Systemic lupus erythematosus: all roads lead to type I interferons

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In recent years, the study of systemic lupus erythematosus (SLE) patients has revealed a central role for type I interferon (IFN) in disease pathogenesis. IFN induces the unabated activation of peripheral dendritic cells, which select and activate autoreactive T cells rather than deleting them, thus failing to induce peripheral tolerance. IFN also directly affects T cells and B cells. Furthermore, immune complexes binding to FcγR and Toll-like receptors provide an amplification loop for IFN production and B-cell activation in SLE. Polymorphisms in genes that control IFN production or its downstream signaling pathway, such as IRF5, might be responsible for some of these alterations. This novel information is leading to the development of IFN antagonists as a potential therapeutic intervention in SLE, thus bringing hope to SLE patients.

Introduction

Patients with systemic lupus erythematosus (SLE) have long been known to display elevated levels of type I interferon (IFN) in their serum. The key role that this cytokine family plays in disease pathogenesis has only emerged, however, in the past few years. We proposed in 2001 that an excess type-I IFN might break peripheral tolerance through the activation of myeloid dendritic cells (DCs). Since then, the roles of type I IFN in two key SLE pathogenic events (i.e. human plasma cell differentiation and activation of CD8 T cells able to generate nucleosomes) have been described. It has also become evident that antigen–antibody complexes containing RNA and DNA activate DCs and B cells through interaction with TLR7/8 and 9, respectively. Thus, lupus-specific autoantigens might act as TLR ligands and contribute to IFN and autoantibody production.

In this article, we will review recent evidence regarding the role of type I IFN in human SLE. We will discuss controversial data on the role of IFN and TLR activation in different murine lupus models. Finally, we will summarize some recent genetic studies that further link the type-I IFN pathway to the pathogenesis of human SLE.

Section snippets

Beyond B and T cells: dendritic cell alterations in SLE

One of the hallmarks of SLE is the loss of tolerance to nuclear antigens and the development of immune complexes that deposit in tissues and cause widespread inflammation. Alteration of T cell–B cell interactions has therefore been proposed as the common pathogenic mechanism that leads to disease [1]. However, the recognition of DCs as efficient stimulators of B and T lymphocytes as well as key controllers of immunity [2] and tolerance [3, 4] has led to the hypothesis that SLE might be driven

IFN-α dysregulation at the center of SLE pathogenesis

Several cytokines have been shown to allow the differentiation of precursor cells into DCs. In particular, IFN-α together with granulocyte-macrophage colony-stimulating factor drive monocytes to become DCs [7, 8, 9]. Accordingly, the DC-inducing property of SLE serum is dependent on IFN-α and correlates with disease activity [5]. Thirteen different IFN-α subtypes together with IFN-β, IFN-ω, IFN-κ and IFN-ɛ/τ (reviewed in [10]) constitute the type I IFN family. A new class of type I IFN-like

IFN-α and immune complexes: the TLR connection and disconnection

The mechanism(s) that leads to unabated production of IFN is currently the subject of debate. There are probably two paths to consider: first, a genetic alteration that prevents the prompt shutdown of IFN production by pDCs; and second, an amplification loop that results from immune complex (IC) activation of pDCs and B cells. We will review the recent studies on the role of ICs and nucleic acids that activate pDCs and B cells by way of Toll-like receptor (TLR)-dependent and -independent

From biology to genomics and back

The genetic basis of human SLE has been the subject of extensive study for more than 20 years. Indeed, genome-wide linkage studies have identified several genetic loci associated to SLE in multiplex families. The multiplicity and complexity of these loci, however, represent a formidable challenge for lupus geneticists. The development in recent years of high-density single nucleotide polymorphism genotyping is allowing both study of previously identified candidate loci and development of

A unified view of SLE pathogenesis

SLE is a remitting disease characterized by flares that progressively result in deterioration of the patient. These flares are often associated with environmental triggers such as viral infections. Infection could trigger the unabated production of IFN-α in SLE patients. We contend that this increased bioavailability of IFN-α is fundamental to SLE pathogenesis. It induces and maintains the generation of mature DCs, tilting the fate of autoreactive T lymphocytes that have escaped central

Conclusions

Alterations of the type I IFN system in SLE were described more than 20 years ago but were forgotten or diluted within the plethora of mouse lupus-like models. The study of SLE patients, however, has recently brought the role of this old cytokine family in the pathogenesis of the disease back into the spotlight. With the help of high throughput technologies, more pieces of the puzzle are being put together. Gene expression profiling, for example, has revealed the almost universal expression of

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors acknowledge support from the Baylor Health Care System Foundation, the Alliance for Lupus Research (to VP), Defense Advanced Research Planning Agency (to JB), The National Institutes of Health (U19 AIO57234-02, P01 CA084512 and R01 CA078846 to JB and R01 AR46589-01 to VP) and the Research Council of Norway (to LF). JB holds the WW Caruth, Jr Chair in Organ Transplantation Immunology. We thank Carson Harrod for editorial help, Karolina Palucka for critical reading of the manuscript

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