Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse Background Strain NOD Donor Strain B6.129S2/SvPas H2 Haplotype g7 Generation N12F5pN1   Donating Investigator Christophe Benoist,   Joslin Diabetes Center

Appearance
pink-eyed, albino
Related Genotype: A/A Tyr^c/Tyr^c

Description
Autoimmune regulator, Aire, located on Chromosome 10, 41.6cm controls, in part, ectopic gene expression involved with tolerance induction, and is specifically involved with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy in humans. Exon 2 and portions of the flanking introns of the Aire gene were deleted by Cre-lox-mediated homologous recombination. Analysis of the mutated Aire transcript identified a frameshift that precludes translation past exon 1. The Aire mutation originated on a 129B6F2 background and was backcrossed to NOD for 12 generations. NOD.Aire deficient mice are normoglycemic, but experience weight loss between 5 and 15 weeks of age. Approximately 79% die spontaneously or must be euthanized due to declining health at between 6 and 14 weeks of age. Pathology indicates lung lesions with generalized pneumonitis, severe exocrine (not endocrine) pancreatitis and lymphocytic infiltration in the liver, salivary, stomach, reproductive systems, and the presence of circulating autoantibodies against ovary, stomach, retina and exocrine pancreas.

This stock is useful in the study of Aire function in autoimmunity and tolerance induction.

Development
To create this mutant the originating investigator employed a targeting vector bearing a loxP site-flanked Pgk-neo cassette inserted into intron 2. An additional single loxP site was placed in intron 1. The targeting construct was electroporated into 129S2/SvPas-derived D3 embryonic stem (ES) cells, and correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric mice were mated with CMV-cre transgenic mice on a C57BL/6 background. Exon 2 and portions of introns 1 and 3 were excised in the offspring. The C57BL/6 Aire deficient stock was then backcrossed to NOD for 12 generations. In 2007, the T1DR received this strain at generation N12F5.

Control Information

	Control
	Wild-type from the colony
	001976 NOD/ShiLtJ
Considerations for Choosing Controls

Related Strains

Strains carrying   Aire^tm1.1Doi allele

004743

B6.129S2-Airetm1.1Doi/J

View Strains carrying   Aire^tm1.1Doi     (1 strain)

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Autoimmune Polyendocrine Syndrome, Type I; APS1 - Models with phenotypic similarity to human disease where etiologies involve orthologs.1

1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Aire^tm1.1Doi/Aire^tm1.1Doi

        NOD.129S2(B6)-Aire^tm1.1Doi/Doi

• life span-post-weaning/aging
• premature death (MGI Ref ID J:107432)
  • 79% of mice die between 6 and 14 weeks of age with the likely cause of death being inflammatory lesions of the lungs with generalized pneumoitis
  • over 95% of the mice die by 20 weeks of age
• growth/size phenotype
• cachexia (MGI Ref ID J:107432)
  • mice are prone to losing weight between 5 and 15 weeks of age with weight loss correlating to the intensity of pancreas or lung inflammation
• immune system phenotype
• increased autoantibody level (MGI Ref ID J:107432)
  • mice generate autoantibodies with a reactivity that mirror the histopathology associated with this mouse strain
  • the autoantibodies generated on the NOD background target numerous tissues including the pancreas
  • the pancreas is not targeted by autoantibodies when the mutant allele is present on other genetic backgrounds
• increased incidence of corneal inflammation (MGI Ref ID J:107432)
  • cornea inflammation occurs in 14% of mice of this background by 20 weeks of age but is not observed when the mutant allele is when the mutant allele is on the SJL or C57BL/6 background
• liver inflammation (MGI Ref ID J:107432)
  • liver inflammation is observed in 86% of mice by 20 weeks of age while no inflammation is present when the mutant allele is on the C57BL/6 backgrounds
• lung inflammation (MGI Ref ID J:107432)
  • lung inflammation is observed in 100% of mice by 20 weeks of age which is a much higher incidence than observed when the mutant allele is on the C57BL/6 background
  • lesions of the lung are severe enough to likely cause the runting and premature death associated with this strain
• ovary inflammation (MGI Ref ID J:107432)
  • 88% of mice exhibit inflammation of the ovaries on this background while no inflammation is observed in C57BL/6 mice carrying the mutant allele
• pancreas inflammation (MGI Ref ID J:107432)
  • all mice exhibit inflammation of the pancreas on this background while no inflammation is observed in C57BL/6 or BALB/c mice carrying this mutant allele
  • the lesions are highly localized within the pancreas and appear to progress from an initial extravasation into the perivascular connective tissue to a front of cell destruction that moves through the exocrine lobe
  • islet cells are spared from destruction and the mice remain normoglycemic through 20 weeks of age
• prostate inflammation (MGI Ref ID J:107432)
  • all mice have inflammation of the prostate by 20 weeks of age
• salivary gland inflammation (MGI Ref ID J:107432)
  • sialitis is observed in all mice by 20 weeks of age which is a much higher incidence than what is observed when the mutant allele is on the C57BL/6 or BALB/c backgrounds
• stomach inflammation (MGI Ref ID J:107432)
  • gastritis occurs in 87% of mice by 20 weeks of age but is rarely observed when the mutant allele is on C57BL/6
• thyroid inflammation (MGI Ref ID J:107432)
  • inflammation of the thyroid occurs in 54% of mice on the NOD background but is not observed in when the mutant allele is present on C57BL/6, BALB/c, or SJL backgrounds
• vision/eye phenotype
• increased incidence of corneal inflammation (MGI Ref ID J:107432)
  • cornea inflammation occurs in 14% of mice of this background by 20 weeks of age but is not observed when the mutant allele is when the mutant allele is on the SJL or C57BL/6 background
• retinal degeneration (MGI Ref ID J:107432)
  • retinal degeneration resulting from autoimmune disease occurs by 20 weeks of age in 93% of mice
• endocrine/exocrine gland phenotype
• pancreas inflammation (MGI Ref ID J:107432)
  • all mice exhibit inflammation of the pancreas on this background while no inflammation is observed in C57BL/6 or BALB/c mice carrying this mutant allele
  • the lesions are highly localized within the pancreas and appear to progress from an initial extravasation into the perivascular connective tissue to a front of cell destruction that moves through the exocrine lobe
  • islet cells are spared from destruction and the mice remain normoglycemic through 20 weeks of age
• prostate inflammation (MGI Ref ID J:107432)
  • all mice have inflammation of the prostate by 20 weeks of age
• salivary gland inflammation (MGI Ref ID J:107432)
  • sialitis is observed in all mice by 20 weeks of age which is a much higher incidence than what is observed when the mutant allele is on the C57BL/6 or BALB/c backgrounds
• thyroid inflammation (MGI Ref ID J:107432)
  • inflammation of the thyroid occurs in 54% of mice on the NOD background but is not observed in when the mutant allele is present on C57BL/6, BALB/c, or SJL backgrounds
• liver/biliary system phenotype
• liver inflammation (MGI Ref ID J:107432)
  • liver inflammation is observed in 86% of mice by 20 weeks of age while no inflammation is present when the mutant allele is on the C57BL/6 backgrounds
• reproductive system phenotype
• ovary inflammation (MGI Ref ID J:107432)
  • 88% of mice exhibit inflammation of the ovaries on this background while no inflammation is observed in C57BL/6 mice carrying the mutant allele
• prostate inflammation (MGI Ref ID J:107432)
  • all mice have inflammation of the prostate by 20 weeks of age
• respiratory system phenotype
• lung inflammation (MGI Ref ID J:107432)
  • lung inflammation is observed in 100% of mice by 20 weeks of age which is a much higher incidence than observed when the mutant allele is on the C57BL/6 background
  • lesions of the lung are severe enough to likely cause the runting and premature death associated with this strain
• digestive/alimentary phenotype
• pancreas inflammation (MGI Ref ID J:107432)
  • all mice exhibit inflammation of the pancreas on this background while no inflammation is observed in C57BL/6 or BALB/c mice carrying this mutant allele
  • the lesions are highly localized within the pancreas and appear to progress from an initial extravasation into the perivascular connective tissue to a front of cell destruction that moves through the exocrine lobe
  • islet cells are spared from destruction and the mice remain normoglycemic through 20 weeks of age
• salivary gland inflammation (MGI Ref ID J:107432)
  • sialitis is observed in all mice by 20 weeks of age which is a much higher incidence than what is observed when the mutant allele is on the C57BL/6 or BALB/c backgrounds
• stomach inflammation (MGI Ref ID J:107432)
  • gastritis occurs in 87% of mice by 20 weeks of age but is rarely observed when the mutant allele is on C57BL/6

Aire^tm1.1Doi/Aire^tm1.1Doi

        NOD.129S2-Aire^tm1.1Doi

• immune system phenotype
• abnormal CD4-positive T cell physiology (MGI Ref ID J:135154)
  • there is increased percentage of CD4 T cells in the spleen that are activated based on surface marker expression (CD62L^lo CD44^hi)
• chronic pancreas inflammation (MGI Ref ID J:135154)
  • mice 10 weeks have age have severe lymphocytic infiltration of the pancreas
• insulitis (MGI Ref ID J:135154)
  • mice 25 weeks of age have intra-islet infiltration of lymphocytes
• lacrimal gland inflammation (MGI Ref ID J:135154)
  • mice 10 weeks of age have severe lymphocytic infiltration of the lacrimal glands
• lung inflammation (MGI Ref ID J:135154)
  • lymphocyte infiltrates are found in mice by 10 weeks of age
• salivary gland inflammation (MGI Ref ID J:135154)
  • mice 10 weeks of age have severe lymphocytic infiltration of the salivary glands
• stomach inflammation (MGI Ref ID J:135154)
  • occurs in mice by 10 weeks of age
• thyroid inflammation (MGI Ref ID J:135154)
  • severe thyroiditis is observed in mice 15 to 25 weeks in age
• uveitis (MGI Ref ID J:135154)
  • retinal lymphocytic infiltration occurs in the eye
• endocrine/exocrine gland phenotype
• chronic pancreas inflammation (MGI Ref ID J:135154)
  • mice 10 weeks have age have severe lymphocytic infiltration of the pancreas
• insulitis (MGI Ref ID J:135154)
  • mice 25 weeks of age have intra-islet infiltration of lymphocytes
• salivary gland inflammation (MGI Ref ID J:135154)
  • mice 10 weeks of age have severe lymphocytic infiltration of the salivary glands
• thyroid inflammation (MGI Ref ID J:135154)
  • severe thyroiditis is observed in mice 15 to 25 weeks in age
• respiratory system phenotype
• lung inflammation (MGI Ref ID J:135154)
  • lymphocyte infiltrates are found in mice by 10 weeks of age
• vision/eye phenotype
• lacrimal gland inflammation (MGI Ref ID J:135154)
  • mice 10 weeks of age have severe lymphocytic infiltration of the lacrimal glands
• uveitis (MGI Ref ID J:135154)
  • retinal lymphocytic infiltration occurs in the eye
• digestive/alimentary phenotype
• chronic pancreas inflammation (MGI Ref ID J:135154)
  • mice 10 weeks have age have severe lymphocytic infiltration of the pancreas
• insulitis (MGI Ref ID J:135154)
  • mice 25 weeks of age have intra-islet infiltration of lymphocytes
• salivary gland inflammation (MGI Ref ID J:135154)
  • mice 10 weeks of age have severe lymphocytic infiltration of the salivary glands
• stomach inflammation (MGI Ref ID J:135154)
  • occurs in mice by 10 weeks of age

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Immunology and Inflammation Research
Autoimmunity (autoimmune pancreatitis and sialoadenitis)
Autoimmunity (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy)

Genes & Alleles

Gene & Allele Information

Allele Symbol		Airetm1.1Doi
Allele Name		targeted mutation 1.1, Christophe Benoist and Diane Mathis
Allele Type		Targeted (knock-out)
Common Name(s)		Aire-;
Mutation Made By		Diane Mathis,   Joslin Diabetes Center
Strain of Origin		129S2/SvPas
ES Cell Line Name		D3
ES Cell Line Strain		129S2/SvPas
Gene Symbol and Name		Aire, autoimmune regulator (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy)
Chromosome		10
Gene Common Name(s)		AIRE1; APECED; APS1; APSI; PGA1;
Molecular Note		The floxed fragment containing exon 2, portions of the surrounding introns, and a neo cassette was excised via cre mediated recombination in vivo. While shortened transcript was detected by RT-PCR analysis of homozygous mutant thymii, sequence analysis of the transcript identified a frameshift mutation resulting from the splicing of exons 1 and 3 that precludes translation past exon 1. [MGI Ref ID J:83422]

Genotyping

Genotyping Information

Genotyping Protocols

Aire^tm1.1Doi, SEP PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Jiang W; Anderson MS; Bronson R; Mathis D; Benoist C. 2005. Modifier loci condition autoimmunity provoked by Aire deficiency. J Exp Med 202(6):805-15. [PubMed: 16172259]  [MGI Ref ID J:107432]

Additional References

Aire^tm1.1Doi related

Anderson MS; Venanzi ES; Chen Z; Berzins SP; Benoist C; Mathis D. 2005. The cellular mechanism of Aire control of T cell tolerance. Immunity 23(2):227-39. [PubMed: 16111640]  [MGI Ref ID J:100515]

Anderson MS; Venanzi ES; Klein L; Chen Z; Berzins SP; Turley SJ; von Boehmer H; Bronson R; Dierich A; Benoist C; Mathis D. 2002. Projection of an immunological self shadow within the thymus by the aire protein. Science 298(5597):1395-401. [PubMed: 12376594]  [MGI Ref ID J:83422]

Chen Z; Benoist C; Mathis D. 2005. How defects in central tolerance impinge on a deficiency in regulatory T cells. Proc Natl Acad Sci U S A 102(41):14735-40. [PubMed: 16203996]  [MGI Ref ID J:102496]

DeVoss J; Hou Y; Johannes K; Lu W; Liou GI; Rinn J; Chang H; Caspi RR; Fong L; Anderson MS. 2006. Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J Exp Med 203(12):2727-35. [PubMed: 17116738]  [MGI Ref ID J:124583]

Devoss JJ; Shum AK; Johannes KP; Lu W; Krawisz AK; Wang P; Yang T; Leclair NP; Austin C; Strauss EC; Anderson MS. 2008. Effector mechanisms of the autoimmune syndrome in the murine model of autoimmune polyglandular syndrome type 1. J Immunol 181(6):4072-9. [PubMed: 18768863]  [MGI Ref ID J:139094]

Dooley J; Erickson M; Farr AG. 2008. Alterations of the medullary epithelial compartment in the Aire-deficient thymus: implications for programs of thymic epithelial differentiation. J Immunol 181(8):5225-32. [PubMed: 18832676]  [MGI Ref ID J:140094]

Gavanescu I; Benoist C; Mathis D. 2008. B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients. Proc Natl Acad Sci U S A 105(35):13009-14. [PubMed: 18755889]  [MGI Ref ID J:139126]

Gavanescu I; Kessler B; Ploegh H; Benoist C; Mathis D. 2007. Loss of Aire-dependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity. Proc Natl Acad Sci U S A 104(11):4583-7. [PubMed: 17360567]  [MGI Ref ID J:119475]

Gray D; Abramson J; Benoist C; Mathis D. 2007. Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire. J Exp Med 204(11):2521-8. [PubMed: 17908938]  [MGI Ref ID J:126040]

Gray DH; Gavanescu I; Benoist C; Mathis D. 2007. Danger-free autoimmune disease in Aire-deficient mice. Proc Natl Acad Sci U S A 104(46):18193-8. [PubMed: 17991771]  [MGI Ref ID J:127308]

Schaller CE; Wang CL; Beck-Engeser G; Goss L; Scott HS; Anderson MS; Wabl M. 2008. Expression of Aire and the early wave of apoptosis in spermatogenesis. J Immunol 180(3):1338-43. [PubMed: 18209027]  [MGI Ref ID J:131354]

Su MA; Giang K; Zumer K; Jiang H; Oven I; Rinn JL; Devoss JJ; Johannes KP; Lu W; Gardner J; Chang A; Bubulya P; Chang HY; Peterlin BM; Anderson MS. 2008. Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire. J Clin Invest 118(5):1712-26. [PubMed: 18414681]  [MGI Ref ID J:135154]

Health & husbandry

Health & Colony Maintenance Information

Currently there no information available for this strain. This may be due to the supply level of this strain.

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Type 1 Diabetes Repository collection.

Control Information

	Control
	Wild-type from the colony
	001976 NOD/ShiLtJ
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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Terms of Use

Terms of Use

General Terms and Conditions

Effective September 26, 2007: License Requirements for Strains using Cre-lox Technology only apply in Canada, see Licenses for Strains using Cre-lox Technology.

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