Dissociation of the genetic loci leading to b1a and NKT cell expansions from autoantibody production and renal disease in B6 mice with an introgressed New Zealand Black chromosome 4 interval.
Previous mapping studies have linked New Zealand Black (NZB) chromosome 4 to several lupus traits, including autoantibody production, splenomegaly, and glomerulonephritis. To confirm the presence of these traits, our laboratory introgressed homozygous NZB chromosome 4 intervals extending from either 114 to 149 Mb or 32 to 149 Mb onto the lupus-resistant C57BL/6 background (denoted B6.NZBc4S and B6.NZBc4L, respectively). Characterization of aged cohorts revealed that B6.NZBc4L mice exhibited a striking increase in splenic B1a and NKT cells in the absence of high titer autoantibody production and significant renal disease. Tissue-specific expansion of these subsets was also seen in the peritoneum and liver for B1a cells and in the bone marrow for NKT cells. Staining with CD1d tetramers loaded with an alpha-galactosylceramide analog (PBS57) demonstrated that the expanded NKT cell population was mainly CD1d-dependent NKT cells. The lack of both cellular phenotypes in B6.NZBc4S mice demonstrates that the genetic polymorphism(s) that result in these phenotypes are on the proximal region of NZB chromosome 4. This study confirms the presence of a locus that promotes the expansion of B1a cells and newly identifies a region that promotes CD1d-restricted NKT cell expansion on NZB chromosome 4. Taken together, the data indicate that neither an expansion of B1a cells and/nor NKT cells is sufficient to promote autoantibody production and ultimately, renal disease.
Loh
Christina
C
Arthritis Centre of Excellence, Toronto Western Research Institute, Toronto, Ontario, Canada.
Cai
Yong-Chun
YC
Bonventi
Gabriel
G
Lajoie
Ginette
G
Macleod
Ralph
R
Wither
Joan E
JE
D000818:Animals; D000917:Antibody Formation; D018949:Antigens, CD1; D055610:Antigens, CD1d; D001323:Autoantibodies / Q000096:biosynthesis*; D049109:Cell Proliferation; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian; D005260:Female; D007674:Kidney Diseases / Q000276:immunology*; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology*; D008177:Lupus Vulgaris / Q000235:genetics; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D013154:Spleen / Q000166:cytology
D018949:Antigens, CD1; D055610:Antigens, CD1d; D001323:Autoantibodies