Volume 12 Supplement 1
Potential role of IFNα in adult lupus
© BioMed Central Ltd. 2010
Published: 14 April 2010
Patients with lupus have a continuous production of IFNα and display an increased expression of IFNα-regulated genes. The reason for the ongoing IFNα synthesis in these patients seems to be an activation of plasmacytoid dendritic cells (pDCs) by immune complexes (ICs), consisting of autoantibodies in combination with DNA-containing or RNA-containing autoantigens. The mechanisms behind the activation of pDCs by such ICs have to some extent been elucidated during the last years. Thus, interferogenic ICs are internalized via the FcγRIIa expressed on pDCs, reach the endosomes and stimulate Toll-like receptor (TLR) 7 or 9, which subsequently leads to IFNα gene transcription. Variants of genes involved in both the IFNα synthesis and response have been linked to an increased risk to develop lupus. Among these genes are interferon regulatory factor 5 (IRF5), which is involved in TLR signaling, and the signal transducer and activator of transcription 4 (STAT4) that interacts with the type I interferon receptor. Produced IFNα may at least partially be responsible for several of the observed alterations in the immune system of lupus patients and contribute to the autoimmune disease process, which will be discussed in the present review. How produced IFNα can contribute to some clinical manifestations will briefly be described, as well as the possible consequences of this knowledge in clinical practice for disease monitoring and therapy
Systemic lupus erythematosus, or lupus, is one of the most intriguing diseases due to its diverse clinical picture, variable course and in the single patient also its unpredictable outcome. The etiopathogenesis of lupus has been studied intensively for many years and the disease has long been regarded as the prototype autoimmune disease. The reason for this is that a large number of different autoantibodies are produced in lupus patients and that most, if not all, cells in the immune system seem to be involved in the disease process.
The most prominent feature in lupus is an immune response to nucleic acid and associated proteins, which results in autoantibody production, immune complex (IC) formation and organ inflammation. In addition, most lupus patients display several signs of an increased IFNα production, which during the past years has attracted much interest regarding the possible role of this cytokine in the disease process. This interest has been further inspired by the observation that IFNα administration to individuals without any autoimmune condition can trigger the production of antinuclear autoantibodies, and occasionally also a lupus syndrome.
In the present review, the possible reason(s) behind the ongoing IFNα production in lupus will be reviewed, as well as the role of IFNα in the etiopathogenesis and the clinical manifestations of the disease. The potential application in clinical practice of our present knowledge of the type I interferon system in lupus will also be discussed.
IFNα in lupus patients
The first described cytokine abnormality in lupus patients was an increased serum level of interferon , which subsequently was characterized as IFNα . Early studies also demonstrated that lupus patients have increased levels of IFNα-induced proteins, such as 2',5'-adenylate synthetase  and MxA . The latter report showed that >90% of lupus patients displayed increased expression of MxA, even if measurable serum IFNα levels could not be detected. Further studies showed that serum IFNα levels correlated to disease activity, but also to signs of immune activation and several clinical disease manifestations .
Functional analysis of type I interferon activity in serum from lupus patients has revealed that there is an association between serum interferon activity and immuno logical phenotype . When genome-wide gene expression profiling became available, several research groups observed that a large proportion of lupus patients have an increased expression of type I interferon-regulated genes (an interferon signature) in peripheral blood mononuclear cells [7–10], but also in affected organs such as the kidneys . The interferon signature was observed in almost all pediatric lupus patients with active disease of recent onset ; in adults with more longlasting and less active disease, in comparison, approximately one-half of the patients displayed the interferon signature [8, 9].
Induction of IFNα production in lupus
The natural interferon-producing cell, also termed the plasmacytoid dendritic cell (pDC), has the unique capacity to secrete up to 109 IFNα molecules per cell in response to viral infections . These cells appear to be the major type I interferon-producing cell for many different interferon inducers, including both viruses and bacteria. The prominent signs of an ongoing IFNα production in lupus therefore raise questions of the natural interferon-producing cell/pDC function and the potential IFNα inducers in these patients.
Natural interferon-producing cells/plasmacytoid dendritic cells
Several studies have shown that the frequency of circulating pDCs is markedly reduced in lupus patients [13–15], although residual single cells upon stimulation have a normal IFNα-producing capacity. The reason for the decreased number of circulating pDCs seems to be a migration of these cells to tissues, because an increased number of pDCs can readily be detected in the skin [16, 17], in lymph nodes  and in renal tissue  from lupus patients. pDCs are furthermore activated in vivo and synthesize IFNα, which indicates that these cells are responsible for the continuous IFNα production in lupus.
The pDCs can be activated to IFNα production via triggering of Toll-like receptor (TLR) 7 or TLR9, which sense single-stranded RNA and CpG-containing DNA, respectively (reviewed in ). These receptors are localized in the endosome to prevent activation by self RNA or DNA. Ligation of the TLRs leads to interaction with the myeloid differentiation factor 88 adaptor protein and subsequent phosphorylation of several transcription factors, among which interferon regulatory factor (IRF) 5 and IRF7 are most important. In addition, the TLR9-mediated induction of type I interferon production requires an intact mammalian target of rapamycin pathway .
Inducers of IFNα in lupus
In the search for an endogenous IFNα inducer in lupus, we noted that sera from such patients contain ICs consisting of autoantibodies and DNA with the capacity to specifically activate pDCs [22, 23]. Further studies revealed that such interferogenic ICs are internalized via the FcγRIIa expressed on pDCs , reach the endosome and stimulate the relevant TLR with subsequent activation of transcription factors and IFNα production . This mechanism for induction of type I interferon production has been demonstrated in vitro for both DNA-containing and RNA-containing ICs. The nucleic-acid-containing autoantigens in the interferogenic ICs can be generated from apoptotic or necrotic cells , which is relevant given the increased apoptosis and reduced clearance of apoptotic cells in lupus . Several molecules are involved in the IFNα response to these ICs. The high-mobility group box 1 protein/receptor for advanced glycation end-products interaction is necessary for the TLR9-induced IFNα production by DNA-containing ICs , whereas C1q decreases the IFNα production by interferogenic ICs .
One obvious question is whether certain individuals have an enhanced IFNα production or sensitivity, which could increase the risk to develop lupus if nucleic-acid-containing ICs appear. The observation that a high serum IFNα activity seems to be a heritable risk factor for lupus  indicates that the genetic control of the type I interferon system is important for the risk to develop this disease (for a comprehensive review, see article S3 in this supplement).
The transcription factor IRF5, which is constitutively expressed in pDCs , was the first identified gene directly involved in IFNα production that was associated with increased risk for lupus . The allele variants with the highest probability of being causal were identified recently, and were shown to affect the IRF5 expression, which is increased in peripheral blood mononuclear cells from lupus patients . An IRF5 risk haplotype is associated with a high serum IFNα activity in patients, and especially in those with autoantibodies to RNA binding proteins or double-stranded DNA , linking lupus genetic susceptibility to the presence of interferogenic ICs.
The IL-1 receptor-associated kinase, which is involved in TLR signaling and IFNα production, is also associated with lupus , which further strengthens the view that the genetic control of the IFNα production is important for the risk to develop lupus. The importance of the TLR pathways in this disease is further underscored by the observations that gene variants of the TNFα-induced protein 3 is associated with increased risk for lupus [41, 42].
Among genes involved in the response to IFNα, the signal transducer and activator of transcription 4 (STAT4) that interacts with the cytoplasmic part of the type I interferon receptor (IFNAR)  is strongly associated with lupus . In lupus patients there is an association between the STAT4 genotype, increased sensitivity to IFNα  and a more severe phenotype, which includes nephritis and the presence of anti-double-stranded DNA autoantibodies [46, 47]. Polymorphisms in the Janus kinase tyrosine kinase 2, which binds to the IFNAR and is required for signaling through this receptor, is also associated with lupus [37, 48].
These data provide further evidence for a link between the IFNα response and the disease process in lupus. Additional susceptibility genes for lupus can be involved in the activation of the type I interferon system by other mechanisms - for instance, via increased production of autoantibodies and subsequent generation of more interferogenic ICs .
Consequences of the ongoing IFNα production in lupus
What are the consequences of the ongoing IFNα synthesis in lupus patients? Produced IFNα will affect most cells in the immune system and can therefore stimulate the central autoimmune process, but IFNα will also contribute to the expression of some clinical signs and symptoms.
IFNα and autoimmunity
The possible role of IFNα as an inducer of lupus was originally suggested by the observation that the administration of IFNα to a patient with a malignant disease induced a lupus syndrome indistinguishable from naturally occurring lupus . During the years, many reports have described the induction of several different autoimmune diseases during prolonged treatment of patients with IFNα . The presence of autoantibodies in patient sera before the onset of IFNα therapy considerably increases the risk for development of clinical overt autoimmune disease during IFNα administration . These observations demonstrate that IFNα has the capacity to both break the tolerance and enhance a smoldering autoimmune process.
The mechanisms behind the pro-autoimmune effects of IFNα are not clear, but there exist several possibilities. First, IFNα can induce increased expression of autoantigens, such as Ro52 [7, 8], but can also promote the release of autoantigens by induction of apoptosis . Secondly, IFNα has multiple effects in both the innate and adaptive immune systems, which best can be described as a general activation of the immune cells. IFNα thus induces dendritic cell maturation and activation, with increased expression of MHC class I and II molecules, chemokines and chemokine receptors, costimulatory molecules such as CD80, CD86, the B-lymphocyte stimulator and a proliferation-inducing ligand . Importantly, IFNα can also induce the expression of TLR7 , which may enhance the responsive ness to interferogenic ICs. The development of helper T cells along the T-helper type 1 pathway is promoted, and cytotoxic T cells are stimulated by type I interferons, due to an increase in dendritic cell cross-presentation, inhibition of T-cell apoptosis as well as stimulation of IL-2 secretion by central memory T cells . Type I interferons cause B-cell activation, differentiation, antibody production and immunoglobulin isotype class switching [57, 58], but can also decrease the selectivity of B cells for CpG-rich DNA and allow stimulation by even non-CpG DNA  - thereby promoting an autoimmune response. Consequently, several IFNα-mediated effects can contribute to the autoimmune process in the pathogenesis of lupus. Figure 1 shows a schematic view of the possible role of IFNα in the disease process.
IFNα production is affected by several cytokines and cells in the immune system. TNFα and IL-10 can downregulate the IC-mediated IFNα production , and TNFα also inhibits the generation of pDCs . The IFNα response is furthermore regulated by several cells in the immune system, such as natural killer cells and monocytes. Natural killer cells promote the IFNα production whereas the monocytes downregulate the type I IFNα response, and this control mechanism may be deficient in lupus patients . The complex interaction between the different cytokines and the immune system in lupus patients may be further clarified by a network-based analysis of abnormally regulated genes in these patients .
IFNα and disease manifestation
Several observations suggest that IFNα may have an important role in some of the clinical manifestations in lupus patients. There is an association between increased serum levels of IFNα and fever, skin rash and leucopenia , which perhaps is not surprising considering these symptoms are commonly seen during viral infections. Among the more specific lupus manifestations, an early study observed that patients with lupus psychosis have detectable levels of IFNα in the cerebrospinal fluid , which is intriguing given the observed neuropsychiatric adverse effects during IFNα treatment . Recently, auto antibodies with the ability to form very potent interferogenic ICs together with RNA-containing autoantigens were demonstrated in the cerebrospinal fluid of lupus patients with neuropsychiatric manifestations . These ICs also induced other chemokines and proinflammatory cytokines of possible relevance for the central nervous system manifestations frequently seen in lupus, which indicates that the interferogenic ICs may be directly involved in central nervous system lupus.
Results from an experimental model suggest that IFNα can drive the nephritis and end organ damage in lupus , and it has been shown that pDCs accumulate in active human lupus nephritis . These observations are in line with the findings that major organ involvement in lupus patients, including nephritis, is connected to a more pronounced IFNα signature  and that IFNα-regulated genes are overexpressed in the glomeruli from lupus nephritis . The role of IFNα in the premature atherosclerosis typically seen in lupus patients is unclear, but IFNα may contribute to the atherosclerotic process by impairing endothelial cell differentiation . Furthermore, pDCs are present in atherosclerotic plaques from carotid lesions where, via produced IFNα, they can act as inflammatory amplifiers and destabilize the plaque .
IFNα in clinical practice
We are at the beginning of an era were the basic knowledge of the type I interferon system in lupus is translated into clinical useful tools for monitoring and treating patients.
IFNα as a biomarker
There is a correlation between the serum levels of IFNα and disease activity in lupus patients, as mentioned above. Owing to difficulties in measuring IFNα in serum, however, most investigators study the interferon signature as a potential biomarker. A more pronounced interferon signature is seen in patients with active disease and major disease manifestations, such as nephritis, cerebritis, hematological manifestations and increased damage index [7, 8, 70–72]. Administration of high doses of corticosteroids to lupus patients with active disease, which induces clinical remission, will normalize the interferon signature . These observations have demonstrated a connection between the IFNα signature and the clinical status of the patients. Whether determination of the interferon-induced gene expression can be used to closely monitor the disease activity in single patients during longitudinal follow-up is uncertain, however, because the interferon signature seems to remain stable in the patients despite changes in disease activity [72, 73]. On the other hand, two preliminary reports have suggested that the interferon-gene profile of peripheral blood cells could predict future disease activity [74, 75].
At the moment, the clinical value of monitoring the IFNα signature during long-term follow-up remains to be established. Two other approaches to follow disease activity are either to look at expression of type I interferon-regulated molecules on cells involved in the disease process, such as Siglec-1 on monocytes , or to measure the level of interferon-regulated chemokines . Interestingly, the interferon-regulated chemokines may also be connected to organ damage .
There is also a possibility that genes within the type I interferon signaling pathway can be used as biomarkers for organ involvement and severity. There is thus an association between the STAT4 genotype and risk for a more severe disease phenotype that includes nephritis [46, 47] and stroke . The latter observation is interesting, because the association between a STAT4 risk variant and stroke was of the same magnitude as the association between stroke and hypertension, indicating that autoimmune processes may be very important for many disease manifestations in lupus, even those that traditionally not are regarded as autoimmune. Furthermore, a combination of risk alleles within the type I interferon signaling pathway dramatically increases the risk for lupus , which illustrates how genetic mapping in the future perhaps could aid in the prediction of risk for disease.
IFNα as a therapeutic target
Because many observations indicate a crucial role for the type I interferon system and IFNα in the etiology and pathogenesis of human lupus, several companies are developing therapies aiming to inhibit the type I interferon production or effects in the disease. This development has been stimulated by the fact that type I IFNAR-knockout murine lupus models have a reduced disease activity [80, 81].
Results from the first phase I clinical trial using a single injection of anti-IFNα monoclonal antibodies in lupus patients were recently reported [82, 83]. The anti-IFNα treatment caused a dose-dependent inhibition of the type I interferon inducible genes in both peripheral blood and skin biopsies, as well a reduction in clinical disease activity. In addition, granulocyte-macrophage colony-stimulating factor, TNFα, IL-10 and IL-1β inducible gene signatures, as well as B-cell activating factor mRNA expression, were neutralized in some patients  - demonstrating the interaction between the type I interferon system and other proinflammatory pathways. The observation that a single injection of an anti-IFNα antibody could give a sustained neutralization of the interferon signature is of particular interest, and supports the view that the ongoing production of interferon in lupus is at least partly a result of a self-perpetuating vicious circle  (Figure 1). No increase in serious viral infections has so far been reported among anti-IFNα-treated patients, which could be due to the fact that besides IFNα there exist several other type I interferons with strong antiviral activity . Whether these latter type I interferons are sufficient potent to protect anti-IFNα-treated lupus patients from serious complications during, for instance, a flu pandemic remains to be established, and can only be addressed in larger clinical trials.
There exist other possible therapeutic targets within the type I interferon system, such as the IFNAR, the BDCA-2 antigen on pDC [14, 85] or oligodeoxyribonucleotide or oligoribonucleotide TLR antagonists . None of these agents have so far been tested in human lupus patients.
In conclusion, the type I interferon system is activated in lupus patients with ongoing IFNα production, which is of major importance for the disease process. The genetic and immunological background to this overproduction of IFNα is to some extent clarified, but several questions still remain to be answered. Despite this, several studies aiming to target the increased IFNα levels or its effects in lupus patients are planned, or are in the early clinical phase. These treatment regimes will hopefully bring relief to our patients without interfering with the normal function of the type I interferon system.
type I interferon receptor
interferon regulatory factor
plasmacytoid dendritic cell
signal transducer and activator of transcription
tumor necrosis factor.
The present work was supported by The Alliance for Lupus Research, the Swedish Research Council, the Dana Foundation, the Swedish Rheumatism Association, the Gustafsson Foundation, the King Gustaf V 80th Birthday Foundation and COMBINE.
This article is part of Arthritis Research & Therapy Volume 12 Supplement 1: The role of IFN alpha in autoimmune disease. The full contents of the supplement are available online at http://arthritis-research.com/supplements/12/S1. Publication of the supplement has been supported with funding from MedImmune, LLC.
- Hooks JJ, Moutsopoulos HM, Geis SA, Stahl NI, Decker JL, Notkins AL: Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med. 1979, 301: 5-8. 10.1056/NEJM197907053010102.View ArticlePubMed
- Ytterberg SR, Schnitzer TJ: Serum interferon levels in patients with systemic lupus erythematosus. Arthritis Rheum. 1982, 25: 401-406. 10.1002/art.1780250407.View ArticlePubMed
- Preble OT, Rothko K, Klippel JH, Friedman RM, Johnston MI: Interferon-induced 2'-5' adenylate synthetase in vivo and interferon production in vitro by lymphocytes from systemic lupus erythematosus patients with and without circulating interferon. J Exp Med. 1983, 157: 2140-2146. 10.1084/jem.157.6.2140.View ArticlePubMed
- von Wussow P, Jakschies D, Hochkeppel H, Horisberger M, Hartung K, Deicher H: MX homologous protein in mononuclear cells from patients with systemic lupus erythematosus. Arthritis Rheum. 1989, 32: 914-918.PubMed
- Bengtsson A, Sturfelt G, Truedsson L, Blomberg J, Alm G, Vallin H, Rönnblom L: Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not antiretroviral antibodies. Lupus. 2000, 9: 664-671. 10.1191/096120300674499064.View ArticlePubMed
- Hua J, Kirou K, Lee C, Crow MK: Functional assay of type I interferon in systemic lupus erythematosus plasma and association with anti-RNA binding protein autoantibodies. Arthritis Rheum. 2006, 54: 1906-1916. 10.1002/art.21890.View ArticlePubMed
- Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, Pascual V: Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003, 197: 711-723. 10.1084/jem.20021553.PubMed CentralView ArticlePubMed
- Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, Shark KB, Grande WJ, Hughes KM, Kapur V, Gregersen PK, Behrens TW: Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci USA. 2003, 100: 2610-2615. 10.1073/pnas.0337679100.PubMed CentralView ArticlePubMed
- Crow MK, Wohlgemuth J: Microarray analysis of gene expression in lupus. Arthritis Res Ther. 2003, 5: 279-287. 10.1186/ar1015.PubMed CentralView ArticlePubMed
- Han GM, Chen SL, Shen N, Ye S, Bao CD, Gu YY: Analysis of gene expression profiles in human systemic lupus erythematosus using oligonucleotide microarray. Genes Immun. 2003, 4: 177-186. 10.1038/sj.gene.6363966.View ArticlePubMed
- Peterson KS, Huang JF, Zhu J, D'Agati V, Liu X, Miller N, Erlander MG, Jackson MR, Winchester RJ: Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli. J Clin Invest. 2004, 113: 1722-1733.PubMed CentralView ArticlePubMed
- Fitzgerald-Bocarsly P, Dai J, Singh S: Plasmacytoid dendritic cells and type I IFN: 50 years of convergent history. Cytokine Growth Factor Rev. 2008, 19: 3-19. 10.1016/j.cytogfr.2007.10.006.PubMed CentralView ArticlePubMed
- Cederblad B, Blomberg S, Vallin H, Perers A, Alm GV, Rönnblom L: Patients with systemic lupus erythematosus have reduced numbers of circulating natural interferon-α-producing cells. J Autoimmun. 1998, 11: 465-470. 10.1006/jaut.1998.0215.View ArticlePubMed
- Blomberg S, Eloranta M-L, Magnusson M, Alm GV, Rönnblom L: Expression of the markers BDCA-2 and -4 and production of interferon-α by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Rheum. 2003, 48: 2524-2532. 10.1002/art.11225.View ArticlePubMed
- Robak E, Sysa-Jedrzejowska A, Robak T, Smolewski P: Peripheral blood lymphocyte apoptosis and circulating dendritic cells in patients with systemic lupus erythematosus: correlation with immunological status and disease-related symptoms. Clin Rheumatol. 2006, 25: 225-233. 10.1007/s10067-005-1163-0.View ArticlePubMed
- Blomberg S, Eloranta M-L, Cederblad B, Nordlind K, Alm GV, Rönnblom L: Presence of cutaneous interferon-a producing cells in patients with systemic lupus erythematosus. Lupus. 2001, 10: 484-490. 10.1191/096120301678416042.View ArticlePubMed
- Farkas L, Beiske K, Lund-Johansen F, Brandtzaeg P, Jahnsen FL: Plasmacytoid dendritic cells (natural interferon-α/β-producing cells) accumulate in cutaneous lupus erythematosus lesions. Am J Pathol. 2001, 159: 237-243.PubMed CentralView ArticlePubMed
- Rönnblom L, Alm GV: The natural interferon-α producing cells in systemic lupus erythematosus. Hum Immunol. 2002, 63: 1181-1193. 10.1016/S0198-8859(02)00757-7.View ArticlePubMed
- Tucci M, Quatraro C, Lombardi L, Pellegrino C, Dammacco F, Silvestris F: Glomerular accumulation of plasmacytoid dendritic cells in active lupus nephritis: role of interleukin-18. Arthritis Rheum. 2008, 58: 251-262. 10.1002/art.23186.View ArticlePubMed
- Gilliet M, Cao W, Liu YJ: Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol. 2008, 8: 594-606. 10.1038/nri2358.View ArticlePubMed
- Cao W, Manicassamy S, Tang H, Kasturi SP, Pirani A, Murthy N, Pulendran B: Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. Nat Immunol. 2008, 9: 1157-1164. 10.1038/ni.1645.PubMed CentralView ArticlePubMed
- Vallin H, Blomberg S, Alm GV, Cederblad B, Rönnblom L: Patients with systemic lupus erythematosus (SLE) have a circulating inducer of interferon-alpha (IFN-α) production acting on leucocytes resembling immature dendritic cells. Clin Exp Immunol. 1999, 115: 196-202. 10.1046/j.1365-2249.1999.00772.x.PubMed CentralView ArticlePubMed
- Vallin H, Perers A, Alm GV, Rönnblom L: Anti-double-stranded DNA antibodies and immunostimulatory plasmid DNA in combination mimic the endogenous IFN-α inducer in systemic lupus erythematosus. J Immunol. 1999, 163: 6306-6313.PubMed
- Båve U, Magnusson M, Eloranta M-L, Perers A, Alm GV, Rönnblom L: FcgRIIa is expressed on natural IFN-α producing cells (plasmacytoid dendritic cells) and is required for the IFN-α production induced by apoptotic cells combined with lupus IgG. J Immunol. 2003, 171: 3296-3302.View ArticlePubMed
- Rönnblom L, Eloranta ML, Alm GV: The type I interferon system in systemic lupus erythematosus. Arthritis Rheum. 2006, 54: 408-420. 10.1002/art.21571.View ArticlePubMed
- Lövgren T, Eloranta ML, Båve U, Alm GV, Rönnblom L: Induction of interferon-α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. Arthritis Rheum. 2004, 50: 1861-1872. 10.1002/art.20254.View ArticlePubMed
- Munoz LE, van Bavel C, Franz S, Berden J, Herrmann M, Vlag van der J: Apoptosis in the pathogenesis of systemic lupus erythematosus. Lupus. 2008, 17: 371-375. 10.1177/0961203308089990.View ArticlePubMed
- Tian J, Avalos AM, Mao SY, Chen B, Senthil K, Wu H, Parroche P, Drabic S, Golenbock D, Sirois C, Hua J, An LL, Audoly L, La Rosa G, Bierhaus A, Naworth P, Marshak-Rothstein A, Crow MK, Fitzgerald KA, Latz E, Kiener PA, Coyle AJ: Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol. 2007, 8: 487-496. 10.1038/ni1457.View ArticlePubMed
- Lood C, Gullstrand B, Truedsson L, Olin AI, Alm GV, Rönnblom L, Sturfelt G, Eloranta ML, Bengtsson AA: C1q inhibits immune complex-induced IFNα production in plasmacytoid dendritic cells. A novel link between C1q deficiency and systemic lupus erythematosus pathogenesis. Arthritis Rheum. 2009, 60: 3081-3091. 10.1002/art.24852.View ArticlePubMed
- Vollmer J, Tluk S, Schmitz C, Hamm S, Jurk M, Forsbach A, Akira S, Kelly KM, Reeves WH, Bauer S, Krieg AM: Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8. J Exp Med. 2005, 202: 1575-1585. 10.1084/jem.20051696.PubMed CentralView ArticlePubMed
- Lövgren T, Eloranta ML, Kastner B, Wahren-Herlenius M, Alm GV, Rönnblom L: Induction of interferon-α by immune complexes or liposomes containing systemic lupus erythematosus autoantigen- and Sjögren's syndrome autoantigen-associated RNA. Arthritis Rheum. 2006, 54: 1917-1927. 10.1002/art.21893.View ArticlePubMed
- Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, Harley JB: Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003, 349: 1526-1533. 10.1056/NEJMoa021933.View ArticlePubMed
- McClain MT, Heinlen LD, Dennis GJ, Roebuck J, Harley JB, James JA: Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry. Nat Med. 2005, 11: 85-89. 10.1038/nm1167.View ArticlePubMed
- Rönnblom L, Alm GV: An etiopathogenic role for the type I IFN system in SLE. Trends Immunol. 2001, 22: 427-431. 10.1016/S1471-4906(01)01955-X.View ArticlePubMed
- Niewold TB, Hua J, Lehman TJ, Harley JB, Crow MK: High serum IFN-α activity is a heritable risk factor for systemic lupus erythematosus. Genes Immun. 2007, 8: 492-502. 10.1038/sj.gene.6364408.PubMed CentralView ArticlePubMed
- Izaguirre A, Barnes BJ, Amrute S, Yeow WS, Megjugorac N, Dai J, Feng D, Chung E, Pitha PM, Fitzgerald-Bocarsly P: Comparative analysis of IRF and IFN-alpha expression in human plasmacytoid and monocyte-derived dendritic cells. J Leukoc Biol. 2003, 74: 1125-1138. 10.1189/jlb.0603255.View ArticlePubMed
- Sigurdsson S, Nordmark G, Göring HH, Lindroos K, Wiman AC, Sturfelt G, Jönsen A, Rantapää-Dahlqvist S, Möller B, Kere J, Koskenmies S, Widen E, Eloranta ML, Julkunen H, Kristjansdottir H, Steinsson K, Alm G, Rönnblom L, Syvänen AC: Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet. 2005, 76: 528-537. 10.1086/428480.PubMed CentralView ArticlePubMed
- Sigurdsson S, Goring HH, Kristjansdottir G, Milani L, Nordmark G, Sandling J, Eloranta ML, Feng D, Sangster-Guity N, Gunnarsson I, Svenungsson E, Sturfelt G, Jonsen A, Truedsson L, Barnes BJ, Alm G, Rönnblom L, Syvanen AC: Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus. Hum Mol Genet. 2008, 17: 872-881. 10.1093/hmg/ddm359.View ArticlePubMed
- Niewold TB, Kelly JA, Flesch MH, Espinoza LR, Harley JB, Crow MK: Association of the IRF5 risk haplotype with high serum interferon-α activity in systemic lupus erythematosus patients. Arthritis Rheum. 2008, 58: 2481-2487. 10.1002/art.23613.PubMed CentralView ArticlePubMed
- Jacob CO, Zhu J, Armstrong DL, Yan M, Han J, Zhou XJ, Thomas JA, Reiff A, Myones BL, Ojwang JO, Kaufman KM, Klein-Gitelman M, McCurdy D, Wagner-Weiner L, Silverman E, Ziegler J, Kelly JA, Merrill JT, Harley JB, Ramsey-Goldman R, Vila LM, Bae SC, Vyse TJ, Gilkeson GS, Gaffney PM, Moser KL, Langefeld CD, Zidovetzki R, Mohan C: Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus. Proc Natl Acad Sci USA. 2009, 106: 6256-6261. 10.1073/pnas.0901181106.PubMed CentralView ArticlePubMed
- Musone SL, Taylor KE, Lu TT, Nititham J, Ferreira RC, Ortmann W, Shifrin N, Petri MA, Kamboh MI, Manzi S, Seldin MF, Gregersen PK, Behrens TW, Ma A, Kwok PY, Criswell LA: Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat Genet. 2008, 40: 1062-1064. 10.1038/ng.202.PubMed CentralView ArticlePubMed
- Graham RR, Cotsapas C, Davies L, Hackett R, Lessard CJ, Leon JM, Burtt NP, Guiducci C, Parkin M, Gates C, Plenge RM, Behrens TW, Wither JE, Rioux JD, Fortin PR, Graham DC, Wong AK, Vyse TJ, Daly MJ, Altshuler D, Moser KL, Gaffney PM: Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet. 2008, 40: 1059-1061. 10.1038/ng.200.PubMed CentralView ArticlePubMed
- Tyler DR, Persky ME, Matthews LA, Chan S, Farrar JD: Pre-assembly of STAT4 with the human IFN-α/β receptor-2 subunit is mediated by the STAT4 N-domain. Mol Immunol. 2007, 44: 1864-1872. 10.1016/j.molimm.2006.10.006.PubMed CentralView ArticlePubMed
- Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, de Bakker PI, Le JM, Lee HS, Batliwalla F, Li W, Masters SL, Booty MG, Carulli JP, Padyukov L, Alfredsson L, Klareskog L, Chen WV, Amos CI, Criswell LA, Seldin MF, Kastner DL, Gregersen PK: STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med. 2007, 357: 977-986. 10.1056/NEJMoa073003.PubMed CentralView ArticlePubMed
- Kariuki SN, Kirou KA, MacDermott EJ, Barillas-Arias L, Crow MK, Niewold TB: Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-α in lupus patients in vivo. J Immunol. 2009, 182: 34-38.PubMed CentralView ArticlePubMed
- Taylor KE, Remmers EF, Lee AT, Ortmann WA, Plenge RM, Tian C, Chung SA, Nititham J, Hom G, Kao AH, Demirci FY, Kamboh MI, Petri M, Manzi S, Kastner DL, Seldin MF, Gregersen PK, Behrens TW, Criswell LA: Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus. PLoS Genet. 2008, 4: e1000084-10.1371/journal.pgen.1000084.PubMed CentralView ArticlePubMed
- Sigurdsson S, Nordmark G, Garnier S, Grundberg E, Kwan T, Nilsson O, Eloranta ML, Gunnarsson I, Svenungsson E, Sturfelt G, Bengtsson AA, Jonsen A, Truedsson L, Rantapaa-Dahlqvist S, Eriksson C, Alm G, Goring HH, Pastinen T, Syvanen AC, Rönnblom L: A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5. Hum Mol Genet. 2008, 17: 2868-2876. 10.1093/hmg/ddn184.PubMed CentralView ArticlePubMed
- Cunninghame Graham DS, Akil M, Vyse TJ: Association of polymorphisms across the tyrosine kinase gene, TYK2 in UK SLE families. Rheumatology (Oxford). 2007, 46: 927-930. 10.1093/rheumatology/kel449.View Article
- Moser KL, Kelly JA, Lessard CJ, Harley JB: Recent insights into the genetic basis of systemic lupus erythematosus. Genes Immun. 2009, 10: 373-379. 10.1038/gene.2009.39.PubMed CentralView ArticlePubMed
- Rönnblom LE, Alm GV, Öberg KE: Possible induction of systemic lupus erythematosus by interferon-a treatment in a patient with a malignant carcinoid tumour. J Intern Med. 1990, 227: 207-210. 10.1111/j.1365-2796.1990.tb00144.x.View ArticlePubMed
- Ioannou Y, Isenberg DA: Current evidence for the induction of autoimmune rheumatic manifestations by cytokine therapy. Arthritis Rheum. 2000, 43: 1431-1442. 10.1002/1529-0131(200007)43:7<1431::AID-ANR3>3.0.CO;2-E.View ArticlePubMed
- Rönnblom LE, Alm GV, Öberg KE: Autoimmunity after α-interferon therapy for malignant carcinoid tumors. Ann Intern Med. 1991, 115: 178-183.View ArticlePubMed
- Strandberg L, Ambrosi A, Espinosa A, Ottosson L, Eloranta ML, Zhou W, Elfving A, Greenfield E, Kuchroo VK, Wahren-Herlenius M: Interferon-alpha induces up-regulation and nuclear translocation of the Ro52 autoantigen as detected by a panel of novel Ro52-specific monoclonal antibodies. J Clin Immunol. 2008, 28: 220-231. 10.1007/s10875-007-9157-0.View ArticlePubMed
- Baccala R, Hoebe K, Kono DH, Beutler B, Theofilopoulos AN: TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity. Nat Med. 2007, 13: 543-551. 10.1038/nm1590.View ArticlePubMed
- Miettinen M, Sareneva T, Julkunen I, Matikainen S: IFNs activate toll-like receptor gene expression in viral infections. Genes Immun. 2001, 2: 349-355. 10.1038/sj.gene.6363791.View ArticlePubMed
- Davis AM, Ramos HJ, Davis LS, Farrar JD: Cutting edge: a T-bet-independent role for IFN-α/β in regulating IL-2 secretion in human CD4+ central memory T cells. J Immunol. 2008, 181: 8204-8208.PubMed CentralView ArticlePubMed
- Jego G, Palucka AK, Blanck JP, Chalouni C, Pascual V, Banchereau J: Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity. 2003, 19: 225-234. 10.1016/S1074-7613(03)00208-5.View ArticlePubMed
- Le Bon A, Thompson C, Kamphuis E, Durand V, Rossmann C, Kalinke U, Tough DF: Cutting edge: enhancement of antibody responses through direct stimulation of B and T cells by type I IFN. J Immunol. 2006, 176: 2074-2078.View ArticlePubMed
- Uccellini MB, Busconi L, Green NM, Busto P, Christensen SR, Shlomchik MJ, Marshak-Rothstein A, Viglianti GA: Autoreactive B cells discriminate CpG-rich and CpG-poor DNA and this response is modulated by IFN-α. J Immunol. 2008, 181: 5875-5884.PubMed CentralView ArticlePubMed
- Båve U, Vallin H, Alm GV, Rönnblom L: Activation of natural interferon-α producing cells by apoptotic U 937 cells combined with lupus IgG and its regulation by cytokines. J Autoimmun. 2001, 17: 71-80. 10.1006/jaut.2001.0519.View ArticlePubMed
- Palucka AK, Blanck JP, Bennett L, Pascual V, Banchereau J: Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proc Natl Acad Sci USA. 2005, 102: 3372-3377. 10.1073/pnas.0408506102.PubMed CentralView ArticlePubMed
- Eloranta ML, Lovgren T, Finke D, Mathsson L, Ronnelid J, Kastner B, Alm GV, Ronnblom L: Regulation of the interferon-α production induced by RNA-containing immune complexes in plasmacytoid dendritic cells. Arthritis Rheum. 2009, 60: 2418-2427. 10.1002/art.24686.View ArticlePubMed
- Lee HM, Mima T, Sugino H, Aoki C, Adachi Y, Yoshio-Hoshino N, Matsubara K, Nishimoto N: Interactions among type I and type II interferon, tumor necrosis factor, and beta-estradiol in the regulation of immune response-related gene expressions in systemic lupus erythematosus. Arthritis Res Ther. 2009, 11: R1-10.1186/ar2584.PubMed CentralView ArticlePubMed
- Shiozawa S, Kuroki Y, Kim M, Hirohata S, Ogino T: Interferon-α in lupus psychosis. Arthritis Rheum. 1992, 35: 417-422. 10.1002/art.1780350410.View ArticlePubMed
- Raison CL, Demetrashvili M, Capuron L, Miller AH: Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs. 2005, 19: 105-123. 10.2165/00023210-200519020-00002.PubMed CentralView ArticlePubMed
- Santer DM, Yoshio T, Minota S, Moller T, Elkon KB: Potent induction of IFN-α and chemokines by autoantibodies in the cerebrospinal fluid of patients with neuropsychiatric lupus. J Immunol. 2009, 182: 1192-1201.PubMed CentralView ArticlePubMed
- Fairhurst AM, Mathian A, Connolly JE, Wang A, Gray HF, George TA, Boudreaux CD, Zhou XJ, Li QZ, Koutouzov S, Banchereau J, Wakeland EK: Systemic IFN-α drives kidney nephritis in B6.Sle123 mice. Eur J Immunol. 2008, 38: 1948-1960. 10.1002/eji.200837925.PubMed CentralView ArticlePubMed
- Denny MF, Thacker S, Mehta H, Somers EC, Dodick T, Barrat FJ, McCune WJ, Kaplan MJ: Interferon-α promotes abnormal vasculogenesis in lupus: a potential pathway for premature atherosclerosis. Blood. 2007, 110: 2907-2915. 10.1182/blood-2007-05-089086.PubMed CentralView ArticlePubMed
- Niessner A, Shin MS, Pryshchep O, Goronzy JJ, Chaikof EL, Weyand CM: Synergistic proinflammatory effects of the antiviral cytokine interferon-α and Toll-like receptor 4 ligands in the atherosclerotic plaque. Circulation. 2007, 116: 2043-2052. 10.1161/CIRCULATIONAHA.107.697789.View ArticlePubMed
- Kirou KA, Lee C, George S, Louca K, Peterson MG, Crow MK: Activation of the interferon-α pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheum. 2005, 52: 1491-1503. 10.1002/art.21031.View ArticlePubMed
- Feng X, Wu H, Grossman JM, Hanvivadhanakul P, FitzGerald JD, Park GS, Dong X, Chen W, Kim MH, Weng HH, Furst DE, Gorn A, McMahon M, Taylor M, Brahn E, Hahn BH, Tsao BP: Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus. Arthritis Rheum. 2006, 54: 2951-2962. 10.1002/art.22044.View ArticlePubMed
- Landolt-Marticorena C, Bonventi G, Lubovich A, Ferguson C, Unnitahn T, Su J, Gladman DD, Urowitz M, Fortin PR, Wither J: Lack of association between the interferon-alpha signature and longitudinal changes in disease activity in systemic lupus erythematosus. Ann Rheum Dis. 2009, 68: 1440-1446. 10.1136/ard.2008.093146.View ArticlePubMed
- Petri M, Singh S, Tesfasyone H, Dedrick R, Fry K, Lal P, Williams G, Bauer J, Gregersen P, Behrens T, Baechler E: Longitudinal expression of type I interferon responsive genes in systemic lupus erythematosus. Lupus. 2009, 18: 980-989. 10.1177/0961203309105529.View ArticlePubMed
- Baechler EC, Batliwalla FM, Ortmann WA, Espe KJ, Hughes KM, Wenberg NH, Kern M, Novitzke JM, Slattery CA, Koeuth T, Bauer JW, Tesfoyne H, Singh S, Petri M, Gregersen PK, Behrens TW: Gene signatures in peripheral blood predict future disease activity in patients with systemic lupus erythematosus. Arthritis Rheum. 2005, 52: S700-
- Petri M, Tesfasyone H, Singh S, Batliwalla F, Gregersen PK, Gillespie E, Ortmann WA, Espe KJ, Hughes KM, Wenberg NH, Slattery CA, Koeuth T, Behrens T: The systemic lupus erythematosus interferon signature is associated with current activity and is also predictive of hematologic and mucocutaneous disease activity at the next visit. Arthritis Rheum. 2005, 52: S464-
- Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, Haupl T, Rudwaleit M, Riemekasten G, Radbruch A, Hiepe F, Burmester GR, Grutzkau A: Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum. 2008, 58: 1136-1145. 10.1002/art.23404.View ArticlePubMed
- Bauer JW, Baechler EC, Petri M, Batliwalla FM, Crawford D, Ortmann WA, Espe KJ, Li W, Patel DD, Gregersen PK, Behrens TW: Elevated serum levels of interferon-regulated chemokines are biomarkers for active human systemic lupus erythematosus. PLoS Med. 2006, 3: e491-10.1371/journal.pmed.0030491.PubMed CentralView ArticlePubMed
- Fu Q, Chen X, Cui H, Guo Y, Chen J, Shen N, Bao C: Association of elevated transcript levels of interferon-inducible chemokines with disease activity and organ damage in systemic lupus erythematosus patients. Arthritis Res Ther. 2008, 10: R112-10.1186/ar2510.PubMed CentralView ArticlePubMed
- Svenungsson E, Gustafsson J, Leonard D, Sandling J, Gunnarsson I, Nordmark G, Jönsen A, Bengtsson AA, Sturfelt G, Rantapää-Dahlqvist S, Elvin K, Sundin U, Garnier S, Simard JF, Sigurdsson S, Padyukov L, Syvänen AC, Rönnblom L: A STAT4risk allele is associated with ischemic cerebrovascular events and antiphospholipid antibodies in systemic lupus erythematosus. Ann Rheum Dis. 2009,
- Santiago-Raber ML, Baccala R, Haraldsson KM, Choubey D, Stewart TA, Kono DH, Theofilopoulos AN: Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice. J Exp Med. 2003, 197: 777-788. 10.1084/jem.20021996.PubMed CentralView ArticlePubMed
- Braun D, Geraldes P, Demengeot J: Type I interferon controls the onset and severity of autoimmune manifestations in lpr mice. J Autoimmun. 2003, 20: 15-25. 10.1016/S0896-8411(02)00109-9.View ArticlePubMed
- Wallac DJ, Petri M, Olsen N, Kirou K, Dennis G, Yao Y, Jallal B, Coyle A, Zeng L, Investigators L, White B: MEDI-545, an anti-interferon alpha monoclonal antibody, shows evidence of clinicla activity in systemic lupus erythematosus. Arthritis Rheum. 2007, 56: S562-S563.
- Yao Y, Richman L, Higgs BW, Morehouse CA, de los Reyes M, Brohawn P, Zhang J, White B, Coyle AJ, Kiener PA, Jallal B: Neutralization of interferon-α/β-inducible genes and downstream effect in a phase I trial of an anti-interferon-a monoclonal antibody in systemic lupus erythematosus. Arthritis Rheum. 2009, 60: 1785-1796. 10.1002/art.24557.View ArticlePubMed
- Pestka S, Krause CD, Walter MR: Interferons, interferon-like cytokines, and their receptors. Immunol Rev. 2004, 202: 8-32. 10.1111/j.0105-2896.2004.00204.x.View ArticlePubMed
- Dzionek A, Sohma Y, Nagafune J, Cella M, Colonna M, Facchetti F, Gunther G, Johnston I, Lanzavecchia A, Nagasaka T, Okada T, Vermi W, Winkels G, Yamamoto T, Zysk M, Yamaguchi Y, Schmitz J: BDCA-2, a novel plasmacytoid dendritic cell-specific type II C-type lectin, mediates antigen capture and is a potent inhibitor of interferon α/β induction. J Exp Med. 2001, 194: 1823-1834. 10.1084/jem.194.12.1823.PubMed CentralView ArticlePubMed
- Barrat FJ, Coffman RL: Development of TLR inhibitors for the treatment of autoimmune diseases. Immunol Rev. 2008, 223: 271-283. 10.1111/j.1600-065X.2008.00630.x.View ArticlePubMed
- Rönnblom L, Pascual V: The innate immune system in SLE: type I interferons and dendritic cells. Lupus. 2008, 17: 394-399. 10.1177/0961203308090020.PubMed CentralView ArticlePubMed