Antibodies

Antibodies

glycoproteins found in serum & tissue fluids which are produced in response to contact with immunogenic foreign molecules. Bind specifically to Ag that induce their formation. HUMORAL IMMUNITY. 5 classes: IgG, IgM,IgA,IgD,IgE- all have same basic Ab structure
1. Structure- Ags bind to variable region, effector function=constant region
  1. Hypervariability in Ig sequence- 3 hypervariable regions HVR3 @ position 90 most variable
    1. Ab binding site- 3 CDR (complementary determining region) on light chain, 3 on heavy
Ig's
1. IgM-predominant Ab in primary response. PENTAMERIC structure in SERUM. Found on CELL SURFACE as a MONOMER
2. IgG- monomer, 4 subclasses, main Ab in serum & tissue fluids
3. IgA-predominant Ab found in SECRETIONS. DIMER/TRIMER. MUCOSAL IMMUNITY
4. IgE- monomer, low serum levels important in ALLERGY & responses against many parasites
5. IgD-monomer at cell surface of B cells. Ag receptor
Clonal selection hypothesis
1. Large pool of B cells each with Ab of one specificity IgM or D. Ab binds Ag specifically=proliferation & differentiation= Ag specific B cells (memory cells) + Specific Ab
Somatic recombination
1. Rearrangement of genetic material (DNA) which encodes the immunoglobulin heavy/light chains (k or L). Process occurs in bone marrow and is Ag independent
2. Kappa light chain recombination: ~40 variable region genes, ~5 joining, 1 constant gene- VJ rearrangement-combinations random= 40 x 5 x 1=200 combinations
3. Lambda light chain- VJ rearrangement=150 combinations
4. Heavy gene rearrangement- D extra gene segment- DJ rearrangement followed by second rearrangment between VDJ=polypeptide. 80 variable x 30 D x 6 J x 1 C= 14,400
5. Additional diversity= junctional: cutting is imprecise when the segments are jined together giving some loss or gain of nucleotides=change in AA seq @ 3rd hyper variable region=differences in Ag binding site/ N-region addition-template independent randon addition catalysed by TERMINAL DEOXYTRANSFERASE-heavy chain only/ Cost-frame shifts-non productive rearrangement in heavy chain
6. Heavy chain diversity (14,400) + Light chain (350) + junctional diversity + N-region insertion= ~10^10
7. How is rearrangement controlled?
  1. Enzymes- recombinase activating genes I & 2 (RAGs) expressed only during rearrangement process-work with normal cellular enzymes. DNA sequences guide the process so that the correct segments are used- Heptamer & nonamer sequences-recombination requires recognition of 12 & 23bp seqs before the DNA can be joined together. Avoids inappropriate joining of sequences
    1. Rearrangement by deletion- looping out-bring recognition seqs together-recombinase produces functional chain gene & rest of DNA lost-no longer copied.
  2. Starts with heavy chain rearrangement-has to have polypeptide on its surface before light chains can be rearranged Always starting with k-if successful it expresses a mature Ig molecule. Starts by expressing IgM, as leaves bone marrow can also express IgD then selected by Ag if encountered
Secondary-time course, shorter lag, extended plateau, Ab titre 10 fold+ higher, class switch eg IgG predominates, affinity increases, memory cells
1. Immunological memory graph
Class switch
1. . IgM & IgD predominantly produced because closest to J in genome-translated to IgM/translated to IgM or D alternative splicing
2. constant region of the heavy chain is changed, but not the variable region of the heavy chain. This switch does not affect the antibody’s specificity for its antigen, but it does alter the effector functions that each class of antibody can execute. The antibody class switch is critically dependent on the type of cytokine that is present. Various cytokines, such as include IL-4, IL-5, IFN-gamma and TGF-beta, are known to be responsible for class switching
3. portions of the antibody heavy chain locus are removed from the chromosome, and the gene segments surrounding the deleted portion are rejoined to retain a functional antibody gene that produces antibody of a different isotype
Increasing the affinity of the Abs produced during a response
1. By making minor changes in the variable region- single AA changes-if it binds better it is selected for
2. Hypermutation of the VH or VL chain sequences-single nucleotide changes. Mutation rate in the VDJ unit is 10^3/10^4 x higher than other sequences in Ig genes
  1. 1 week after primary immunisations-first start to see mutations=if useful outcompete other B cells & continues to produce a response & leads to more mutations/ 2 weeks after primary immunisations-more mutations

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	Erstellt von tanitia.dooley vor fast 13 Jahre