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SUMMARYThere is evidence that nephritis is dominated by a Th1 immune response in systemic lupus erythematosus. Since IL-18 promotes polarization of the immune response toward Th1, we investigated the role of this cytokine in lupus nephritis (LN). A total of 133 lupus patients and 44 healthy subjects were enrolled. Demographic and clinical characteristics with renal biopsy data were recorded. IL-18 along with IFN-g and IL-4, two prototypical of Th1 and Th2 cytokines, were measured in serum by ELISA. Peripheral blood lymphocytes were analysed by flow cytometry for IFN-g and IL-4. IL-18 expression was determined by immunohistochemistry in 13 renal biopsy specimens from patients with LN and 2 controls. Serum IL-18 was higher in lupus patients than in controls. Levels of IL-18 correlated with urinary microalbumin and were increased in patients with LN when compared to those without LN. IL-18 expression was also increased within the glomeruli of nephritic patients and was primarily detected within the mesangial matrix and in infiltrating mononuclear cells. Measurement of IFN-g and IL-4 in either sera or peripheral blood lymphocytes showed high IFN-g along with low IL-4 expression in LN patients compared to patients without nephritis. A positive correlation between serum IL-18 and IFNg levels was found. IL-18 may play a prominent role in the pathogenesis of LN by promoting a cytokine imbalance towards a Th1 immune response. Measurement of IL-18 may be helpful for the early identification of lupus patients with LN and may help gauge the response to treatment in patients with active LN undergoing treatment.

Intraperitoneal injection of the hydrocarbon oil pristane into normal mice leads to a lupus-like autoimmune syndrome. Although advances in defining the roles of cellular and humoral mediators involved in this syndrome have been made, the mechanisms that initiate a break in tolerance leading to autoimmunity remain unknown. We describe in this study that pristane induces apoptosis both in vivo and in vitro. Pristane arrests cell growth and induces cell death by apoptosis via the mitochondrial pathway of caspase activation in a dose-dependent manner. Nuclear autoantigens created by pristane-induced apoptosis of lymphoid cells within the peritoneal cavity in the setting of a profoundly altered cytokine milieu may be the initiating event in the development of autoimmunity in this syndrome. These findings suggest that apoptosis may be a critical initial event in the pathogenesis of pristane-induced lupus and are of potential relevance for human systemic lupus erythematosus.

Summary Bone remodelling is severely affected in myeloma bone disease as a consequence of skeletal metastatization of malignant plasma cells. We investigated whether defective bone replacement is dependent on increased osteoblast apoptosis and/or on deregulated events within the bone microenvironment. Circulating tumour necrosis factor (TNF)‐α, interferon‐γ, interleukin (IL)‐1β, and IL‐6 levels were higher in myeloma patients with overt bone disease, whose osteoblasts constitutively overexpressed Fas, DR4/DR5 complex as receptors to TNF‐related apoptosis inducing ligand, intercellular adhesion molecule‐1 (ICAM‐1), and monocyte chemotactic protein‐1 (MCP‐1). They were functionally exhausted and promptly underwent apoptosis in vitro, in contrast to the minor tendency to death detected in control osteoblasts from patients without bone involvement and normal donors. Osteoblasts dramatically enhanced their apoptosis in co‐cultures with MCC‐2 myeloma cells and upregulated both ICAM‐1 and MCP‐1 in a manner similar to control osteoblasts. Pretreating MCC‐2 cells with soluble ICAM‐1 led to a striking inhibition of their adhesion to osteoblasts, suggesting that the ICAM‐1/lymphocyte function‐associated antigen‐1 system plays a role in the reciprocal membrane contact to trigger apoptogenic signals. Our data suggest that, in the myeloma bone microenvironment, both high cytokine levels and physical interaction of malignant plasma cells with osteoblasts drive the accelerated apoptosis in these cells leading to defective new bone formation.

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.