Sei sulla pagina 1di 13

REVIEWS

REVIEWS Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis Chandra Mohan and Chaim Putterman

Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis

Chandra Mohan and Chaim Putterman

Abstract | Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder that has a broad spectrum of effects on the majority of organs, including the kidneys. Approximately 40–70% of patients with SLE will develop lupus nephritis. Renal assault during SLE is initiated by genes that breach immune tolerance and promote autoantibody production. These genes might act in concert with other genetic factors that augment innate immune signalling and IFN-I production, which in turn can generate an influx of effector leucocytes, inflammatory mediators and autoantibodies into end organs, such as the kidneys. The presence of cognate antigens in the glomerular matrix, together with intrinsic molecular abnormalities in resident renal cells, might further accentuate disease progression. This Review discusses the genetic insights and molecular mechanisms for key pathogenic contributors in SLE and lupus nephritis. We have categorized the genes identified in human studies of SLE into one of four pathogenic events that lead to lupus nephritis. We selected these categories on the basis of the cell types in which these genes are expressed, and the emerging paradigms of SLE pathogenesis arising from murine models. Deciphering the molecular basis of SLE and/or lupus nephritis in each patient will help physicians to tailor specific therapies.

Mohan, C. & Putterman, C. Nat. Rev. Nephrol. 11, 329–341 (2015); published online 31 March 2015; doi:10.1038/nrneph.2015.33

Department of Bioengineering, University of Houston, 3605 Cullen Boulevard, Houston, TX 77204, USA (C.M.). Division of Rheumatology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA (C.P.).

Correspondence to:

C.M.

cmohan@

central.uh.edu

Introduction

Systemic lupus erythematosus (SLE) is a chronic auto­ immune inflammatory disease that can affect the major­ ity of organs and tissues. The clinical presentations of SLE can range from mild to severe and the course of the disease is unpredictable, with periods of remission and flares. Lupus nephritis is a severe consequence of SLE and an important driver of morbidity and mortality in SLE. Lupus nephritis affects ~40–70% of patients with SLE, with the exact incidence dependent on ethnicity, age group, and gender. Both systemic and intra­renal events are important in the pathogenesis of lupus nephritis. 14 At the systemic level, both the adaptive and innate branches of the immune system contribute to the devel­ opment of SLE. The two predominant cell types involved in the adaptive immune system, B lymphocytes (B cells) and T lymphocytes (T cells), are both essential for the development of lupus nephritis. 26 B cells are pathogenic in SLE because of the autoantibodies (for example, anti­ DNA antibodies and anti­nucleosome antibodies) and cytokines that they produce. 7,8 T cells drive the systemic and intra­renal activation of B cells. Subtypes of T cells, including type 1 T­helper (T H 1) cells, type 17 T­helper (T H 17) cells, and CD3 + CD4 CD8 ‘double negative’ T H cells, have been implicated in the pathogenesis of lupus nephritis. 911 The innate immune system contrib­ utes to the pathogenesis of SLE in multiple ways. In the early stages of disease, dendritic and other myeloid cells

Competing interests The authors declare no competing interests.

activate T cells, and produce key mediators such as B­cell activating factor; this effect results in the activation of the adaptive immune system. 1214 Activation of the sys­ temic immune system leads to the generation of effec­ tor T cells and autoantibodies that can subsequently target organs, such as the kidneys. 13,15,16 These effectors, together with numerous soluble mediators, elicit chronic inflammation within glomerular and tubulointerstitial sites in the kidneys. By contrast, the contribution of intrinsic renal cells versus systemic leucocytes in the pathogenesis of lupus nephritis is poorly understood. Detailed reports describing the systemic and intra­renal events in the pathogenesis of lupus nephritis have been reviewed elsewhere. 6,13,1520 The present Review categorizes the genes implicated in SLE according to the cell types and molecular path­ ways in which they are expressed, to gain insight into the key pathogenic contributors that lead to lupus nephritis. We first introduce the methods by which novel genetic loci have been identified and the functional studies performed to characterize candidate genes. Next, we discuss the genes that are implicated in the activation of the adaptive and innate immune systems, as well as those that are involved in the intra­renal processes that promote tissue damage. We conclude by discussing the potential molecules that might affect the amount of accessible chromatin that is generated from apoptotic cells. While the organization of SLE and lupus nephri­ tis candidate genes into these particular pathways is not fixed and alternate classification schemes might also be

NATURE REVIEWS | NEPHROLOGY

nrneph

2015.33_JUN15.indd

329

VOLUME 11 | JUNE 2015 | 329

12/05/2015

16:08

REVIEWS Key points ■ Some genes implicated in systemic lupus erythematosus (SLE) and lupus nephritis

REVIEWS

Key points

Some genes implicated in systemic lupus erythematosus (SLE) and lupus nephritis might contribute to the pathology of disease by breaching immune tolerance and promoting autoantibody production

A subset of SLE and/or lupus nephritis genes might augment innate immune signalling and IFN-I production; other SLE genes might modulate the molecular pathways that lead to renal tissue damage

Genes that affect the accessibility and handling of apoptotic material and chromatin might also contribute to SLE and/or lupus nephritis

The presence of cognate antigens on the glomerular matrix, together with intrinsic molecular abnormalities in resident renal cells, could further accentuate disease progression in lupus nephritis

Differential involvement of the above-listed mechanisms in patients could potentially explain the wide spectrum of clinical phenotypes observed among individuals with SLE and lupus nephritis

suitable, we find the following categories to be a useful framework for understanding the genetic contributions to SLE and lupus nephritis.

Gene discovery

Genome-wide association studies

Genome­wide association studies (GWAS) that aimed to identify genetic loci linked with SLE were initiated more than 6 years ago. 1721 Thus far, >10 GWAS have been con­ ducted using samples obtained from patients with SLE that encompass multiple ethnic groups, and have collec­ tively identified >50 genes associated with SLE. Although the focus of these GWAS has not been exclusive to lupus nephritis, the inclusion of patients with lupus nephritis in these studies has provided important insights into the potential pathogenic pathways that lead to both SLE and lupus nephritis. Several genes identified from GWAS and additional candidate genes have been validated in independent patient cohorts as being associated with SLE or lupus nephritis. Table 1 lists some of the key genes that have been implicated in the pathogenesis of SLE and/or lupus nephritis; this list is not exhaustive and additional studies are ongoing.

Genetic aberrations implicated in SLE

Although numerous genes have been implicated in SLE and/or lupus nephritis (Table 1), questions remain as to their function in disease pathology. Firstly, the spe­ cific causative mutations and subsequent molecular alterations that contribute to the disease phenotype have not been firmly established for many of the identi­ fied candidate genes. Coding region single nucleotide polymorphisms (SNPs), polymorphisms that lead to differential alternative splicing, polymorphisms in the 3' untranslated region (UTR) that influence gene expres­ sion, and copy number variants (CNVs) have all been documented. This catalogue of implicated molecular variations in each gene is likely to expand as more infor­ mation becomes available from deep sequencing studies that are currently in progress. Secondly, the association between these candidate genes and SLE or lupus nephri­ tis has only been inferred from studies using murine models that have been engineered to either lack or overexpress the gene (using knockouts or transgenics,

respectively); some of these associations have been reviewed elsewhere. 22 Additional murine models should be generated that mimic more closely the type of genetic mutations that are observed among human patients with SLE and lupus nephritis; these specific mutations (SNPs, CNVs and splice isoforms) should be subsequently validated for their ability to promote SLE in genetically engineered murine models.

Categorizing genes implicated in SLE

The identified genes implicated in SLE can be assigned to one of four functional categories: genes that affect lym­ phocyte activation, particularly B cells; genes that affect innate immune signalling, notably NF­κB activation and IFN­I signalling; genes that might function within the kidneys, potentially promoting renal tissue damage; and genes that influence the handling of apoptotic debris, chromatin, and immune complexes bearing these anti­ gens. These categories have been designated on the basis of a priori information regarding the cell types in which the identified genes are expressed and their known molecular function; however, alternative pathways and models cannot be excluded.

Genetic composition of SLE and lupus nephritis

Although a given patient might harbour mutations in multiple genes from a given functional category, whether the inheritance of one or more genes from each category proposed above is required for the development of SLE and/or lupus nephritis is unclear. Murine models of SLE and/or lupus nephritis have been insightful in this respect as genes from all four categories have been implicated through both forward and reverse genetic approaches. 2326 Congenic dissection (where multiple genes mediating a polygenic disease are separated into a collection of congenic strains) and congenic reconstitu­ tion studies (involving genetic crossing of each separate congenic strain) of SLE­associated polymorphic vari­ ants have generated three main findings. Firstly, genes

that only affect lymphocyte function might lead to the production of antinuclear antibodies or IgM polyreac­ tivity but not lupus nephritis, suggesting that simply the presence of these antibodies is not sufficient for renal pathology to ensue. Secondly, genes that activate innate immune signalling in isolation might result in the pro­ duction of intermediate levels of anti­DNA antibodies (compared to polygenic strains with complete SLE) and non­proliferative glomerulonephritis. Finally, the epi­ static interaction between genes from multiple categories

is required for severe lupus nephritis to develop. 2730 The

emerging concept of genetic interaction is exemplified by

a series of congenic dissection and reconstitution studies that have been performed using the C57Bl/6 (B6) mouse strain, as illustrated in Figure 1. 27,2932 Through extrapolation of the genetic data obtained from murine congenic dissection and reconstitution studies, it could be predicted that genes from mul­ tiple functional categories would act in concert to promote lupus nephritis in human patients. Although

it is apparent which functional pathways the majority of

330 | JUNE 2015 | VOLUME 11

nrneph

2015.33_JUN15.indd

330

www.nature.com/nrneph

12/05/2015

16:08

Table 1 | Susceptibility genes implicated in human SLE or LN*

 

Gene name

Association with SLE

Association with LN

Lymphocyte signalling

BANK1

Yes 168170

Unknown

BLK

Yes 169175

Yes 70

CD80

Yes 63

Unknown

CSK

Yes 50

Unknown

ETS1

Yes 169,172,174,175

Unknown

HLA DR

Yes 58,59,174

Yes 70,71

IL-10

Yes 176,177

Unknown

LYN

Yes 178

Unknown

PP2A

Yes 74

Unknown

PRDM1 (BLIMP1)

Yes 177,179

Unknown

PRKCB

Yes 180

Unknown

PTPN22

Yes 51,53,181183

Unknown

RasGRP3

Yes 172,184

Unknown

STAT4

Yes 170,172,174,175,185,186

Yes 70,72

TNFSF4 (OX40L)

Yes 169,170,172,175,187

Yes 76,77

Innate immune signalling

IFIH1

Yes 188,189

Unknown

IKZF1

Yes 172,175,189,190

Yes 81

ILT3

Yes 24

Unknown

IRAK1

Yes 107,191,192

Unknown

IRF5

Yes 23,169,172,175,193–196

Yes 70,83

IRF7

Yes 197,198

Unknown

IRF8

Yes 189,199,200

Unknown

TLR7

Yes 201,202

Unknown

TLR9

Yes 203

Yes 87

TNFAIP3 (A20)

Yes 21,169,172,174,175,204

Yes 101

TNIP3 (ABIN3)

Yes 172,177

Yes 94

TYK2

Yes 161,189

Unknown

UBE2L3

Yes 205,206

Unknown

Intra-renal signalling

ACE

Yes 125

Yes 125

COL25A1

Yes 126

Unknown

KLK

Yes 127

Yes 127

LAMC2

Yes 126

Unknown

Immune complex clearance

ATG5

Yes 179

Unknown

DNAse1

Yes 207

Unknown

FCGR2A, 3A, 3B

Yes 95100,170,186

Yes 96

ITGAM

Yes 170,186,208–210

Yes 77,102,106

TREX1

Yes 211

Unknown

*Susceptibility genes implicated in SLE or LN have been functionally organized into four pathogenic cascades. Additional genes associated with SLE have not been listed but are reviewed elsewhere. 25 Abbreviations: LN, lupus nephritis; SLE, systemic lupus erythematosus.

SLE­associated genes are most likely to impact, for some genes the functional pathway is unclear. For example, complement genes and proteins could potentially exert effects on several pathways, including chromatin handling and B­cell activation.

REVIEWS

Adaptive immune system activation

Modulation of B-cell receptor signalling

T cells, B cells and autoantibodies have been shown to

have an essential function in lupus nephritis, with the majority of the evidence originating from mechanistic studies performed in mice. 1,1720 A conglomerate of SLE­ associated genes collectively regulates B­cell signalling via the B­cell receptor, BCR (Figure 2). BANK1 is a scaffold adaptor protein primarily expressed in B cells that amplifies B­cell signalling by linking the activa­ tion of Src­family kinases, such as LYN, with the acti­ vation of the IP3 receptor, leading to calcium influx. Stimulation of BCR facilitates the association of BANK1 with PLCγ2, resulting in PLCγ2 activation, expression

of IP3 and DAG, and subsequent activation of PRKCB,

another gene implicated in SLE. 3336 RasGRP3—one of the downstream molecules acti­

vated by the BCR pathway—has also been implicated

in SLE (Figure 2). RasGRP3 amplifies downstream Ras­

mediated ERK and MAPK signalling in B cells, and is

associated with B­cell proliferation and antibody pro­ duction. PRKCB and RasGRP3 are expressed in B cells,

T cells, myeloid cells, and endothelial cells, and thus

could contribute to the progression of SLE through

several different pathways. 3741 Although genetic manip­ ulation studies of Bank1 and Rasgrp3 are yet to be pub­ lished, the available data suggest that PRKCB might be necessary for the development of SLE and lupus nephritis

in mice. 42

Src-family tyrosine kinases

Three SLE­associated B­cell genes, LYN, BLK and CSK, are Src­family tyrosine kinases that might have direct or indirect inhibitory roles on BCR signalling. 4246 The fact that Lyn­deficient mice develop B­cell hyperactivity with associated autoimmunity is well documented. 4446 The inhibitory effect of LYN on B­cell signalling is mediated

in part by phosphorylation and subsequent activation

of the inhibitory B­cell surface receptors, CD22 and

FcGR2B. The CD22 and FcGR2B receptors function through SHIP and SHP­1 phosphatases and dampen B­cell activation as a consequence. 43 One function of BLK is to promote the interaction between BANK1 and PLCγ2 (Figure 2). Reduced

expression of BLK is associated with reduced numbers

of pre­B cells and marginal zone B cells. Reduced expres­

sion of BLK can also promote renal disease in B6 mice

that are prone to SLE. 47,48

The third Src­family kinase, CSK, can phosphory­ late and regulate LYN. 49 Overexpression of CSK is observed among patients with SLE that carry the CSK risk allele, and leads to increased phosphorylation of LYN; this effect is associated with elevated production

of antibodies and transitional B cells. 50

PTPN22

PTPN22 has been implicated in several autoimmune diseases, including SLE, and the effect of a disease­ associated variant of Ptpn22 on systemic autoimmun­ ity has been verified using murine models. 51 PTPN22

ity has been verified using murine models. 5 1 PTPN22 NATURE REVIEWS | NEPHROLOGY nrneph 2015.33_JUN15.indd

NATURE REVIEWS | NEPHROLOGY

nrneph

2015.33_JUN15.indd

331

VOLUME 11 | JUNE 2015 | 331

12/05/2015

16:08

REVIEWS Wild-type C57Bl/6 a Gene 1 e.g. Ly108 Adaptive immunity Ly108 Gene 2 e.g. Sle3

REVIEWS

Wild-type

C57Bl/6

a

Gene 1

e.g. Ly108

Adaptive

immunity

Ly108

Gene 2

e.g. Sle3

b

Innate

immunity

Ly108

Sle3

Gene 3

e.g. Klk

c

End-organ

disease

Ly108

Sle3

Klk

Figure 1 | Stepwise evolution of systemic lupus erythematosus (SLE) as a function of genetic load. The schematic depicts how genetic dissection studies in the mouse have been used to investigate the evolution and pathology of SLE. 27,2931 The genetic intervals Sle1 and Sle3 were initially mapped in the NZM2410 lupus-prone strain, and subsequently bred to the C57Bl/6 (B6) background as congenic intervals. These genetic dissection studies demonstrated that genes associated with SLE might contribute to disease pathogenesis in multiple ways, including breaching lymphocyte tolerance, activating innate immunity and regulating inflammation within the end organs. a | Ly108, identified as a culprit gene within the Sle1 genetic interval, was introgressed onto the C57Bl/6 background, resulting in activation of the adaptive immune system. b | The addition of the Sle3 genetic interval, which activates innate immunity, results in robust autoimmune phenotypes in the bicongenic strain. c | Finally, the presence of genes (for example, Klk) that regulate function in the end-organs, such as the kidneys, leads to fully developed SLE.

regulates CSK and can modulate the BCR and T­cell receptor signalling threshold and downstream activa­ tion of AKT in both B cells and T cells. 3236,42 In addition to activating B cells, PTPN22 also modulates the extent of the regulatory T (T REG ) cell pool, and affects myeloid cell­signalling. 5255 Specifically, the numbers of thymic and T REG cells vary inversely with the levels of PTPN22, 54 whereas PTPN22 deficiency reduces IFN­I production and augments inflammation. 55 At present, it is not fully understood how LYN, BLK, CSK and PTPN22 interact to fine­tune BCR signalling, or how SNPs in various genes within this axis might impact the overall strength of the signalling cascade. Given that SNPs in all of the above genes can modulate the extent of BCR signalling, it would be interesting to determine whether an increasing number of genetic hits in this pathway confer increased risk for SLE or lupus nephritis; data to support this concept are currently lacking.

Interaction of BCRs with Toll-like receptors

Interaction between the signalling pathways triggered by the BCR and Toll­like receptors (TLRs) can serve to amplify B­cell signalling. SLE autoantigens, such as DNA and RNA, can also bind to TLRs such as TLR9 and TLR7. 56 This interaction in turn activates a signal­ ling pathway that is shared with innate immune cells, involving MYD88, IRAK4 and IRAK1, which eventu­ ally leads to the activation of NF­κB, IRF5, and IRF7 (Figure 2). These transcription factors are responsible for the increased survival of B cells, autoantibody produc­ tion and the production of several cytokines, including IFN­I. Importantly, several molecules in this pathway constitute SLE­associated genes, including TLR7, IRAK1, IRF5, IRF7, and molecules that regulate NF­κB activa­ tion such as UBE2L3, TNFAIP3 and TNIP3 (Figure 2). These genes will be discussed in the analysis of the innate immune system.

Cross-talk between T cells and B cells

SLE­associated genes might mediate cross­talk between lymphocytes. B cells are able to endocytose and process

the autoantigens that they bind to, and subsequently present autoantigen­derived peptides to T H cells through their MHC­II molecules, as demonstrated for nucleosome­derived histone epitopes. 57 MHC­II mol­ ecules, notably HLA-DR2 and HLA­DR3, represent two of the best characterized genes with the strongest association with SLE; 58,59 however, the available infor­ mation with regard to their role in SLE is difficult to interpret. Multiple HLA-DR2 and HLA-DR3 alleles, as well as several additional HLA alleles, are associated with SLE. The strength of the association and specific allele(s) implicated in SLE depends on the ethnic group and clinical presentation being studied. 5860 Different SLE­associated HLA MHC­II alleles have documented associations with other autoimmune diseases, such as diabetes mellitus and Sjögren syndrome. 60 Co­stimulatory molecular pairs, such as CD28– CD80, CD40–CD40L and OX40–OX40L (also known as TNFSF4), also have an important function in the bilat­ eral amplification of lymphocyte cross­talk (Figure 2). 61 Among these co­stimulatory molecules, OX40L and CD80 have been implicated in susceptibility to SLE (Table 1). 1720,62,63 Interaction between OX40 and CD123 or TNFSF4 on activated T cells might result in the gener­ ation of IL­10­producing T REG cells. 62 These same pairs of co­stimulatory molecules might also regulate the inter­ action between specialized antigen­presenting cells, such as dendritic cells, and T cells (Figure 2).

Generation of immune effector cells The activation of B cells and T cells leads to the gen­ eration of effector cells, which can subsequently cause tissue injury. Such effector cells include plasma cells and T H 17 cells, both of which have been implicated in the pathogenesis of lupus nephritis. 6467 ETS1 and PRDM1 (also known as BLIMP1) are two molecules that can regu­ late the generation of both plasma cells and T H 17 cells. Evidence suggests that expression of the mRNA transcript for the negative regulator ETS1 is reduced in peripheral blood mononuclear cells of patients with SLE, and Ets1 ablation leads to SLE in mice. 68,69 Conversely, blockade

332 | JUNE 2015 | VOLUME 11

nrneph

2015.33_JUN15.indd

332

www.nature.com/nrneph

12/05/2015

16:08

TLR7*

TLR9*

TLR8

T cell

CD80*

CD28

OX40L*

OX40

CD40

CD40L

MHCII*

TCR

Antigen-

presenting

cell

(dendritic

cell)

PTPN22*

CSK*

STAT4*

PP2A*

Nuclear antigen

B-cell receptor

B-cell

receptor

signalling

IP3

CSK*

LYN*

BANK1*

PLC γ2

DAG

BLK1*

PRKCB*

RasGRP3*

Ras

ERK

ETS1*

PRDM1*

T 17

H

cells

Plasma

cells

PTPN22*

Endosome

REVIEWS

B cell

Myd88

TRAF6

IRAK4

 

IRAK1*

UBE2L3*

TNFAIP3*

NF-κ B

IRF5*

IRF7*

TNIP3*

Nucleus

Increased survival

Cytokine

IFN-I

antibody production

production

production

IFN-I antibody production production production Figure 2 | Gene products associated with systemic lupus

Figure 2 | Gene products associated with systemic lupus erythematosus (SLE) that might affect the adaptive immune system. The schematic shows some of the interactions and signalling pathways involving known SLE genes (denoted by an asterisk) that have the potential to influence lymphocyte function. These genes have been divided into three groups, depending on the cell type in which they are expressed: antigen-presenting cells (dendritic cells), T cells, and B cells. The overall result of signalling pathways in these three cell types is the production of effector cells, including T H 17 cells and plasma cells. The black arrows represent activation and bar-headed lines represent inhibition of the target gene or process. The dashed lines represent the overall response. Abbreviations: TCR, T-cell receptor; T H 17 cells, T-helper 17 cells; TLR, Toll-like receptor.

or deficiency of PRDM1 reduces the severity of SLE in mice. 70,71 Both genetic evidence from human GWAS and mechanistic studies in mice, therefore, underscore the importance of the generation of T H 17 cells and plasma cells in the pathogenesis of SLE. Both mouse models of SLE and patients with SLE exhibit increased levels of IL­17 production and increased numbers of circulating T H 17 cells that correlate with disease activity. 72 Furthermore, IL­17 deficiency pro­ tects mice from the development of SLE­associated glo­ merulonephritis, although conflicting evidence has also been reported. 72,73 Polymorphisms in PPP2A detected in patients with SLE are associated with elevated expres­ sion of the PP2A catalytic subunit (PP2Ac) in T cells and decreased IL­2 production, which can be regulated by miRNA–155. 74,75 A transgenic mouse overexpressing Pp2ac showed increased T­cell production of IL­17 and high susceptibility to the development of antibody­mediated nephritis. Blockade of IL­17 by intraperitoneal antibody administration markedly reduced proteinuria and histo­ logical damage in this transgenic mouse model. 76 PP2Ac has been shown to deregulate the IL-17 locus via enhanced histone 3 acetylation; this effect was identified in both T cells of Pp2ac transgenic mice and in patients with SLE. 77 Some of the disease genes in this category have already shown an association with lupus nephritis, as summa­ rized in Table 1. These associations include SNPs in BLK,

HLA DRB1, STAT4 and OX40L. The presence of SNPs in OX40L and expression levels of OX40L on the surface of peripheral blood mononuclear cells are both associated with lupus nephritis. 62,7884

Activation of innate immune signalling

Modulation of IFN-I signalling SLE in both paediatric and adult patients is increas­ ingly recognized to have a molecular signature that is characterized by over­activation of the IFN­I signal­ ling pathway. 85 IFN­I signalling is important in myeloid cells, including monocytes and dendritic cells, and might also have important functions in resident renal cells. 86,87 Previous studies suggest a possible genetic basis for the increased expression of IFN-I observed in SLE; SNPs in several genes in this pathway are associated with SLE (Table 1). Signalling via the IFN­I receptor is regulated by JAK1, TYK2 and various STAT proteins, includ­ ing STAT4. Importantly, SNPs in TYK2 and STAT4 are associated with SLE (Figure 3). Another SLE­associated gene, IKZF1, regulates the transcription of STAT4, and polymorphisms in IKZF1 are also associated with lupus nephritis (Figure 3). 88

JAK–STAT signalling

Activation of STAT4 occurs not only in lympho­ cytes but also in activated monocytes and dendritic

NATURE REVIEWS | NEPHROLOGY

nrneph

2015.33_JUN15.indd

333

VOLUME 11 | JUNE 2015 | 333

12/05/2015

16:08

REVIEWS   IL-12     Immune IL-23 complex IFN-I   IFNAR     JAK1 TYK2*

REVIEWS

 

IL-12

 
 

Immune

IL-23

complex

IFN-I

 

IFNAR

 
 

JAK1

TYK2*

 

Endosome

 
 

STATs

 

IKZF1*

STAT4*

TLR7*

TLR8

TLR9*

 

IFN-I-induced

genes

 

IRF5*

IRF7*

 

Myd88

IFIH1*

 

IRAK4

ILT3*

 

IRAK1*

IRF5*

IRF7*

 

Cytokine

 

IFN-I

production

production

 

FCGR2A*

FCGR3A*

FCGR3B*

ITGAM*

LYN*

Activation

Multiple

and

signalling

phagocytosis

pathways

UBE2L3*

TNFAIP3*

TNIP3*

Nucleus

Myeloid cell

TRAF6

NF- κ B

Increased

survival

Figure 3 | Gene products associated with systemic lupus erythematosus (SLE) that might affect innate immune signalling. The schematic illustrates the signalling pathways that occur in myeloid cells that involve genes that could influence innate immune cell function (denoted by an asterisk). Three myeloid cell surface receptors (ITGAM, FcR family receptors and IFNAR) are illustrated from which signalling cascades are initiated upon presentation of immune complexes. The overall response is regulation of gene transcription that results in the modulation of cell survival and the production of cytokines and IFN-I. The black arrows represent activation and bar-headed lines represent inhibition of the target gene or process. The dashed lines represent the overall response. Abbreviation:

TLR, Toll-like receptor.

cells; indeed, monocytes from the kidneys of patients with autoimmune diseases also express high levels of STAT4. 8990 Although the JAK–STAT pathway has been shown to mediate the progression of renal fibrosis, the specific disease contributions of TYK2, STAT4 and IKZF1 in intrinsic renal cells are currently unknown. Interestingly, patients with SLE who harbour SNPs in STAT4 develop symptoms of the disease at an earlier age compared to patients who do not carry these SNPs; these patients also exhibit high levels of anti­ dsDNA antibodies and develop severe lupus nephri­ tis. 80 Furthermore, Stat4 deficiency in mice aggravates lupus nephritis, as compared to mice that are Stat4­ sufficient. 81 Given that diverse cell types express STAT4, dissecting the cellular and molecular mechanisms by which SNPs in this gene contribute to lupus nephritis poses a considerable challenge.

Activation of IFN receptor by interleukins

IL­12 and IL­23 can activate the IFN α/β receptor (IFNAR), which results in increased production of IFN­I. 91,92 Consequently, a large number of genes that are regulated by IFN­I become activated, constituting

the most prominent SLE­associated RNA signature. 71 Some of these IFN­I­regulated genes, such as IRF5, IRF7, ILT3 and IFIH1, are SLE­associated genes, and some can in turn regulate the expression of IFN­I and other disease­associated cytokines. 93 Of note, the IRF5 allele implicated in SLE is associated with high serum IFN­I activity and the development of anti­dsDNA anti­ bodies. 23 Similarly, the ILT3 disease­associated allele correlates with elevated IFN­I and TNF expression among patients with SLE. 24 The increased production of IFN­I that is driven by these disease alleles is expected to initiate a positive feedback loop that rapidly increases IFN­I production (Figure 3). The pathogenic importance of this axis is also underscored by the observation that genetic ablation or pharmacological blockade of key molecules in this axis, such as IRF5, suppresses SLE in mice. 25 Furthermore, SNPs in IRF5 are associated with lupus nephritis in patients. 26,70 Finally, emerging evi­ dence suggests that genetic aberrations in multiple genes within the IFN­I pathway might confer increased disease susceptibility, as exemplified by the genetic interaction between IRF5, IKZF1 and STAT4. 94

Fc receptors for immunoglobulin The Fc receptors (FcRs) for IgG represent another family of receptors that have a prominent role in the activity of myeloid cells. SNPs and CNVs affecting multiple members of this family, including FCGR2A, FCGR3A and FCGR3B, have been associated with SLE and LN. 95100 Interestingly, some of the SNPs and CNVs in FcRs associated with lupus nephritis are characterized by reduced FcR expression on the myeloid cell surface membrane; this observation has led to the hypothesis that reduced FcR­mediated immune complex clearance might contribute to lupus nephritis. 9698 Total ablation of FcRs, however, prevents the development of lupus nephritis despite the presence of anti­DNA antibodies. 101 These data suggest that myeloid cells are the major cell type through which FcR expression can influence the pathogenesis of lupus nephritis. 102 FcRs not only activate myeloid cells, but also enable these cells to endocytose immune complexes. 103 Immune complexes present in SLE might harbour nuclear anti­ gens, such as RNA and DNA, allowing the endocytosed immune complexes to activate endosomal TLRs such as TLR7, TLR8 and TLR9. 104 Activation of these TLRs recruit MYD88 and a series of additional molecules, including IRAK4, IRAK1 and TRAF6, which together initiate various transcriptional programmes, including those driven by NF­κB, IRF5 and IRF7 (Figure 3). 105 These transcriptional processes have important func­ tions in augmenting proinflammatory cytokine pro­ duction, including IFN­I. Several of these molecules, including TLR7, TLR9, IRAK1, IRF5 and IRF7 have been implicated as SLE­causative genes, among which, TLR9 and IRF5 have been directly associated with lupus nephritis in patients. 26,106 In addition, genetic ablation or pharmacological blockade in mouse models of SLE have established a pathogenic role for Tlr7, Irak1 and Irf5 in this disease. 25,107109 Enhancing Tlr7 expression through

334 | JUNE 2015 | VOLUME 11

nrneph

2015.33_JUN15.indd

334

www.nature.com/nrneph

12/05/2015

16:08

FCGR3B*

FCGR3A*

FCGR2A*

TLR7*

TLR9*

TLR8

Fc

ITGAM*

Myeloid

cell

Glomerular

matrix

TREX1*

DNAse1*

C1*

C2*

C3*

C4*

KLK*

ACE*

LAMC2*

COL25A1*

Multiple

signalling

pathways

FCGR2A*

FCGR3A*

FCGR3B*

Immune

complex

Endosome

Myd88

TRAF6

IRAK4

 

IRAK1*

UBE2L3*

TNFAIP3*

NF-

κ B

IRF5*

IRF7*

TNIP3*

Nucleus

Resident

renal cell

 

Increased

Cytokine

IFN-I

survival

production

production

Figure 4 | Gene products associated with systemic lupus erythematosus (SLE) that might affect intra-renal events leading to lupus nephritis. The schematic depicts genes associated with SLE that might exert effects on intra-renal events that lead to lupus nephritis (denoted by an asterisk). Myeloid cells present to resident renal cells via Fc receptors, which act in concert with complement molecules (C1–C4). Upon stimulation by an immune complex, resident renal cells can initiate multiple signalling pathways that culminate in the activation of NF-κB, IRF5 and IRF7. In this way, gene transcription can be modulated, with subsequent effects on cell survival, cytokine production and expression of IFN-I. The black arrows represent activation and bar-headed lines represent inhibition of the target gene or process. The dashed lines represent the overall response. Abbreviation:

TLR, Toll-like receptor.

gene duplication confers susceptibility to SLE and lupus nephritis in mice. 108,109 Multiple lines of evidence there­ fore support the critical importance of this molecular axis in the pathogenesis of SLE and lupus nephritis.

Modulation of NF- κ B activation Activation of NF­κB has been implicated in both SLE and lupus nephritis. NF­κB can be negatively regulated by TNFAIP3 (also known as A20) and TNIP3 (also known as ABIN3), either independently, or in concert. 110 TNIP3 can bind to TNFAIP3 to facilitate NF­κB inhibition. 110 UBE2L3 is an E2 ubiquitin­conjugating enzyme that can regulate the level of NF­κB activation and result­ ant cell proliferation. 111 SNPs in TNFAIP3, TNIP3 and UBE3L3 have shown an association with SLE in human patients (Figure 3). 112 Whether multiple perturbations to this pathway have an incremental effect on NF­κB activation remains to be explored. Murine studies have offered further evidence to support the importance of this pathway in SLE progression. Reduced expres­ sion of TNFAIP3 in B cells augments the production of autoantibodies and germinal centre type B cells, and the development of renal disease. 113 TNFAIP3 and TNIP3

REVIEWS

have also shown associations with lupus nephritis in human patients. 114,115 ITGAM (also known CD11B or MAC­1) is a myeloid­ specific adhesion molecule with multiple ligands, includ­ ing ICAM1, ICAM2, C3bi and FGA. 116118 ITGAM exhibits diverse functions under normal physiological conditions, including mediating myeloid­cell activation (leading to production of NF­κB, IL­6 and TNF), phago­ cytosis, uptake of immune complexes, and facilitating interactions between myeloid cells, lymphocytes, plate­ lets and endothelial cells. 116118 The ITGAM Arg77His allele has reduced binding efficiency for ICAM1, and thus has a potential effect on cell adhesion. The Arg77His allele correlates with severe disease manifestations of SLE, including lupus nephritis, as well as haematological

and neurological phenotypes. 84,119,120

Intra-renal promotion of tissue damage

Activation of T cells and B cells in the kidney

Genes associated with SLE can contribute to the patho­ genesis of lupus nephritis either directly or indirectly. Cells involved in the adaptive arm of the immune system (B cells and T cells) are known to infiltrate the kidneys. Previous work has documented the existence of struc­

tures reminiscent of germinal centres and other lym­ phocyte clusters within the inflamed kidneys of patients with lupus nephritis. 65 All of the genes described above in the adaptive immune system can potentially influence lupus nephritis by activating T cells and B cells, both systemically and within the kidneys.

Activation of intra-renal myeloid cells

Cells of the innate immune system, such as macrophages and neutrophils, are present in large numbers within the kidneys of patients with lupus nephritis. All of the genes known to affect innate immune signalling, which were outlined in the section describing the innate immune system, can potentially influence the progres­ sion of lupus nephritis by activating intra­renal myeloid cells. 121,122 In addition, some of these genes, notably ITGAM and FcR, could potentially affect the level of recruitment of myeloid cells to the glomerular matrix via cognate binding sites on the immune complexes deposited in the glomeruli. 122 Polymorphic variants of ITGAM and/or FcR that result in increased binding to complement components (for example, C3b) or the Fc fragment of IgG could possibly augment myeloid cell recruitment and activation (Figure 4); however, the biochemical and mechanistic evidence to support this hypothesis is currently lacking. Conversely, evidence exists to support reduced levels of FcR and reduced FcR binding ability to IgGs among patients with SLE, as will be discussed below.

Immune complex clearance from the glomeruli Evidence suggests that SLE­associated genetic poly­ morphisms might regulate the clearance of immune complexes from glomerular tissue. SLE­associated SNPs in FCGR2A (Arg131) and FCGR3A (Phe158) might impair affinity for IgG binding. 95,96 Likewise, CNVs in

for IgG binding. 9 5 , 9 6 Likewise, CNVs in NATURE REVIEWS | NEPHROLOGY nrneph

NATURE REVIEWS | NEPHROLOGY

nrneph

2015.33_JUN15.indd

335

VOLUME 11 | JUNE 2015 | 335

12/05/2015

16:08

REVIEWS FCGR3B could reduce the cell surface expression levels of this receptor. 9 8 –

REVIEWS

FCGR3B could reduce the cell surface expression levels of this receptor. 98100 Both of these effects could act to reduce the uptake and clearance of immune complexes from the glomerular matrix, not only by the infiltrating myeloid cells, but also by resident mesangial cells, which are known to upregulate the same FcRs upon stimula­ tion with IFN­γ. The effect of FcR expression on infil­ trating myeloid cells seemed to be more important in the pathogenesis of lupus nephritis as compared to the effect of expression of FcR on renal­resident cells, in a direct comparison. 102

Glomerular deposition of nuclear material Genes associated with SLE might augment the amount and accessibility of nucleosomal material available for deposition on the glomerular matrix, as will be discussed further in the next section. Strong experimental evidence supports the notion that nuclear antigens expressed within the glomerular matrix can serve as points of inter­ action with anti­nuclear antibodies (Figure 4). 123 Genes that regulate DNA turnover (for example, DNASE1 and TREX1), autophagy, and complement levels, therefore, might regulate the amount of nuclear material that is deposited on the glomerular matrix, as well as the subsequent accumulation of immune complexes and leucocyte recruitment. 124

Genetic regulation of resident renal cells

SLE­associated genetic polymorphisms might regu­ late specific disease pathways within resident renal cells, including mesangial cells, podocytes, glomerular endothelial cells and tubular epithelial cells. Potential SLE genes in this category include ACE, 125 extracellular matrix molecules (COL25A1 and LAMC2), 126 KLK 127 and genes that activate the IFN­I, TLR and NF­κB signalling pathways (Figure 4). Kidneys damaged by nephritis express multiple TLRs; 128,129 furthermore, renal cells grown in culture, such as mesangial cells, podocytes, glomerular endothelial cells and tubular epi­ thelial cells, express multiple TLRs and are responsive to cognate TLR ligands. 129135 Expression of the innate signalling axes downstream of TLR activation, including MYD88, TRAF6 and TNFAIP3, has been documented in renal cells. 136139 SLE genes that influence immune signalling could impact disease in two ways: firstly, by affecting the infiltration of leucocytes, and secondly, by affecting the intrinsic properties of renal cells. Another possi­ bility is that some SLE genes might produce differen­ tial effects systemically and intra­renally, as illustrated by CD80. CD80 usually mediates leucocyte cross­talk in the immune system but has a dramatically different function within podocytes. 140142 Specifically, stimula­ tion of TLR3 and TLR4 results in upregulation of CD80 in podocytes in an NF­κB­dependent manner, which leads to abrogation of the glomerular filtration barrier and consequent proteinuria. 141 Nephropathies charac­ terized by this molecular feature could be treated with selected biologic therapies, 143 although the underlying mechanisms require further exploration.

Novel lupus nephritis candidate genes In addition to the genes discussed above, further molecules might be important in mediating lupus nephritis that have not yet been implicated as disease genes in GWAS. One such example is CAMK4. In mice with SLE, inhibition of CAMK4 is associated with decreased IL­2 production in T cells, decreased cell proliferation, and decreased IL­6 pro­ duction in PDGF­stimulated mesangial cells. 144 Ablation of Camk4 in the lupus­prone murine strain MRL/lpr, resulted in reduced glomerulonephritis, accompanied by reduced cytokine production by T cells and macrophages. 144 Other murine studies have also been informative in this respect. A series of congenic dissection studies in the New Zealand mixed strain SLE mouse model (NZM2328) have facilitated the separation of genes that contribute to autoantibody production from those that promote acute glomerulonephritis, chronic glomerulonephritis and end­stage renal disease. 145147 A 1.34 Mb region containing 45 genes at the distal end of chromosome 1 (the Cgnz1 locus) was associated with chronic glomerulonephritis, whereas the corresponding allele from non­autoimmune mice conferred resistance to end­organ damage. Although the exact gene within the Cgnz1 locus is yet to be identi­ fied, this genomic region contains several potentially interesting candidate genes that influence metabolism and cell survival. These congenic dissection studies are important for two reasons. Firstly, the separation between autoantibodies and nephritis can explain the rare clinical situation of kidney disease in patients with SLE without appreciable autoantibody titres. Secondly, the concept of genes that afford protection from target organ damage changes some of our long­held notions regard­ ing the pathogenesis of lupus nephritis, clarifies the large between­patient variability in disease expression that can be observed, and has important potential implications for treatment recommendations. 146,147

Accessibility of apoptotic debris

The final category of molecules that contribute to the pathology of SLE comprises genes that could impact the circulating or local tissue levels of accessible chro­ matin, which is predominantly generated from apop­ totic cells and immune complexes. These genes include DNASE1, TREX1, FcR, ITGAM, C1Q (and related comple­ ment components) and ATG5. 148150 Although deficien­ cies of many of these genes are associated with SLE, the underlying mechanisms contributing to disease pathology remain unclear. 148 In particular, ATG5 might serve a key function in podocyte biology, as multiple nephropathies can be induced when ATG5 gene function is impaired. 151 Importantly, podocyte­specific deletion of Atg5 in a murine model resulted in the accumulation of ubiqui­ tinated and oxidized proteins, endoplasmic reticulum stress, and proteinuria, indicating that autophagy is an important homeostatic mechanism for maintaining podocyte function and preventing glomerular injury. 151

Exposure of nuclear autoantigens

Previous research has established that nuclear antigens are targeted in SLE, which is characterized by a strong

336 | JUNE 2015 | VOLUME 11

nrneph

2015.33_JUN15.indd

336

www.nature.com/nrneph

12/05/2015

16:08

serological response to DNA, histones and ribonuclear proteins. 152,153 These nuclear antigens are not usually exposed to the immune system as they are sequestered within cellular and nuclear membranes. Consequently, numerous studies have aimed to uncover the processes by which nuclear autoantigens become exposed and drive SLE­associated autoimmune responses. 149,150,154 Although several known pathways can lead to cell death (with more being discovered), apoptosis remains the dominant mechanism by which cells die. Rapid clearance of apoptotic cells prevents immunogenicity or the ability to initiate an inflammatory response. Experimental evi­ dence suggests that accumulation of apoptotic debris, which can occur as a result of failure of this clearance machinery, is an important contributor to autoimmunity

in SLE. 155,156

Clearance of apoptotic cells Multiple ligands, receptors, opsonins, and other mol­ ecule classes are involved in the clearance of apoptotic cells and other debris associated with the processes of cell death. Genetic knockout and pharmacological studies in mice have demonstrated how genes affecting autoantigen clearance could promote the production of anti­nuclear autoantibodies and trigger other features of SLE. 149 Nevertheless, few of these genes have thus far been implicated in SLE among human patients. Some illustrative examples in murine models include defi­ ciency of Tyro-3, Axl and Mertk (also known as Tam)— receptors that are important for binding to apoptotic cells and their subsequent engulfment—that results in the development of autoantibodies, arthritis, skin rashes and glomerular immune complex deposition. 157 Mice deficient in T­cell IgG4 (TIM­4), which binds the phosphatidyl serine residues exposed on the surface of apoptotic cells, exhibit anti­dsDNA antibodies and elevated B­cell and T­cell activation. 158 Other proteins that regulate apoptotic cell clearance include MFGE8, MBL2, APCS, and CRP. 149,150

NETosis

NETosis is a specialized form of cell death that occurs primarily in neutrophils, during which neutrophil extracellular traps (NETs) are released. NETs comprise a mesh of DNA and histones, as well as the content of cytoplasmic granules and other key mediators, such as HMGB1. 159 NETs are becoming increasingly recognized as a major source of nuclear antigens and other inflam­ matory stimuli that can help drive autoimmunity in SLE. 159,160 NETs form more easily in patients with SLE as compared to healthy controls, and NET clearance is impaired in patients with SLE, 159 perhaps owing to the presence of anti­DNASE1 or anti­NET antibodies. 154 NETs can stimulate dendritic cells to secrete IFN­I, and might also cause direct damage to tissues. 159 DNASE1 is essential for the degradation of NETs and hence is pivotal to their clearance. Mice deficient in Dnase1 develop an SLE­like syndrome, and many patients with SLE exhibit decreased DNASE1 activity. Furthermore, genetic mutations in DNASE1 have been linked to SLE

REVIEWS

in patients. 149,150 Whether any of the genes associated with susceptibility to SLE or lupus nephritis have an impact on NETosis remains to be established.

Opsonization

Opsonization of apoptotic cells by serum proteins has a pivotal role in cell clearance. The opsonin C1Q is addi­ tionally involved in the clearance of NETs and has been closely linked with SLE. 161,162 C1q­deficient mice develop antinuclear autoimmunity, and almost all patients with C1Q deficiency develop SLE. Moreover, anti­C1Q anti­ bodies are frequently found in patients with SLE, which can induce a functional state of C1Q deficiency and hinder the clearance of apoptotic cells. 163 Other comple­ ment proteins, such as C2, C3, and C4, might be neces­ sary for phagocytosis; indeed, genetic associations with SLE have been described not only for C1Q, but also with mutations in C2, C4, CR3 and complement inhibi­ tors. 163 Finally, although the association between C1Q and SLE has been attributed to the clearance of dying cells, findings from some studies have suggested a role of complement proteins in several other areas perti­ nent to the pathogenesis of SLE, including regulation of lymphocytes and expression of IFN­I. 163

Conclusions

Genetic studies of SLE and lupus nephritis have already highlighted more than 50 potential candidate genes that contribute to disease pathology, many of which can be subdivided into one of four key molecular pathways. Although many more genes are likely to be identified in the coming years, the molecular pathways implicated by these disease genes yield insights into some of the key steps that might be important for the pathogenesis of lupus nephritis. Genes that breach immune tolerance and promote autoantibody production, notably anti­ dsDNA, might act in concert with genes that augment innate immune signalling and IFN­I production to gen­ erate waves of effector leucocyte secretion and release

of inflammatory mediators and autoantibodies that together initiate renal assault. 164166 The presence of cognate antigens in the glomerular matrix, together with intrinsic molecular abnormalities in resident renal cells, might further accentuate the progression of the disease among patients with lupus nephritis. 164,167 Differential activation of the various molecular pathways discussed

in this Review could conceivably lead to the diverse clini­

cal presentations of SLE and lupus nephritis. Deciphering

the molecular basis of disease in each patient would

help physicians to tailor therapy accordingly. Patients with genetic polymorphisms that lead to activation of

B cells or T cells might, for example, benefit from thera­

peutics that target specific signalling molecules or co­ stimulatory pathways encoded by the disease genes. Patients with SLE risk alleles that promote end­organ inflammation might benefit from therapeutics that target the implicated pathways within the kidneys. The field is yet to arrive at such a level of sophisti­ cation, where therapies can potentially be tailored to the genotype of the patient. Firstly, the spectrum of

to the genotype of the patient. Firstly, the spectrum of NATURE REVIEWS | NEPHROLOGY nrneph 2015.33_JUN15.indd

NATURE REVIEWS | NEPHROLOGY

nrneph

2015.33_JUN15.indd

337

VOLUME 11 | JUNE 2015 | 337

12/05/2015

16:08

REVIEWS genes responsible for SLE is still evolving, and the spe­ cific genetic aberrations responsible

REVIEWS

genes responsible for SLE is still evolving, and the spe­ cific genetic aberrations responsible for disease within each implicated gene are only starting to be elucidated. Secondly, better biomarkers are required to rapidly clas­ sify patients according to the molecular disease pathways they might harbour. Thirdly, a better armamentarium of therapeutics is warranted, targeting the respective disease pathways. Finally, clinical trials need to be conducted to evaluate if pathway­tailored therapy does indeed reduce long­term morbidity and mortality in patients with SLE. Clearly, the next decade will witness intense activity in all of these quarters.

Review criteria

The articles for this Review were selected as follows: we first identified all genes that have been implicated in SLE and/or lupus nephritis and validated by further analytical techniques. Publications relating to these genes and their reported functions were gathered from PubMed and Google Scholar using the gene name as a search term. Additional search terms included “lupus”, “SLE”, “nephritis”, “genetics” and “GWAS”. Further articles were identified from the reference lists of these publications. The search was confined to articles published in English, and all years of publication were included.

1. Feldman, C. H. et al. Epidemiology and sociodemographics of systemic lupus erythematosus and lupus nephritis among US adults with Medicaid coverage, 2000–2004. Arthritis Rheum. 65, 753–763 (2013).

2. Rahman, A. & Isenberg, D. A. Systemic lupus erythematosus. N. Engl. J. Med. 358, 929–939

(2008).

3. Schwartz, N., Goilav, B. & Putterman, C. The pathogenesis, diagnosis and treatment of lupus nephritis. Curr. Opin. Rheumatol. 26, 502–509

(2014).

4. Tsokos, G. C. Systemic lupus erythematosus. N. Engl. J. Med. 365, 2110–2121 (2011).

5. Sang, A., Zheng, Y. Y. & Morel, L. Contributions of

B cells to lupus pathogenesis. Mol. Immunol. 62,

329–338 (2014).

6. Davidson, A. & Aranow, C. Lupus nephritis:

lessons from murine models. Nat. Rev. Rheumatol. 6, 13–20 (2010).

7. Reddy, V., Jayne, D., Close, D. & Isenberg, D. B-cell depletion in SLE: clinical and trial experience with rituximab and ocrelizumab and implications for study design. Arthritis Res. Ther. 15 (Suppl. 1), S2 (2013).

8. Liu, Y. & Anders, H. J. Lupus nephritis: from pathogenesis to targets for biologic treatment. Nephron Clin. Pract. (2014).

9. Okamoto, A. et al. Kidney-infiltrating CD4+ T-cell clones promote nephritis in lupus-prone mice.

Kidney Int. 82, 969–979 (2012).

10. Zhang, Z., Kyttaris, V. C. & Tsokos, G. C. The role

of IL-23/IL-17 axis in lupus nephritis. J. Immunol.

183, 3160–3169 (2009).

11. Miyake, K., Akahoshi, M. & Nakashima, H. Th subset balance in lupus nephritis. J. Biomed. Biotechnol. 2011, 980286 (2011).

12. Aringer, M., Gunther, C. & Lee-Kirsch, M. A. Innate immune processes in lupus erythematosus. Clin. Immunol. 147, 216–222

(2013).

13. Lech, M. & Anders, H. J. The pathogenesis

of lupus nephritis. J. Am. Soc. Nephrol. 24,

1357–1366 (2013).

14. Kiefer, K., Oropallo, M. A., Cancro, M. P. &

Marshak-Rothstein, A. Role of type I interferons

in the activation of autoreactive B cells.

Immunol. Cell Biol. 90, 498–504 (2012).

15. Bagavant, H. & Fu, S. M. Pathogenesis of kidney disease in systemic lupus erythematosus. Curr. Opin. Rheumatol. 21, 489–494 (2009).

16. Nowling, T. K. & Gilkeson, G. S. Mechanisms

of tissue injury in lupus nephritis. Arthritis Res.

Ther. 13, 250 (2011).

17. Guerra, S. G., Vyse, T. J. & Cunninghame Graham, D. S. The genetics of lupus:

a functional perspective. Arthritis Res. Ther.

14, 211 (2012).

18. Flesher, D. L., Sun, X., Behrens, T. W., Graham, R. R. & Criswell, L. A. Recent advances

in the genetics of systemic lupus erythematosus. Expert Rev. Clin. Immunol. 6, 461–479 (2010).

19. Crispin, J. C., Hedrich, C. M. & Tsokos, G. C. Gene-function studies in systemic lupus erythematosus. Nat. Rev. Rheumatol. 9, 476–484 (2013).

20. Deng, Y. & Tsao, B. P. Genetic susceptibility to systemic lupus erythematosus in the genomic era. Nat. Rev. Rheumatol. 6, 683–692

(2010).

21. Graham, R. R. et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat. Genet. 40, 1059–1061 (2008).

22. Guo, Y., Orme, J. & Mohan, C. A genopedia of lupus genes - lessons from gene knockouts. Curr. Rheumatol. Rev. 9, 90–99 (2013).

23. Niewold, T. B. et al. 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. 71, 463–468 (2012).

24. Jensen, M. A. et al. Functional genetic polymorphisms in ILT3 are associated with decreased surface expression on dendritic cells and increased serum cytokines in lupus patients. Ann. Rheum. Dis. 72, 596–601 (2013).

25. Richez, C. et al. IFN regulatory factor 5 is required for disease development in the FcgammaRIIB–/–Yaa and FcgammaRIIB–/– mouse models of systemic lupus erythematosus. J. Immunol. 184, 796–806

(2010).

26. Qin, L. et al. Association of IRF5 gene polymorphisms and lupus nephritis in a Chinese population. Nephrology (Carlton) 15, 710–713

(2010).

27. Morel, L. et al. Genetic reconstitution of systemic lupus erythematosus immunopathology with polycongenic murine strains. Proc. Natl Acad. Sci. USA 97, 6670–6675 (2000).

28. Mohan, C. et al. Genetic dissection of Sle pathogenesis: Sle3 on murine chromosome 7 impacts T cell activation, differentiation, and cell death. J. Immunol. 162, 6492–6502 (1999).

29. Xie, S. & Mohan, C. Divide and conquer—the power of congenic strains. Clin. Immunol. 110, 109–111 (2004).

30. Henry, T. & Mohan, C. Systemic lupus erythematosus—recent clues from congenic strains. Arch. Immunol. Ther. Exp. (Warsz.) 53, 207–212 (2005).

31. Mohan, C. et al. Genetic dissection of lupus pathogenesis: a recipe for nephrophilic autoantibodies. J. Clin. Invest. 103, 1685–1695

(1999).

32. Morel, L. et al. Functional dissection of systemic lupus erythematosus using congenic mouse strains. J. Immunol. 158, 6019–6028 (1997).

33. Vaughn, S. E. et al. Genetic susceptibility to

lupus: the biological basis of genetic risk found

in B cell signaling pathways. J. Leukoc. Biol. 92,

577–591 (2012).

34. Avalos, A. M., Meyer-Wentrup, F. & Ploegh, H. L. B-cell receptor signaling in lymphoid malignancies and autoimmunity. Adv. Immunol. 123, 1–49 (2014).

35. Shao, W. H. & Cohen, P. L. The role of tyrosine

kinases in systemic lupus erythematosus and their potential as therapeutic targets. Expert Rev. Clin. Immunol. 10, 573–582 (2014).

36. Castillejo-Lopez, C. et al. Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK. Ann. Rheum. Dis. 71, 136–142 (2012).

37. Coughlin, J. J. et al. RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor-Ras signaling. J. Immunol. 175, 7179–7184 (2005).

38. Shao, B. et al. Hyperglycaemia promotes human brain microvascular endothelial cell apoptosis via induction of protein kinase C-βI and prooxidant enzyme NADPH oxidase. Redox Biol. 2, 694-701 (2014).

39. Liu, L. et al. PKCβII acts downstream of chemoattractant receptors and mTORC2 to regulate cAMP production and myosin II activity

in neutrophils. Mol. Biol. Cell 25, 1446–145

(2014).

40. Zheng, Y. et al. Phosphorylation of RasGRP3 on threonine 133 provides a mechanistic link between PKC and Ras signaling systems in

B cells. Blood 105, 3648–3654. (2005).

41. Roberts, D. M. et al. A vascular gene trap screen defines RasGRP3 as an angiogenesis-regulated gene required for the endothelial response to phorbol esters. Mol. Cell Biol. 24, 10515–10528

(2004).

42. Oleksyn, D. et al. Protein kinase Cβ is required for lupus development in Sle mice. Arthritis Rheum. 65, 1022–1031 (2013).

43. Yu, C. C., Mamchak, A. A. & DeFranco, A. L. Signaling mutations and autoimmunity. Curr. Dir. Autoimmun. 6, 61–88 (2003).

44. Lamagna, C. et al. B cell-specific loss of Lyn kinase leads to autoimmunity. J. Immunol. 192,

919–928 (2014).

45. Hua, Z. et al. Requirement for MyD88 signaling

in B cells and dendritic cells for germinal center

anti-nuclear antibody production in Lyn-deficient mice. J. Immunol. 192, 875–885 (2014).

46. Yu, C. C., Yen, T. S., Lowell, C. A. & DeFranco, A. L. Lupus-like kidney disease in mice deficient in the Src family tyrosine kinases Lyn and Fyn. Curr. Biol. 11, 34–38 (2001).

47. Samuelson, E. M. et al. Blk haploinsufficiency impairs the development, but enhances the functional responses, of MZ B cells. Immunol. Cell Biol. 90, 620–629 (2012).

338 | JUNE 2015 | VOLUME 11

nrneph

2015.33_JUN15.indd

338

www.nature.com/nrneph

12/05/2015

16:08

REVIEWS

48.

Samuelson, E. M. et al. Reduced B lymphoid

Hata, A. et al. Functional analysis of Csk in signal

erythematosus. Arthritis Rheum. 48, 1332–1342

kinase (Blk) expression enhances

(2003).

86. Fairhurst, A. M. et al. Type I interferons produced by resident renal cells may promote

87. Triantafyllopoulou, A. et al. Proliferative lesions

88. He, C. F. et al. TNIP1, SLC15A4, ETS1, RasGRP3

proinflammatory cytokine production and

68. Yang, W. et al. Genome-wide association study

end-organ disease in autoantibody-mediated

induces nephrosis in C57BL/6-lpr/lpr mice.

in

Asian populations identifies variants in ETS1

glomerulonephritis. J. Immunol. 183,

49.

PLoS ONE 9, e92054 (2014).

and WDFY4 associated with systemic lupus erythematosus. PLoS Genet. 6, e1000841

6831–6838 (2009).

transduction through the B-cell antigen receptor.

(2010).

and metalloproteinase activity in murine lupus

Mol. Cell Biol. 14, 7306–7313 (1994).

69. Wang, D. et al. Ets-1 deficiency leads to altered

nephritis mediated by type I interferons and

50.

Manjarrez-Orduno, N. et al. CSK regulatory

B

cell differentiation, hyperresponsiveness to

macrophages. Proc. Natl Acad. Sci. USA 107,

polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation. Nat. Genet. 44, 1227–1230

TLR9 and autoimmune disease. Int. Immunol. 17, 1179–1191 (2005).

70. Kim, S. J. et al. Tolerogenic function of Blimp-1

3012–3017 (2010).

and IKZF1 are associated with clinical features

(2012).

in

dendritic cells. J. Exp. Med. 208, 2193–2199

of systemic lupus erythematosus in a Chinese

51.

Dai, X. et al. A disease-associated PTPN22

(2011).

Han population. Lupus 19, 1181–1186 (2010).

variant promotes systemic autoimmunity in murine models. J. Clin. Invest. 123, 2024–2036

71. Zhou, Z. et al. Blimp-1 siRNA inhibits B cell differentiation and prevents the development

89. Frucht, D. M. et al. STAT4 is expressed in activated peripheral blood monocytes, dendritic

(2013).

of

lupus in mice. Hum. Immunol. 74, 297–301

cells, and macrophages at sites of Th1-mediated

52.

Bayley, R. et al. The autoimmune-associated

(2013).

inflammation. J. Immunol. 164, 4659–4664

genetic variant PTPN22 R620W enhances

72. Amarilyo, G., Lourenco, E. V., Shi, F. D. &

 

(2000).

neutrophil activation and function in patients with rheumatoid arthritis and healthy individuals. Ann. Rheum. Dis. http://dx.doi.org/10.1136/

La Cava, A. IL-17 promotes murine lupus. J. Immunol. 193, 540–543 (2014).

73. Schmidt, T. et al. Function of the Th17/

90. Kaplan, M. H. STAT4: a critical regulator of inflammation in vivo. Immunol. Res. 31, 231–242 (2005).

annrheumdis-2013-204796.

interleukin-17A immune response in murine

91. Iwakura, Y. & Ishigame, H. The IL-23/IL-17 axis

53.

Zhang, J. et al. The autoimmune disease-

lupus nephritis. Arthritis Rheumatol. 67,

 

in inflammation. J. Clin. Invest. 116, 1218–1222

associated PTPN22 variant promotes calpain-

475–487 (2015).

(2006).

mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell

74. Tan, W. et al. Association of PPP2CA polymorphisms with systemic lupus

92. Ivashkiv, L. B. & Donlin, L. T. Regulation of type I interferon responses. Nat. Rev. Immunol. 14,

hyperresponsiveness. Nat. Genet. 43, 902–907

erythematosus susceptibility in multiple ethnic

 

36–49 (2014).

(2011).

groups. Arthritis Rheum. 63, 2755–2763

93. Elkon, K. B. & Stone, V. V. Type I interferon and

94. Dang, J. et al. Gene-gene interactions of IRF5,

54.

Brownlie, R. J. et al. Lack of the phosphatase

(2012).

(2011).

systemic lupus erythematosus. J. Interferon

PTPN22 increases adhesion of murine regulatory T cells to improve their immunosuppressive function. Sci. Signal. 5, ra87

75. Lashine, Y. A., Salah, S., Aboelenein, H. R. & Abdelaziz, A. I. Correcting the expression of miRNA-155 represses PP2Ac and enhances the release of IL-2 in PBMCs of juvenile SLE

Cytokine Res. 31, 803–812 (2011).

STAT4, IKZF1 and ETS1 in systemic lupus erythematosus. Tissue Antigens 83, 401–408

55.

Ivashkiv, L. B. PTPN22 in autoimmunity: different

(2013).

patients. Lupus 24, 240–247 (2014).

 

(2014).

cell and different way. Immunity 25, 91–93

76. Crispin, J. C. et al. Cutting edge: protein phosphatase 2A confers susceptibility

95. Karassa, F. B. et al. The Fc gamma RIIIA - F158 allele is a risk factor for the development of

56.

Leadbetter, E. A. et al. Chromatin-IgG complexes

to

autoimmune disease through an

lupus nephritis: a meta-analysis. Kidney Int. 63,

activate B cells by dual engagement of IgM and

IL-17-dependent mechanism. J. Immunol. 188,

1475–1482 (2003).

Toll-like receptors. Nature 416, 603–607 (2002).

3567–3571 (2012).

96. Brown, E. E., Edberg, J. C. & Kimberly, R. P.

97. Floto, R. A. et al. Loss of function of a lupus-

57.

Mohan, C., Adams, S., Stanik, V. & Datta, S. K. Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J. Exp. Med. 177, 1367–1381 (1993).

77. Apostolidis, S. A. et al. Protein phosphatase 2A enables expression of interleukin 17 (IL-17) through chromatin remodeling. J. Biol. Chem. 288, 26775–26784 (2013).

Fc receptor genes and the systemic lupus erythematosus diathesis. Autoimmunity 40, 567–581 (2007).

58.

Barcellos, L. F. et al. High-density SNP screening

Graham, R. R. et al. Specific combinations of

78. Richman, I. B. et al. European genetic ancestry

associated FcgammaRIIb polymorphism

of the major histocompatibility complex in

is

associated with a decreased risk of lupus

through exclusion from lipid rafts. Nat. Med. 11,

systemic lupus erythematosus demonstrates

nephritis. Arthritis Rheum. 64, 3374–3382

1056–1058 (2005).

strong evidence for independent susceptibility

(2012).

98. Breunis, W. B. et al. Copy number variation

(2009).

59.

regions. PLoS Genet. 5, e1000696 (2009).

79. Taylor, K. E. et al. Risk alleles for systemic lupus erythematosus in a large case-control collection

at the FCGR locus includes FCGR3A, FCGRXXXXX2C and FCGR3B but not FCGR2A

HLA-DR2 and DR3 class II haplotypes contribute graded risk for disease susceptibility and

and associations with clinical subphenotypes. PLoS Genet. 7, e1001311 (2011).

and FCGR2B. Hum. Mutat. 30, E640–E650

autoantibodies in human SLE. Eur. J. Hum. Genet. 15, 823–830 (2007).

80. Taylor, K. E. et al. Specificity of the STAT4 genetic association for severe disease manifestations

99. Fanciulli, M. et al. FCGR3B copy number variation

60.

Fernando, M. M. et al. Defining the role of the

of

systemic lupus erythematosus. PLoS Genet.

is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat. Genet. 39,

MHC in autoimmunity: a review and pooled

4, e1000084 (2008).

 

721–723 (2007).

analysis. PLoS Genet. 4, e1000024 (2008).

81. Jacob, C. O. et al. Pivotal role of Stat4 and Stat6

100. Morris, D. L. et al. Evidence for both copy

61.

Sharpe, A. H. Mechanisms of costimulation.

Farres, M. N., Al-Zifzaf, D. S., Aly, A. A. &

in

the pathogenesis of the lupus-like disease in

number and allelic (NA1/NA2) risk at the

62.

Immunol. Rev. 229, 5–11 (2009).

the New Zealand mixed 2328 mice. J. Immunol. 171, 1564–1571 (2003).

FCGR3B locus in systemic lupus erythematosus. Eur. J. Hum. Genet. 18, 1027–1031 (2010).

Abd Raboh, N. M. OX40/OX40L in systemic lupus erythematosus: association with disease activity and lupus nephritis. Ann. Saudi Med. 31, 29–34 (2011).

82. Rajabi, P., Alaee, M., Mousavizadeh, K. & Samadikuchaksaraei, A. Altered expression of TNFSF4 and TRAF2 mRNAs in peripheral blood mononuclear cells in patients with systemic

101. Clynes, R., Dumitru, C. & Ravetch, J. V. Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science 279, 1052–1054

64.

Shah, K. et al. Dysregulated balance of Th17

lupus erythematosus: association with

 

(1998).

and Th1 cells in systemic lupus erythematosus. Arthritis Res. Ther. 12, R53 (2010).

atherosclerotic symptoms and lupus nephritis. Inflamm. Res. 61, 1347–1354 (2012).

102. Bergtold, A. et al. FcR-bearing myeloid cells are responsible for triggering murine lupus nephritis.

65.

Chang, A. et al. In situ B cell-mediated immune

J.

Immunol. 177, 7287–7295 (2006).

responses and tubulointerstitial inflammation in human lupus nephritis. J. Immunol. 186,

83. Zhou, X. J. et al. A replication study from Chinese supports association between lupus-risk allele

in

TNFSF4 and renal disorder. Biomed. Res. Int.

103. Sánchez-Mejorada, G. & Rosales, C. Signal transduction by immunoglobulin Fc receptors.

1849–1860 (2011).

2013, 597921 (2013).

J.

Leukoc. Biol. 63, 521–533 (1998).

66.

Neubert, K. et al. The proteasome inhibitor

84. Sanchez, E. et al. Phenotypic associations of

104. Celhar, T., Magalhães, R. & Fairhurst, A. M. TLR7

bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat. Med. 14, 748–755 (2008).

genetic susceptibility loci in systemic lupus erythematosus. Ann. Rheum. Dis. 70, 1752–1757 (2011).

and TLR9 in SLE: when sensing self goes wrong. Immunol. Res. 53, 58–77 (2012).

105. Shrivastav, M. & Niewold, T. B. Nucleic acid

67.

Jacobi, A. M. et al. Correlation between circulating CD27high plasma cells and disease activity in patients with systemic lupus

85. Obermoser, G. & Pascual, V. The interferon-alpha signature of systemic lupus erythematosus. Lupus 19, 1012–1019 (2010).

sensors and type I interferon production in systemic lupus erythematosus. Front. Immunol. 4, 319 (2013).

lupus erythematosus. Front. Immunol. 4, 319 (2013). NATURE REVIEWS | NEPHROLOGY nrneph 2015.33_JUN15.indd 339

NATURE REVIEWS | NEPHROLOGY

nrneph

2015.33_JUN15.indd

339

VOLUME 11 | JUNE 2015 | 339

12/05/2015

16:08

REVIEWS 106. Zhou, X. J. et al. Association of TLR9 gene polymorphisms with lupus nephritis

REVIEWS

106. Zhou, X. J. et al. Association of TLR9 gene polymorphisms with lupus nephritis in a Chinese Han population. Clin. Exp. Rheumatol. 28, 397–400 (2010).

107. Jacob, C. O. et al. Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus. Proc. Natl Acad. Sci. USA 106, 6256–6261 (2009).

108. Barrat, F. J. et al. Treatment of lupus-prone mice with a dual inhibitor of TLR7 and TLR9 leads to reduction of autoantibody production and amelioration of disease symptoms. Eur. J. Immunol. 37, 3582–3586 (2007).

109. Christensen, S. R. et al. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25, 417–428

(2006).

110. Verstrepen, L. et al. ABINs: A20 binding inhibitors of NF-kappa B and apoptosis signaling. Biochem. Pharmacol. 78, 105–114

(2009).

111. Lewis, M. J. et al. BE2L3 polymorphism amplifies NF-κB activation and promotes plasma cell development, linking linear ubiquitination to multiple autoimmune diseases. Am. J. Hum. Genet. 96, 221–234 (2015).

112. Zuo, X. B. et al. Variants in TNFSF4, TNFAIP3, TNIP1, BLK, SLC15A4 and UBE2L3 interact to confer risk of systemic lupus erythematosus

in Chinese population. Rheumatol. Int. 34,

459–464 (2014).

113. Hovelmeyer, N. et al. A20 deficiency in B cells enhances B-cell proliferation and results in the development of autoantibodies. Eur. J. Immunol.

41, 595–601 (2011).

114. Caster, D. J. et al. ABIN1 dysfunction as a genetic basis for lupus nephritis. J. Am. Soc. Nephrol. 24, 1743–1754 (2013).

115. Bates, J. S. et al. Meta-analysis and imputation identifies a 109 kb risk haplotype spanning TNFAIP3 associated with lupus nephritis and hematologic manifestations. Genes Immun. 10, 470–477 (2009).

116. Zhou, Y. et al. Multiple lupus-associated ITGAM variants alter Mac-1 functions on neutrophils. Arthritis Rheum. 65, 2907–2916 (2013).

117. Fagerholm, S. C. et al. The CD11b-integrin (ITGAM) and systemic lupus erythematosus. Lupus 22, 657–663 (2013).

118. Ross, G. D. & Ve˘tvicka, V. CR3 (CD11b, CD18):

a phagocyte and NK cell membrane receptor

with multiple ligand specificities and functions. Clin. Exp. Immunol. 92, 181–184 (1993).

119. Kim-Howard, X. et al. ITGAM coding variant (rs1143679) influences the risk of renal disease, discoid rash and immunological manifestations in patients with systemic lupus erythematosus with European ancestry. Ann. Rheum. Dis. 69, 1329–1332 (2010).

120. Yang, W. et al. ITGAM is associated with disease susceptibility and renal nephritis of systemic lupus erythematosus in Hong Kong Chinese and Thai. Hum. Mol. Genet. 18, 2063–2070 (2009).

121. Orme, J. & Mohan, C. Macrophages and neutrophils in SLE-An online molecular catalog. Autoimmun. Rev. 11, 365–372 (2012).

122. Crispín, J. C., Hedrich, C. M. & Tsokos, G. C. Gene-function studies in systemic lupus erythematosus. Nat. Rev. Rheumatol. 9, 476–484 (2013).

123. Seredkina, N. et al. Lupus nephritis: enigmas, conflicting models and an emerging concept. Mol. Med. 19, 161–169 (2013).

124. Rekvig, O. P. & Van der Vlag, J. The pathogenesis and diagnosis of systemic lupus erythematosus:

still not resolved. Semin. Immunopathol. 36, 301–311 (2014).

125. Zhou, T. B. et al. Relationship between angiotensin-converting enzyme insertion/ deletion gene polymorphism and systemic lupus erythematosus/lupus nephritis: a systematic review and metaanalysis. J. Rheumatol. 39, 686–693 (2012).

126. Chung, S. A. et al. Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production. PLoS Genet. 7, e1001323 (2011).

127. Liu, K. et al. Kallikrein genes are associated with lupus and glomerular basement membrane- specific antibody-induced nephritis in mice and humans. J. Clin. Invest. 119, 911–923 (2009).

128. Ciferska, H. et al. Expression of nucleic acid binding Toll-like receptors in control, lupus and transplanted kidneys--a preliminary pilot study. Lupus 17, 580–585 (2008).

129. Papadimitraki, E. D. et al. Glomerular expression of toll-like receptor-9 in lupus nephritis but not in normal kidneys: implications for the amplification of the inflammatory response. Lupus 18, 831–835 (2009).

130. Patole, P. S. et al. Expression and regulation of Toll-like receptors in lupus-like immune complex glomerulonephritis of MRL-Fas(lpr) mice. Nephrol. Dial. Transplant. 21, 3062–3073 (2006).

131. Ka, S. M. et al. Mesangial cells of lupus-prone mice are sensitive to chemokine production. Arthritis Res. Ther. 9, R67 (2007).

132. Liu, S. et al. TRAF6 knockdown promotes survival and inhibits inflammatory response to lipopolysaccharides in rat primary renal proximal tubule cells. Acta Physiol. (Oxf.) 199, 339–346

(2010).

133. Benigni, A. et al. Involvement of renal tubular Toll-like receptor 9 in the development of tubulointerstitial injury in systemic lupus. Arthritis Rheum. 56, 1569–1578 (2007).

134. Machida, H. et al. Expression of Toll-like receptor 9 in renal podocytes in childhood-onset active and inactive lupus nephritis. Nephrol. Dial. Transplant. 25, 2530–2537 (2010).

135. Frieri, M. et al. Toll-like receptor 9 and vascular endothelial growth factor levels in human kidneys from lupus nephritis patients. J. Nephrol. 25, 1041–1046 (2012).

136. Lichtnekert, J. et al. Trif is not required for immune complex glomerulonephritis: dying cells activate mesangial cells via Tlr2/Myd88 rather than Tlr3/Trif. Am. J. Physiol. Renal Physiol. 296, F867–F874 (2009).

137. Kunter, U. et al. Combined expression of A1 and A20 achieves optimal protection of renal proximal tubular epithelial cells. Kidney Int. 68, 1520–1532 (2005).

138. Lutz, J. et al. The A20 gene protects kidneys from ischaemia/reperfusion injury by suppressing pro-inflammatory activation. J. Mol. Med. (Berl.) 86, 1329–1339 (2008).

139. da Silva, C. G. et al. Hepatocyte growth factor preferentially activates the anti-inflammatory arm of NF-κB signaling to induce A20 and protect renal proximal tubular epithelial cells from inflammation. J. Cell Physiol. 227, 1382–1390

(2012).

140. Reiser, J. et al. Induction of B7–1 in podocytes is associated with nephrotic syndrome. J. Clin. Invest. 113, 1390–1397 (2004).

141. Shimada, M. et al. Toll-like receptor 3 ligands induce CD80 expression in human podocytes via an NF-κB-dependent pathway. Nephrol. Dial. Transplant. 27, 81–89 (2012).

142. Ishimoto, T. et al. Toll-like receptor 3 ligand, polyIC, induces proteinuria and glomerular CD80, and increases urinary CD80 in mice. Nephrol. Dial. Transplant. 28, 1439–1446

(2013).

143. Yu, C. C. et al. Abatacept in B7-1-positive proteinuric kidney disease. N. Engl. J. Med. 369, 2416–2423 (2013).

144. Ichinose, K. et al. Cutting edge: calcium/ calmodulin-dependent protein kinase type IV is essential for mesangial cell proliferation and lupus nephritis. J. Immunol. 187, 5500–5504

(2011).

145. Fu, S. M., Deshmukh, U. S. & Gaskin, F. Pathogenesis of systemic lupus erythematosus revisited 2011: end organ resistance to damage, autoantibody initiation and diversification, and HLA-DR. J. Autoimmun. 37, 104–112 (2011).

146. Ge, Y. et al. Cgnz1 allele confers kidney resistance to damage preventing progression of immune complex-mediated acute lupus glomerulonephritis. J. Exp. Med. 210, 2387–2401 (2013).

147. Dai, C. et al. Genetics of systemic lupus erythematosus: immune responses and end organ resistance to damage. Curr. Opin. Immunol. 31, 87–96 (2014).

148. Guo, Y., Orme, J. & Mohan, C. A genopedia of lupus genes - lessons from gene knockouts. Curr. Rheumatol. Rev. 9, 90–99 (2013).

149. Shao, W. H. & Cohen, P. L. Disturbances of apoptotic cell clearance in systemic lupus erythematosus. Arthritis Res. Ther. 13, 202

(2011).

150. Pieterse, E. & Van der Vlag, J. Breaking immunological tolerance in systemic lupus erythematosus. Front. Immunol. 5, 164 (2014).

151. Hartleben, B. et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J. Clin. Invest. 120, 1084–1096 (2010).

152. Yaniv, G. et al. A volcanic explosion of autoantibodies in systemic lupus erythematosus:

a diversity of 180 different antibodies found in

SLE patients. Autoimmun. Rev. 14, 75–79 (2015).

153. Mehra, S. & Fritzler, M. J. The spectrum of anti- chromatin/nucleosome autoantibodies:

independent and interdependent biomarkers of disease. J. Immunol. Res. 2014, 368274 (2014).

154. Gatto, M. et al. Emerging and critical issues in the pathogenesis of lupus. Autoimmun. Rev. 12, 523–536 (2013).

155. Rekvig, O. P. & Van der Vlag, J. The pathogenesis and diagnosis of systemic lupus erythematosus:

still not resolved. Semin. Immunopathol. 36, 301–311 (2014).

156. Munoz, L. E. et al. The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat. Rev. Rheumatol. 6, 280–289 (2010).

157. Cohen, P. L. et al. Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J. Exp. Med. 196, 135–140 (2002).

158. Rodriguez-Manzanet, R. et al. T and B cell hyperactivity and autoimmunity associated with niche-specific defects in apoptotic body clearance in TIM-4-deficient mice. Proc. Natl Acad. Sci. USA 107, 8706–8711 (2010).

159. Knight, J. S. & Kaplan, M. J. Lupus neutrophils:

‘NET’ gain in understanding lupus pathogenesis. Curr. Opin. Rheumatol. 24, 441–450 (2012).

160. Magna, M. & Pisetsky, D. S. The role of HMGB1

in the pathogenesis of inflammatory and

autoimmune diseases. Mol. Med. 20, 138–146

(2014).

161. Cunninghame Graham, D. S., Akil, M. & Vyse, T. J. Association of polymorphisms across the tyrosine kinase gene, TYK2 in UK SLE families. Rheumatology (Oxford) 46, 927–930 (2007).

162. Mevorach, D. Clearance of dying cells and systemic lupus erythematosus: the role of C1q and the complement system. Apoptosis 15, 1114–1123 (2010).

340 | JUNE 2015 | VOLUME 11

nrneph

2015.33_JUN15.indd

340

www.nature.com/nrneph

12/05/2015

16:08

REVIEWS

163.

Leffler, J., Bengtsson, A. A. & Blom, A. M. The complement system in systemic lupus erythematosus: an update. Ann. Rheum. Dis. 73, 1601–1606 (2014).

systemic lupus erythematosus. Rheumatology (Oxford) 50, 682–688 (2011).

181. Vang, T. et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function

198. Salloum, R. et al. Genetic variation at the IRF7/ PHRF1 locus is associated with autoantibody profile and serum interferon-alpha activity in lupus patients. Arthritis Rheum. 62, 553–561

164.

Saxena, R., Mahajan, T. & Mohan, C. Lupus

Liu, Y. & Anders, H. J. Lupus nephritis: from

variant. Nat. Genet. 37, 1317–1319 (2005).

(2010).

165.

nephritis: current update. Arthritis Res. Ther. 13, 240 (2011).

pathogenesis to targets for biologic treatment. Nephron Clin. Pract. 128, 224–231 (2014).

182. Arechiga, A. F. et al. Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs B cell signaling. J. Immunol. 182, 3343–3347 (2009).

199. Baccala, R. et al. Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus. Proc. Natl Acad. Sci. USA 110, 2940–2945 (2013).

166.

Liu, Z. & Davidson, A. Taming lupus-a new understanding of pathogenesis is leading to clinical advances. Nat. Med. 18, 871–882

183. Menard, L. et al. The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J. Clin. Invest. 121, 3635–44 (2011).

200. Lessard, C. J. et al. Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large- scale multiracial replication study. Am. J. Hum.

(2012).

184. Wang, C. et al. Genes identified in Asian

Genet. 90, 648–660 (2012).

167.

Putterman, C. New approaches to the renal pathogenicity of anti-DNA antibodies in systemic lupus erythematosus. Autoimmun. Rev. 2, 7–11

SLE GWASs are also associated with SLE in Caucasian populations. Eur. J. Hum. Genet. 21, 994–999 (2013).

201. Shen, N. et al. Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus. Proc. Natl Acad.

(2004).

185. Namjou, B. et al. High-density genotyping of STAT4

Sci. USA 107, 15838–15843 (2010).

168.

Kozyrev, S. V. et al. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat. Genet. 40, 211–216

reveals multiple haplotypic associations with systemic lupus erythematosus in different racial groups. Arthritis Rheum. 60, 1085–1095 (2009).

202. Deng, Y. et al. MicroRNA-3148 modulates allelic expression of toll-like receptor 7 variant associated with systemic lupus erythematosus.

(2008).

186. Harley, J. B. et al. Genome-wide association scan

PLoS Genet. 9, e1003336 (2013).

169.

Yang, W. et al. Genome-wide association study

in women with systemic lupus erythematosus

203. Zhang, J. et al. Association study of TLR-9

in

Asian populations identifies variants in ETS1

identifies susceptibility variants in ITGAM, PXK,

polymorphisms and systemic lupus

and WDFY4 associated with systemic lupus

KIAA1542 and other loci. Nat. Genet. 40,

erythematosus in northern Chinese Han

erythematosus. PLoS Genet. 6, e1000841

204–210 (2008).

population. Gene 533, 385–388 (2014).

(2010).

187. Manku, H. et al. Trans-ancestral studies fine

188. Molineros, J. E. et al. Admixture mapping in

189. Cunninghame Graham, D. S. et al. Association

190. Westra, H. J. et al. Systematic identification

191. Kaufman, K. M. et al. Fine mapping of Xq28:

204. Wang, S. et al. An enhancer element harboring

170.

Sanchez, E. et al. Identification of novel genetic

(2011).

map the SLE-susceptibility locus TNFSF4.

variants associated with systemic lupus

susceptibility loci in African American lupus patients in a candidate gene association study. Arthritis Rheum. 63, 3493–3501

PLoS Genet. 9, e1003554 (2013).

lupus identifies multiple functional variants within IFIH1 associated with apoptosis,

erythematosus engages the TNFAIP3 promoter to influence A20 expression. PLoS Genet. 9, e1003750 (2013).

171.

Hom, G. et al. Association of systemic lupus

inflammation, and autoantibody production.

205. Agik, S. et al. The autoimmune disease risk allele of UBE2L3 in African American patients

172.

erythematosus with C8orf13-BLK and ITGAM- ITGAX. N. Engl. J. Med. 358, 900–909 (2008).

PLoS Genet. 9, e1003222 (2013).

of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with

with systemic lupus erythematosus: a recessive effect upon subphenotypes. J. Rheumatol. 39, 73–8 (2012).

Han, J. W. et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat. Genet. 41, 1234–1237

(2009).

systemic lupus erythematosus. PLoS Genet. 7, e1002341 (2011).

of trans eQTLs as putative drivers of known

206. Wang, S. et al. A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus. Genes Immun. 13, 380–387 (2012).

173.

Guthridge, J. M. et al. Two functional lupus-

(2014).

disease associations. Nat. Genet. 45,

207. Shin, H. D. et al. Common DNase I polymorphism associated with autoantibody production among

associated BLK promoter variants control cell-type- and developmental-stage-specific

1238–1243 (2013).

systemic lupus erythematosus patients. Hum. Mol. Genet. 13, 2343–2350 (2004).

transcription. Am. J. Hum. Genet. 94, 586–598

both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple

208. Han, S. et al. Evaluation of imputation-based association in and around the integrin-alpha-M

209. Rhodes, B. et al. The rs1143679 (R77H) lupus

174.

Okada, Y. et al. A genome-wide association study

Lee, H. S. et al. Ethnic specificity of lupus-

(ITGAM) gene and replication of robust

175.

identified AFF1 as a susceptibility locus for systemic lupus eyrthematosus in Japanese. PLoS Genet. 8, e1002455 (2012).

associated loci identified in a genome-wide association study in Korean women. Ann. Rheum. Dis. 73, 1240–1245 (2014).

ancestral groups. Ann. Rheum. Dis. 72, 437–444 (2013).

192. Koelsch, K. A. et al. Functional characterization of the MECP2/IRAK1 lupus risk haplotype in human T cells and a human MECP2 transgenic mouse. J. Autoimmun. 41, 168–174 (2013).

193. Graham, R. R. et al. A common haplotype of interferon regulatory factor 5 (IRF5) regulates

association between a non-synonymous functional variant within ITGAM and systemic lupus erythematosus (SLE). Hum. Mol. Genet. 18, 1171–1180 (2009).

associated variant of ITGAM (CD11b) impairs complement receptor 3 mediated functions

63.

Yang, W. et al. Meta-analysis followed by replication identifies loci in or near CDKN1B,

Liu, P. et al. IL-10 gene polymorphisms and

splicing and expression and is associated

in human monocytes. Ann. Rheum. Dis. 71, 2028–2034 (2012).

176.

TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians. Am. J. Hum. Genet. 92, 41–51 (2013).

susceptibility to systemic lupus erythematosus:

with increased risk of systemic lupus erythematosus. Nat. Genet. 38, 550–555 (2006).

194. Graham, R. R. et al. Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proc. Natl Acad. Sci. USA 104, 6758–6763 (2007).

210. Fossati-Jimack, L. et al. Phagocytosis is the main CR3-mediated function affected by the lupus- associated variant of CD11b in human myeloid cells. PLoS One 8, e57082 (2013).

a

meta-analysis. PLoS One 8, e69547 (2013).

195. Sigurdsson, S. et al. Comprehensive evaluation

211. Namjou, B. et al. Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes

177.

Gateva, V. et al. A large-scale replication study

(2009).

of the genetic variants of interferon regulatory

Immun. 12, 270–279 (2011).

identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat. Genet. 41, 1228–1233

factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus. Hum. Mol. Genet. 17, 872–881 (2008).

Acknowledgements The authors would like to acknowledge the editorial assistance of Simanta Pathak, University of Houston,

178.

Lu, R. et al. Genetic associations of LYN with systemic lupus erythematosus. Genes Immun. 10, 397–403 (2009).

196. Lofgren, S. E. et al. Promoter insertion/deletion in the IRF5 gene is highly associated with susceptibility to systemic lupus erythematosus

(2010).

USA. Relevant studies in Dr. Putterman’s laboratory were supported by grants from the NIH, DK090319 and AR048692. Dr. Putterman is currently a Weston

179.

Zhou, X. J. et al. Genetic association of PRDM1-

in distinct populations, but exerts a modest

Visiting Professor at the Weizmann Institute.

ATG5 intergenic region and autophagy with systemic lupus erythematosus in a Chinese population. Ann. Rheum. Dis. 70, 1330–1337

effect on gene expression in peripheral blood mononuclear cells. J. Rheumatol. 37, 574–578

Author contributions Both authors researched the data for the article,

(2011).

197. Fu, Q. et al. Association of a functional IRF7

provided substantial contributions to discussions of