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Specificity of the interaction between the receptor and epitope is determined by the amino acid sequence of the receptor ( tailoring the glove ). If the glove is too big, the glove falls off. If the glove is too small, you can t get your hand into it. If the glove is missing fingers& *   )Examples of Receptor-Epitope Interactions * Enzymatic reactions Antigen recognition Antigen-Antibody reactions Biological chaperones (stress proteins) Cellular communications Cell-mediated cytotoxicity Cellular homing (MALT, chemotaxis, etc.)&     Basic Immunoglobulin Structure(    %The Prototype Immunoglobulin Molecule&&( & JHeavy Chains (five types: a, g, m, d, e) Light Chains (two types: l and k ) Fab fragment Fc fragment Constant and variable regions Carbohydrate Disulfide linkagesVW   Immunoglobulin G (IgG)(  2 Heavy and 2 Light chains 2 Fab and 1 Fc fragment 4 Subclasses (IgG1, IgG2, IgG3, IgG4) Mol. Wt. 150,000 ~70-75% of serum immunoglobulin. The major antibody of the secondary immune response Change in affinity with time   Immunoglobulin M (IgM)(  10 Heavy and 10 Light chains 10 Fab and 5 Fc fragments Mol. Wt. ~900,000 <10% of serum immunoglobulin. Single J Chain (15 kDA) The predominant "early" antibody Most primitive immunoglobulin No change in affinity with time  Immunoglobulin A (IgA)(  wMonomeric- Serum IgA ~15-20% of serum immunoglobulins 2 Heavy and 2 Light 2 Subclasses (IgA1 and IgA2) Found in serum x !Secretory Immunoglobulin A (sIgA)""( " 4 heavy chains and 4 light chains (dimeric) J-Chain and secretory component The major immunoglobulin of secretions Not found in serum   Immunoglobulin E (IgE)(  2 Heavy and 2 Light chains Mol. 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L   Study Guide How are antigenic determinants formed? An immune response to a single microorganism represents the collection of all of the immune responses to all of the  immunogenic epitopes that comprise that microorganism. Can you imagine how an immune response to one microorganism might react with another microorganism?0 8 8&  d H  0j ^ ? a( 0 aY (  )  # l̆mճmճ1 ? +7   u)Study Guide This is an important concept.*  *    H1 ?N.   H  0j ^ ? a( 0 0$( v, M $V $ # ltmճmճ1 ? +7   VStudy Guide How might a hormone be used for communications between unlike cell types?W L W  $  H1 ?N.   H $ 0j ^ ? a( 0 @0O(  0^ 0 61? h 0  H1 ?N.   ! 0 # lYmճmճ1 ? L   m!Study Guide Can you describe the major regions of an immunoglobulin molecule? What distinguishes the immunoglobulin classes from one another? What is shared between classes? What is the significance of the variable regions? What is the significance of the Fab, the Fc, disulfide linkages? 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Specificity of the interaction between the receptor and epitope is determined by the amino acid sequence of the receptor ( tailoring the glove ). If the glove is too big, the glove falls off. If the glove is too small, you can t get your hand into it. If the glove is missing fingers& *  )Examples of Receptor-Epitope Interactions *Enzymatic reactions Antigen recognition Antigen-Antibody reactions Biological chaperones (stress proteins) Cellular communications Cell-mediated cytotoxicity Cellular homing (MALT, chemotaxis, etc.)  Basic Immunoglobulin Structure(   %The Prototype Immunoglobulin Molecule&&( &JHeavy Chains (five types: a, g, m, d, e) Light Chains (two types: l and k ) Fab fragment Fc fragment Constant and variable regions Carbohydrate Disulfide linkagesVW  Immunoglobulin G (IgG)( 2 Heavy and 2 Light chains 2 Fab and 1 Fc fragment 4 Subclasses (IgG1, IgG2, IgG3, IgG4) Mol. Wt. 150,000 ~70-75% of serum immunoglobulin. The major antibody of the secondary immune response Change in affinity with time  Immunoglobulin M (IgM)( 10 Heavy and 10 Light chains 10 Fab and 5 Fc fragments Mol. Wt. ~900,000 <10% of serum immunoglobulin. Single J Chain (15 kDA) The predominant "early" antibody Most primitive immunoglobulin No change in affinity with time Immunoglobulin A (IgA)( wMonomeric- Serum IgA ~15-20% of serum immunoglobulins 2 Heavy and 2 Light 2 Subclasses (IgA1 and IgA2) Found in serum x!Secretory Immunoglobulin A (sIgA)""( "4 heavy chains and 4 light chains (dimeric) J-Chain and secretory component The major immunoglobulin of secretions Not found in serum  Immunoglobulin E (IgE)( 2 Heavy and 2 Light chains Mol. Wt. ~190,000 Trace serum protein Note CH4 region on H chain Associated with atopic or anaphylactic hypersensitivity May play role in immunity to helminthic parasites   Immunoglobulin D (IgD)( 2 heavy and 2 light chains <1% of serum immunoglobulins Serves as a membrane receptor on B lymphocytes May play role in antigen-stimulated lymphocyte differentiation  Take Home Lessons ZWhat is the basic immunoglobulin structure? What are the characteristics or features of the various fragments of the immunoglobulin molecule? How is the specificity of an antibody  defined by the amino acid sequence of the immunoglobulin molecule? 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