Nephritogenic autoantibodies but absence of nephritis in Il-12p35-deficient mice with pristane-induced lupus.
BACKGROUND
There is strong evidence that Th1 cytokines are essential for disease in murine models of lupus. Interleukin-12 (IL-12) is essential for Th1 cell differentiation and induces interferon-gamma (IFN-gamma) production. Paradoxically, it has been suggested that an IL-12 defect drives the pathogenesis of lupus, although its precise role remains unclear. We investigated the role of IL-12 for lupus-like disease induced by pristane. IL-12p35-deficient (-/-) and control (+/+) BALB/c mice were treated with pristane or phosphate-buffered saline (PBS).


METHODS
Proteinuria was measured and renal pathology evaluated 10 months after treatment. Sera were analyzed for autoantibodies and total immunoglobulin levels. Cytokine expression and production was analyzed.


RESULTS
Pristane induced nephritogenic autoantibodies and renal immunoglobulin and complement deposition in both IL-12 -/- and +/+ mice. However, proliferative pathology and proteinuria were absent in IL-12-/- mice, whereas pristane induced severe nephritis in one third of the +/+ mice. As expected, cytokine balance was skewed toward a Th2 response in pristane-treated IL-12 -/- mice.


CONCLUSIONS
These data indicate that renal immune complex deposition can occur in the absence of IL-12p35, but that structural renal damage requires the presence of IL-12p35 or mediators induced by this molecule, such as IFN-gamma. In contrast to the abrogation of nephritogenic autoantibodies by the lack of IFN-gamma, such antibodies are induced by pristane in IL-12p35-deficient mice. Absence of structural renal disease, despite the presence of nephritogenic autoantibodies in pristane-treated IL-12-/- mice, indicates that antibody deposition alone is not sufficient for the development of lupus nephritis in this model.
Calvani
Nicola
N
Department of Medicine, Division of Rheumatology & Clinical Immunology, University of Florida, Gainesville, Florida, USA.
Satoh
Minoru
M
Croker
Byron P
BP
Reeves
Westley H
WH
Richards
Hanno B
HB
D000818:Animals; D001323:Autoantibodies / Q000032:analysis*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006942:Hypergammaglobulinemia / Q000139:chemically induced; D018664:Interleukin-12 / Q000172:deficiency*; D053765:Interleukin-12 Subunit p35; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008181:Lupus Nephritis / Q000139:chemically induced* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D021122:Protein Subunits / Q000172:deficiency*; D013729:Terpenes
D001323:Autoantibodies; D016207:Cytokines; D053765:Interleukin-12 Subunit p35; D021122:Protein Subunits; D013729:Terpenes; D018664:Interleukin-12; C009042:pristane