Deficiency of the type I interferon receptor protects mice from experimental lupus.

Abstract

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.

CONCLUSION:

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.

• Authors: Dina C Nacionales, Kindra M Kelly-Scumpia, Pui Y Lee, Jason S Weinstein, Robert Lyons, Eric Sobel, Minoru Satoh, Westley H Reeves
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 56 Issue 11 Pg. 3770-83 (Nov 2007) ISSN: 0004-3591 [Print] United States
• PMID: 17968932 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• Ifnar1 protein, mouse
• Immunosuppressive Agents
• Terpenes
• Receptor, Interferon alpha-beta
• pristane

Topics

• Animals
• Autoantibodies (blood)
• Disease Models, Animal
• Female
• Gene Expression (immunology)
• Immunosuppressive Agents
• Lupus Erythematosus, Systemic (chemically induced, genetics, immunology)
• Lupus Nephritis (chemically induced, genetics, immunology)
• Lymphoid Tissue (immunology)
• Male
• Mice
• Mice, Mutant Strains
• Receptor, Interferon alpha-beta (genetics)
• Terpenes