gene cluster polymorphisms & autoimmunity

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Gene cluster polymorphisms &

autoimmunity

IMM430H1S: March 2005Zenon Harley

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The Paper

5. Discussion

4. Lupus model

3. Strain analysis

2. DNA sleuthing

1. Summary

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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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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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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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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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DNA sleuthing

2. DNA sleuthing

1. Summary

5. Discussion

4. Lupus model

3. Strain analysis

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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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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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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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DNA sleuthing

2. DNA sleuthing

1. Summary

5. Discussion

4. Lupus model

3. Strain analysis

• Structural polymorphisms

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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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DNA sleuthing

2. DNA sleuthing

1. Summary

5. Discussion

4. Lupus model

3. Strain analysis

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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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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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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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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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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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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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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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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

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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

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Lupus model

5. Discussion

3. Strain analysis

2. DNA sleuthing

1. Summary

4. Lupus model

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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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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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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