Bxs6 interacts with Gpab1 on chromosome 9. Homozygosity for BXSB/MpJ alleles at Bxs6 in conjunction with C57BL/6 alleles at Gpab1 further enhances gp70 autoantibody titers and gp70 immune complex levels.
The Yaa locus on chromosome Y enhances nephritis phenotypes in the presence of Bxs6.
Mapping and Phenotype information for this QTL, its variants and associated markers
Highly significant linkage to gp70 autoantibody production and gp70 immune complex production mapped to 37 cM on mouse Chromosome 13 near D13Mit253 (LOD=36.7) in a BXSB/MpJ x (C57BL/10Ola x BXSB/MpJ)F1 backcross population. A total of 97 polymorphic markers were screened at an average spacing of 20 cM. This locus also showed linkage to glomerulonephritis and is named Bxs6 (BXSB/MpJ autoimmune neprhitis 6). Parental strain BXSB/MpJ displays significantly elevated gp70 titers and gp70 immune complex levelscompared to parental strain C57BL/10Ola.
A separate backcross population of C57BL/10Ola x (C57BL/10Ola x BXSB/MpJ)F1 animals was analyzed and Bxs6 mapped to the same location on chromosome 13 with LOD=19.9 for gp70 autoantibody titers and gp70 immune complex levels, but did not display linkage to glomerulonephritis.
The Bxs6 QTL interval spans markers D13Mit64 (30 cM), D13Mit253 (37 cM) and D13Mit233 (45 cM). Homozygosity for BXSB/MpJ-derived alleles at Bxs6 confer increased levels of gp70 immune complex and gp70 autoantibody titers and increased incidence and severity of glomerulonephritis. Gv1 at 36 cM is a previously identified viral antigen locus located near Bxs6. Yaa1 at 35 cM is a gp70 immune complex QTL previously mapped in an NZW x B6 crossthat is also located near Bxs6.
Analysis of Bxs6<BXSB/MpJ> homozygous animals from the BXSB/MpJ x (C57BL/10Ola x BXSB/MpJ)F1 backcross population detected an interacting locus at 57.9 cM on mouse Chromosome 9 near D9Mit57. This locus is named Gpab1 (gp70autoantibody titers 1). C57BL/6J alleles at Gpab1 derived from the BXSB/MpJ parental strain confer increased gp70 autoantibody titers in conjunction with homozygous BXSB/MpJ alleles at Bxs6.
Congenic line analysis was used to confirm and refine previously mapped QTL Bxs6 (BXSB/MpJ autoimmune nephritis 6) on mouse Chromosome 13 near D13Mit253 (37 cM). BXSB/MpJ-derived DNA from D13Mit3 (10 cM) to D13Mit78 (75 cM) was introgressed onto a C57BL/10Ola genetic background. This congenic encompasses the Bxs6 locus and is designated B10.BXSB-(D13Mit3-D13Mit78). Parental strain BXSB/MpJ displays increased gp70 autoantibody titers and susceptibility to autoimmune nephritis whereas parental strain C57BL/10Ola is resistant. A second congenic line carrying BXSB/MpJ-derived DNA from D13Mit122 (36 cM) to D13Mit233 (45 cM) on a C57BL/10Ola genetic background was also constructed. This congenic line, designated B10.BXSB-(D13Mit122-D13Mit233) is phenotypicallyidentical to that of the first congenic line B10.BXSB-(D13Mit3-D13Mit78). Authors state data for B10.BXSB-(D13Mit3-D13Mit78) was presented for their publication. Congenic animals were also bred to carry the Y chromosome autoimmune susceptibility locus Yaa(accelerated autoimmunity and lymphoproliferation transposition). The derivative congenic line is designated B10.BXSB-(D13Mit3-D13Mit78) Yaa.
B10.BXSB-(D13Mit3-D13Mit78) animals displayed significantly increased gp70 antibody titers and significantly increased levels of gp70 immune complex formation compared to animals from background strain C57BL/10Ola. B10.BXSB-(D13Mit3-D13Mit78) Yaa animals displayed greater gp70 titers, increased gp70 immune complex levels, increased nephritis incidence and severity, splenomegaly and decreased survival compared to B10.BXSB-Yaa animals. These findings suggest the Bxs6 locus confers nephritis susceptibility and the Yaa locus enhances nephritis phenotypes. The gp70 titers and gp70 immune complex levels were significantly lower in female animals compared to males of both congenic lines. Authors hypothesize a second locus may be present within the Bxs6 interval that influences gp70 immune complex formation.
The Bxs6 locus does not show significant association to antinuclear antibody production, however a trend was observed toward increased anti-ssDNA and anti-dsDNA antibody titers in B10.BXSB-(D13Mit3-D13Mit78) Yaa animals compared to B10.BXSB-Yaa animals. B10.BXSB-(D13Mit3-D13Mit78) animals also displayed a trend towards increased antinuclear antibody levels compared to C57BL/10Ola inbred animals.
Fine map analysis using a population of BXSB/MpJ x (C57BL/10Ola x BXSB/MpJ)F1 backcross animals refined the Bxs6 locus to a 18.9 Mb interval between 59.7 Mb and 78.6 Mb. Further refinement of Bxs6 was employed by comparing SNPs between BXSB/MpJ and a closely related strain BXSB/MpJScr-ll. A 15.1 Mb region between 59.7 Mb (D13Mit186) and 74.8 Mb (D13Mit98) is deemed the most likely location of Bxs6although the region between 78 Mb and 78.6 Mb cannot be excluded at this time. Sgp3 (37.5 cM) and Gv1 (36 cM) are previously identified autoimmunity QTLs colocalizing with Bxs6.