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Problemthe immune system makes over one billion different antibody proteins
In 1950s: central dogma stated DNAto RNAto protein One gene for each protein Required millions of genes just for the immune system Does not seem possible, but most scientists thought it might be Today we know the human genome is less than 30,000 genes So, what is really going on???
Current theory must account for the following known properties of antibodies
B lymphocyte development
Tonegawas demonstration
1976used restriction enzymes and DNA probes to show that germ cell DNA contained several smaller DNA segments compared to DNA taken from developed lymphocytes (myeloma cells)
Randomness in joining process helps generate diversity by creating hypervariable of antigen binding site
Some rearrangements are productive, others are non-productive: frame shift alterations are non-productive
Diversity calculations
Combination of heavy and light chains adds final diversity of variable region
8262 possible heavy chain combinations 320 light chain combinations Over 2 million combinations P and N nucleotide additions and subtractions multiply this by 104 Possible combinations over 1010
Location of variability occurs within CDR regions of V domains (antigen binding sites)
Class switching among constant regions: generation of IgG, IgA and IgE with same antigenic determinantsidiotypes
Understanding of immunoglobulin structure and formation has opened up a new world of possibilities
Monoclonal antibodies Engineering mice with human immune systems Generating chimeric and hybrid antibodies for clinical use Abzymes: antibodies with enzyme capability