Dichotomic effects of IFN-γ on the development of systemic lupus erythematosus-like syndrome in MRL-lpr / lpr mice (original) (raw)
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Type I Interferon controls the onset and severity of autoimmune manifestations in lpr mice
Journal of Autoimmunity, 2003
Type I Interferons (IFN-I) are immunoregulatory cytokines that enhance activation and survival of many cellular components of the immune system. In the present work, we evaluated the effect of IFN-I on the development of the lymphoproliferative disorder in Fas-defective lpr mice. We report that sustained injection of polyinosinic:polycytidylic acid, a potent inducer of IFN-I, in B6 lpr mice resulted in a dramatic aggravation of the renal disease, higher titers of autoantibodies, a 10-fold increase in serum Ig and accumulation of activated lymphocytes. Moreover, introducing a null mutation for the IFN-I-Receptor gene into the lpr background resulted in dramatic decrease of immune complexes deposition in the kidney and reduced lymphadenopathy. While several recent reports correlated serum levels of IFN-with disease activity in systemic Lupus erythematosus patients, our findings establish a causal link from IFN-I production to the onset and severity of another related autoimmune syndrome.
Interferon-α accelerates murine systemic lupus erythematosus in a T cell-dependent manner
Arthritis & Rheumatism, 2010
Objective-To investigate the mechanism for lupus acceleration by interferon alpha (IFNα) in NZB/W mice. Methods-NZB/W mice were treated with an adenovirus expressing IFNα. T cells were depleted in some mice with an anti-CD4 antibody. The production of anti-dsDNA antibodies was measured by ELISA and ELISpot assays. Germinal centers and antibody-secreting cells (ASCs) in spleens and IgG deposition and leukocyte infiltrates in kidneys were visualized by immunofluorescence staining. The phenotype of splenic cells was determined by flow cytometry. Finally, somatic hypermutation and gene usage in heavy chain variable regions of IgG2a and IgG3 were studied by single cell PCR. Results-IFNα accelerated lupus in NZB/W mice is associated with elevated serum levels of IgG2 and IgG3 anti-dsDNA antibodies, and accumulation of many IgG ASCs in the spleen, which do not develop into long-lived plasma cells. Furthermore, IgG2a and IgG3 antibodies in these mice are highly somatically mutated and use distinct repertoires of VH genes. The induction of SLE in these mice is associated with an increase in B cell TLR7 expression, increased serum levels of BAFF, IL-6 and TNFα, and induction of T cells expressing IL-21. Although IFNα drives a T-independent increase in serum levels of IgG, autoantibody induction and the development of nephritis are both completely dependent on CD4 T cell help. Conclusion-Our study shows that although IFNα activates both innate and adaptive immune responses in NZB/W mice, CD4 T cells are necessary for IFNα driven induction of anti-dsDNA antibodies and clinical SLE.
IFN- Confers Resistance of Systemic Lupus Erythematosus Nephritis to Therapy in NZB/W F1 Mice
The Journal of Immunology, 2011
The critical role of IFN-a in the pathogenesis of human systemic lupus erythematosus has been highlighted in recent years. Exposure of young lupus-prone NZB/W F1 mice to IFN-a in vivo leads to an accelerated lupus phenotype that is dependent on T cells and is associated with elevated serum levels of BAFF, IL-6, and TNF-a, increased splenic expression of IL-6 and IL-21, formation of large germinal centers, and the generation of large numbers of short-lived plasma cells that produce IgG2a and IgG3 autoantibodies. In this study, we show that both IgG2a and IgG3 autoantibodies are pathogenic in IFN-a-accelerated lupus, and their production can be dissociated by using low-dose CTLA4-Ig. Only high-dose CTLA4-Ig attenuates both IgG2a and IgG3 autoantibody production and significantly delays death from lupus nephritis. In contrast, BAFF/APRIL blockade has no effect on germinal centers or the production of IgG anti-dsDNA Abs but, if given at the time of IFN-a challenge, delays the progression of lupus by attenuating systemic and renal inflammation. Temporary remission of nephritis induced by combination therapy with cyclophosphamide, anti-CD40L Ab, and CTLA4-Ig is associated with the abrogation of germinal centers and depletion of shortlived plasma cells, but relapse occurs more rapidly than in conventional NZB/W F1 mice. This study demonstrates that IFN-a renders NZB/W F1 relatively resistant to therapeutic intervention and suggests that the IFN signature should be considered when randomizing patients into groups and analyzing the results of human clinical trials in systemic lupus erythematosus.
Arthritis research, 2001
The classification of T helper cells into type 1 (Th1) and type 2 (Th2) led to the hypothesis that Th1 cells and their cytokines (interleukin [IL]-2, interferon [IFN]-gamma) are involved in cell-mediated autoimmune diseases, and that Th2 cells and their cytokines (IL-4, IL-5, IL-10, IL-13) are involved in autoantibody(humoral)-mediated autoimmune diseases. However, this paradigm has been refuted by recent studies in several induced and spontaneous mouse models of systemic lupus erythematosus, which showed that IFN-gamma is a major effector molecule in this disease. These and additional findings, reviewed here, suggest that these two cross-talking classes of cytokines can exert autoimmune disease-promoting or disease-inhibiting effects without predictability or strict adherence to the Th1-versus-Th2 dualism.
A Novel Type I IFN-Producing Cell Subset in Murine Lupus
The Journal of Immunology, 2008
Excess type I IFNs (IFN-I) have been linked to the pathogenesis of systemic lupus erythematosus (SLE). Therapeutic use of IFN-I can trigger the onset of SLE and most lupus patients display up-regulation of a group of IFN-stimulated genes (ISGs). Although this “IFN signature” has been linked with disease activity, kidney involvement, and autoantibody production, the source of IFN-I production in SLE remains unclear. 2,6,10,14-Tetramethylpentadecane-induced lupus is at present the only model of SLE associated with excess IFN-I production and ISG expression. In this study, we demonstrate that tetramethylpentadecane treatment induces an accumulation of immature Ly6Chigh monocytes, which are a major source of IFN-I in this lupus model. Importantly, they were distinct from IFN-producing dendritic cells (DCs). The expression of IFN-I and ISGs was rapidly abolished by monocyte depletion whereas systemic ablation of DCs had little effect. In addition, there was a striking correlation between...
Clinical and Experimental Immunology, 1997
SUMMARY Transient expression of IFN-γ and IL-2 mRNA and its control by post-transcriptional and suppressive mechanisms were analysed in phytohaemagglutinin-induced peripheral blood mononuclear cells (PBMC) from 47 patients with SLE and 31 age-matched normal donors, using quantitative hybridization with antisense RNA probes. In SLE, basal levels of gene expression did not deviate from those of normal donors, but strongly aberrant patterns were obtained upon induction. The ratio of subjects exhibiting highly inducible IFN-γ gene expression in their PBMC to those showing moderate or low inducibility was increased five-fold in SLE (P = 0.003). High inducibility was observed for 43% of SLE patients and was equally pronounced in partial remission, mild or active disease. Inducibility of IL-2 mRNA, by contrast, remained similar to that for normal donors. However, regulation of IFN-γ gene expression differed for mild SLE. Patients with mild disease showing high inducibility of IFN-γ mRNA in...