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Announcements. Case Studies: There are three case studies that were provided: Case 10, 11, & 12. Please do case study 10 & 12 only. Case 11 was provided for information that may assist with Case 12. Due Feb 15, 2008 Exam 1: Question 20: correct answer was B and E.

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Announcements

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  1. Announcements • Case Studies: • There are three case studies that were provided: Case 10, 11, & 12. Please do case study 10 & 12 only. Case 11 was provided for information that may assist with Case 12. • Due Feb 15, 2008 • Exam 1: • Question 20: correct answer was B and E. • Will give full credit for one or the other but realize that having one answer is not correct.

  2. Read over information in text… see me if you have questions.

  3. Generation of Ig diversity in B cells prior to encounter with Antigen.

  4. Germ Line Theory: A single gene is present for each antibody. Would Require 1011- 1015 Ab genes! 1,000,000,000,000,000 Somatic Variation Theory: genome carries a small # of Ig genes & recombination &/or mutation leads to large repertoire somatic cells. W. Dreyer & J. Bennett, 1965: Proposed gene segments V & C. Susumu Tonegawa & N. Hozumi, 1976 Early Theories explaining the generation of Ab diversity:

  5. Immunobiology, Janeway, Fig 4.1 Germline (nonlymphoid): C2 C2 C2 v1 v2 v3 B cell: C2 v2 Experiment demonstrating gene rearrange-ment in Ig genes. Similar to the one done by N. Hozumi & S. Tonegawa

  6. Genetics Minireview: L= Leader sequence: • @ 5' end of the transcript • Encodes for a signal sequence or short peptide: • ~20AA • Directs through ER & Golgi. Outside of the cell

  7. ~13 AA 1st95-101 AA Parham: 65 VH, 27 DH, 6 JH, 1 0 CH (1 for each isotype) Janeway: ~40 VH, 25 DH, 6 JH, 10 CH Kuby: 39 VH, 23 DH, 6 JH 10 CH Germline organization of the Ig genes: ~30 Vl, 4 Jl,& 4 Cl 40 Vk, 5 Jk, & 1Ck

  8. What part of the protein is encoded by each segment? • Light Chains: • V domain: V & J segment • CDR1 & CDR2 encoded in the V segment. • CDR3 is encoded at the V & J junction. • C domain: C segment • Heavy Chains: • V domain: V, D, & J segment • CDR1 & CDR2 is encoded in the V segment. • CDR3 is encoded in the D junction with J • C domain: C segment

  9. Gene Rearrangement to produce the genetic material to encode for the V region of Ig occurs during B cell development • Rearrangement of the V gene region occurs prior to Ag stimulation. • Cell is not expressing Ig.

  10. The Segments are randomly selected at random for joining! • Combinatorial Diversity

  11. Parham numbers of heavy chain: • 65 V X 27 D X 6 J • = 10, 530 combinations • 10,530 X (200 + 120) = 3.37 X 106 total combinations. • Janeway: • 40 V X 25 D X 6 J= • 6,000 combinations. • 6000 X (200+120) = 1.92 X 106 total combinations.

  12. Mechanism for Ig Gene Segment Recombination How does the appropriate segments join? What prevents inter-chromosomal recombinations from occurring?

  13. What is the mechanism behind the recombination event to make a V region? • 1. Signal in DNA to flag the location of recombination. • Recombination Signal Sequence- RSS • 2. Recombination enzymes

  14. RSS: • Heptamer (23 or 12 bp spacer) nonamer Fig. 2.17 in text

  15. Rules for Recombination: • Recombination only occurs between gene segments on the same chromosome. • 12/23 rule- • A gene segment flanked by an RSS with 12 bp spacer must join to a gene segment flanked with a 23 bp spacer. • Prevents incorrect segment joining.

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