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Gene cluster polymorphisms & autoimmunity

Gene cluster polymorphisms & autoimmunity. IMM430H1S: March 2005 Zenon Harley. The Paper. 1. Summary. 2. DNA sleuthing. 3. Strain analysis. 4. Lupus model. 5. Discussion. Summary. 1 in 2,000 Canadians have lupus (10x more in women) The cause is unknown Diagnosis is difficult.

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Gene cluster polymorphisms & autoimmunity

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  1. Gene cluster polymorphisms & autoimmunity IMM430H1S: March 2005 Zenon Harley

  2. The Paper 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  3. Summary • 1 in 2,000 Canadians have lupus (10x more in women) • The cause is unknown • Diagnosis is difficult 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  4. Summary • Lupus studied in a mouse model because of congenics. • Isolate lupus-causing genes from a lupus-prone mouse and cause lupus in a healthy mouse. 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  5. DNA sleuthing • Lupus-prone mouse: NZ2410 • Non-lupus-prone mouse: B6 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  6. DNA sleuthing • Known causative interval: Sle1 1. Summary 2. DNA sleuthing Sle1a,b,c 3. Strain analysis 4. Lupus model 5. Discussion

  7. DNA sleuthing 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  8. DNA sleuthing • Two congenic strains: B6.Sle1b and B6.FcR 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  9. DNA sleuthing • Gender-biased anti-nuclear antibody production. 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  10. DNA sleuthing • Molecular map: 0.9Mb • Sequencing: 24 expressed genes, 19 in spleen • SLAM/CD2 family 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion Telomeric FcR Telomeric Sle1b

  11. DNA sleuthing • Structural polymorphisms 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  12. DNA sleuthing • RT-PCR analysis of expression levels in lymphocytes. 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  13. DNA sleuthing 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  14. Strain analysis • Does this polymorphism contribute to autoimmunity in other mouse strains? 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  15. Strain analysis • ANA production compared to B6 mice. 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  16. Lupus model • How do polymorphisms among different strains contribute to autoimmunity? 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  17. Lupus model • Ly108 is known to have alternative splice forms 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  18. Lupus model • Ly108-1 is favoured in Lupus-prone congenic strains 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  19. Lupus model • RT-PCR using isoform-specific primers: B6 and B6.Sle1b 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  20. Lupus model • Additional possible isoform in B6.Sle1b and NZW 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  21. Lupus model • T-cell stimulation 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion (1) T-cell stimulus, (2) Streptavidin, (3) Ionomycin, (4) MnCl2

  22. Lupus model • T-cell stimulation 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion (1) T-cell stimulus, (2) Streptavidin, (3) Ionomycin, (4) MnCl2

  23. Lupus model 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  24. Discussion • Epistatic interactions BB = black Bb = black bb = brown CC = normal Cc = normal cc = albino 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  25. Discussion • Polymorphisms diversify the immune response. • Favoured by natural selection due to diversity of pathogens. 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

  26. Discussion • Disease not always caused by a “bad” allele. • Immunity and autoimmunity involve a number of complex and inter-dependent pathways. • This presents a major therapeutic challenge. 1. Summary 2. DNA sleuthing 3. Strain analysis 4. Lupus model 5. Discussion

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