Deficiency of type I interferon contributes to Sle2-associated component lupus phenotypes.
OBJECTIVE
Studies in mice and humans have implicated type I interferon (IFN-I) in the pathogenesis of lupus. Given that the locus for IFN-I is positioned within the Sle2 murine lupus susceptibility interval on chromosome 4, we undertook this study to investigate whether differences in IFN-I levels might potentially contribute to the phenotypes ascribed to this locus.


METHODS
IFN-I, anti-IFN-I, isotype control antibody, or phosphate buffered saline was administered to C57BL/6 and B6.Sle2 mice, and the serologic and cellular phenotypes were studied. In addition, B6.Sle2 mice were examined for structural and expression polymorphisms in the IFN-I gene.


RESULTS
In both B6.Sle2 congenic mice and C57BL/6 control mice, antibody-mediated blockade of IFN-I augmented serum autoantibody levels and boosted B1a cell numbers. Administration of IFN-I ameliorated these 2 features previously attributed to this disease locus. Importantly, compared with B6 controls, B6.Sle2 mice had reduced levels of IFN-I in their sera and cell culture supernatants, following stimulation. Although several sequence polymorphisms were noted in the Sle2 alleles of various IFN-I genes, it was not established whether any of the noted sequence variations were causally related to the observed phenotypes.


CONCLUSIONS
Unexpectedly, reduction of IFN-I levels reproduced the serologic and cellular phenotypes previously associated with the Sle2 lupus susceptibility interval. Placing these findings in the context of other studies, the effect of IFN-I on systemic autoimmunity appears to be far more complex than originally perceived.
Li
Jianwei
J
University of Texas Southwestern Medical School, Dallas 75390-8884, USA.
Liu
Yang
Y
Xie
Chun
C
Zhu
Jiankun
J
Kreska
Desi
D
Morel
Laurence
L
Mohan
Chandra
C
D000818:Animals; D000974:Antibodies, Antinuclear; D015551:Autoimmunity / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D016898:Interferon-alpha / Q000235:genetics* / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics* / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011110:Polymorphism, Genetic
D000974:Antibodies, Antinuclear; D016898:Interferon-alpha; D016899:Interferon-beta