulator, which upregulates at APC surface in presence of microbe
      
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        Signal 1 and 2  growth and cytokine production of T cell
        
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    Cross-presentation of extracellular peptides by MHC I is needed so that CD8 T cells can get activated!
    
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      ??????
      
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  Early T cell activation, growth, cytokine production
  
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    Clonal expansion
    
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      Activated T cell begins to divide A LOT
      
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      Daughter cells (clones) have same TcR and same MHC-peptide specificity
      
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    T cells make growth factors to support their growth
    
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      Interleukin 2 (IL-2)
      
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        Interleukin/lymphokine: soluble proteins make by immune cells
        
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        Production stimulated by TcR stim
        
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      T cell increases high-affinity Il-2 receptor as well
      
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         autocrine signaling loop
        
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      Also paracrine function of IL-2 on other cells
      
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        B cell differentiation
        
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        Growth factor for NK cells
        
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  Turning off immune response
  
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    Activated T cells begin expressing CTLA-4
    
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    CTLA-4 binds strongly to CD80 and 86, replacing CD28  inhibitory signal
    
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    Lack of CTLA-4 function can cause inflammatory disorders, tissue injury
    
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  Superantigens
  
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    Some bacteria/viruses make proteins that are superantigens bc they stimulate lost of diff T cells
    
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    Bind to sides of MHC II and Vb region of TcR, gluing APC and TcR together
    
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    Tons of cytokine production  vascular leakage, shock
    
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    Staphylococcal enterotoxins (food poisoning, toxic shock syndrome)
    
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  What to know
  
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    How the TCR recognizes antigen
    
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    Coreceptors involved in T cell activation
    
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    What is costimulation?
    
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    Clonal expansion of antigen specific T cells
    
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    Role of cytokines in T cell activation
    
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    Inhibition of T cell activation by CTLA-4
    
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    What are superantigens?
    

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  T cell selection
  
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    T cell precursors migrate to thymus (progenitor cells committed to T cell lineage)
    
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    Most die within thymus
    
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    T cells undergo gene rearrangement in thymus  TcR expressed on thymocytes
    
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      Have CD4 and CD8 = double positive thymocytes
      
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      Many can’t express usable TcR
      
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    Positive selection: cells with TcR that weakly binds to MHC I or II survive
    
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      Thymic epithelial cells in thymic cortex are the presenting cells, present lots of peptides that would normally be expressed elsewhere
      
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      Then express only CD4 or 8 depending on if they bind MHC I or II
      
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    Negative selection: cells with TcR that strongly binds to MHC I or II die
    
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      Autoreactive, so may cause problems in periphery
      
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      DC, mac, medullary epithelium are the presenting cells
      
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    Select T cells that recognize self MHC and foreign peptide, not self peptide!
    
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    Regulatory T cells: possibly come from cells with very high affinity for self
    
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      CD4 cells that suppress immune responses when exported to periphery
      
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      Inhibit via cytokine production (active) and interaction with other cells (passive)
      
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  Lymphocyte trafficking and recirculation: speed dating btwn lymphocytes and DC’s
  
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    Naïve B and T cells (have not found their antigen yet) recirculate through secondary lymph organs
    
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    Adhesion molecules on surface let them attach to endothelial cells to exit blood stream via HEV
    
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    Homing adhesion molecules attach to specific molecules on endothelial cells (addressins) in certain sites ---------------------
    
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      Allows lymphocytes to target mucosal or peripheral lymph node areas
      
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      MALT: lymphocytes stimulated in one MALT site will migrate to other MALT sites via homing
      
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    Once activated, lymphocytes alter chemokine receptors so they can go into blood stream and infection
    
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  Tolerance
  
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    Antigen-specific T or B cells reactive to self tissues may be:
    
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      Clonally deleted
      
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      Made functionally unresponsive
      
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      Prevented from responding (suppressed)
      
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      Lacking antigen-specific receptor or MHC element (CD4/8)
      
  • 
    Tolerance is specific
    
    • 
      Can still respond to other antigens
      
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      May be partial (e.g. weak/altered immune response)
      
    • 
      Can be humoral or cellular
      
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    Central tolerance
    
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      Clonally deleting T and B self-reactives in the thymus and marrow (i.e. negative selection)
      
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      Antigen exposure during development
      
      • 
        Virus in neonate may be seen as self  deletion of lymphocytes responsive to it
        
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    Peripheral tolerance
    
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      Some autoreactive T cells make it to the periphery
      
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      If self-antigen is on an APC when the APC also happens to have antigen particles, autoreactive T cell can get costimulation and respond; otherwise, they won’t respond  anergy (expression of proapopotic proteins or of death receptor and death receptor ligands Fas/Fas-L)
      
    • 
      CD4 T regulatory cells can keep T cells from responding
      
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  Effector cells in T cell immunity -----------------------------------------------
  
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    Activation requires:
    
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      Specific signal via TcR
      
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      General costimulatory signal
      
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    Activation  autocrine growth factors (IL-2), alters cells surface molecules (for trafficking), inc membrane proteins to trigger other cells (e.g. CD154), production of cytokines
    
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  CD8 cytotoxic T cells (CTL): recognize MHC I
  
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    Host resistance to pathogens that live in cytosol (e.g. viruses)
    
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    Recognize pathogens via MHC I
    
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    Killing mechanisms
    
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      Lyse cells they bind to with perforin and granzymes  pores in cell membrane  apoptosis
      
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      Release factors (TNF-alpha, IFN-gamma) onto cells they bind to or express molecules on surface (Fas-L) that trigger apoptosis
      
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  CD4 helper T cells (Th): recognize MHC II
  
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    Early mature cells: Th0
    
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      Broad spectrum of cytokines
      
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    Later mature cells: Th1, Th2, Th17
    
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      Th1: inflammatory responses (activate mac and CTL) via cytokines IFN-gamma, IL-2, TNF-alpha
      
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        Intracellular microbes – help macrophages become completely activated (IFN, TNF)
        
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        Makes cytokines that recruit macrophages and inc release from marrow (GM-CSF, IL-3)
        
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        TNF promotes adhesion of macrophages to endothelial cells at infection site
        
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        Induce B cells to make IgG
        
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        IFN-gamma: prevents induction of Th2; increase production of cytokines that inc Th1 differentiation (pos feedback)
        
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      Th2: help B cells grow/differentiate via cytokines IL-4, IL-5, IL-13
      
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        Induce B cells to make Ig, isotype switching, affinity maturation!! Via:
        
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        Cytokines
        
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          IL-4  IgE  IgE binds to mast cells  mast cells make IL-4  Th2 induction (pos fdbck)
          
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          Allergic rxns
          
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        Surface molecules that engage B cells
        
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        IL-5  eosinophil production in marrow (worms, large parasites)
        
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      Th17: inflammation, autoimmunity, inflammatory disorders via IL-17
      
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  CD4 regulatory T cells (Treg)
  
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    Usually derived from strongly self-reacting CD4 cells in the thymus; become T reg with IL-2 and Foxp3
    
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    Suppress T cell immune responses in thymus (inhibit activation) and periphery (inhibit effector function)
    
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    Maintain tolerance to self-proteins
    
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    Contact-dependent mechanism that reduces inflammatory response via IL-10, TGF-beta
    
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  Cytokines
  
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    Act like hormones and NTs for cellular communication
    
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    Proteins, peptides, or glycoproteins
    
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    Interleukins, interferons, etc
    
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    Have lots of functions; related to allergies, cancer, inflammatory disease, immune reconstitution
    
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    Cytokines enhance or suppress cell-mediated immunity  treatment of autoimmunity, cancer, etc.
    
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  What to know
  
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    Thymic structure
    
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    T cell development in the thymus
    
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    What is MHC restriction? Why is this important?
    
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    Mechanisms of central vs peripheral tolerance
    
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    T cell trafficking in the periphery and into tissue
    
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    Role of cytokines in T cell effector cell development
    
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    Mechanisms of CD8+ T cell function
    
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    CD4+ T cell subsets and their function in immunity