Email updates

Keep up to date with the latest news and content from Arthritis Research & Therapy and BioMed Central.

This article is part of the series Systemic lupus erythematosus.

Highly Accessed Review

The genetics of lupus: a functional perspective

Sandra G Guerra12, Timothy J Vyse12 and Deborah S Cunninghame Graham12*

Author Affiliations

1 Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, Great Maze Pond, London, SE1 9RT, UK

2 Academic department of Rheumatology, Division of Immunology, Infection and Inflammatory Diseases, School of Medicine, King's College London, Great Maze Pond, London, SE1 9RT, UK

For all author emails, please log on.

Arthritis Research & Therapy 2012, 14:211  doi:10.1186/ar3844


The electronic version of this article is the complete one and can be found online at: http://arthritis-research.com/content/14/3/211


Published:29 May 2012

© 2012 BioMed Central Ltd

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic component and is characterized by chronic inflammation and the production of anti-nuclear auto-antibodies. In the era of genome-wide association studies (GWASs), elucidating the genetic factors present in SLE has been a very successful endeavor; 28 confirmed disease susceptibility loci have been mapped. In this review, we summarize the current understanding of the genetics of lupus and focus on the strongest associated risk loci found to date (P <1.0 × 10−8). Although these loci account for less than 10% of the genetic heritability and therefore do not account for the bulk of the disease heritability, they do implicate important pathways, which contribute to SLE pathogenesis. Consequently, the main focus of the review is to outline the genetic variants in the known associated loci and then to explore the potential functional consequences of the associated variants. We also highlight the genetic overlap of these loci with other autoimmune diseases, which indicates common pathogenic mechanisms. The importance of developing functional assays will be discussed and each of them will be instrumental in furthering our understanding of these associated variants and loci. Finally, we indicate that performing a larger SLE GWAS and applying a more targeted set of methods, such as the ImmunoChip and next generation sequencing methodology, are important for identifying additional loci and enhancing our understanding of the pathogenesis of SLE.

Introduction

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by hyperactive T and B cells, auto-antibody production, and immune complex(IC) deposition [1]. SLE has a prevalence of approximately 1 in 2,500 in European populations [2] and is more frequent in those of non-European ancestry. SLE affects predominantly women (the female-to-male ratio is 9:1) of child-bearing age and is characterized by variable clinical features, including malar rash, glomerulonephritis, arthritis, and neuropsychiatric disease [3]. Although the exact etiology of lupus is not fully understood, a strong genetic link has been identified through the use of association and family studies. The heritability of SLE is approximately 66%; the rates of concordance are 24% to 56% in monozygotic twins and 2% to 4% in dizygotic twins [4,5].

To date, genome-wide association studies (GWASs) have identified more than 30 associated loci. In Table 1, we show the variants that have reached genome-wide significance (1.0 × 10−8) in one or more GWASs, a metaanalysis, or replication studies. We have also included the Fcγ locus, because it contains multiple associated variants, including a confirmed copy number variation (CNV) in SLE. However, these loci account for less than 10% of the genetic heritability [6].

Table 1. A summary of loci associated with systemic lupus erythematosus in one or more genome-wide association studies, a meta-analysis, and replication studies (P <1

GWASs in SLE have been useful tools for expanding the genetic understanding of SLE by identifying new loci and replicating previously associated loci. In this review, we categorize these risk loci into a number of pathways on the basis of the current understanding of the potential role for the locus in SLE. We note that the clinical heterogeneity of SLE is mirrored by the diversity of the pathways reported to contain the associated loci from the genetic studies, apoptosis, innate immune response, ubiquitination, and phagocytosis (Table 1). Therefore, this review aims to highlight the known function(s) of the associated loci and to indicate where further functional studies are needed to elucidate the pathogenic mechanisms in lupus.

Contribution of apoptosis to SLE pathogenesis

Apoptosis is a well-defined process of programmed cell death and does not immediately release the intracellular content into the extracellular environment [7,8]. In healthy individuals, dead or dying cells are cleared by macrophages in an inherently anti-inflammatory way. However, in patients with SLE, apoptosis has been reported to be defective and plays a role in disease manifestation [9]. Patients with SLE demonstrate defective clearance of apoptotic cells, which evokes a secondary transition into necrotic cell death [10]. During apoptosis, cells shrink and change morphology by engulfing self-antigens, forming membrane-bound blebs that are exposed on the cell surface. Once engulfed, these blebs carry on their surface intracellular proteins, which can act as a source of auto-antigens, a tendency that is enhanced if clearance is defective [11,12]. With defective clearance of apoptotic blebs, cells undergo secondary necrosis, releasing nuclear auto-antigens [13]. This process triggers the production of inflammatory cytokines and interferon-alpha (IFNα) [10], promoting lymphocyte loss of self-tolerance, auto-antibody production, and IC deposition. The ICs can bind low-affinity FcγRIIa, expressed on plasmacytoid dendritic cells (pDCs). After endocytosis of the ICs, Toll-like receptor 7/9 (TLR7/9) is activated through the DNA/RNA presented by IC [14] and this in turn stimulates the production of IFN by pDCs (Figure 1). This production of IFN propagates chronic inflammation and loss of tolerance, both of that patients with SLE have an increased rate of lymphocyte apoptosis [15], which is possibly due to increased activation of these cells. Mutations in a number of loci associated with SLE have been reported to propagate defective clearance of apoptotic cells and increased apoptosis.

thumbnailFigure 1. The impaired immune system in patients with systemic lupus erythematosus (SLE). Defective apoptotic clearance allows deposition of immune complexes which can stimulate B and T cells. Hyperactive B cells then produce auto-antibodies which activate complement, causing tissue damage. Plasmacytoid dendritic cells (pDCs) activated by immune complexes then release excessive interferon α/β (IFNα/β), again causing tissue damage. At each pathway, the known associated loci are indicated. All of the loci produce loss of both self-tolerance and autoimmunity, as seen in SLE. APC, antigen-presenting cell; BANK1, B-cell scaffold protein with ankyrin repeats 1; BLK, B lymphoid tyrosine kinase; HLA-DRB1, human leukocyte antigen-DRB1; IFIH1, interferon-induced helicase 1; IL10, interleukin-10; IRF, interferon regulatory factor; ITGAM, integrin, alpha M; LYN, V-yes-1 Yamaguchi sarcoma viral-related oncogene homolog; MHC, major histocompatibility complex; Mφ, microphage; NCF2, neutrophil cytosolic factor 2; PRDM1-ATG5, PR domain containing 1, with ZNF domain-autophagy-related 5 homolog; PTPN22, protein tyrosine phosphatase, non-receptor type 22; RasGRP3, RAS guanyl releasing protein 3; STAT4, signal transducer and activator of transcription 4; TCR, T-cell receptor; TNFAIP3, tumor necrosis factor, alpha-induced protein 3; TNFSF4, tumor necrosis factor superfamily, member 4; TNIP1, TNFAIP3- interacting protein 1; UBE2L3, ubiquitin-conjugating enzyme E2L 3.

ITGAM

ITGAM encodes the α-chain of αMβ2-intergin (CD11b) [16] and plays a role in phagocytosis and leukocyte adhesion [17]. GWASs have reported that variants at this locus are associated with SLE, and single-nucleotide polymorphism (SNP) rs9888739 showed the strongest association (P = 1.61 × 10−23, odds ratio (OR) = 1.62). However, a trans-ancestral study in European-Americans and African-Americans [18] indicated the causal variant as rs1143679, which has been reported to cause two functional changes in ITGAM. The first of these functional changes is an amino acid mutation at R77H (Arg-His) which modifies the tertiary and quaternary structures of the αMβ2 ligand-binding domain [18]. αMβ2-integrin interacts with a number of ligands such as intracellular adhesion molecule 1 (ICAM-1) and the complement C3 degradation product, C3bi; these ligands play a role in leukocyte activation, migration, and phagocytosis [16]. Variants in the αMβ2 ligand-binding domain may alter binding affinity, hence leukocyte trafficking, phagocytosis [16], and IC clearing [19]. The second functional change is with rs1143679, which impairs the phagocytosis of C3bi-coated particles [20] and propagates the deficient clearance of ICs and increased inflammation [20]. However, the exact mechanism of how both of these variants influence the pathogenesis of SLE warrants further investigation.

Fcγ receptors

The FCGR genes encode diverse Fcγ receptors that recognize the Fc portion of immunoglobulin G (IgG) molecules. Several missense polymorphisms in FCGR2A, FCGR2B, and FCGR3A [21-23] are associated with SLE. Three of the five FCGR genes (FCGR3A, FCGR2C, and FCGR3B) have been reported to show CNV [24] and expression of Fcγ receptors on the cell surface is dependent on the number of copies expressed [25,26]. A CNV that resulted in a reduced number of FCGR3B molecules expressed on the cell surface of neutrophils is associated with SLE. The exact mechanism by which the CNV incorporating FCGR3B promotes disease is not fully established, although reduced binding of ICs by neutrophils is a possible mechanism.

The role of ubiquitination in SLE

Ubiquitination is still an incompletely understood biochemical process by which proteins are post-translationally modified through the addition of single ubiquitin molecules or polyubiquitin chains. During ubiquitination, proteins may be tagged for protelolytic degradation by the proteosome. Ubiquitination has also been reported to regulate transcription factors and intracellular kinase activity [27]. Genes that encode these different components of the protein modification system have been reported to be associated with SLE.

TNFAIP3 and TNIP1

TNFAIP3 encodes the ubiquitin-editing enzyme A20 [28,29], which alters ubiquitin patterns, which then alter targeting for proteosome degradation and termination of nuclear factor-kappa-B (NF-κB)-derived pro-inflammatory responses. This occurs through the ubiquitination of IKKγ and phosphorylation of IκBα [30,31], facilitating the release of NF-κB (Figure 2). A20 is a key regulator of NF-κB through ubiquitin modifications of receptor-interacting protein kinase (RIP) and tumor necrosis factor receptor-associated kinase 6 (TRAF6) [32].Multiple associations have been found in TNFAIP3 in a range of autoimmune diseases [28]; of these associations, rs2230926 has shown the strongest significance (P = 1.37×10−17, OR = 1.72) in SLE. This non-synonymous SNP [33] causes an amino acid change from a Phe-Cys. This amino acid change propagates A20 protein to be less effective at inhibiting tumor necrosis factor (TNF)-induced NF-κB activity [34]. Variants at this locus could potentially lead to reduced inhibitory activity of NF-κB and reduced expression of A20.

thumbnailFigure 2. The role of A20 in the nuclear factor-kappa-B (NF-κB) pathway. A20 ubiquitinates TRAF6, which is bound to the IKK complex (IKKγ, IKKα, and IKKβ). The IKK complex then becomes phosphorylated, propagating proteasomal degradation of IKβα and, in turn, allowing NF-κB translocation to the nucleus and propagating target gene transcription. IKK, IκB kinase; IRAK, interleukin-1 receptor-associated kinase; MyD88, myeloid diff erentiation primary response gene (88); P, phosphate; TRAF6, tumor necrosis factor receptor-associated kinase 6.

Owing to increased NF-κB signaling, Tnfaip3/mice develop spontaneous inflammation and lymphocyte cell death [35]. This shows the importance of TNFAIP3 in NF-κB regulation through the ubiquitination of adaptors such as RIP [35]. Therefore, it can be seen that TNFAIP3 is an important locus that contributes to SLE pathogenesis through its downregulation. The downregulation of TNFAIP3 facilitates hyperactive NF-κB signaling, chronic inflammation, and reduced apoptosis, all characteristics of SLE.

TNIP1, an adaptor protein that binds to A20, has also been reported to be associated with SLE. TNIP1 is expressed on lymphocytes and its expression is inducedby NF-κB [36]. However, overexpression of TNIP1 inhibits NF-κB activation by TNF [37]. Variants in TNIP1 could potentially play a role in negatively regulating the NF-κB pathway [38]. SNP rs7708392 has been reportedto play a role in TNIP1 splicing, rendering the inhibition of the NF-κB pathway less effective. This would propagate pro-inflammatory responses and chronic inflammation. This variant has been shown to be associated with Caucasian and Asian populations [36].

UBE2L3

UBE2L3 is a ubiquitin-carrier enzyme gene and is expressed widely on all lymphocytes [39]. It plays a key role in the maturation of transcription factors (for example, p53 and p105, the latter of which is an NF-κB precursor) [40,41]. This enzyme regulates IFN through TLR7/9 [42,43]. The exact mechanism of UBE2L3 is still not fully understood, but variants in this locus have been shown to be associated with SLE (rs463426,P = 1.48×10−16, OR = 0.78).

Abnormalities of lymphocyte development in SLE

SLE is associated with multiple dysfunctions in many lymphocyte subsets. SLE T cells have been reported to show inappropriate tissue homing, increased secretion of pro-inflammatory cytokines [44], and activation of both dendritic cells (DCs) and B cells [45]. A number of loci have been found to be associated with lymphocyte differentiation and SLE, as described below.

ETS1 and IKZF1

ETS1 and IKZF1 are transcription factors that regulate lymphocyte differentiation and lymphocyte development [46,47]. ETS1 has been reported as a negative regulator of B-cell differentiation and T helper 17 (Th17) cell proliferation [48]. Patients with SLE demonstrate a reduced expression of ETS1, which may contribute to abnormal B-cell differentiation into immunoglobulin-secreting plasma cells and an increased number of Th17 cells [49-51]. While having increased proliferation of Th17 cells causes increased inflammation through the secretion of interleukin-17 (IL-17), ETS1-deficient Th1 cells secrete higher amounts of anti-inflammatory cytokine IL-10 [52]. Interestingly, these ETS1-deficient Th1 cells have reduced secretion of IL-2, which is a potent Th17 inhibitor [52]. The top associated variant at this locus, rs6590330 (P = 1.77×10−25, OR = 1.37), could potentially play a role in decreasing ETS1 expression.

Patients with SLE have also been reported to express low IKZF1 levels in peripheral blood [48]. The strongest association found at this locus is rs4917014 (P = 2.75×10−23, OR = 1.23) [53], which may play a role in downregulating IKZF1 expression. This reduced level of expression contributes to SLE pathogenesis through interactions with other genes; for example, IKZF1 has been reported to play a role in trans-activating STAT4, a confirmed risk locus in SLE [54]. IKZF1 is important for lymphocyte differentiation [55] and regulation of self-tolerance through B-cell receptor (BCR) signaling [56]. Downregulation of this locus would therefore promote loss of self-tolerance, a hallmark of SLE.

Inappropriate B-cell physiology in SLE

Hyperactive B cells play an important role in the pathogenesis of SLE. With the production of auto-antibodies and prolonged cell life, B-cell regulation is important in the maintenance of immune balance. B cells of patients with SLE have been shown to present auto-antigens, induce CD4+ T helper cells (Th1/Th2), inhibit T regulatory cells, and secrete pro-inflammatory cytokines [57]. A number of key loci have been reported to be associated with SLE and are described below.

BANK1, BLK, and LYN

The gene products of BANK1, BLK, and LYN operate in the BCR signaling pathway and have been reported to be associated with SLE [58], which together attest to the importance of this pathway in disease pathogenesis.rs10516487, located in the BANK1-binding region [59], has shown the strongest association with SLE (P = 3.1 × 10−10, OR = 1.38). After B-cell activation, BANK1 becomes tyrosine-phosphorylated, resulting in phosphorylation of type 1 inositol-1,2,4-triphosphate(IP(3)R). This phosphorylation event serves to augment calcium mobilization and hence B-cell activation [60]. The associated variant at BANK1 increases its expression by influencing splicing efficiency, creating a splicing enhancer [59]. The expression increase propagatesstronger binding affinity between BANK1 and IP(3)R, resulting in hyper-responsiveness [61]. Cells expressing the risk allele of this variant also have higher protein levels, which can sustain BCR signaling and hyperactive B cells, as shown in SLE [59].

Associated allelic variants in BLK (rs7812879,P = 2.09×10−24, OR = 0.69) and LYN (rs7829819,P = 5.40×10−9, OR = 0.77), in comparison with BANK1, have been shown to decrease their respective expressions [61,62]. LYN kinase mediates inhibitory signals from CD22, which modulates the B-cell activation threshold [63]. Downregulation of LYN causes hyper-responsiveness of BCR stimulation, triggering autoimmunity [64] asshown in Lyn/mice [65]. Compared with BLK, which affects pre-BCR signaling, active BLK enhances BCR responsiveness [66]. Blk/mice have shown no phenotype [67]; thus, an interaction with BANK1 could potentially explain the association with SLE [61]. As LYN and BLK share similarities of genomic structure [64], it is believed that, in BCR signaling, BLK plays a role similar to that of LYN.

RasGRP3

RasGRP3 regulates Ras-ERK signaling, which is crucial in lymphocyte development and activity [68], and is involved in B-cell proliferation and immunoglobulin production [53]. rs13385731 (P = 1.25 × 10−15, OR = 0.70) at the RasGRP3 locus has been reported to be associated with SLE and may cause an underexpression of RasGRP3, which blocks its inhibitory role in B-cell proliferation.

NCF2

NCF2 is a cytosolic subunit of NADPH oxidase, which is expressed on B cells [69]. It is thought to play a role in the increased production and release of free radicals, propagating B-cell activation. rs10911363 (P = 2.87 × 10−11, OR = 1.18) has been shown to have reached genome-wide significance in SLE [69] and could play a role in increased NCF2 expression in patients with SLE.

Dysregulation of T cells in SLE

Patients with SLE demonstrate an increased number of CD3+CD4CD8T cells and Th17 cells and a variable effect on T regulatory cells [44]. These T-cell subsets together lead to increased inflammation, B-cell interaction, and tissue damage [45]. SLE T cells engage the CD3-TCR faster and earlier, leading to increased signaling and intracellular calcium levels. These increased calcium levels may lead to increased expression of CD40L, increasing transcription of cAMP-responsive element modulator (CREM), which would produce hyperactive T cells [70]. However, data on T regulatory cell expression in SLE have been variable. Some reports suggest that T regulatory cells, such as CD4+CD25+ T cells, are deficient in SLE [71]. However, others report enrichment for this cell type [72,73], perhaps relating toheterogeneity in the definitions of regulatory cells using cell-surface markers. It has also been reported that SLE T cells, compared with control T cells, undergo an increased rate of apoptosis, which again will contribute to SLE pathogenesis. As described below, there are a number of associated loci whose gene products play a key role in T-cell development and TCR signaling and have been reported to be associated with SLE.

STAT4

STAT4 is a Th1 transcription factor that has been reported to mediate Th1 T-cell response, Th1 cytokines, IL-12 and IL-23 [74,75], and IFNγ signaling [76,77]. rs7574865 has been reported to have the strongest association with SLE (P = 5.17 × 10−42, OR = 1.51) and has also been described for other autoimmune diseases such as rheumatoid arthritis (RA) [74], Sjögren's syndrome [78], inflammatory bowel disease, and type 1 diabetes(T1D) [79]. rs7574865 has been described as being associated with many SLE clinical features, such as lupus nephritis [80]. STAT4 propagates a Th1 T-cell response, increasing IFNγ release [81]. As seen in Figure 1, this influx of IFNγ would target organs such as the kidneys, propagating further IFNγ release and chronic inflammation. rs7574865 may act to increase STAT4 expression and hence IFNγ production. Further reports have shown that other associated variants, such as rs7582694 (intronic), show overexpression of the risk allele (C) in mesenchymal cells but not in B cells [82]. Th is STAT4 risk allele was also reported to be overexpressed in cells carrying the risk haplotype in comparison with cells not carrying this haplotype [82].

PTPN22

PTPN22 encodes the lymphoid tyrosine phosphate protein, LYP, which is involved in the down regulation of T-cell activation through the inter action with cytoplasmic tyrosine kinase (CSK) and suppression of T regulatory cells [83]. rs2476601 (P = 3.4 × 10−12, OR = 1.35) has been reported to be associated with SLE and also with T1D and RA [84]. Furthermore, a trans-ancestral study has shown that rs2476601 is associated with SLE in Europeans, Hispanics, and African-Americans [85]. The associated variant causes the amino acid change of Arg-Try, preventing PTPN22 interaction with CSK [86,87]. However, the experimental evidence suggests that rs2476601 reduces TCR signaling [88]. Furthermore, PTPN22 expressing the associated risk allele (A) has been reported to bind CSK less effectively than those expressing the G allele, producing hyper-responsive T cells [85]. Therefore, the current experimental evidence does not give us the full understanding of PTPN22 function and warrants further investigation.

TNFSF4 (OX40L)

TNFSF4 is expressed on the surface of antigen-presenting cells (APCs), B cells, and macrophages, and its unique ligand CD123 (OX40) is expressed on activated CD4+ and CD8+ T cells [89]. The strongest association in TNFSF4 is with the upstream variant rs2205960 (P = 2.5 × 10−32, OR = 1.46), and protective and risk haplotypes that carry alternate alleles of rs2205960 have been observed [90]. The risk haplotype has been reported to be associated with increased TNFSF4 transcript levels [91,92]. This increased expression of OX40L promotes OX40/OX40L interactions and increases the co-stimulatory signal between APCs and T cells, and this in turn increases T-cell survival and thereby propagates autoimmunity. OX40L has been shown in vitro to inhibit the generation of IL-10-producing T regulatory cells needed for tolerance, and it is known that mutations in this pathway cause loss of tolerance and autoimmunity [93].

Defective antigen presentation in SLE

HLA-DRB1/MHC

The major histocompatibility complex (MHC) region has been shown to exert the strongest genetic association and effect in SLE to date; the top association was found atHLA-DRB1 (P = 2.0 × 10−60, OR = 1.98). Studies examining the association with HLA class II have implicated both HLA-DRB1*03:01 and HLA-DRB1*15:01 [94] in SLE. The MHC is composed of 250 genes subdivided into three classes (I, II, and III) with a strong linkage disequilibrium (LD) spanning the region. There appear to be multiple independent signals at the MHC in SLE, accounting for the overall strength of the association seen with the region. One paper reported a 180-kb region of class II, spanning HLA-DRB1, HLA-DQA1, and HLADQB [95], whereas the second signal was found in a marker of the class III gene SKIV2L. Other immunologically relevant genes such as complement C4A and C4B are also in this region of MHC. The strong LD covering the extended MHC region makes it difficult to identify whether the association arises from the associated variants currently identified or from variants within this LD region. For this reason, further fine mapping of the region is needed and the region may also benefit from trans-ancestral mapping [96].

The interferon signature and its regulation in SLE

More than half of patients with SLE show a dysregulation in the expression of genes in the IFN pathway [97]. The type I IFNs are potent cytokines (IFNα and IFNβ) and also mediate the Th1 response, sustain activated T cells, sustain B-cell survival, and lower the B-cell activation threshold [98]. These responses propagate pro-inflammatory cytokines, contributing to chronic inflammation and tissue damage [14]. IFN also acts as a bridging mechanism between the innate and adaptive immune systems. However, it is unclear whether elevated IFN is the causal effect of SLE or whether it further propagates disease intensity. Given the genetic role of IRF5 and a number of other genes in the IFN pathway, it is likely thatIFN exerts a pathway effect in the pathogenesis of disease.

IRF5, IRF7, and IRF8

IRF5, IRF7, and IRF8 are transcription factors that play a role in type 1 IFN signaling and immune cell development [99]. SNPs in IRF5, IRF7, and IRF8 (P = 5.8 × 10−24, OR = 1.88; P = 3.0 × 10−10, OR = 0.78; and P = 1.24 × 10−8, OR = 1.17, respectively) (as shown in Table 1) have been shown to be associated with increased risk of SLE [98]. These variants have been shown to increase the levels of IRF5, IRF7, and IRF8 transcript and protein expressions [100]. Of these three loci, IRF5 exhibits the largest effect. An IRF5 risk haplotype has been observed and carries multiple mutations, including rs2004640, which has been reported to create a novel splicing variant. Another variant found at the 3' untranslated region, rs10954213, has been reported to create a more functional polyadenlyation site, which creates a more stable transcript [101]. Variants in the IRF5 locus influence alternatively spliced transcripts, which alter or prolong IRF5 expression. Hence, increased expression of IRF5 propagates increased IFNα production. Little is reported for IRF7 and IRF8; therefore, these loci warrant further investigation to determine the functional consequences of the associated variants.

IFIH1

IFIH1 is a DEAD box helicase that senses intracellular RNA and induces IFN (type 1) activation [102]. Variants at this locus have been associated with other autoimmune diseases such as T1D [103], autoimmune thyroid disease [104], and psoriasis [105]. The top associated SNP in SLE is rs1990760 (P = 1.63 × 10−8, OR = 1.23), which has been shown to increase expression of IFIH1. This increased expression could contribute to an IFN cascade initiated by nucleic acids.

TYK2

TYK2 plays an important role in the pro-inflammatory immune response, being involved in cytokine signaling and the phosphorylation of IFN receptors, triggering a type 1 IFN response [69]. Variants in TYK2 have been reported to increase type 1 IFN gene expression [106] and deregulate the Th1/Th17 response. Th17 cells are pro-inflammatory, and their differentiation is dependent on IL-6 and transforming growth factor-beta (TGFβ), both of which are cytokines that are regulated by TYK2 [107]. The top associated SNP in SLE, rs280519 (P = 3.88 × 10−8), has been shown to play a role in increasing gene expression and IFN production. Variants propagating increased TYK2 function have also been reported to lead to a pro-inflammatory phenotype with increased levels of Th1/Th17 cells [107]. Multiple variants in TYK2 have been reported to be associated with other autoimmune and inflammatory diseases [108].

Known intergenic interactions in SLE

From the published GWASs, we are able to identify associated variants for SLE in intergenic regions in addition to those in coding regions of genes. When intergenic loci are identified, it is important to ascertain the functional consequence of the variant on the neighboring genes. Indeed, until a molecular mechanism is fully elucidated, one cannot conclude that any associated allele will primarily exert its pathological effect by influencing the function of the gene that is closest by genomic distance.

PRDM1-ATG5

The PRDM1-ATG5 gene region has shown a significant association with increased risk of SLE at the intergenic variant rs548234 (P = 5.1 × 10−12, OR = 1.25) [109]. This variant has been shown to increase the expression of ATG5 in individuals who are homozygous for the C allele [109]. Since ATG5 is important for the formation of autophagosomes [110], increased expression of this gene increases autophagy, which in turn stimulates the IFNα and NF-κB pathways [109] and exacerbates the immune response. However, PRDM1 (BLIMP1) has been reported to play a role in B-cell differentiation [111], and so variants that affect PRDM1 could allow plasma cell differentiation, which further propagates hyperactive B cells and auto-antibody production. PRDM1 has also been reported to maintain immune tolerance and has been shown to alter DC function in female mice that lack PRDM1 expression on DCs. These mice also develop lupus-like auto-antibodies [112]. Therefore, both ATG5 and PRDM1 could potentially have causal effects for lupus. Consequently, further experiments will be required to establish whether one (or perhaps both) of these genes plays a role in genetic susceptibility to SLE.

CD44-PDHX

One trans-ancestral study (Europeans, African-Americans,and Asians) reported two intergenic SNPs between PDHX-CD44 [113]. PDHX plays a role in the pyruvate dehydrogenase complex, and CD44 is an integral cell membrane glycoprotein, which plays a role in cell-cell interactions and regulation of IFNγ and LCK [58]. Variants in CD44 alone have been shown to be associated with SLE [58]. CD4+ and CD8+ T cells of patients withSLE have been shown to overexpress CD44, causing an influx of IFNγ, inflammation, and tissue damage [113]. This fact suggests that the intergenic associations are pointing toward CD44 as a more likely candidate gene for SLE than PDHX.

Conclusions

In this review, we describe the key loci that have been associated with SLE to date. We have shown the importance of these genes in their most relevant related pathways (Figure 1). However, to fully understand these associations, fine-mapping studies using targeted genotyping chips, such as the ImmunoChip, will be required. These types of studies will lead to the identification of additional variants that can then be used for functional studies to elucidate the molecular mechanisms operating in lupus. The additional advantage of the ImmunoChip platform is that it allows us to look for a commonality of associations across immune-related diseases.

To date, in lupus, there have been a number of relatively small GWASs, which nonetheless have been quite successful in identifying the strongest causal genetic effects in terms of both significance, in which a P value quantifies whether the difference in allele frequency between SLE cases and healthy controls is likely to occur solely by chance, and the effect size, which quantifies the amount of the observed difference between affected and unaffected individuals. However, as previously mentioned, these studies have been able to identify only approximately 10% of the genetic heritability. GWASs in SLE which are much larger than those previously undertaken will be necessary in order to expand the number of SLE-associated loci significantly. To fully explore the genetics of SLE, it is important to study high-risk groups, such as those with African or Amerindian ancestry. This will allow greater understanding of SLE across different ethnicities and will allow fine mapping of the associated loci. Such studies are currently under way.

Finally, fbuilding upon these GWASs and replication studies, functional and targeted assays (for example, next-generation sequencing) are needed. These studies enable us to identify rare variants, using methods such asnext-generation sequencing, and to provide greater understanding of the biology of SLE and hence the pathogenesis of this disease. In summary, the genetics of SLE is still not fully understood, but by undertaking additional genetic studies and consequential functional assays we will obtain a much greater understanding of the etiology of the disease.

Autoimmune Basis of Rheumatic Diseases

This article is part of a series on Systemic lupus erythematosus, edited by David Pisetsky, which can be found online at http://arthritis-research.com/series/lupus webcite

This series forms part of a special collection of reviews covering major autoimmune rheumatic diseases, available at: http://arthritis-research.com/series/abrd webcite

Abbreviations

APC: antigen-presenting cell; BCR: B-cell receptor; CNV: copy number variation; CSK: cytoplasmic tyrosine kinase; DC: dendritic cell; GWAS: genome-wide association study; IC: immune complex; IFN: interferon; IL: interleukin; IP(3) R: type 1 inositol-1,2,4-triphosphate; LD: linkage disequilibrium; MHC: major histocompatibility complex; NF-κB: nuclear factor-kappa-B; OR: odds ratio; pDC: plasmacytoid dendritic cell; RA: rheumatoid arthritis; RIP: receptor-interacting protein kinase; SLE: systemic lupus erythematosus; SNP: single-nucleotide polymorphism; TCR: T-cell receptor; Th: T helper; T1D: type 1 diabetes; TLR7/9: Toll-like receptor 7/9.

Competing interests

The authors declare that they have no competing interests.

References

  1. Perl A: Pathogenic mechanisms in systemic lupus erythematosus.

    Autoimmunity 2010, 43:1-6. PubMed Abstract | Publisher Full Text OpenURL

  2. Johnson AE, Gordon C, Palmer RG, Bacon PA: The prevalence and incidence of systemic lupus erythematosus in Birmingham, England. Relationship to ethnicity and country of birth.

    Arthritis Rheum 1995, 38:551-558. PubMed Abstract | Publisher Full Text OpenURL

  3. Lipsky PE: Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity.

    Nat Immunol 2001, 2:764-766. PubMed Abstract | Publisher Full Text OpenURL

  4. Block SR, Winfield JB, Lockshin MD, D'Angelo WA, Christian CL: Studies of twins with systemic lupus erythematosus. A review of the literature and presentation of 12 additional sets.

    Am J Med 1975, 59:533-552. PubMed Abstract | Publisher Full Text OpenURL

  5. Deapen D, Escalante A, Weinrib L, Horwitz D, Bachman B, Roy-Burman P, Walker A, Mack TM: A revised estimate of twin concordance in systemic lupus erythematosus.

    Arthritis Rheum 1992, 35:311-318. PubMed Abstract | Publisher Full Text OpenURL

  6. Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA, Sun X, Ortmann W, Kosoy R, Ferreira RC, Nordmark G, Gunnarsson I, Svenungsson E, Padyukov L, Sturfelt G, Jönsen A, Bengtsson AA, Rantapää-Dahlqvist S, Baechler EC, Brown EE, Alarcón GS, Edberg JC, Ramsey-Goldman R, McGwin G Jr, Reveille JD, Vilá LM, Kimberly RP, Manzi S, Petri MA, Lee A, Gregersen PK, et al.: A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus.

    Nat Genet 2009, 41:1228-1233. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  7. Kerr JF, Wyllie AH, Currie AR: Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.

    Br J Cancer 1972, 26:239-257. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  8. Salmon M, Gordon C: The role of apoptosis in systemic lupus erythematosus.

    Rheumatology (Oxford) 1999, 38:1177-1183. Publisher Full Text OpenURL

  9. Bannister KM, Hay J, Clarkson AR, Woodroffe AJ: Fc-specific reticuloendothelial clearance in systemic lupus erythematosus and glomerulonephritis.

    Am J Kidney Dis 1984, 3:287-292. PubMed Abstract OpenURL

  10. Munoz LE, Lauber K, Schiller M, Manfredi AA, Herrmann M: The role of defective clearance of apoptotic cells in systemic autoimmunity.

    Nat Rev Rheumatol 2010, 6:280-289. PubMed Abstract | Publisher Full Text OpenURL

  11. Herrmann M, Voll RE, Zoller OM, Hagenhofer M, Ponner BB, Kalden JR: Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus.

    Arthritis Rheum 1998, 41:1241-1250. PubMed Abstract | Publisher Full Text OpenURL

  12. Suber T, Rosen A: Apoptotic cell blebs: repositories of autoantigens and contributors to immune context.

    Arthritis Rheum 2009, 60:2216-2219. PubMed Abstract | Publisher Full Text OpenURL

  13. Muñoz LE, Janko C, Grossmayer GE, Frey B, Voll RE, Kern P, Kalden JR, Schett G, Fietkau R, Herrmann M, Gaipl US: Remnants of secondarily necrotic cells fuel inflammation in systemic lupus erythematosus.

    Arthritis Rheum 2009, 60:1733-1742. PubMed Abstract | Publisher Full Text OpenURL

  14. Elkon KB, Stone VV: Type I interferon and systemic lupus erythematosus.

    J Interferon Cytokine Res 2011, 31:803-812. PubMed Abstract | Publisher Full Text OpenURL

  15. Lorenz HM, Grunke M, Hieronymus T, Herrmann M, Kuhnel A, Manger B, Kalden JR: In vitro apoptosis and expression of apoptosis-related molecules in lymphocytes from patients with systemic lupus erythematosus and other autoimmune diseases.

    Arthritis Rheum 1997, 40:306-317. PubMed Abstract | Publisher Full Text OpenURL

  16. Nath SK, Han S, Kim-Howard X, Kelly JA, Viswanathan P, Gilkeson GS, Chen W, Zhu C, McEver RP, Kimberly RP, Alarcón-Riquelme ME, Vyse TJ, Li QZ, Wakeland EK, Merrill JT, James JA, Kaufman KM, Guthridge JM, Harley JB: A nonsynonymous functional variant in integrin-alpha(M) (encoded by ITGAM) is associated with systemic lupus erythematosus.

    Nat Genet 2008, 40:152-154. PubMed Abstract | Publisher Full Text OpenURL

  17. Anaya JM, Kim-Howard X, Prahalad S, Cherñavsky A, Cañas C, Rojas-Villarraga A, Bohnsack J, Jonsson R, Bolstad AI, Brun JG, Cobb B, Moser KL, James JA, Harley JB, Nath SK: Evaluation of genetic association between an ITGAM non-synonymous SNP (rs1143679) and multiple autoimmune diseases.

    Autoimmun Rev 2012, 11:276-280. PubMed Abstract | Publisher Full Text OpenURL

  18. Han S, Kim-Howard X, Deshmukh H, Kamatani Y, Viswanathan P, Guthridge JM, Thomas K, Kaufman KM, Ojwang J, Rojas-Villarraga A, Baca V, Orozco L, Rhodes B, Choi CB, Gregersen PK, Merrill JT, James JA, Gaffney PM, Moser KL, Jacob CO, Kimberly RP, Harley JB, Bae SC, Anaya JM, Alarcón-Riquelme ME, Matsuda K, Vyse TJ, Nath SK: Evaluation of imputation-based association in and around the integrin-alpha-M (ITGAM) gene and replication of robust association between a non-synonymous functional variant within ITGAM and systemic lupus erythematosus (SLE).

    Hum Mol Genet 2009, 18:1171-1180. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  19. Hepburn AL, Mason JC, Wang S, Shepherd CJ, Florey O, Haskard DO, Davies KA: Both Fcgamma and complement receptors mediate transfer of immune complexes from erythrocytes to human macrophages under physiological flow conditions in vitro.

    Clin Exp Immunol 2006, 146:133-145. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  20. MacPherson M, Lek HS, Prescott A, Fagerholm SC: A systemic lupus erythematosus-associated R77H substitution in the CD11b chain of the Mac-1 integrin compromises leukocyte adhesion and phagocytosis.

    J Biol Chem 2011, 286:17303-17310. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  21. Karassa FB, Trikalinos TA, Ioannidis JP: The Fc gamma RIIIA-F158 allele is a risk factor for the development of lupus nephritis: a meta-analysis.

    Kidney Int 2003, 63:1475-1482. PubMed Abstract | Publisher Full Text OpenURL

  22. Brown EE, Edberg JC, Kimberly RP: Fc receptor genes and the systemic lupus erythematosus diathesis.

    Autoimmunity 2007, 40:567-581. PubMed Abstract | Publisher Full Text OpenURL

  23. Floto RA, Clatworthy MR, Heilbronn KR, Rosner DR, MacAry PA, Rankin A, Lehner PJ, Ouwehand WH, Allen JM, Watkins NA, Smith KG: Loss of function of a lupus-associated FcgammaRIIb polymorphism through exclusion from lipid rafts.

    Nat Med 2005, 11:1056-1058. PubMed Abstract | Publisher Full Text OpenURL

  24. Breunis WB, van Mirre E, Geissler J, Laddach N, Wolbink G, van der Schoot E, de Haas M, de Boer M, Roos D, Kuijpers TW: Copy number variation at the FCGR locus includes FCGR3A, FCGR2C and FCGR3B but not FCGR2A and FCGR2B.

    Hum Mutat 2009, 30:E640-E650. PubMed Abstract | Publisher Full Text OpenURL

  25. Fanciulli M, Norsworthy PJ, Petretto E, Dong R, Harper L, Kamesh L, Heward JM, Gough SC, de Smith A, Blakemore AI, Froguel P, Owen CJ, Pearce SH, Teixeira L, Guillevin L, Cunninghame Graham DS, Pusey CD, Cook HT, Vyse TJ, Aitman TJ: FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity.

    Nat Genet 2007, 39:721-723. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  26. Morris DL, Roberts AL, Witherden AS, Tarzi R, Barros P, Whittaker JC, Cook TH, Aitman TJ, Vyse TJ: Evidence for both copy number and allelic (NA1/NA2) risk at the FCGR3B locus in systemic lupus erythematosus.

    Eur J Hum Genet 2010, 18:1027-1031. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  27. Weissman AM: Themes and variations on ubiquitylation.

    Nat Rev Mol Cell Biol 2001, 2:169-178. PubMed Abstract | Publisher Full Text OpenURL

  28. Vereecke L, Beyaert R, van Loo G: Genetic relationships between A20 /TNFAIP3, chronic inflammation and autoimmune disease.

    Biochem Soc Trans 2011, 39:1086-1091. PubMed Abstract | Publisher Full Text OpenURL

  29. Sestak AL, Furnrohr BG, Harley JB, Merrill JT, Namjou B: The genetics of systemic lupus erythematosus and implications for targeted therapy.

    Ann Rheum Dis 2011, 70(Suppl 1):i37-i43. PubMed Abstract | Publisher Full Text OpenURL

  30. Beyaert R, Heyninck K, Van Huff el S: A20 and A20-binding proteins as cellular inhibitors of nuclear factor-kappa B-dependent gene expression and apoptosis.

    Biochem Pharmacol 2000, 60:1143-1151. PubMed Abstract | Publisher Full Text OpenURL

  31. Hitotsumatsu O, Ahmad RC, Tavares R, Wang M, Philpott D, Turer EE, Lee BL, Shiffin N, Advincula R, Malynn BA, Werts C, Ma A: The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals.

    Immunity 2008, 28:381-390. PubMed Abstract | Publisher Full Text OpenURL

  32. Adrianto I, Wen F, Templeton A, Wiley G, King JB, Lessard CJ, Bates JS, Hu Y, Kelly JA, Kaufman KM, Guthridge JM, Alarcón-Riquelme ME, BIOLUPUS and GENLES Networks, Anaya JM, Bae SC, Bang SY, Boackle SA, Brown EE, Petri MA, Gallant C, Ramsey-Goldman R, Reveille JD, Vila LM, Criswell LA, Edberg JC, Freedman BI, Gregersen PK, Gilkeson GS, Jacob CO, James JA, Kamen DL, et al.: Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus.

    Nat Genet 2011, 43:253-258. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  33. Deng Y, Tsao BP: Genetic susceptibility to systemic lupus erythematosus in the genomic era.

    Nat Rev Rheumatol 2010, 6:683-692. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  34. 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. PubMed Abstract | Publisher Full Text OpenURL

  35. Wertz IE, O'Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, Wu P, Wiesmann C, Baker R, Boone DL, Ma A, Koonin EV, Dixit VM: De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling.

    Nature 2004, 430:694-699. PubMed Abstract | Publisher Full Text OpenURL

  36. Kawasaki A, Ito S, Furukawa H, Hayashi T, Goto D, Matsumoto I, Kusaoi M, Ohashi J, Graham RR, Matsuta K, Behrens TW, Tohma S, Takasaki Y, Hashimoto H, Sumida T, Tsuchiya N: Association of TNFAIP3 interacting protein 1, TNIP1 with systemic lupus erythematosus in a Japanese population: a case-control association study.

    Arthritis Res Ther 2010, 12:R174. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  37. Oshima S, Turer EE, Callahan JA, Chai S, Advincula R, Barrera J, Shifrin N, Lee B, Benedict Yen TS, Woo T, Malynn BA, Ma A: ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development.

    Nature 2009, 457:906-909. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  38. 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, Gaff ney PM: Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus.

    Nat Genet 2008, 40:1059-1061. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  39. Agik S, Franek BS, Kumar AA, Kumabe M, Utset TO, Mikolaitis RA, Jolly M, Niewold TB: The autoimmune disease risk allele of UBE2L3 in African American patients with systemic lupus erythematosus: a recessive effect upon subphenotypes.

    J Rheumatol 2012, 39:73-78. PubMed Abstract | Publisher Full Text OpenURL

  40. Moynihan TP, Cole CG, Dunham I, O'Neil L, Markham AF, Robinson PA: Fine-mapping, genomic organization, and transcript analysis of the human ubiquitin-conjugating enzyme gene UBE2L3.

    Genomics 1998, 51:124-127. PubMed Abstract | Publisher Full Text OpenURL

  41. Nuber U, Schwarz S, Kaiser P, Schneider R, Scheffner M: Cloning of human ubiquitin-conjugating enzymes UbcH6 and UbcH7 (E2-F1) and characterization of their interaction with E6-AP and RSP5.

    J Biol Chem 1996, 271:2795-2800. PubMed Abstract | Publisher Full Text OpenURL

  42. Orozco G, Eyre S, Hinks A, Bowes J, Morgan AW, Wilson AG, Wordsworth P, Steer S, Hocking L, UKRAG consortium, Thomson W, Worthington J, Barton A: Study of the common genetic background for rheumatoid arthritis and systemic lupus erythematosus.

    Ann Rheum Dis 2011, 70:463-468. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  43. Chuang TH, Ulevitch RJ: Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors.

    Nat Immunol 2004, 5:495-502. PubMed Abstract | Publisher Full Text OpenURL

  44. Crispin JC, Oukka M, Bayliss G, Cohen RA, Van Beek CA, Stillman IE, Kyttaris VC, Juang YT, Tsokos GC: Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys.

    J Immunol 2008, 181:8761-8766. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  45. Zhou Y, Yuan J, Pan Y, Fei Y, Qiu X, Hu N, Luo Y, Lei W, Li Y, Long H, Sawalha AH, Richardson B, Lu Q: T cell CD40LG gene expression and the production of IgG by autologous B cells in systemic lupus erythematosus.

    Clin Immunol 2009, 132:362-370. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  46. Sullivan KE, Piliero LM, Dharia T, Goldman D, Petri MA: 3' polymorphisms of ETS1 are associated with different clinical phenotypes in SLE.

    Hum Mutat 2000, 16:49-53. PubMed Abstract | Publisher Full Text OpenURL

  47. Hu W, Sun L, Gao J, Li Y, Wang P, Cheng Y, Pan T, Han J, Liu Y, Lu W, Zuo X, Sheng Y, Yao S, He C, Yu Z, Yin X, Cui Y, Yang S, Zhang X: Down-regulated expression of IKZF1 mRNA in peripheral blood mononuclear cells from patients with systemic lupus erythematosus.

    Rheumatol Int 2011, 31:819-822. PubMed Abstract | Publisher Full Text OpenURL

  48. Yang W, Shen N, Ye DQ, Liu Q, Zhang Y, Qian XX, Hirankarn N, Ying D, Pan HF, Mok CC, Chan TM, Wong RW, Lee KW, Mok MY, Wong SN, Leung AM, Li XP, Avihingsanon Y, Wong CM, Lee TL, Ho MH, Lee PP, Chang YK, Li PH, Li RJ, Zhang L, Wong WH, Ng IO, Lau CS, Sham PC, Lau YL, Asian Lupus Genetics Consortium: Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus.

    PLoS Genet 2010, 6:e1000841. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  49. Bories JC, Willerford DM, Grevin D, Davidson L, Camus A, Martin P, Stehelin D, Alt FW: Increased T-cell apoptosis and terminal B-cell differentiation induced by inactivation of the Ets-1 proto-oncogene.

    Nature 1995, 377:635-638. PubMed Abstract | Publisher Full Text OpenURL

  50. Eyquem S, Chemin K, Fasseu M, Chopin M, Sigaux F, Cumano A, Bories JC: The development of early and mature B cells is impaired in mice defi cient for the Ets-1 transcription factor.

    Eur J Immunol 2004, 34:3187-3196. PubMed Abstract | Publisher Full Text OpenURL

  51. Wang D, John SA, Clements JL, Percy DH, Barton KP, Garrett-Sinha LA: Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease.

    Int Immunol 2005, 17:1179-1191. PubMed Abstract | Publisher Full Text OpenURL

  52. Leng RX, Pan HF, Chen GM, Feng CC, Fan YG, Ye DQ, Li XP: The dual nature of Ets-1:focus to the pathogenesis of systemic lupus erythematosus.

    Autoimmun Rev 2011, 10:439-443. PubMed Abstract | Publisher Full Text OpenURL

  53. Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z, Xu JH, Cai ZM, Huang W, Zhao GP, Xie HF, Fang H, Lu QJ, Xu JH, Li XP, Pan YF, Deng DQ, Zeng FQ, Ye ZZ, Zhang XY, Wang QW, Hao F, Ma L, Zuo XB, Zhou FS, Du WH, Cheng YL, Yang JQ, Shen SK, Li J, et al.: Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus.

    Nat Genet 2009, 41:1234-1237. PubMed Abstract | Publisher Full Text OpenURL

  54. Yap WH, Yeoh E, Tay A, Brenner S, Venkatesh B: STAT4 is a target of the hematopoietic zinc-finger transcription factor Ikaros in T cells.

    FEBS Lett 2005, 579:4470-4478. PubMed Abstract | Publisher Full Text OpenURL

  55. Georgopoulos K, Bigby M, Wang JH, Molnar A, Wu P, Winandy S, Sharpe A: The Ikaros gene is required for the development of all lymphoid lineages.

    Cell 1994, 79:143-156. PubMed Abstract | Publisher Full Text OpenURL

  56. Wojcik H, Griffiths E, Staggs S, Hagman J, Winandy S: Expression of a non-DNA-binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis.

    Eur J Immunol 2007, 37:1022-1032. PubMed Abstract | Publisher Full Text OpenURL

  57. Sanz I, Lee FE: B cells as therapeutic targets in SLE.

    Nat Rev Rheumatol 2010, 6:326-337. PubMed Abstract | Publisher Full Text OpenURL

  58. Ramos PS, Williams AH, Ziegler JT, Comeau ME, Guy RT, Lessard CJ, Li H, Edberg JC, Zidovetzki R, Criswell LA, Gaffney PM, Cunninghame Graham DS, Graham RR, Kelly JA, Kaufman KM, Brown EE, Alarcón GS, Petri MA, Reveille JD, McGwin G, Vilá LM, Ramsey-Goldman R, Jacob CO, Vyse TJ, Tsao BP, Harley JB, Kimberly RP, Alarcón-Riquelme ME, Langefeld CD, Moser KL: Genetic analyses of interferon pathway-related genes reveal multiple new loci associated with systemic lupus erythematosus.

    Arthritis Rheum 2011, 63:2049-2057. PubMed Abstract | Publisher Full Text OpenURL

  59. Kozyrev SV, Abelson AK, Wojcik J, Zaghlool A, Linga Reddy MV, Sanchez E, Gunnarsson I, Svenungsson E, Sturfelt G, Jönsen A, Truedsson L, Pons-Estel BA, Witte T, D'Alfonso S, Barizzone N, Danieli MG, Gutierrez C, Suarez A, Junker P, Laustrup H, González-Escribano MF, Martin J, Abderrahim H, Alarcón-Riquelme ME: Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus.

    Nat Genet 2008, 40:211-216. PubMed Abstract | Publisher Full Text OpenURL

  60. Yokoyama K, Su I, Tezuka T, Yasuda T, Mikoshiba K, Tarakhovsky A, Yamamoto T: BANK regulates BCR-induced calcium mobilization by promoting tyrosine phosphorylation of IP(3) receptor.

    EMBO J 2002, 21:83-92. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  61. Castillejo-López C, Delgado-Vega AM, Wojcik J, Kozyrev SV, Thavathiru E, Wu YY, Sánchez E, Pöllmann D, López-Egido JR, Fineschi S, Domínguez N, Lu R, James JA, Merrill JT, Kelly JA, Kaufman KM, Moser KL, Gilkeson G, Frostegård J, Pons-Estel BA, D'Alfonso S, Witte T, Callejas JL, Harley JB, Gaffney PM, Martin J, Guthridge JM, Alarcón-Riquelme ME: Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK.

    Ann Rheum Dis 2012, 71:136-142. PubMed Abstract | Publisher Full Text OpenURL

  62. Huck S, Le CR, Youinou P, Zouali M: Expression of B cell receptor-associated signaling molecules in human lupus.

    Autoimmunity 2001, 33:213-224. PubMed Abstract | Publisher Full Text OpenURL

  63. Xu Y, Beavitt SJ, Harder KW, Hibbs ML, Tarlinton DM: The activation and subsequent regulatory roles of Lyn and CD19 after B cell receptor ligation are independent.

    J Immunol 2002, 169:6910-6918. PubMed Abstract | Publisher Full Text OpenURL

  64. Lu R, Vidal GS, Kelly JA, Delgado-Vega AM, Howard XK, Macwana SR, Dominguez N, Klein W, Burrell C, Harley IT, Kaufman KM, Bruner GR, Moser KL, Gaffney PM, Gilkeson GS, Wakeland EK, Li QZ, Langefeld CD, Marion MC, Divers J, Alarcón GS, Brown EE, Kimberly RP, Edberg JC, Ramsey-Goldman R, Reveille JD, McGwin G Jr, Vilá LM, Petri MA, Bae SC, et al.: Genetic associations of LYN with systemic lupus erythematosus.

    Genes Immun 2009, 10:397-403. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  65. Hibbs ML, Tarlinton DM, Armes J, Grail D, Hodgson G, Maglitto R, Stacker SA, Dunn AR: Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease.

    Cell 1995, 83:301-311. PubMed Abstract | Publisher Full Text OpenURL

  66. Fan Y, Tao JH, Zhang LP, Li LH, Ye DQ: Association of BLK (rs13277113, rs2248932) polymorphism with systemic lupus erythematosus: a metaanalysis.

    Mol Biol Rep 2011, 38:4445-4453. PubMed Abstract | Publisher Full Text OpenURL

  67. Texido G, Su IH, Mecklenbrauker I, Saijo K, Malek SN, Desiderio S, Rajewsky K, Tarakhovsky A: The B-cell-specific Src-family kinase Blk is dispensable for B-cell development and activation.

    Mol Cell Biol 2000, 20:1227-1233. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  68. Stone JC: Regulation of Ras in lymphocytes: get a GRP.

    Biochem Soc Trans 2006, 34:858-861. PubMed Abstract | Publisher Full Text OpenURL

  69. Cunninghame Graham DS, Morris DL, Bhangale TR, Criswell LA, Syvanen AC, Ronnblom L, Behrens TW, Graham RR, Vyse TJ: Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with systemic lupus erythematosus.

    PLoS Genet 2011, 7:e1002341. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  70. Liossis SN, Hoffman RW, Tsokos GC: Abnormal early TCR/CD3-mediated signaling events of a snRNP-autoreactive lupus T cell clone.

    Clin Immunol Immunopathol 1998, 88:305-310. PubMed Abstract | Publisher Full Text OpenURL

  71. Sawla P, Hossain A, Hahn BH, Singh RP: Regulatory T cells in systemic lupus erythematosus (SLE); Role of peptide tolerance.

    Autoimmun Rev 2011, in press. OpenURL

  72. Suárez A, López P, Gómez J, Gutiérrez C: Enrichment of CD4+ CD25high T cell population in patients with systemic lupus erythematosus treated with glucocorticoids.

    Ann Rheum Dis 2006, 65:1512-1517. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  73. Lin SC, Chen KH, Lin CH, Kuo CC, Ling QD, Chan CH: The quantitative analysis of peripheral blood FOXP3-expressing T cells in systemic lupus erythematosus and rheumatoid arthritis patients.

    Eur J Clin Invest 2007, 37:987-996. PubMed Abstract | Publisher Full Text OpenURL

  74. 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. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  75. Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O'Shea JJ: Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4.

    Immunol Rev 2004, 202:139-156. PubMed Abstract | Publisher Full Text OpenURL

  76. Farrar JD, Smith JD, Murphy TL, Leung S, Stark GR, Murphy KM: Selective loss of type I interferon-induced STAT4 activation caused by a minisatellite insertion in mouse Stat2.

    Nat Immunol 2000, 1:65-69. PubMed Abstract | Publisher Full Text OpenURL

  77. Morinobu A, Gadina M, Strober W, Visconti R, Fornace A, Montagna C, Feldman GM, Nishikomori R, O'Shea JJ: STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation.

    Proc Natl Acad Sci USA 2002, 99:12281-12286. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  78. Korman BD, Alba MI, Le JM, Alevizos I, Smith JA, Nikolov NP, Kastner DL, Remmers EF, Illei GG: Variant form of STAT4 is associated with primary Sjogren's syndrome.

    Genes Immun 2008, 9:267-270. PubMed Abstract | Publisher Full Text OpenURL

  79. Martínez A, Varadé J, Márquez A, Cénit MC, Espino L, Perdigones N, Santiago JL, Fernández-Arquero M, de la Calle H, Arroyo R, Mendoza JL, Fernández-Gutiérrez B, de la Concha EG, Urcelay E: Association of the STAT4 gene with increased susceptibility for some immune-mediated diseases.

    Arthritis Rheum 2008, 58:2598-2602. PubMed Abstract | Publisher Full Text OpenURL

  80. Kawasaki A, Ito I, Hikami K, Ohashi J, Hayashi T, Goto D, Matsumoto I, Ito S, Tsutsumi A, Koga M, Arinami T, Graham RR, Hom G, Takasaki Y, Hashimoto H, Behrens TW, Sumida T, Tsuchiya N: Role of STAT4 polymorphisms in systemic lupus erythematosus in a Japanese population: a case-control association study of the STAT1-STAT4 region.

    Arthritis Res Ther 2008, 10:R113. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  81. Li P, Cao C, Luan H, Li C, Hu C, Zhang S, Zeng X, Zhang F, Zeng C, Li Y: Association of genetic variations in the STAT4 and IRF7/KIAA1542 regions with systemic lupus erythematosus in a Northern Han Chinese population.

    Hum Immunol 2011, 72:249-255. PubMed Abstract | Publisher Full Text OpenURL

  82. Sigurdsson S, Nordmark G, Garnier S, Grundberg E, Kwan T, Nilsson O, Eloranta ML, Gunnarsson I, Svenungsson E, Sturfelt G, Bengtsson AA, Jönsen A, Truedsson L, Rantapää-Dahlqvist S, Eriksson C, Alm G, Göring HH, Pastinen T, Syvänen 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. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  83. Aksoy R, Duman T, Keskin O, Duzgun N: No association of PTPN22 R620 W gene polymorphism with rheumatic heart disease and systemic lupus erythematosus.

    Mol Biol Rep 2011, 38:5393-5396. PubMed Abstract | Publisher Full Text OpenURL

  84. Criswell LA, Pfeiffer KA, Lum RF, Gonzales B, Novitzke J, Kern M, Moser KL, Begovich AB, Carlton VE, Li W, Lee AT, Ortmann W, Behrens TW, Gregersen PK: Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes.

    Am J Hum Genet 2005, 76:561-571. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  85. Lea WW, Lee YH: The association between the PTPN22 C1858T polymorphism and systemic lupus erythematosus: a meta-analysis update.

    Lupus 2011, 20:51-57. PubMed Abstract | Publisher Full Text OpenURL

  86. Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, Ardlie KG, Huang Q, Smith AM, Spoerke JM, Conn MT, Chang M, Chang SY, Saiki RK, Catanese JJ, Leong DU, Garcia VE, McAllister LB, Jeff ery DA, Lee AT, Batliwalla F, Remmers E, Criswell LA, Seldin MF, Kastner DL, Amos CI, Sninsky JJ, Gregersen PK: A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis.

    Am J Hum Genet 2004, 75:330-337. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  87. Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, MacMurray J, Meloni GF, Lucarelli P, Pellecchia M, Eisenbarth GS, Comings D, Mustelin T: A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.

    Nat Genet 2004, 36:337-338. PubMed Abstract | Publisher Full Text OpenURL

  88. Vang T, Congia M, Macis MD, Musumeci L, Orrú V, Zavattari P, Nika K, Tautz L, Taskén K, Cucca F, Mustelin T, Bottini N: Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant.

    Nat Genet 2005, 37:1317-1319. PubMed Abstract | Publisher Full Text OpenURL

  89. Gourh P, Arnett FC, Tan FK, Assassi S, Divecha D, Paz G, McNearney T, Draeger H, Reveille JD, Mayes MD, Agarwal SK: Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis.

    Ann Rheum Dis 2010, 69:550-555. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  90. Cunninghame Graham DS, Graham RR, Manku H, Wong AK, Whittaker JC, Gaffney PM, Moser KL, Rioux JD, Altshuler D, Behrens TW, Vyse TJ: Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus.

    Nat Genet 2008, 40:83-89. PubMed Abstract | Publisher Full Text OpenURL

  91. Chang YK, Yang W, Zhao M, Mok CC, Chan TM, Wong RW, Lee KW, Mok MY, Wong SN, Ng IO, Lee TL, Ho MH, Lee PP, Wong WH, Lau CS, Sham PC, Lau YL: Association of BANK1 and TNFSF4 with systemic lupus erythematosus in Hong Kong Chinese.

    Genes Immun 2009, 10:414-420. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  92. Gramaglia I, Jember A, Pippig SD, Weinberg AD, Killeen N, Croft M: The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion.

    J Immunol 2000, 165:3043-3050. PubMed Abstract | Publisher Full Text OpenURL

  93. Farres MN, Al-Zifzaf DS, Aly AA, Abd Raboh NM: OX40/OX40L in systemic lupus erythematosus: association with disease activity and lupus nephritis.

    Ann Saudi Med 2011, 31:29-34. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  94. Fernando MM, Stevens CR, Sabeti PC, Walsh EC, McWhinnie AJ, Shah A, Green T, Rioux JD, Vyse TJ: Identification of two independent risk factors for lupus within the MHC in United Kingdom families.

    PLoS Genet 2007, 3:e192. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  95. International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN), Harley JB, Alarcón-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, Tsao BP, Vyse TJ, Langefeld CD, Nath SK, Guthridge JM, Cobb BL, Mirel DB, Marion MC, Williams AH, Divers J, Wang W, Frank SG, Namjou B, Gabriel SB, Lee AT, Gregersen PK, Behrens TW, Taylor KE, Fernando M, Zidovetzki R, Gaffney PM, Edberg JC, Rioux JD, Ojwang JO, et al.: 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. PubMed Abstract | Publisher Full Text OpenURL

  96. Fernando MM, Freudenberg J, Lee A, Morris DL, Boteva L, Rhodes B, Gonzalez-Escribano MF, Lopez-Nevot MA, Navarra SV, Gregersen PK, Martin J, IMAGEN, Vyse TJ: Transancestral mapping of the MHC region in systemic lupus erythematosus identifies new independent and interacting loci at MSH5, HLA-DPB1 and HLA-G.

    Ann Rheum Dis 2012, 71:777-784. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  97. 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. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  98. Ronnblom L: The type I interferon system in the etiopathogenesis of autoimmune diseases.

    Ups J Med Sci 2011, 116:227-237. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  99. Salloum R, Niewold TB: Interferon regulatory factors in human lupus pathogenesis.

    Transl Res 2011, 157:326-331. PubMed Abstract | Publisher Full Text OpenURL

  100. Feng D, Stone RC, Eloranta ML, Sangster-Guity N, Nordmark G, Sigurdsson S, Wang C, Alm G, Syvänen AC, Rönnblom L, Barnes BJ: Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus.

    Arthritis Rheum 2010, 62:562-573. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  101. Cunninghame Graham DS, Manku H, Wagner S, Reid J, Timms K, Gutin A, Lanchbury JS, Vyse TJ: Association of IRF5 in UK SLE families identifi es a variant involved in polyadenylation.

    Hum Mol Genet 2007, 16:579-591. PubMed Abstract | Publisher Full Text OpenURL

  102. Robinson T, Kariuki SN, Franek BS, Kumabe M, Kumar AA, Badaracco M, Mikolaitis RA, Guerrero G, Utset TO, Drevlow BE, Zaacks LS, Grober JS, Cohen LM, Kirou KA, Crow MK, Jolly M, Niewold TB: Autoimmune disease risk variant of IFIH1 is associated with increased sensitivity to IFN-alpha and serologic autoimmunity in lupus patients.

    J Immunol 2011, 187:1298-1303. PubMed Abstract | Publisher Full Text OpenURL

  103. Smyth DJ, Cooper JD, Bailey R, Field S, Burren O, Smink LJ, Guja C, Ionescu-Tirgoviste C, Widmer B, Dunger DB, Savage DA, Walker NM, Clayton DG, Todd JA: A genome-wide association study of nonsynonymous SNPs identifi es a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region.

    Nat Genet 2006, 38:617-619. PubMed Abstract | Publisher Full Text OpenURL

  104. Sutherland A, Davies J, Owen CJ, Vaikkakara S, Walker C, Cheetham TD, James RA, Perros P, Donaldson PT, Cordell HJ, Quinton R, Pearce SH: Genomic polymorphism at the interferon-induced helicase (IFIH1) locus contributes to Graves' disease susceptibility.

    J Clin Endocrinol Metab 2007, 92:3338-3341. PubMed Abstract | Publisher Full Text OpenURL

  105. Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2, Strange A, Capon F, Spencer CC, Knight J, Weale ME, Allen MH, Barton A, Band G, Bellenguez C, Bergboer JG, Blackwell JM, Bramon E, Bumpstead SJ, Casas JP, Cork MJ, Corvin A, Deloukas P, Dilthey A, Duncanson A, Edkins S, Estivill X, Fitzgerald O, Freeman C, Giardina E, Gray E, Hofer A, Hüffmeier U, Hunt SE, Irvine AD, Jankowski J, et al.: A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.

    Nat Genet 2010, 42:985-990. PubMed Abstract | Publisher Full Text OpenURL

  106. Järvinen TM, Hellquist A, Koskenmies S, Einarsdottir E, Koskinen LL, Jeskanen L, Berglind L, Panelius J, Hasan T, Ranki A, Kere J, Saarialho-Kere U: Tyrosine kinase 2 and interferon regulatory factor 5 polymorphisms are associated with discoid and subacute cutaneous lupus erythematosus.

    Exp Dermatol 2010, 19:123-131. PubMed Abstract | Publisher Full Text OpenURL

  107. Ishizaki M, Akimoto T, Muromoto R, Yokoyama M, Ohshiro Y, Sekine Y, Maeda H, Shimoda K, Oritani K, Matsuda T: Involvement of tyrosine kinase-2 in both the IL-12/Th1 and IL-23/Th17 axes in vivo.

    J Immunol 2011, 187:181-189. PubMed Abstract | Publisher Full Text OpenURL

  108. Tao JH, Zou YF, Feng XL, Li J, Wang F, Pan FM, Ye DQ: Meta-analysis of TYK2 gene polymorphisms association with susceptibility to autoimmune and infl ammatory diseases.

    Mol Biol Rep 2011, 38:4663-4672. PubMed Abstract | Publisher Full Text OpenURL

  109. Zhou XJ, Lu XL, Lv JC, Yang HZ, Qin LX, Zhao MH, Su Y, Li ZG, Zhang H: Genetic association of PRDM1-ATG5 intergenic region and autophagy with systemic lupus erythematosus in a Chinese population.

    Ann Rheum Dis 2011, 70:1330-1337. PubMed Abstract | Publisher Full Text OpenURL

  110. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N: The role of autophagy during the early neonatal starvation period.

    Nature 2004, 432:1032-1036. PubMed Abstract | Publisher Full Text OpenURL

  111. Garaud JC, Schickel JN, Blaison G, Knapp AM, Dembele D, Ruer-Laventie J, Korganow AS, Martin T, Soulas-Sprauel P, Pasquali JL: B cell signature during inactive systemic lupus is heterogeneous: toward a biological dissection of lupus.

    PLoS One 2011, 6:e23900. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  112. Kim SJ, Zou YR, Goldstein J, Reizis B, Diamond B: Tolerogenic function of Blimp-1 in dendritic cells.

    J Exp Med 2011, 208:2193-2199. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  113. Lessard CJ, Adrianto I, Kelly JA, Kaufman KM, Grundahl KM, Adler A, Williams AH, Gallant CJ, Marta E, Alarcón-Riquelme on behalf of the BIOLUPUS and GENLES Networks, Anaya JM, Bae SC, Boackle SA, Brown EE, Chang DM, Criswell LA, Edberg JC, Freedman BI, Gregersen PK, Gilkeson GS, Jacob CO, James JA, Kamen DL, Kimberly RP, Martin J, Merrill JT, Niewold TB, Park SY, Petri MA, Pons-Estel BA, et al.: Identification of a systemic lupus erythematosus susceptibility locus at 11p13 between PDHX and CD44 in a multiethnic study.

    Am J Hum Genet 2011, 88:83-91. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL