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The genetics of type I interferon in systemic lupus erythematosus
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The genetics of type I interferon in systemic lupus erythematosus Paola G Bronson1, Christina Chaivorapol2, Ward Ortmann1, Timothy W Behrens1 and Robert R Graham1 The discovery that type I interferon (IFN)-inducible genes were strongly upregulated in peripheral blood in SLE over a decade ago sparked interest in understanding the relationship between type I IFN and SLE. Genome-wide association studies provide strong genetic evidence that type I IFNs are important for SLE risk. Of 47 genetic variants associated with SLE, over half (27/ 47, 57%) can be linked to type I IFN production or signaling. The recent identification of single gene mutations for disorders that share features with SLE – Aicardi–Goutie`res syndrome, chilblain lupus, and spondyloenchondrodysplasia – provide additional support for the hypothesis that type I IFNs are central drivers of SLE pathogenesis. These insights provide significant focus for efforts to tackle SLE therapeutically. Addresses 1 Department of Human Genetics, Genentech, Inc., South San Francisco, CA 94080, USA 2 Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA 94080, USA Corresponding author: Behrens, Timothy W ([email protected])
Here, we review evidence from genomic, candidate gene, and genomewide association studies (GWAS), together with recent findings from monogenic SLE and SLE-related diseases, that support the hypothesis that type I interferons (IFNs) are key factors in SLE pathogenesis.
Pleiotropic effects of type I IFN and related pathways Type I IFNs (13 IFN-a isotypes, IFN-b, IFN-e, IFN-k, and IFN-v) are produced primarily by plasmacytoid dendritic cells (pDCs), and are regulated by engagement of cell membrane or endosomal receptors, such as certain toll-like receptors (TLRs) (TLR 3, 7/8, 9), that recognize nucleic acids in viruses, bacteria and protozoa. Intracellular viral RNA and DNA are recognized by a specialized set of receptors (e.g. RIG-I, IFIH1) that also trigger type I IFN production. Type I IFN binds to the ubiquitously expressed IFNAR1/2 receptor, which engages signaling through the JAK1 and TYK2 protein kinases, leading to regulation of expression of hundreds of downstream genes (reviewed in [3,4]).
Current Opinion in Immunology 2012, 24:530–537 This review comes from a themed issue on Autoimmunity: Insights from human genomics Edited by Soumya Raychaudhuri and Stephen S Rich For a complete overview see the Issue and the Editorial Available online 10th August 2012 0952-7915/$ – see front matter, Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.coi.2012.07.008
Introduction SLE is characterized by IgG autoantibodies to highly conserved nuclear antigens such as double-stranded DNA (dsDNA), histones and ribonuclear proteins. Immune complexes comprised of IgG and self-antigens deposit in tissues and blood vessels, including skin, kidneys, and pleura/pericardium, leading to end-organ disease. Additional autoantibodies directly target cell surface antigens, causing cytopenias and other pathologies. Similar to most autoimmune diseases, human leukocyte antigen (HLA) genes are associated with increased SLE risk, with strongest evidence for the class II HLA alleles DRB1*15:01 and DRB1*03:01 [1]. Although the survival rate for SLE has improved greatly over the years, patients are 2.5 times more likely to die than the general population [2], and there is a pressing need to develop new therapies. Current Opinion in Immunology 2012, 24:530–537
Type I IFNs have pleiotropic effects in the immune system. The diverse mechanisms by which elevated type I IFNs may influence SLE development and pathogenesis include: (a) upregulating expression of cytokines and chemokines; (b) increasing maturation of monocytes and dendritic cells; (c) activating autoreactive B and T cells; (d) increasing production of autoantibodies through effects on plasma cell differentiation; and (e) inducing apoptosis in the immune system [5–8].
The IFN gene expression signature and IFN-a in SLE Using microarray gene expression analysis, we generated initial data in 1999 showing that about two-thirds of adult SLE patients exhibited elevated expression of type I IFN-inducible genes in peripheral blood cells, and coined the term ‘IFN signature’ [9]. Additional groups reported similar findings in SLE [10,11,12], and subsequently the IFN signature was found to be prominent in Sjo¨gren’s syndrome, dermatomyositis, subacute cutaneous lupus and discoid lupus erythematosus [13–16]. A subset of subjects with psoriasis, rheumatoid arthritis and recent-onset type 1 diabetes also exhibit IFN gene signatures in tissue and blood cells [17,18]. Multiple sclerosis patients do not have an IFN signature, and, in fact, recombinant IFN-b is used as a therapeutic for multiple sclerosis. www.sciencedirect.com
The genetics of type I interferon in systemic lupus erythematosus Bronson et al. 531
Before the identification of the IFN signature, a few earlier studies had suggested that type I IFNs were present in the blood of SLE (e.g. [19]). A series of studies by Ro¨nnblom and colleagues demonstrated that SLE immune complexes in blood could induce production of type I IFNs in vitro [20,21]. The connection between immune complexes, TLRs and SLE pathogenesis has been an intense focus of investigation in many laboratories. Important studies from Shlomchik, Marshak-Rothstein and others have demonstrated a key role for TLR 7/ 9 in murine SLE models [22], and have shown that stimulation of TLR 7/9 by nucleic acid-containing SLE immune complexes initiates B cell and dendritic cell activation, and the production of cytokines including type I IFN [23,24,25]. Longitudinal studies have shown that the IFN gene signature in blood is generally stable and not clinically useful for predicting disease flares [26,27,28]. By contrast, IFN-inducible chemokines have some ability to predict renal and extra-renal flares [29]. IFN-inducible cytokines and chemokines are prominent in SLE, and were present at higher levels in IFN-high patients compared to IFN-low patients [30]. Importantly, IFN-low patients had elevated IFN-inducible cytokines and chemokines relative to healthy controls [30]. It was also shown recently that about 25% of SLE patients have endogenous anti-IFN-a autoantibodies (AIAA) in blood [31], at a percentage significantly higher than previous estimates of 0–12% [32–35]. Most AIAA+ patients had lower serum type I IFN levels, reduced IFN-pathway activity and lower disease activity compared to AIAA-patients, suggesting that endogenous AIAA may have effects on the course of SLE [31]. The presence of the IFN signature, IFN-inducible chemokines, and endogenous AIAA in SLE are consistent with chronic and inappropriate activation of the type I IFN pathway.
Genetic risk for SLE and the type I IFN pathway An important development over the past 5 years has been the identification of genes that associate with SLE and that map into the type I IFN pathway. An initial candidate gene study by Sigurdsson et al. [36] found an association of the transcription factor interferon regulatory factor 5 (IRF5) with SLE. Further genetic and functional studies identified a single risk haplotype for IRF5 characterized by three functional alleles [37,38]. The non-risk haplotypes for IRF5 contain a splice site mutation in an alternative promoter for the gene, a deletion in exon 6, and a mutated consensus polyadenylation site in the 30 UTR that leads to reduced expression of IRF5 mRNA. IRF5 is activated by engagement of TLR 7/9, and is important for SLE development in the mouse [39]. IRF5 haplotypes have been linked to IFN-a levels in human SLE [40]. In addition, Syva¨nen and colleagues recently www.sciencedirect.com
reported that IRF5 target genes, as assessed by chromatin immunoprecipitation (CHIP) of stimulated peripheral blood cells of SLE patients, were enriched for type I IFN regulated genes compared to healthy controls [41]. Together, these studies of IRF5 firmly established a genetic link between TLR signaling, downstream cytokine production including type I IFN, and SLE. Subsequent GWAS and candidate gene studies have further emphasized this point [42,43,44–50]. Of the current group of 47 independent confirmed SLE variants (those reaching genome-wide levels of statistical significance, defined here as P < 5 108), a quarter (N = 11, 23%) are located in or around 7 genes with a known key role in type I IFN production or signaling: IRF5, IRF7, IRAK1, TNFAIP3, TNIP1, IFIH1 and TYK2 (see Figure 1). IRF7 is a transcription factor found in pDCs that is critical for TLR signaling leading to type I IFN production [51]. IRF7 interacts with the TLR adaptors MyD88 and TRIF [52], and hetero-dimerizes with IRF5. The top risk variant in this region is the intronic rs4963128*C SNP located in PHRF1, a gene directly upstream of IRF7; the risk haplotype includes the entire IRF7 gene [43,53]. IRAK1 is also critical for the TLR 7/8/9 signaling and type I IFN production, and mediates signaling through MyD88. Breeding of IRAK1 knockout alleles onto mouse models of SLE completely abrogated SLE-related phenotypes (e.g. IgM and IgG autoantibodies, lymphocytic activation, and renal disease) and these mice showed reduced dendritic cell hyperactivity [54]. The proposed risk variants in IRAK1 are two independent missense mutations: rs1059702*A and rs1059703*G. TNFAIP3 (A20) and TNIP1 (ABIN1) are ubiquitin ligases that regulate TLR signaling through interactions with TRAF proteins downstream of TLRs [55–57]. The proposed risk haplotypes are tagged by the variants TNFAIP3/OLIG3 rs6920220*A, TNFAIP3 rs5029937*T, and TNIP rs7708392*C [45,53,58]. IFIH1 (MDA5) is a cytosolic sensor of dsRNA that triggers phosphorylation of IRF7 and IRF3 and subsequent type I IFN production. SLE is associated with the IFIH1 missense mutation rs1990760*T [59]; homozygotes carrying this risk variant have been reported to exhibit higher IFIH1 expression [60]. In addition, the protective allele rs1990760*C marks a haplotype associated with reduced IFIH1 expression [61], consistent with rare loss-of-function alleles of IFIH1 that are protective from type 1 diabetes [62]. Robinson et al. [63] reported association between this variant and increased IFN-a induced gene expression in peripheral blood cells in anti-dsDNA+ SLE patients. Chronic type I IFN levels in transgenic IFIH1 murine models triggered autoimmunity – accelerated production of switched autoantibodies, increased glomerulonephritis, and early lethality – only Current Opinion in Immunology 2012, 24:530–537
532 Autoimmunity: Insights from human genomics
Figure 1
Type I IFN Production ITGAM
UBE2L3
Nucleic acids Rig-I-like receptor signaling pathway
?
ssRNA dsRNA (short)
RIG-I
dsRNA (long)
IFIH1
ssRNA
Type I IFN Signaling
ATG5
TNIP1
TNFAIP3
IRF5
TNFα
TRAF6
MAPK signaling pathway
IL12B
IRAK1
IRF7
TLR7/8 MyD88
unmethylated CpG DNA
IFN-α IFN-β
JAK-STAT signaling pathway IFNAR receptor
TYK2
TLR9 STAT4
Toll-like receptor signaling
Expression of Type I IFN-inducible genes
FCGR2A receptor
ELF1
IRF8
HLA-DRB1
IL10R receptor IKZF1
SLC15A4 TNFSF4 dsRNA
Complement clearance
TLR3
TRIF
IL10
C2 CFB
Current Opinion in Immunology
Confirmed SLE risk loci that map upstream and downstream of type I interferon. Toll-like receptors (TLRs) respond to enveloped viruses and some bacteria and protozoa in plasmacytoid dendritic cells (pDCs). Cytosolic sensors of viral replication (IFIH1, RIG-I) detect viral RNA or DNA in non-pDCs. Loci highlighted in red boxes represent confirmed SLE risk loci. Black solid arrows between loci represent direct interactions. Blue dotted arrows between loci represent indirect interactions. Direct interactions are defined as interactions where the two gene products directly interact, and represent the ‘core’ type I IFN genes (see Genetic risk for SLE and the type I IFN pathway). Indirect interactions are defined as interactions where the two gene products do not directly interact but are upstream or downstream of interactions with other gene products. Interactions were curated mainly from the literature, as well as from the KEGG Pathway Database (URL: http:// www.genome.jp/kegg/pathway.html).
when combined with a SLE-susceptible genetic background (FCGR2B deficiency) [64].
therapeutic targets for SLE. However, they may not be representative of sporadic SLE.
The protein kinase TYK2 directly interacts with the IFNAR1/2 receptor and mediates downstream signaling [65]. SLE is associated with the intronic TYK2 rs280519*A variant [59], which is in linkage disequilibrium (correlated) with a non-synonymous allele of TYK2 first reported by Syva¨nen and colleagues [36].
Recent data on rare single gene variants that lead to either SLE or SLE-like disease further support the idea that inappropriate activation of type I IFN is on the causal pathway for SLE (see Table 1). Complement deficiencies, including C1q, were the first of the familial forms of lupus to be identified (reviewed in [66]). Individuals homozygous for loss of function alleles in C1q develop lupus with high penetrance (>90%). A recent study showed that C1q deficient patients have greatly elevated IFN-a in serum and cerebrospinal fluid [67]. C1q also inhibits IFN-a production by pDCs and monocytes [68], and C1q deficiency leads to defective suppression of IFN-a in response to nucleoprotein containing immune complexes [68,69].
In addition to the ‘core’ type I IFN genes discussed above, a number of additional confirmed SLE loci (N = 16) can be indirectly mapped either upstream or downstream of type I interferon (see Figure 1). Together, over half of the confirmed SLE variants (27/47, 57%) have a role in either the production or downstream signaling of type I interferon.
Single gene lupus-related disorders of the type I IFN pathway In addition to studying sporadic SLE, it is worthwhile to examine highly penetrant phenotypes with a clinical presentation that is similar to or shared with SLE. These single-gene, or Mendelian, disorders can offer insight into Current Opinion in Immunology 2012, 24:530–537
Deficiencies in other complement pathway members (C2, C3, C1R, CFI, and CFH) have additionally been associated with increased risk of SLE [69–76]. Complement deficient individuals may have reduced clearance of immune complexes and apoptotic debris leading to activation of the type I IFN pathway. Supporting this view, www.sciencedirect.com
The genetics of type I interferon in systemic lupus erythematosus Bronson et al. 533
Table 1 Single gene SLE and SLE-like disorders associated with increased type I IFN production or signaling Genetic deficiency
Disorder SLE a
Complement C1q
AGS b
CHLE c
R R R R R
D
SPENCD d
Re
Extracellular nucleic acid DNASE1 Df DNASE1L3 D Intracellular nucleic acid TREX1 D RNASEH2A RNASEH2B RNASEH2C SAMHD1 Increased TLR signaling ACP5 (TRAP) Ig
D R
a
Multisystem involvement with typical SLE autoantibody profiles. Aicardi–Goutie`res syndrome: variable, congenital encephalopathy and systemic inflammatory phenotype. c Familial chilblain lupus erythematosus: recurrent chilblains (skin lesions). d Spondyloenchondrodysplasia: immuno-osseus dysplasia, intracranial calcification and variable autoimmune features. e Recessive inheritance pattern. f Dominant inheritance pattern. g Incomplete penetrance.
Mutations in TREX1 are also linked to chilblain SLE, a limited form of SLE-like skin disease, and in sporadic SLE (0.5% of cases) [82,83,84]. Mutations in tartrate-resistant acid phosphatase (TRAP) cause the SPENCD syndrome [85,86], which is characterized by metaphyseal abnormalities, mental retardation, spasticity and SLE-like autoimmunity. SPENCD patients have high levels of circulating IFNa and a prominent IFN gene signature [86]. TRAP is an abundant protein present in osteoclasts, macrophages and dendritic cells. A major substrate for TRAP is osteopontin. Osteopontin is physically associated with MyD88 and other signaling molecules downstream of TLR9, and is required for the production of type I IFN by pDCs in response to TLR9 stimulation [87]. Hyper-phosphorylation of osteopontin in the absence of TRAP may drive excessive type I IFN production and SLE-like pathologies in patients with the SPENCD syndrome [88–90].
b
loss of function alleles of DNASE1 and DNASE1L3, soluble enzymes that serve to clear extracellular DNA, are also associated with familial SLE [77,78]. Several recent studies have identified causative genes for the lupus-like diseases Aicardi–Goutie`res syndrome (AGS), chilblain lupus erythematosus and spondyloenchondrodysplasia (SPENCD). Importantly, each of these disorders has been linked to dysregulated type I IFN production and SLE-like disease (Table 1). AGS is an early-onset progressive encephalopathy with basal ganglia calcifications that presents in early childhood, and has an extremely poor prognosis. Children with AGS have a lymphocytosis and increased type I IFN in cerebrospinal fluid, without evidence for neonatal viral infection. Patients have autoantibodies, systemic inflammation and a prominent IFN gene signature in blood. Most cases of AGS are caused by recessive mutations in either the DNase 30 repair exonuclease 1 gene (TREX1), the RNase H2 subunits A, B, or C (RNASEH2A/B/C) or the sterile alpha motif domain and HD domain-containing protein 1 (SAMHD1) [79]. Data from a mouse knockout model suggest that TREX1 functions to suppress the accumulation of endogenous retroelements [80,81], which can activate the type I IFN pathway. Similar roles have been proposed for SAMHD1 and RNASEH2 in limiting the accumulation of endogenous intracellular nucleic acids. www.sciencedirect.com
Together, these various human knockouts provide additional evidence that chronic activation of the type I IFN pathway is central in the development of SLE.
Type I IFN as a therapeutic target in SLE Developing novel therapeutics for SLE is particularly important because there are so few effective therapies for SLE available today. The FDA recently approved Belimumab, a human monoclonal antibody that inhibits the B-lymphocyte stimulator (BLyS), for use in non-renal SLE, and it is the first SLE therapeutic approved in over five decades. The relatively modest clinical benefits reported in the pivotal trials for Belimumab suggest the optimal patient subset for this drug has not yet been identified [91–93]. Given the evidence reviewed above, it is perhaps not surprising that there are also several early phase clinical studies investigating monoclonal antibodies against type I IFN or the type I IFN receptor in SLE (reviewed by [94,95]): Rontalizumab (Genentech, Inc., South San Francisco, CA) (NCT00962832); Sifalimumab (MEDI545; NCT01283139) and MEDI-546 (NCT01438489) (Medimmune LLC, Gaithersburg, MD) [96]. Rontalizumab and Sifalimumab neutralize IFN-a subtypes, while MEDI-546 blocks the a subunit of the IFN-a/b receptor (IFNAR). Data from murine models also support the importance of type I IFN in SLE. IFNAR-deficient lupus-prone NZBWF1 mice have ameliorated lupus: reduced anti-erythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA autoantibodies, renal disease, and mortality [97]. After extensive safety testing in preclinical models, Genentech has completed a phase I escalating single and multiple dose trial evaluating safety, tolerability, and pharmacokinetics of Rontalizumab (a humanized IgG1 Current Opinion in Immunology 2012, 24:530–537
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monoclonal antibody targeting all IFN-a isotypes) in adults with mild SLE (J McBride et al., abstract in Arthritis Rheum: 2009:S775–S776). Importantly, the IFN gene signature was modulated in patients receiving 3 mg/kg or higher doses of Rontalizumab. Based on overall acceptable safety, pharmacokinetics and pharmacodynamics, Rontalizumab was moved into a phase II clinical trial in 2010 in adults with moderate to severe non-renal SLE. Similarly, Sifalimumab has also been shown to modulate the IFN signature in SLE patients in phase I trials, and was moved into a phase II trial in 2011 in adults with moderate to severe non-renal SLE [96]. MEDI-546 entered a phase II trial in 2012 in adults with moderate to several non-renal SLE with an inadequate response to standard of care treatment for SLE. These clinical trials will provide the first tests of the hypotheses that modulating type I IFNs in humans modulates disease activity.
Conclusions In aggregate, the evidence supporting the direct involvement of type I IFNs in SLE pathogenesis is quite compelling: (a) IFN-a immunotherapy can induce lupus [98]; (b) circulating immune complexes from SLE blood can initiate type I IFN production; (c) there are prominent IFN regulated gene and cytokine signatures in SLE; (d) polymorphisms in IFN pathway genes are associated with SLE in GWAS studies; and (e) several single gene disorders cause increased type I IFN and SLE or SLElike symptoms. The genetic data in particular suggest that targeting the type I IFN pathway in SLE may prove beneficial in treating this disease.
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Current Opinion in Immunology 2012, 24:530–537
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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. 37. Graham RR, Kozyrev SV, Baechler EC, Reddy MV, Plenge RM, Bauer JW, Ortmann WA, Koeuth T, Gonzalez Escribano MF, PonsEstel B et al.: A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet 2006, 38:550-555. 38. Graham RR, Kyogoku C, Sigurdsson S, Vlasova IA, Davies LR, Baechler EC, Plenge RM, Koeuth T, Ortmann WA, Hom G et al.: Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proc Natl Acad Sci USA 2007, 104:6758-6763. This study identified a single haplotype in IRF5 associated with SLE that contains three functional alleles. The conserved wild-type allele is risk for SLE, and haplotypes containing the functional mutations are protective. 39. Richez C, Yasuda K, Bonegio RG, Watkins AA, Aprahamian T, Busto P, Richards RJ, Liu CL, Cheung R, Utz PJ: IFN regulatory factor 5 is required for disease development in the Fc-gammaRIIBS/S Yaa and Fc-gamma-RIIBS/S mouse models of systemic lupus erythematosus. J Immunol 2010, 184:796. 40. Niewold TB, Kelly JA, Kariuki SN, Franek BS, Kumar AA, Kaufman KM, Thomas K, Walker D, Kamp S, Frost JM: IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus. Ann Rheum Dis 2012, 71:463-469. 41. Wang C, Sandling JK, Hagberg N, Berggren O, Sigurdsson S, Karlberg O, Ro¨nnblom L, Eloranta ML, Syva¨nen AC: Genomewide profiling of target genes for the systemic lupus erythematosus-associated transcription factors IRF5 and STAT4. Ann Rheum Dis 2012. http://dx.doi.org/10.1136/ annrheumdis-2012-201364. Published online first: 23 June 2012. 42. Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S, Lee AT, Chung SA, Ferreira RC, Pant PV et al.: Association of systemic lupus erythematosus with C8orf13-BLK and ITGAMITGAX. N Engl J Med 2008, 358:900-909. These were the first two large-scale genome-wide association studies in SLE. 43. Harley JB, Alarcon-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, Tsao BP, Vyse TJ, Langefeld CD: Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 2008, 40:204-210. These were the first two large-scale genome-wide association studies in SLE. 44. Kozyrev SV, Abelson AK, Wojcik J, Zaghlool A, Linga Reddy MV, Sanchez E, Gunnarsson I, Svenungsson E, Sturfelt G, Jonsen A et al.: Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat Genet 2008, 40:211-216. 45. Graham RR, Cotsapas C, Davies L, Hackett R, Lessard CJ, Leon JM, Burtt NP, Guiducci C, Parkin M, Gates C et al.: Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet 2008, 40:1059-1061. 46. Yang W, Shen N, Ye DQ, Liu Q, Zhang Y, Qian XX, Hirankarn N, Ying D, Pan HF, Mok CC et al.: Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet 2010, 6:e1000841.
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82. Rice G, Newman WG, Dean J, Patrick T, Parmar R, Flintoff K, Robins P, Harvey S, Hollis T, O’Hara A et al.: Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi–Goutieres syndrome. Am J Hum Genet 2007, 80:811-815. 83. Crow YJ, Hayward BE, Parmar R, Robins P, Leitch A, Ali M, Black DN, Van Bokhoven H, Brunner HG, Hamel BC: Mutations in the gene encoding the 30 -50 DNA exonuclease TREX1 cause Aicardi–Goutieres syndrome at the AGS1 locus. Nat Genet 2006, 38:917-920. Mutations in the DNA exonuclease TREX1 gene are found in some patients with Aicardi–Goutie`res syndrome (AGS) and familial chilblain lupus erythematosus (CHLE) and are rare causes of SLE. TREX1 mutations drive type I interferon production. 84. Lee-Kirsch MA, Gong M, Chowdhury D, Senenko L, Engel K, Lee YA, de Silva U, Bailey SL, Witte T, Vyse TJ et al.: Mutations in the gene encoding the 30 -50 DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet 2007, 39:1065-1067. Mutations in the DNA exonuclease TREX1 gene are found in some patients with Aicardi–Goutie`res syndrome (AGS) and familial chilblain lupus erythematosus (CHLE) and are rare causes of SLE. TREX1 mutations drive type I interferon production. 85. Lausch E, Janecke A, Bros M, Trojandt S, Alanay Y, De Laet C, Hubner CA, Meinecke P, Nishimura G, Matsuo M et al.: Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity. Nat Genet 2011, 43:132-137. These studies showed that mutations in the TRAP gene cause the complex disorder spondyloenchondrodysplasia (SPENCD), which often has features of lupus, and showed that type I interferon is upregulated by a novel mechanism. 86. Briggs TA, Rice GI, Daly S, Urquhart J, Gornall H, Bader Meunier B, Baskar K, Baskar S, Baudouin V, Beresford MW: Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature. Nat Genet 2011, 43:127-131. These studies showed that mutations in the TRAP gene cause the complex disorder spondyloenchondrodysplasia (SPENCD), which often has features of lupus, and showed that type I interferon is upregulated by a novel mechanism. 87. Shinohara ML, Lu L, Bu J, Werneck MB, Kobayashi KS, Glimcher LH, Cantor H: Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells. Nat Immunol 2006, 7:498-506. 88. Suter A, Everts V, Boyde A, Jones SJ, Lullmann-Rauch R, Hartmann D, Hayman AR, Cox TM, Evans MJ, Meister T et al.:
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The genetics of type I interferon in systemic lupus erythematosus Paola G Bronson1, Christina Chaivorapol2, Ward Ortmann1, Timothy W Behrens1 and Robert R Graham1 The discovery that type I interferon (IFN)-inducible genes were strongly upregulated in peripheral blood in SLE over a decade ago sparked interest in understanding the relationship between type I IFN and SLE. Genome-wide association studies provide strong genetic evidence that type I IFNs are important for SLE risk. Of 47 genetic variants associated with SLE, over half (27/ 47, 57%) can be linked to type I IFN production or signaling. The recent identification of single gene mutations for disorders that share features with SLE – Aicardi–Goutie`res syndrome, chilblain lupus, and spondyloenchondrodysplasia – provide additional support for the hypothesis that type I IFNs are central drivers of SLE pathogenesis. These insights provide significant focus for efforts to tackle SLE therapeutically. Addresses 1 Department of Human Genetics, Genentech, Inc., South San Francisco, CA 94080, USA 2 Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA 94080, USA Corresponding author: Behrens, Timothy W ([email protected])
Here, we review evidence from genomic, candidate gene, and genomewide association studies (GWAS), together with recent findings from monogenic SLE and SLE-related diseases, that support the hypothesis that type I interferons (IFNs) are key factors in SLE pathogenesis.
Pleiotropic effects of type I IFN and related pathways Type I IFNs (13 IFN-a isotypes, IFN-b, IFN-e, IFN-k, and IFN-v) are produced primarily by plasmacytoid dendritic cells (pDCs), and are regulated by engagement of cell membrane or endosomal receptors, such as certain toll-like receptors (TLRs) (TLR 3, 7/8, 9), that recognize nucleic acids in viruses, bacteria and protozoa. Intracellular viral RNA and DNA are recognized by a specialized set of receptors (e.g. RIG-I, IFIH1) that also trigger type I IFN production. Type I IFN binds to the ubiquitously expressed IFNAR1/2 receptor, which engages signaling through the JAK1 and TYK2 protein kinases, leading to regulation of expression of hundreds of downstream genes (reviewed in [3,4]).
Current Opinion in Immunology 2012, 24:530–537 This review comes from a themed issue on Autoimmunity: Insights from human genomics Edited by Soumya Raychaudhuri and Stephen S Rich For a complete overview see the Issue and the Editorial Available online 10th August 2012 0952-7915/$ – see front matter, Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.coi.2012.07.008
Introduction SLE is characterized by IgG autoantibodies to highly conserved nuclear antigens such as double-stranded DNA (dsDNA), histones and ribonuclear proteins. Immune complexes comprised of IgG and self-antigens deposit in tissues and blood vessels, including skin, kidneys, and pleura/pericardium, leading to end-organ disease. Additional autoantibodies directly target cell surface antigens, causing cytopenias and other pathologies. Similar to most autoimmune diseases, human leukocyte antigen (HLA) genes are associated with increased SLE risk, with strongest evidence for the class II HLA alleles DRB1*15:01 and DRB1*03:01 [1]. Although the survival rate for SLE has improved greatly over the years, patients are 2.5 times more likely to die than the general population [2], and there is a pressing need to develop new therapies. Current Opinion in Immunology 2012, 24:530–537
Type I IFNs have pleiotropic effects in the immune system. The diverse mechanisms by which elevated type I IFNs may influence SLE development and pathogenesis include: (a) upregulating expression of cytokines and chemokines; (b) increasing maturation of monocytes and dendritic cells; (c) activating autoreactive B and T cells; (d) increasing production of autoantibodies through effects on plasma cell differentiation; and (e) inducing apoptosis in the immune system [5–8].
The IFN gene expression signature and IFN-a in SLE Using microarray gene expression analysis, we generated initial data in 1999 showing that about two-thirds of adult SLE patients exhibited elevated expression of type I IFN-inducible genes in peripheral blood cells, and coined the term ‘IFN signature’ [9]. Additional groups reported similar findings in SLE [10,11,12], and subsequently the IFN signature was found to be prominent in Sjo¨gren’s syndrome, dermatomyositis, subacute cutaneous lupus and discoid lupus erythematosus [13–16]. A subset of subjects with psoriasis, rheumatoid arthritis and recent-onset type 1 diabetes also exhibit IFN gene signatures in tissue and blood cells [17,18]. Multiple sclerosis patients do not have an IFN signature, and, in fact, recombinant IFN-b is used as a therapeutic for multiple sclerosis. www.sciencedirect.com
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Before the identification of the IFN signature, a few earlier studies had suggested that type I IFNs were present in the blood of SLE (e.g. [19]). A series of studies by Ro¨nnblom and colleagues demonstrated that SLE immune complexes in blood could induce production of type I IFNs in vitro [20,21]. The connection between immune complexes, TLRs and SLE pathogenesis has been an intense focus of investigation in many laboratories. Important studies from Shlomchik, Marshak-Rothstein and others have demonstrated a key role for TLR 7/ 9 in murine SLE models [22], and have shown that stimulation of TLR 7/9 by nucleic acid-containing SLE immune complexes initiates B cell and dendritic cell activation, and the production of cytokines including type I IFN [23,24,25]. Longitudinal studies have shown that the IFN gene signature in blood is generally stable and not clinically useful for predicting disease flares [26,27,28]. By contrast, IFN-inducible chemokines have some ability to predict renal and extra-renal flares [29]. IFN-inducible cytokines and chemokines are prominent in SLE, and were present at higher levels in IFN-high patients compared to IFN-low patients [30]. Importantly, IFN-low patients had elevated IFN-inducible cytokines and chemokines relative to healthy controls [30]. It was also shown recently that about 25% of SLE patients have endogenous anti-IFN-a autoantibodies (AIAA) in blood [31], at a percentage significantly higher than previous estimates of 0–12% [32–35]. Most AIAA+ patients had lower serum type I IFN levels, reduced IFN-pathway activity and lower disease activity compared to AIAA-patients, suggesting that endogenous AIAA may have effects on the course of SLE [31]. The presence of the IFN signature, IFN-inducible chemokines, and endogenous AIAA in SLE are consistent with chronic and inappropriate activation of the type I IFN pathway.
Genetic risk for SLE and the type I IFN pathway An important development over the past 5 years has been the identification of genes that associate with SLE and that map into the type I IFN pathway. An initial candidate gene study by Sigurdsson et al. [36] found an association of the transcription factor interferon regulatory factor 5 (IRF5) with SLE. Further genetic and functional studies identified a single risk haplotype for IRF5 characterized by three functional alleles [37,38]. The non-risk haplotypes for IRF5 contain a splice site mutation in an alternative promoter for the gene, a deletion in exon 6, and a mutated consensus polyadenylation site in the 30 UTR that leads to reduced expression of IRF5 mRNA. IRF5 is activated by engagement of TLR 7/9, and is important for SLE development in the mouse [39]. IRF5 haplotypes have been linked to IFN-a levels in human SLE [40]. In addition, Syva¨nen and colleagues recently www.sciencedirect.com
reported that IRF5 target genes, as assessed by chromatin immunoprecipitation (CHIP) of stimulated peripheral blood cells of SLE patients, were enriched for type I IFN regulated genes compared to healthy controls [41]. Together, these studies of IRF5 firmly established a genetic link between TLR signaling, downstream cytokine production including type I IFN, and SLE. Subsequent GWAS and candidate gene studies have further emphasized this point [42,43,44–50]. Of the current group of 47 independent confirmed SLE variants (those reaching genome-wide levels of statistical significance, defined here as P < 5 108), a quarter (N = 11, 23%) are located in or around 7 genes with a known key role in type I IFN production or signaling: IRF5, IRF7, IRAK1, TNFAIP3, TNIP1, IFIH1 and TYK2 (see Figure 1). IRF7 is a transcription factor found in pDCs that is critical for TLR signaling leading to type I IFN production [51]. IRF7 interacts with the TLR adaptors MyD88 and TRIF [52], and hetero-dimerizes with IRF5. The top risk variant in this region is the intronic rs4963128*C SNP located in PHRF1, a gene directly upstream of IRF7; the risk haplotype includes the entire IRF7 gene [43,53]. IRAK1 is also critical for the TLR 7/8/9 signaling and type I IFN production, and mediates signaling through MyD88. Breeding of IRAK1 knockout alleles onto mouse models of SLE completely abrogated SLE-related phenotypes (e.g. IgM and IgG autoantibodies, lymphocytic activation, and renal disease) and these mice showed reduced dendritic cell hyperactivity [54]. The proposed risk variants in IRAK1 are two independent missense mutations: rs1059702*A and rs1059703*G. TNFAIP3 (A20) and TNIP1 (ABIN1) are ubiquitin ligases that regulate TLR signaling through interactions with TRAF proteins downstream of TLRs [55–57]. The proposed risk haplotypes are tagged by the variants TNFAIP3/OLIG3 rs6920220*A, TNFAIP3 rs5029937*T, and TNIP rs7708392*C [45,53,58]. IFIH1 (MDA5) is a cytosolic sensor of dsRNA that triggers phosphorylation of IRF7 and IRF3 and subsequent type I IFN production. SLE is associated with the IFIH1 missense mutation rs1990760*T [59]; homozygotes carrying this risk variant have been reported to exhibit higher IFIH1 expression [60]. In addition, the protective allele rs1990760*C marks a haplotype associated with reduced IFIH1 expression [61], consistent with rare loss-of-function alleles of IFIH1 that are protective from type 1 diabetes [62]. Robinson et al. [63] reported association between this variant and increased IFN-a induced gene expression in peripheral blood cells in anti-dsDNA+ SLE patients. Chronic type I IFN levels in transgenic IFIH1 murine models triggered autoimmunity – accelerated production of switched autoantibodies, increased glomerulonephritis, and early lethality – only Current Opinion in Immunology 2012, 24:530–537
532 Autoimmunity: Insights from human genomics
Figure 1
Type I IFN Production ITGAM
UBE2L3
Nucleic acids Rig-I-like receptor signaling pathway
?
ssRNA dsRNA (short)
RIG-I
dsRNA (long)
IFIH1
ssRNA
Type I IFN Signaling
ATG5
TNIP1
TNFAIP3
IRF5
TNFα
TRAF6
MAPK signaling pathway
IL12B
IRAK1
IRF7
TLR7/8 MyD88
unmethylated CpG DNA
IFN-α IFN-β
JAK-STAT signaling pathway IFNAR receptor
TYK2
TLR9 STAT4
Toll-like receptor signaling
Expression of Type I IFN-inducible genes
FCGR2A receptor
ELF1
IRF8
HLA-DRB1
IL10R receptor IKZF1
SLC15A4 TNFSF4 dsRNA
Complement clearance
TLR3
TRIF
IL10
C2 CFB
Current Opinion in Immunology
Confirmed SLE risk loci that map upstream and downstream of type I interferon. Toll-like receptors (TLRs) respond to enveloped viruses and some bacteria and protozoa in plasmacytoid dendritic cells (pDCs). Cytosolic sensors of viral replication (IFIH1, RIG-I) detect viral RNA or DNA in non-pDCs. Loci highlighted in red boxes represent confirmed SLE risk loci. Black solid arrows between loci represent direct interactions. Blue dotted arrows between loci represent indirect interactions. Direct interactions are defined as interactions where the two gene products directly interact, and represent the ‘core’ type I IFN genes (see Genetic risk for SLE and the type I IFN pathway). Indirect interactions are defined as interactions where the two gene products do not directly interact but are upstream or downstream of interactions with other gene products. Interactions were curated mainly from the literature, as well as from the KEGG Pathway Database (URL: http:// www.genome.jp/kegg/pathway.html).
when combined with a SLE-susceptible genetic background (FCGR2B deficiency) [64].
therapeutic targets for SLE. However, they may not be representative of sporadic SLE.
The protein kinase TYK2 directly interacts with the IFNAR1/2 receptor and mediates downstream signaling [65]. SLE is associated with the intronic TYK2 rs280519*A variant [59], which is in linkage disequilibrium (correlated) with a non-synonymous allele of TYK2 first reported by Syva¨nen and colleagues [36].
Recent data on rare single gene variants that lead to either SLE or SLE-like disease further support the idea that inappropriate activation of type I IFN is on the causal pathway for SLE (see Table 1). Complement deficiencies, including C1q, were the first of the familial forms of lupus to be identified (reviewed in [66]). Individuals homozygous for loss of function alleles in C1q develop lupus with high penetrance (>90%). A recent study showed that C1q deficient patients have greatly elevated IFN-a in serum and cerebrospinal fluid [67]. C1q also inhibits IFN-a production by pDCs and monocytes [68], and C1q deficiency leads to defective suppression of IFN-a in response to nucleoprotein containing immune complexes [68,69].
In addition to the ‘core’ type I IFN genes discussed above, a number of additional confirmed SLE loci (N = 16) can be indirectly mapped either upstream or downstream of type I interferon (see Figure 1). Together, over half of the confirmed SLE variants (27/47, 57%) have a role in either the production or downstream signaling of type I interferon.
Single gene lupus-related disorders of the type I IFN pathway In addition to studying sporadic SLE, it is worthwhile to examine highly penetrant phenotypes with a clinical presentation that is similar to or shared with SLE. These single-gene, or Mendelian, disorders can offer insight into Current Opinion in Immunology 2012, 24:530–537
Deficiencies in other complement pathway members (C2, C3, C1R, CFI, and CFH) have additionally been associated with increased risk of SLE [69–76]. Complement deficient individuals may have reduced clearance of immune complexes and apoptotic debris leading to activation of the type I IFN pathway. Supporting this view, www.sciencedirect.com
The genetics of type I interferon in systemic lupus erythematosus Bronson et al. 533
Table 1 Single gene SLE and SLE-like disorders associated with increased type I IFN production or signaling Genetic deficiency
Disorder SLE a
Complement C1q
AGS b
CHLE c
R R R R R
D
SPENCD d
Re
Extracellular nucleic acid DNASE1 Df DNASE1L3 D Intracellular nucleic acid TREX1 D RNASEH2A RNASEH2B RNASEH2C SAMHD1 Increased TLR signaling ACP5 (TRAP) Ig
D R
a
Multisystem involvement with typical SLE autoantibody profiles. Aicardi–Goutie`res syndrome: variable, congenital encephalopathy and systemic inflammatory phenotype. c Familial chilblain lupus erythematosus: recurrent chilblains (skin lesions). d Spondyloenchondrodysplasia: immuno-osseus dysplasia, intracranial calcification and variable autoimmune features. e Recessive inheritance pattern. f Dominant inheritance pattern. g Incomplete penetrance.
Mutations in TREX1 are also linked to chilblain SLE, a limited form of SLE-like skin disease, and in sporadic SLE (0.5% of cases) [82,83,84]. Mutations in tartrate-resistant acid phosphatase (TRAP) cause the SPENCD syndrome [85,86], which is characterized by metaphyseal abnormalities, mental retardation, spasticity and SLE-like autoimmunity. SPENCD patients have high levels of circulating IFNa and a prominent IFN gene signature [86]. TRAP is an abundant protein present in osteoclasts, macrophages and dendritic cells. A major substrate for TRAP is osteopontin. Osteopontin is physically associated with MyD88 and other signaling molecules downstream of TLR9, and is required for the production of type I IFN by pDCs in response to TLR9 stimulation [87]. Hyper-phosphorylation of osteopontin in the absence of TRAP may drive excessive type I IFN production and SLE-like pathologies in patients with the SPENCD syndrome [88–90].
b
loss of function alleles of DNASE1 and DNASE1L3, soluble enzymes that serve to clear extracellular DNA, are also associated with familial SLE [77,78]. Several recent studies have identified causative genes for the lupus-like diseases Aicardi–Goutie`res syndrome (AGS), chilblain lupus erythematosus and spondyloenchondrodysplasia (SPENCD). Importantly, each of these disorders has been linked to dysregulated type I IFN production and SLE-like disease (Table 1). AGS is an early-onset progressive encephalopathy with basal ganglia calcifications that presents in early childhood, and has an extremely poor prognosis. Children with AGS have a lymphocytosis and increased type I IFN in cerebrospinal fluid, without evidence for neonatal viral infection. Patients have autoantibodies, systemic inflammation and a prominent IFN gene signature in blood. Most cases of AGS are caused by recessive mutations in either the DNase 30 repair exonuclease 1 gene (TREX1), the RNase H2 subunits A, B, or C (RNASEH2A/B/C) or the sterile alpha motif domain and HD domain-containing protein 1 (SAMHD1) [79]. Data from a mouse knockout model suggest that TREX1 functions to suppress the accumulation of endogenous retroelements [80,81], which can activate the type I IFN pathway. Similar roles have been proposed for SAMHD1 and RNASEH2 in limiting the accumulation of endogenous intracellular nucleic acids. www.sciencedirect.com
Together, these various human knockouts provide additional evidence that chronic activation of the type I IFN pathway is central in the development of SLE.
Type I IFN as a therapeutic target in SLE Developing novel therapeutics for SLE is particularly important because there are so few effective therapies for SLE available today. The FDA recently approved Belimumab, a human monoclonal antibody that inhibits the B-lymphocyte stimulator (BLyS), for use in non-renal SLE, and it is the first SLE therapeutic approved in over five decades. The relatively modest clinical benefits reported in the pivotal trials for Belimumab suggest the optimal patient subset for this drug has not yet been identified [91–93]. Given the evidence reviewed above, it is perhaps not surprising that there are also several early phase clinical studies investigating monoclonal antibodies against type I IFN or the type I IFN receptor in SLE (reviewed by [94,95]): Rontalizumab (Genentech, Inc., South San Francisco, CA) (NCT00962832); Sifalimumab (MEDI545; NCT01283139) and MEDI-546 (NCT01438489) (Medimmune LLC, Gaithersburg, MD) [96]. Rontalizumab and Sifalimumab neutralize IFN-a subtypes, while MEDI-546 blocks the a subunit of the IFN-a/b receptor (IFNAR). Data from murine models also support the importance of type I IFN in SLE. IFNAR-deficient lupus-prone NZBWF1 mice have ameliorated lupus: reduced anti-erythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA autoantibodies, renal disease, and mortality [97]. After extensive safety testing in preclinical models, Genentech has completed a phase I escalating single and multiple dose trial evaluating safety, tolerability, and pharmacokinetics of Rontalizumab (a humanized IgG1 Current Opinion in Immunology 2012, 24:530–537
534 Autoimmunity: Insights from human genomics
monoclonal antibody targeting all IFN-a isotypes) in adults with mild SLE (J McBride et al., abstract in Arthritis Rheum: 2009:S775–S776). Importantly, the IFN gene signature was modulated in patients receiving 3 mg/kg or higher doses of Rontalizumab. Based on overall acceptable safety, pharmacokinetics and pharmacodynamics, Rontalizumab was moved into a phase II clinical trial in 2010 in adults with moderate to severe non-renal SLE. Similarly, Sifalimumab has also been shown to modulate the IFN signature in SLE patients in phase I trials, and was moved into a phase II trial in 2011 in adults with moderate to severe non-renal SLE [96]. MEDI-546 entered a phase II trial in 2012 in adults with moderate to several non-renal SLE with an inadequate response to standard of care treatment for SLE. These clinical trials will provide the first tests of the hypotheses that modulating type I IFNs in humans modulates disease activity.
Conclusions In aggregate, the evidence supporting the direct involvement of type I IFNs in SLE pathogenesis is quite compelling: (a) IFN-a immunotherapy can induce lupus [98]; (b) circulating immune complexes from SLE blood can initiate type I IFN production; (c) there are prominent IFN regulated gene and cytokine signatures in SLE; (d) polymorphisms in IFN pathway genes are associated with SLE in GWAS studies; and (e) several single gene disorders cause increased type I IFN and SLE or SLElike symptoms. The genetic data in particular suggest that targeting the type I IFN pathway in SLE may prove beneficial in treating this disease.
Acknowledgements
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We would like to thank A. Manoharan and H. Sun for their invaluable assistance in curating the published SLE literature for genetic associations.
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