gene cluster polymorphisms & autoimmunity
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
![Page 1: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/1.jpg)
Slide 1 of 30
Gene cluster polymorphisms &
autoimmunity
IMM430H1S: March 2005Zenon Harley
![Page 2: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/2.jpg)
Slide 2 of 30
The Paper
5. Discussion
4. Lupus model
3. Strain analysis
2. DNA sleuthing
1. Summary
![Page 3: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/3.jpg)
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
![Page 4: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/4.jpg)
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
![Page 5: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/5.jpg)
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
![Page 6: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/6.jpg)
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
![Page 7: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/7.jpg)
Slide 7 of 30
DNA sleuthing
2. DNA sleuthing
1. Summary
5. Discussion
4. Lupus model
3. Strain analysis
![Page 8: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/8.jpg)
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
![Page 9: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/9.jpg)
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.
![Page 10: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/10.jpg)
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
![Page 11: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/11.jpg)
Slide 11 of 30
DNA sleuthing
2. DNA sleuthing
1. Summary
5. Discussion
4. Lupus model
3. Strain analysis
• Structural polymorphisms
![Page 12: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/12.jpg)
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.
![Page 13: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/13.jpg)
Slide 13 of 30
![Page 14: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/14.jpg)
Slide 14 of 30
DNA sleuthing
2. DNA sleuthing
1. Summary
5. Discussion
4. Lupus model
3. Strain analysis
![Page 15: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/15.jpg)
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
![Page 16: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/16.jpg)
Slide 16 of 30
![Page 17: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/17.jpg)
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.
![Page 18: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/18.jpg)
Slide 18 of 30
![Page 19: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/19.jpg)
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
![Page 20: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/20.jpg)
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
![Page 21: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/21.jpg)
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
![Page 22: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/22.jpg)
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
![Page 23: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/23.jpg)
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
![Page 24: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/24.jpg)
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) MnCl2
![Page 25: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/25.jpg)
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) MnCl2
![Page 26: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/26.jpg)
Slide 26 of 30
![Page 27: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/27.jpg)
Slide 27 of 30
Lupus model
5. Discussion
3. Strain analysis
2. DNA sleuthing
1. Summary
4. Lupus model
![Page 28: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/28.jpg)
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
![Page 29: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/29.jpg)
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
![Page 30: Gene cluster polymorphisms & autoimmunity](https://reader036.vdocuments.us/reader036/viewer/2022062309/56814a96550346895db7a449/html5/thumbnails/30.jpg)
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