B6.Cg-Sle1^NZM2410/Aeg Yaa/DcrJ

Stock number: 021569
Research areas: Developmental Biology Research, Endocrine Deficiency Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Mouse/Human Gene Homologs

Description

B6.Sle1yaa males are C57BL/6J-congenic animals with the NZM2410/Aeg-derived systemic lupus erythmatosus susceptibility 1 locus and the BXSB/MpJ-derived Yaa-containing Y chromosome; resulting in chronic immune activation and autoimmune pathology. These mice may be useful in studying the type I IFN-responsive gene signature in autoimmune kidney and lupus pathogenesis. B6.Sle1yaa mice are also ideal for breeding with other mutant/transgenic mice already on the C57BL/6 genetic background. This bicongenic B6.Sle1yaa strain is also called B6.Sle1^NZM2410/Aeg Yaa , B6.(D1Dcr2-D1Dcr19)^NZM2410/J Yaa or B6.Sle1^NZM2410/J Yaa.

Detailed description

B6.Sle1yaa males are C57BL/6J-congenic animals carrying the systemic lupus erythmatosus susceptibility 1 quantitative trait locus from NZM2410/Aeg inbred mice (Stock No. 002676) and the mutant Yaa-containing Y chromosome from BXSB/MpJ inbred mice (Stock No. 000740).

While B6.yaa males have no overt autoimmune disease, homozygous addition of Sle1 (which contains the autoimmune-predisposing Slam/Cd2 haplotype) causes B6.Sle1yaa males to develop spontaneous lupus-like autoimmune syndrome with numerous immunological aberrations similarly to BXSB/MpJ inbred males. Specifically, mortality in B6.Sle1yaa males starts at ~12-15 weeks of age with 50% lethality by ~30-38 weeks of age. In addition, B6.Sle1yaa males exhibit severe kidney pathology characterized by hyalanized end-stage disease in most kidney glomeruli. Significant levels of auto-antibodies are detectable by 6-8 weeks, and IgG auto-antibodies against dsDNA and kidney glomerular antigens increase dramatically with onset of severe glomerulonephritis around 4-6 months. The CD4+ T cell lineage is dysregulated in B6.Sle1yaa males: early and progressive CD4+ T cell activation leads to increased IFN γ-secreting cells and, eventually, to a chronic-activation induced replicative senescence phenotype (limitation in the number of times that cells can divide).

B6.Sle1 females do not have the Yaa-containing Y chromosome, and have normal lifespan with little or no evidence of autoimmune disease by nine months of age. B6.Sle1 females develop a benign autoimmunity characterized by the production of IgG anti-chromatin auto-antibodies (increased levels compared to C57BL/6). Minimal CD4+ T cell lineage dysregulation is observed in B6.Sle1 females.

Development

The laboratory of Dr. Edward K. Wakeland (University of Florida; including Drs. Laurence Morel and Chandra Mohan) identified the Sle1^NZM2410/Aeg quantitative trait locus. Sle1^NZM2410/Aeg is a region of mouse chromosome 1 derived from New Zealand Mixed/Aeg 2410 inbred mice (NZM2410 or NZM2410/Aeg; Stock No. 002676) that confers susceptibility to systemic lupus erythmatosus (SLE). In 2010, Dr. Derry C. Roopenian (The Jackson Laboratory) obtained C57BL/6-congenic Sle1^NZM2410/Aeg animals (B6.Sle1) from Dr. Mohan (while at University of Texas Southwestern Medical Center) as JAX Stock No. 012722. B6.Sle1 females were used for breeding as described below. Dr. Roopenian reports the NZM2410/Aeg donor interval is defined as D1Dcr2-D1Dcr19.

BXSB/MpJ inbred males (Stock No. 000740) have the Y-linked autoimmune accelerator locus (Yaa) on the Y chromosome. Yaa is the result of a duplication of an ~4 Mbp telomeric segment near the pseudoautosomal region of the X chromosome onto the Y chromosome. The duplicated segment contains 19 genes, including toll-like receptor 7 (Tlr7) and phosphoribosyl pyrophosphate synthetase 2 (Prps2). The BXSB/MpJ-derived Yaa locus is attributed to the SLE-like autoimmune disease characteristics observed in BXSB/MpJ males. Dr. Derry C. Roopenian obtained C57BL/6J-congenic males with the BXSB/MpJ-derived Y chromosome from Stock No. 000483, and further backcrossed them onto C57BL/6J; creating Stock No. 004007. The B6.yaa males were used for breeding as described below.

To generate the bicongenic B6.Sle1yaa strain, B6.Sle1 females were bred with B6.yaa males. The colony was subsequently maintained by breeding homozygous females with homozygous males. In 2013, Dr. Roopenian sent some B6.Sle1yaa mice at generation N7F9 to The Jackson Laboratory Repository (Autoimmune Resource) to establish Stock No. 021569. This bicongenic B6.Sle1yaa strain is also called B6.Sle1^NZM2410/Aeg Yaa , B6.(D1Dcr2-D1Dcr19)^NZM2410/J Yaa or B6.Sle1^NZM2410/J Yaa.

Allele

Symbol: Yaa
Name: accelerated autoimmunity and lymphoproliferation
MGI accession ID: MGI:1856277
Generation method: Spontaneous
Synonyms: Is(XOfd1-Mid1;Y)1Mp; Tp(X;Y)1Ekw
Marker symbol: Yaa
Marker name: accelerated autoimmunity and lymphoproliferation transposition
Marker synonyms: Tp(X;Y)1Ekw
Chromosome: Y
Strain of origin: SB/Le
Molecular note: An approximately 4 MB region of the X chromosome that includes at least 13 known genes (spanning from Ofd1 to Mid1) was translocated to the Y chromosome adjacent to the pseudoautosomal region. Increased RNA expression of Msl3, Tlr7, Tmsb4x and Rab9 was detected in follicular B cells.

Allele

Symbol: Sle1^NZM2410/Aeg
Name: NZM2410/Aeg
MGI accession ID: MGI:2154331
Generation method: QTL
Synonyms: Sle1^NZM2410
Marker symbol: Sle1
Marker name: systemic lupus erythmatosus susceptibility 1
Chromosome: 1
Strain of origin: NZM2410/Aeg