title: Breaking tolerance to double stranded DNA, nucleosome, and other nuclear antigens is not required for the pathogenesis of lupus glomerulonephritis.
abstract: In lupus-prone NZM2328 mice, a locus Cgnz1 on chromosome 1 was linked to chronic glomerulonephritis, severe proteinuria, and early mortality in females. A locus Adnz1 on chromosome 4 was linked to antinuclear antibody (ANA) and anti-double stranded DNA (dsDNA) antibody (Ab) production. In this investigation, two congenic strains, NZM2328.C57L/Jc1 (NZM.C57Lc1) and NZM2328.C57L/Jc4 (NZM.C57Lc4), were generated by replacing the respective genetic intervals containing either Cgnz1 or Adnz1 with those from C57L/J, a nonlupus-prone strain. The NZM.C57Lc1 females had markedly reduced incidence of chronic glomerulonephritis and severe proteinuria. NZM.C57Lc4 females had chronic glomerulonephritis and severe proteinuria without circulating ANA, anti-dsDNA, and antinucleosome Ab. These data confirm the linkage analysis. Unexpectedly, NZM.C57Lc1 females had little anti-dsDNA and related Ab, suggesting the presence of a second locus Adnz2 on chromosome 1. The diseased NZM.C57Lc4 kidneys had immune complexes by immunofluorescence and electron microscopy. The eluates from these kidneys did not contain ANA, anti-dsDNA, and antinucleosome Ab, indicative of the presence of non-anti-dsDNA nephritogenic Ab. Thus, breaking tolerance to dsDNA and chromatin is not required for the pathogenesis of lupus nephritis. These results reaffirm that anti-dsDNA and related Ab production and chronic glomerulonephritis are under independent genetic control. These findings have significant implications in the pathogenesis of systemic lupus erythematosus.
authors.affiliation: The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Waters
authors.forename: Marcia
authors.initials: M
authors.lastname: McDuffie
authors.forename: Harini
authors.initials: H
authors.lastname: Bagavant
authors.forename: Umesh S
authors.initials: US
authors.lastname: Deshmukh
authors.forename: Felicia
authors.initials: F
authors.lastname: Gaskin
authors.forename: Chao
authors.initials: C
authors.lastname: Jiang
authors.forename: Kenneth S K
authors.initials: KS
authors.lastname: Tung
authors.forename: Shu Man
authors.initials: SM
authors.lastname: Fu
mesh_terms: D000818:Animals; D020296:Animals, Congenic; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D001324:Autoantigens; D002467:Cell Nucleus / Q000276:immunology; D004247:DNA / Q000276:immunology*; D005260:Female; D008181:Lupus Nephritis / Q000209:etiology* / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D009707:Nucleosomes / Q000276:immunology*; D017634:Self Tolerance / Q000235:genetics
chemical_list: D000974:Antibodies, Antinuclear; D001324:Autoantigens; D009707:Nucleosomes; D004247:DNA