title: Role of Th1 and Th2 cytokines in the pathogenesis of systemic autoimmune diseases
Creators: name: Esfandiari, Ehsanollah
Publisher: name: University of Glasgow
Year: 2001
Subjects: subject: Immunology
subject: FOS: Clinical medicine

description: Systemic lupus erythematosus (SLE), is a prototypic systemic autoimmune disease characterised by multi-system involvement, female preference, activation of T-cells, B-cell hyper-activity, autoantibody production and immune complex deposition. The origin of the defects leading to pathogenicity in systemic lupus erythematosus, is still controversial. The therapeutic strategies today for treatment of lupus disease are mainly based on a general suppression of the immune system with uncertainty about their long-term effects. The underlying mechanism for the development of the disease is yet to be clarified. Cytokines play a critical role in regulating the quantitative and qualitative responses of T cells, B cells, macrophages, and other cell types. Many cytokine disorders have been reported in both SLE patients and the animal models but findings are often difficult to reconcile especially differences between data from the in vitro and in vivo studies. In the murine model, it was suggested that the balance of Th1/Th2 cytokines related to the pathogenesis of SLE. Recent evidence clearly demonstrates that Th1 cytokines are involved in the immuno-pathogenesis of SLE. Several factors are required for optimal induction of Th1 activity, chief among them are IL-12 and IL-18. IL-12 promoted IFN-gamma dependent renal injury in MRL/lpr mice, which develop spontaneous lupus-like autoimmune disease. In order to understand the mechanism of immune regulation in SLE, I carried out detailed analysis of the nature and pathological relevance of Th1 and Th2 cytokines, IL-12 and IL-18 in particular, in the pathogenesis of SLE. I found that serum fi-om patients with SLE contained significantly higher concentrations of IL-18 than normal individuals. To investigate the potential role of IL-18 in SLE, I studied the effect of recombinant-IL-18 on MRL/lpr mice, which develop spontaneous lupus-like autoimmune disease. MRL/lpr mice produced significantly more IL-18 as disease progressed compared with the wild-type MRL/++ mice. MRL/lpr mice injected daily with IL-18 or IL-18 + IL-12 resulted in accelerated proteinuria, glomerulonephritis, and vasculitis. In contrast, the treatment had no effect on the control MRL/++ mice. IL-18 and IL-18 + IL-12-treated MRL/lpr mice produced more inflammatory cytokines (LFN-gamma, TNF-alpha and IL-6) compared with untreated MRL/lpr mice. IL-18-treated MRL/r mice also exhibited the butterfly facial rashes characteristic of clinical SLE. In contrast, MRL/lpr mice treated with a combination of IL-18 and IL-12, while showing more severe vasculitis than those treated with IL-18 alone, did not present any facial rash. Histological analysis of the facial lesion revealed extensive epidermal thickening with intense inflammatory cell infiltrate and immunoglobulin deposition accompanied by extensive apoptosis in the IL-18-treated mice compared with control or IL-12 + IL-18 treated mice. IL-18 may thus be a novel target for therapeutic intervention of spontaneous autoimmune diseases. Elevated levels of IL-12 (p40/p70) have been reported in MRL/lpr serum and have been linked to increased nitric oxide production and disease activity. Therefore, studies were also performed to determine whether IL-12 and nitric oxide (NO) play a significant role (similar to MRL/lpr mice) in induction of the disease in NZB/W mice a lupus-like model with different genetic backgrounds from MRL/lpr mice and with intact Fas. The results demonstrate that serum of NZB/W FI mice contains higher level of total IL-12 (p40/p70) than control mice and IL-12 is increased in correlation with disease of this lupus-like strain. In himians, the serum level of total IL-12 is significantly higher in SLE patients than control individuals. Whole blood culture from SLE patients also showed higher IL-12 production, when cultured with LPS and IFN-gamma, compared with control individuals. Results presented in this thesis demonstrate that IL-18 and IL-12 play important roles in the induction of SLE through the activation of Th1 cells.