Genetic complementation results in augmented autoantibody responses to lupus-associated antigens.
Lupus-prone female New Zealand Mixed (NZM)2328 mice develop high titers of anti-nuclear and anti-dsDNA autoantibodies. Despite high expression of type I IFNs, these mice do not develop autoantibodies to the small nuclear ribonucleoprotein (snRNP) complex. Thus, additional genetic factors must regulate the generation of anti-snRNP autoantibodies. In contrast, despite much lower expression of type 1 IFNs, the diabetes-prone NOD mice spontaneously make anti-snRNP autoantibodies, albeit at a low incidence. To determine whether combination of high type I IFN response of NZM mice with appropriate susceptibility genes of NOD mice would result in anti-snRNP Ab response, cohorts of (NZM2328 x NOD)F(1) mice were generated and characterized for development of autoimmunity. In comparison with parental strains, the PBMCs from F(1) mice showed intermediate expression of type I IFN-responsive genes and augmented expression of IL-6 transcripts. TLR7 expression was similar in all strains. The F(1) mice had very high incidence and titer of anti-snRNP autoantibodies, anti-nuclear Abs, and anti-dsDNA autoantibodies. The levels of anti-snRNP autoantibody correlated with the expression levels of type I IFN-responsive genes. None of the F(1) mice developed diabetes, and only female mice developed severe renal disease. Our data demonstrate that only in presence of appropriate susceptibility genes, anti-snRNP autoantibodies are induced and type I IFNs amplify this response. A synergy between IL-6 and type I IFNs might be critical for amplifying overall autoantibody responses in systemic lupus erythematosus. In NZM/NOD F(1) mouse, genetic complementation between NZM and NOD genes leads to expression of phenotypes similar to those seen in certain lupus patients.
Sim
Davis L
DL
Department of Microbiology, University of Virginia, School of Medicine, Charlottesville, VA 22908, USA.
Bagavant
Harini
H
Scindia
Yogesh M
YM
Ge
Yan
Y
Gaskin
Felicia
F
Fu
Shu Man
SM
Deshmukh
Umesh S
US
D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000097:blood / Q000502:physiology; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000097:blood / Q000502:physiology; D001323:Autoantibodies / Q000096:biosynthesis* / Q000097:blood / Q000502:physiology; D004247:DNA / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology; D005260:Female; D005816:Genetic Complementation Test; D007370:Interferon Type I / Q000096:biosynthesis / Q000235:genetics; D008181:Lupus Nephritis / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D008814:Mice, Inbred NZB; D017411:Ribonucleoproteins, Small Nuclear / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology
D000276:Adjuvants, Immunologic; D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D007370:Interferon Type I; D008562:Membrane Glycoproteins; D017411:Ribonucleoproteins, Small Nuclear; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D004247:DNA