Antibody structure function and generation of diversity

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Unformatted text preview: Antibody Structure, Function and Generation of Diversity Figure 21 What is an Antigen? A substance that can be specifically recognized by Tcells, Bcells or the antibody molecule. Requirements for Antigenicity Foreignness High Molecular weight The more foreign the greater the antigenicity Self nonself discrimination Minimal Molecular Weight is required < 1000 not antigenic 10006000 sometimes antigenic > 6000 always antigenic Requirements for Antigenicity Chemical complexity complexity = antigenicity Examples Homopolymer of an amino acid No Antigenicity Protein Highly Antigenic Requirements for Antigenicity Degradability If the substance can not be broken down it can not be processed and presented to the cells of the acquired immune system. If the substance is broken down too quickly it won't be around long enough to stimulate an immune response. Kinds of Antigens Carbohydrates Proteins Lipids Nucleic Acids Proteins Proteins are excellent antigens. Most common immune responses are to proteins. The greater the complexity of the protein the greater its antigenicity. Antigenic Determinates (Epitopes) Figure 29 Figure 210 Figure 211 Figure 22 Heavy Chains Five kinds of heavy chains in humans , , , and The heavy chain determines the class (isotype) of the antibody molecule IgA, IgD, IgG, IgM and IgE Each Class of Ig has different functions Each antibody molecule has a single type of heavy chain. Light Chains Two kinds of light chains in humans and Each antibody molecule has a single type of light chain 60 % of human antibodies contain light chains Figure 24 IgG Has 4 subclasses (IgG1, IgG2, IgG3, and IgG4) Exists as a Monomer Can cross the placenta Can activate complement Functions in intravascular and extra vascular spaces IgG (cont.) Good opsonin Can facilitate agglutination and precipitation Excellent neutralizing antibody makes up about 80% of the immunoglobulin in serum (13.5 mg/ml) Long biological halflife (23 days) IgM Exist as a monomer or pentamer Monomeric form serves as the Bcell antigen receptor Pentameric form found in serum Pentamer is excellent agglutinating antibody Single molecule of pentamer bound to antigen can activate complement IgM (cont.) Most of activity is restricted to intra vascular spaces Makes up 510% of the immunoglobulin in serum (1.5 mg/ml) Pentmer is associated with a Jchain Is the first antibody produced in response to antigen. Short biological halflife (5 days) Figure 226 IgA Two subclasses (IgA1 and IgA2) Exists as a monomer or a dimer 1015% of immunoglobulin in serum The IgA dimer is the major antibody molecule found in secretions (Secretory IgA) Monomeric form is found in serum Can serve as an opsonin IgA (cont) Secretory IgA is associated with a Jchain and an additional polypeptide chain called the secretory component. Daily production of secretory IgA is greater than that of any other immunoglobulin class (510 grams a day are secreted) Figure 230 Secretory IgA IgE Monomer Binds specifically to mast cells and basophils via special Fc receptors Important in allergy Very low serum concentration (0.3 g/ml) Important in antiparasite defense? IgD Monomer Serves as the Bcell antigen receptor along with monomeric IgM Role in serum is unknown Makes up about 0.2% of immunoglobulin in serum (30 g/ml) IgG Subclasses The structural characteristics that distinguish the subclasses from one another are the size of the hinge region and the number and position of interchain disulfide bonds between the heavy chains. Subtle amino acid differences between the subclasses affect the biological activity of the molecules IgG Subclasses (cont.) IgG1, IgG3 and IgG4 cross the placenta. IgG3 is the most effective activator of the complement system. IgG1 is next followed by IgG2 which is relatively inefficient. IgG4 will not activate complement. IgG1 and IgG3 are the best opsonins. IgG4 is intermediate and IgG2 is poor. Figure 228 Figure 229 The Relationship of Structure and Function in the Ig Molecule Figure 23 The Antigen Binding Site Figure 25 Figure 27 The Generation of Diversity In Antibody Molecules Diversity In Immunoglobulins We produce more different antibody molecules than all other proteins of the body combined. We produce more different antibodies than there are gene in our genome. Obviously we are not talking one gene = one protein here!!! Multiple Mechanisms are Involved in Generating Diversity Multiple Vregion exons in the genome Recombination of these Vregion exons to form the variable regions of the antibody Recombination of the variable region with a constant region exon to form the antibody chain gene. Random association of heavy and light chains Multiple Mechanisms are Involved in Generating Diversity (cont.) Somatic Mutation Junctional flexibility P and N nucleotide additions Figure 214 Figure 215 Figure 216 Light chain genes recombine V and J Basics of Ig Gene rearrangement exons to form the variable region of the light chain. Heavy chain genes recombine V, D, and J exons to form the variable region of the heavy chain. Every cell has two light chain gene Basics of Ig Gene rearrangement (cont.) complexes , two light chain gene complexes and two heavy chain gene complexes ( one maternal, one paternal) In Bcells these genes are rearranged as a first step in their maturation process. These genes are never rearranged in other cell types. Recombinases are important in the Basics of Ig Gene rearrangement (cont.) process RAG1 and RAG2 are involved. Two genes whose products are required to activate recombinases Knockout mice lacking either RAG1 or RAG 2 are deficient in both T and Bcells Light Chain Synthesis Basics of Ig Gene rearrangement (cont.) The variable region of the light chain consists of around 108 amino acids The variable region is coded for by two exons v exon 95 amino acids J exon 13 amino acids Heavy Chain Synthesis Basics of Ig Gene rearrangement (cont.) The variable region of the heavy chain is coded from three exons DJ recombination occurs first A key feature is the presence of multiple exons coding for constant regions ( , , 3, 1, 1, 2, 4, , 2) v exon 95 amino acids d and j exons 13 amino acids Heavy chain synthesis Basics of Ig Gene rearrangement (cont.) The constant region exons closest to the rearranged VDJ are transcribed first during B cell development. Alternate splicing results in the formation of or heavy chains. Figure 220 Figure 221 Class Switching Basics of Ig Gene rearrangement (cont.) Necessary for the proper functioning of the immune system Allows cells to switch to the production of a different class of antibody with the same antigen binding site Involves further Ig gene rearrangement Occurs in mature Bcells Dependent on antigenic stimulation, Tcell contact and Tcell produced cytokines Figure 227 Important "Players" in Immunoglobulin Gene Rearrangement Recombination signal sequences RSS P nucleotides N nucleotides Somatic mutation of variable regions Recombinases Figure 217 Figure 218 Figure 219 Figure 223 Figure 224 Affinity Maturation Figure 225 Allelic Exclusion Review Figure 231 Figure 232 ...
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This note was uploaded on 04/05/2008 for the course HSCI 3540 taught by Professor Gallagher during the Spring '06 term at East Tennessee State University.

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