ReviewThe type I interferon system in the development of lupus
Introduction
The type I IFN system was for many years primarily regarded as a defense system against viral infections, because type I IFN is rapidly produced during viral invasion and secreted IFN protect target cells from being infected. Subsequent studies revealed that the type I IFNs also can activate cells in the innate and adaptive immune system, making the type I IFN system an important actor in the cellular and humoral immune response. The early observation that many patients with systemic autoimmune rheumatic diseases have increased production of type I IFN [1], [2] was, however, largely unnoticed until case reports described development of autoimmune diseases during long-term IFN-α treatment of patients with malignant diseases [3]. When increased expression of type I IFN regulated genes (an IFN signature) was described in lupus [4], [5], [6], scientists and clinicians were spurred to investigate the role of the type I IFN system in this disease. Subsequent studies revealed that the IFN signature is not unique for lupus, but can also be found in other autoimmune diseases [7]. The two observations that (i) IFN-α therapy can induce autoimmunity and that (ii) many autoimmune conditions have a prominent IFN signature, suggest that the type I IFN system has a pivotal role in the etiopathogenesis of these diseases. During the last years, several observations have been made with regard to possible reasons for the continuous type I IFN synthesis in lupus and its importance for the etiopathogenesis. Among possible explanations for the increased type I IFN production are risk genes linked to both the production and response to IFN-α as well as presence of endogenous inducers of type I IFN production. However the role of the different environmental risk factors for lupus in the type I IFN response is largely unknown and is of course an important area for further studies. In the present review we will describe the observations concerning the type I IFN system in lupus, possible reasons behind the increased IFN-α production as well as consequences of IFN-α action on the immune system. We will also provide some suggestions of how some well-known environmental risk factors for lupus can contribute to the initiation of the type I IFN system activation and the ongoing IFN-α synthesis.
Section snippets
Type I interferon system
The type I IFN system can be broadly defined as the type I IFN inducers and cells and molecules involved in the pathways leading to production and effects of type I IFN. The type I IFN multigene family consists of several structurally related genes that can be divided into five classes (IFN-α, -β, -ω, -ɛ and -κ) of which IFN-α can be further divided into 13 subtype genes. In common, all type I IFN genes, except IFN-κ, lack introns and type I IFN proteins bind to the same heterodimeric type I
Lupus
The incidence of lupus varies in different populations, but is around 5 cases per 100,000 persons among Northern Europeans [37]. The disease is therefore much more rare than rheumatoid arthritis, but since lupus is regarded as the prototype autoimmune disease much attention has been drawn to possible etiopathogenic mechanisms behind lupus.
The type I IFN system in lupus
The ongoing IFN-α production in lupus patients is an interesting phenomenon, which seems to be of major importance in the development of the autoimmune disease process. Here, we summarize the present knowledge of the type I IFN system in lupus patients.
The type I IFN system and the environment in lupus
The connection between the type I IFN system and the environment is obvious, because the main function of this system is to provide a fast and vigorous response when viruses are encountered [13]. The development of lupus as well as disease flares has been reported in connection of viral infections [108], [109], which strengthens the hypothesis that lupus sometimes can be caused by an unusual strong IFN-α response in genetically susceptible individuals. Furthermore, anti-SSA antibodies, which
The type I IFN system in the lupus disease process
A possible scenario for the development of lupus is summarized in Fig. 2. An initial infection by a virus induces type I IFN production and release of cellular material from dying cells. The extracellular autoantigens from apoptotic and necrotic cells then trigger B cells to autoantibody production against RNA and DNA binding proteins in individuals prone to autoimmune reactions. ICs will be formed, which act as endogenous type I IFN inducers that cause a prolonged stimulation of type I IFN
Conclusions
An activated type I IFN system is important in the pathogenesis of lupus and several other autoimmune diseases that display a type I IFN signature. Much is known about the endogenous type I IFN inducers and the molecular pathways that cause the continuous IFN-α production. However, the regulation of type I IFN system and the functional role of many gene variants associated with lupus are less understood. To elucidate the in vivo impact of the disease associated genes and the environmental
Acknowledgements
This work was supported by grants from the Swedish Research Council, Alliance for Lupus Research, the Dana Foundation, Combine, the Swedish Rheumatism Association, the Torsten and Ragnar Söderberg Foundation and the King Gustaf V 80-year Foundation.
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