BXSB.Cg-Fcgrt^tm1Dcr Tg(FCGRT)99Dcr/J

Stock number: 025099
Research areas: Immunology, Inflammation and Autoimmunity Research, Mouse/Human Gene Homologs, Research Tools

Description

FcRn-deficient hFcRn(Tg99) BXSB.Yaa mice (BXSB.FcRn-/- hFcRn(Tg99) or BXSB.Yaa FcRn-/- hFcRn(Tg99)) are a BXSB-congenic strain with endogenous mouse FcRn expression knocked out and replaced with expression of the human FcRn α-chain transgene under the control of its natural human promoter. These mice may be useful in evaluating thepharmacokinetics/pharmacodynamics of human immunoglobulin G and/or human therapeutic antibodies in an autoimmune disease setting.

Detailed description

BXSB/MpJ inbred males (Stock No. 000740) develop a spontaneous lupus-like autoimmune syndrome: mortality starts at ~13 weeks of age with 50% lethality by ~30 weeks and 76% lethality by ~40 weeks. BXSB/MpJ inbred females develop a greatly attenuated form of autoimmune disease because they lack Yaa.

BXSB.FcRn-/- mice are described and available as Stock No. 021455. Mice homozygous for the FcRn knockout allele (FcRn-/-) lack the Fc receptor (FcRn), which normally functions to enhance the presentation of immune-complexed antigens by MHC class II molecules and is critical for maintaining normal concentrations of immunoglobulin G (IgG) antibodies and serum albumin. BXSB.FcRn-/- mice are viable and fertile, with ~50% reduction in IgG. Both homozygous and heterozygous mice develop spontaneous lupus-like autoimmune syndrome similarly to BXSB/MpJ inbred mice.

Stock No. 025099: FcRn-deficient hFcRn(Tg99) BXSB.Yaa mice (BXSB.FcRn-/- hFcRn(Tg99) or BXSB.Yaa FcRn-/- hFcRn(Tg99)) are a BXSB-congenic strain with endogenous mouse FcRn expression knocked out and replaced with expression of the human FcRn α-chain transgene under the control of its natural human promoter. Mice homozygous for the FcRn null allele and hemizygous for the hFcRn(Tg99) transgene (FcRn-/- hFcRn(Tg99)) are viable and fertile. The donating investigator reports that FcRn-/- hFcRn(Tg99) animals develop spontaneous lupus-like autoimmune syndrome similarly to that of BXSB.FcRn-/- mice and BXSB/MpJ inbred mice. While the phenotype of FcRn-/- hFcRn(Tg99) mice is not fully characterized to date (June 2014), they may be expected to have reduced IgG levels. Because human FcRn protects human IgG and does not protect mouse IgG, these FcRn-/- hFcRn(Tg99) mice are ideal for evaluating the pharmacokinetics/pharmacodynamics of human therapeutic antibodies in an autoimmune disease setting.

Of note, C57BL/6J-congenic mice harboring the FcRn null allele and the same transgene with different insertion site [hFcRn(Tg32)] are described and available from The Jackson Laboratory Repository as Stock No. 014565.

Development

BXSB.FcRn-/- hFcRn(Tg99) mice are a BXSB-congenic "humanized" FcRn strain; carrying the FcRn null allele and a transgene expressing human FcRn. The knockout mutation and human transgene are described below.

The FcRn knockout allele (FcRn^-; Fcgrt^tm1Dcr) was designed by Dr. Derry C. Roopenian (The Jackson Laboratory) to replace 1588 nucleotides (encoding promoter sequence 5' of the transcriptional start site, exon1, intron 2, and most of exon2) of the Fcgrt gene (Fc receptor, IgG, alpha chain transporter) on chromosome 7 with a PGK-Neo^r cassette. The vector was electroporated into 129X1/SvJ-derived ESV/J-1182 (RW4) embryonic stem cells. FcRn^- mice backcrossed for at least 12 generations onto the BXSB/MpJ genetic background (BXSB.FcRn^-) are described and available as Stock No. 021455. BXSB.FcRn^- mice were used for breeding as below.

The hFcRn transgenic line 99 [hFcRn(Tg99)] mice were created by Dr. Roopenian. It has the same transgene construct as hFcRn transgenic line 32 (Stock No. 014565). The transgene genomic insertion sites of line 99 and line 32 are not characterized to date. The hFcRn transgene is an ~34 kbp cosmid clone with the complete ~11 kbp human FCGRT gene (as well as ~10 kbp of 5' and 3' flanking sequences). This construct was microinjected into fertilized BXSB/MpJ mouse eggs. Founder animal Tg#99 was bred to BXSB/MpJ. The resulting transgenic colony was maintained on the BXSB/MpJ genetic background by breeding transgenic mice together for several generations. These BXSB.hFcRn(Tg99) mice were used for breeding as below.

To generate the BXSB.FcRn^- hFcRn(Tg99) animals (Stock No. 025099), The Jackson Laboratory Repository Autoimmune Resource bred BXSB.FcRn^- and BXSB.hFcRn(Tg99) together. Male mice have the BXSB/MpJ-derived Y chromosome that contains the Y-linked autoimmune accelerator locus (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: Fcgrt^tm1Dcr
Name: targeted mutation 1, Derry C Roopenian
MGI accession ID: MGI:3511510
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: FcRn^-
Marker symbol: Fcgrt
Marker name: Fc receptor, IgG, alpha chain transporter
Marker synonyms: alpha-chain; FcgammaRn; FCRN; neonatal Fc receptor
Chromosome: 7
Strain of origin: 129X1/SvJ
Molecular note: Sequence from exon 1 and part of exon2 was replaced with a PGK-neo cassette. Quantitative PCR of liver cDNA indicated the absence of mRNA. Western blot analysis of neonatal intestinal extracts failed to reveal protein product.

Allele

Symbol: Tg(FCGRT)99Dcr
Name: transgene insertion 99, Derry C Roopenian
MGI accession ID: MGI:5572931
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: hFcRn(Tg99)
Marker symbol: Tg(FCGRT)99Dcr
Marker name: transgene insertion 99, Derry C Roopenian
Chromosome: UN
Strain of origin: BXSB/MpJ
Expressed genes: FCGRT,Fc fragment of IgG receptor and transporter,human
Molecular note: A 34Kb fragment of a BAC containing the entire human FCGRT , Fc fragment of IgG, receptor, transporter, alpha, gene (approximately 11kb) and approximately 10kb of flanking sequence was sublconed into a SuperCos vector. Founder line 99 was established.