Deficiency of the type I interferon receptor protects mice from experimental lupus.
OBJECTIVE
Systemic lupus erythematosus (SLE) is diagnosed according to a spectrum of clinical manifestations and autoantibodies associated with abnormal expression of type I interferon (IFN-I)-stimulated genes (ISGs). The role of IFN-I in the pathogenesis of SLE remains uncertain, partly due to the lack of suitable animal models. The objective of this study was to examine the role of IFN-I signaling in the pathogenesis of murine lupus induced by 2,6,10,14-tetramethylpentadecane (TMPD).


METHODS
IFN-I receptor-deficient (IFNAR(-/-)) 129Sv mice and wild-type (WT) 129Sv control mice were treated intraperitoneally with TMPD. The expression of ISGs was measured by real-time polymerase chain reaction. Autoantibody production was evaluated by immunofluorescence and enzyme-linked immunosorbent assay. Proteinuria and renal glomerular cellularity were measured and renal immune complexes were examined by immunofluorescence.


RESULTS
Increased ISG expression was observed in the peripheral blood of TMPD-treated WT mice, but not in the peripheral blood of TMPD-treated IFNAR(-/-) mice. TMPD did not induce lupus-specific autoantibodies (anti-RNP, anti-Sm, anti-double-stranded DNA) in IFNAR(-/-) mice, whereas 129Sv controls developed these specificities. Although glomerular immune complexes were present in IFNAR(-/-) mice, proteinuria and glomerular hypercellularity did not develop, whereas these features of glomerulonephritis were found in the TMPD-treated WT controls. The clinical and serologic manifestations observed in TMPD-treated mice were strongly dependent on IFNAR signaling, which is consistent with the association of increased expression of ISGs with lupus-specific autoantibodies and nephritis in humans.


CONCLUSIONS
Similar to its proposed role in human SLE, signaling via the IFNAR is central to the pathogenesis of autoantibodies and glomerulonephritis in TMPD-induced lupus. This lupus model is the first animal model shown to recapitulate the "interferon signature" in peripheral blood.
Nacionales
Dina C
DC
University of Florida College of Medicine, Gainesville, Florida, USA.
Kelly-Scumpia
Kindra M
KM
Lee
Pui Y
PY
Weinstein
Jason S
JS
Lyons
Robert
R
Sobel
Eric
E
Satoh
Minoru
M
Reeves
Westley H
WH
D000818:Animals; D001323:Autoantibodies / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000276:immunology; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology*; D008181:Lupus Nephritis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D008221:Lymphoid Tissue / Q000276:immunology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D053633:Receptor, Interferon alpha-beta / Q000235:genetics*; D013729:Terpenes
D001323:Autoantibodies; C508032:Ifnar1 protein, mouse; D007166:Immunosuppressive Agents; D013729:Terpenes; D053633:Receptor, Interferon alpha-beta; C009042:pristane