Type I Interferon Blockade in Systemic Lupus Erythematosus
Type I Interferon Blockade in Systemic Lupus Erythematosus
SLE is an autoimmune condition characterized by loss of tolerance to chromatin constituents and the production of ANAs. The majority of SLE patients display spontaneous expression of type I IFN-induced genes in circulating mononuclear cells and peripheral tissues, and type I IFNs play a role in the pathogenesis of the disease via the sustained activation of autoreactive T and B cells necessary for the production of pathogenic autoantibodies. Several IFN-blocking strategies are currently being evaluated in clinical trials: monoclonal antibodies directed against IFN-α and type I IFN-α receptor (IFNAR), as well as active immunization against IFN-α. This review describes the rationale behind these trials and the results obtained, and discusses the perspectives for further development of these drugs.
SLE is characterized by a break in T and B cell tolerance to autoantigens, and the production of autoantibodies directed against chromatin constituents (nucleosomes, single- and double-stranded DNA, RNPs). These antibodies play a pathogenic role, as has been well documented in the case of anti-double-stranded DNA antibodies, which bind to the glomerular basal membrane to activate complement and cause SLE nephritis.
The pathogenesis of SLE is a multistep process in which genetic, environmental and immunological factors play a role. The identification of an IFN signature in expression profiling studies performed on patients' blood cells was an important step forward. It enabled researchers to integrate numerous observations into one pathogenic scheme in which the excessive production of type I IFNs is central to the development of the disease. Hence, several IFN-blocking agents have been developed and tested in phase I and phase II clinical studies.
Overall, the results of these trials indicate that IFN-α blockade produces a significant effect on the expression of IFN-induced genes in vivo. At this point, however, they do not show consistent effects on clinical and/or biological manifestations of the disease. Here we will explore how type I IFNs are involved in the pathogenesis of SLE and what may be expected from further studies on IFN blockade in SLE. In particular, we will show that several redundant mechanisms lead to the induction of type I IFN genes, including, but not restricted to, overexpression of IFN-α family members. Despite the well-documented role of IFN-α in the pathogenesis of the disease, it is possible that, in some situations, additional mechanisms need to be targeted in order to produce significant clinical changes.
Abstract and Introduction
Abstract
SLE is an autoimmune condition characterized by loss of tolerance to chromatin constituents and the production of ANAs. The majority of SLE patients display spontaneous expression of type I IFN-induced genes in circulating mononuclear cells and peripheral tissues, and type I IFNs play a role in the pathogenesis of the disease via the sustained activation of autoreactive T and B cells necessary for the production of pathogenic autoantibodies. Several IFN-blocking strategies are currently being evaluated in clinical trials: monoclonal antibodies directed against IFN-α and type I IFN-α receptor (IFNAR), as well as active immunization against IFN-α. This review describes the rationale behind these trials and the results obtained, and discusses the perspectives for further development of these drugs.
Introduction
SLE is characterized by a break in T and B cell tolerance to autoantigens, and the production of autoantibodies directed against chromatin constituents (nucleosomes, single- and double-stranded DNA, RNPs). These antibodies play a pathogenic role, as has been well documented in the case of anti-double-stranded DNA antibodies, which bind to the glomerular basal membrane to activate complement and cause SLE nephritis.
The pathogenesis of SLE is a multistep process in which genetic, environmental and immunological factors play a role. The identification of an IFN signature in expression profiling studies performed on patients' blood cells was an important step forward. It enabled researchers to integrate numerous observations into one pathogenic scheme in which the excessive production of type I IFNs is central to the development of the disease. Hence, several IFN-blocking agents have been developed and tested in phase I and phase II clinical studies.
Overall, the results of these trials indicate that IFN-α blockade produces a significant effect on the expression of IFN-induced genes in vivo. At this point, however, they do not show consistent effects on clinical and/or biological manifestations of the disease. Here we will explore how type I IFNs are involved in the pathogenesis of SLE and what may be expected from further studies on IFN blockade in SLE. In particular, we will show that several redundant mechanisms lead to the induction of type I IFN genes, including, but not restricted to, overexpression of IFN-α family members. Despite the well-documented role of IFN-α in the pathogenesis of the disease, it is possible that, in some situations, additional mechanisms need to be targeted in order to produce significant clinical changes.
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