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Slide 1 of 30 Gene cluster polymorphisms & autoimmunity IMM430H1S: March 2005 Zenon Harley
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Slide 2 of 30 The Paper 5. Discussion 4. Lupus model 3. Strain analysis 2. DNA sleuthing 1. Summary
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Slide 3 of 30 Summary 1 in 2,000 Canadians have lupus (10x more in women) The cause is unknown Diagnosis is difficult 5. Discussion 4. Lupus model 3. Strain analysis 2. DNA sleuthing 1. Summary
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Slide 4 of 30 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. 5. Discussion 4. Lupus model 3. Strain analysis 2. DNA sleuthing 1. Summary
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Slide 5 of 30 DNA sleuthing Lupus-prone mouse: NZ2410 Non-lupus-prone mouse: B6 2. DNA sleuthing 1. Summary 5. Discussion 4. Lupus model 3. Strain analysis
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Slide 6 of 30 DNA sleuthing 2. DNA sleuthing 1. Summary 5. Discussion 4. Lupus model 3. Strain analysis Sle1a,b,c Known causative interval: Sle1
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Slide 7 of 30 DNA sleuthing 2. DNA sleuthing 1. Summary 5. Discussion 4. Lupus model 3. Strain analysis
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Slide 8 of 30 DNA sleuthing 2. DNA sleuthing 1. Summary 5. Discussion 4. Lupus model 3. Strain analysis Two congenic strains: B6.Sle1b and B6.FcR
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Slide 9 of 30 DNA sleuthing 2. DNA sleuthing 1. Summary 5. Discussion 4. Lupus model 3. Strain analysis Gender-biased anti-nuclear antibody production.
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Slide 10 of 30 DNA sleuthing 2. DNA sleuthing 1. Summary 5. Discussion 4. Lupus model 3. Strain analysis Molecular map: 0.9Mb Sequencing: 24 expressed genes, 19 in spleen SLAM/CD2 family Telomeric FcR Telomeric Sle1b
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Slide 11 of 30 DNA sleuthing 2. DNA sleuthing 1. Summary 5. Discussion 4. Lupus model 3. Strain analysis Structural polymorphisms
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Slide 12 of 30 DNA sleuthing 2. DNA sleuthing 1. Summary 5. Discussion 4. Lupus model 3. Strain analysis RT-PCR analysis of expression levels in lymphocytes.
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Slide 14 of 30 DNA sleuthing 2. DNA sleuthing 1. Summary 5. Discussion 4. Lupus model 3. Strain analysis
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Slide 15 of 30 Strain analysis Does this polymorphism contribute to autoimmunity in other mouse strains? 5. Discussion 4. Lupus model 2. DNA sleuthing 1. Summary 3. Strain analysis
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Slide 17 of 30 Strain analysis 5. Discussion 4. Lupus model 2. DNA sleuthing 1. Summary 3. Strain analysis ANA production compared to B6 mice.
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Slide 19 of 30 Lupus model How do polymorphisms among different strains contribute to autoimmunity? 5. Discussion 3. Strain analysis 2. DNA sleuthing 1. Summary 4. Lupus model
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Slide 20 of 30 Lupus model 5. Discussion 3. Strain analysis 2. DNA sleuthing 1. Summary 4. Lupus model Ly108 is known to have alternative splice forms
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Slide 21 of 30 Lupus model 5. Discussion 3. Strain analysis 2. DNA sleuthing 1. Summary 4. Lupus model Ly108-1 is favoured in Lupus- prone congenic strains
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Slide 22 of 30 Lupus model 5. Discussion 3. Strain analysis 2. DNA sleuthing 1. Summary 4. Lupus model RT-PCR using isoform-specific primers: B6 and B6.Sle1b
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Slide 23 of 30 Lupus model 5. Discussion 3. Strain analysis 2. DNA sleuthing 1. Summary 4. Lupus model Additional possible isoform in B6.Sle1b and NZW
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Slide 24 of 30 Lupus model T-cell stimulation 5. Discussion 3. Strain analysis 2. DNA sleuthing 1. Summary 4. Lupus model (1) T-cell stimulus, (2) Streptavidin, (3) Ionomycin, (4) MnCl 2
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Slide 25 of 30 Lupus model T-cell stimulation 5. Discussion 3. Strain analysis 2. DNA sleuthing 1. Summary 4. Lupus model (1) T-cell stimulus, (2) Streptavidin, (3) Ionomycin, (4) MnCl 2
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Slide 27 of 30 Lupus model 5. Discussion 3. Strain analysis 2. DNA sleuthing 1. Summary 4. Lupus model
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Slide 28 of 30 Discussion Epistatic interactions 4. Lupus model 3. Strain analysis 2. DNA sleuthing 1. Summary 5. Discussion BB = black Bb = black bb = brown CC = normal Cc = normal cc = albino
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Slide 29 of 30 Discussion Polymorphisms diversify the immune response. Favoured by natural selection due to diversity of pathogens. 4. Lupus model 3. Strain analysis 2. DNA sleuthing 1. Summary 5. Discussion
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Slide 30 of 30 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. 4. Lupus model 3. Strain analysis 2. DNA sleuthing 1. Summary 5. Discussion
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