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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

Introduction
Systemic lupus erythematosus (SLE) is a chronic auto­ activate T cells, and produce key mediators such as B-cell
immune inflammatory disease that can affect the major­ activating factor; this effect results in the activation of
ity of organs and tissues. The clinical presentations the adaptive immune system.12–14 Activation of the sys­
of SLE can range from mild to severe and the course of temic immune system leads to the generation of effec­
the disease is unpredictable, with periods of remission tor T cells and autoantibodies that can subsequently
and flares. Lupus nephritis is a severe consequence of target organs, such as the kidneys.13,15,16 These effectors,
SLE and an important driver of morbidity and mortality together with numerous soluble mediators, elicit chronic
in SLE. Lupus nephritis affects ~40–70% of patients with inflammation within glomerular and tubulointerstitial
SLE, with the exact incidence dependent on ethnicity, age sites in the kidneys. By contrast, the contribution of
group, and gender. Both systemic and intra-renal events intrinsic renal cells versus systemic leucocytes in the
are important in the pathogenesis of lupus nephritis.1–4 pathogenesis of lupus nephritis is poorly understood.
At the systemic level, both the adaptive and innate Detailed reports describing the systemic and intra-renal
branches of the immune system contribute to the devel­ events in the pathogenesis of lupus nephritis have been
opment of SLE. The two predominant cell types involved reviewed elsewhere.6,13,15–20
in the adaptive immune system, B lymphocytes (B cells) The present Review categorizes the genes implicated
and T lymphocytes (T cells), are both essential for the in SLE according to the cell types and molecular path­
development of lupus nephritis.2–6 B cells are pathogenic ways in which they are expressed, to gain insight into the
in SLE because of the autoantibodies (for example, anti- key pathogenic contributors that lead to lupus nephritis.
Department of
DNA antibodies and anti-nucleosome anti­bodies) and We first introduce the methods by which novel genetic
Bioengineering, cytokines that they produce.7,8 T cells drive the systemic loci have been identified and the functional studies
University of Houston, and intra-renal activation of B cells. Subtypes of T cells, performed to characterize candidate genes. Next, we
3605 Cullen Boulevard,
Houston, TX 77204, including type 1 T‑helper (TH1) cells, type 17 T-helper discuss the genes that are implicated in the activation
USA (C.M.). Division of (T H17) cells, and CD3 +CD4 –CD8 – ‘double negative’ of the adaptive and innate immune systems, as well as
Rheumatology, Albert
Einstein College of
TH cells, have been implicated in the pathogenesis of those that are involved in the intra-renal processes that
Medicine, 1300 Morris lupus nephritis.9–11 The innate immune system contrib­ promote tissue damage. We conclude by discussing the
Park Avenue, Bronx, utes to the pathogenesis of SLE in multiple ways. In the potential mol­e cules that might affect the amount of
NY 10461, USA (C.P.).
early stages of disease, dendritic and other myeloid cells accessible chromatin that is generated from apoptotic
Correspondence to: cells. While the organization of SLE and lupus nephri­
C.M.
cmohan@ Competing interests tis candidate genes into these particular pathways is not
central.uh.edu The authors declare no competing interests. fixed and alternate classification schemes might also be

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Key points respectively); some of these associations have been


reviewed elsewhere.22 Additional murine models should
■■ Some genes implicated in systemic lupus erythematosus (SLE) and lupus
be generated that mimic more closely the type of genetic
nephritis might contribute to the pathology of disease by breaching immune
tolerance and promoting autoantibody production mutations that are observed among human patients with
■■ A subset of SLE and/or lupus nephritis genes might augment innate immune SLE and lupus nephritis; these specific mutations (SNPs,
signalling and IFN-I production; other SLE genes might modulate the molecular CNVs and splice isoforms) should be subsequently
pathways that lead to renal tissue damage validated for their ability to promote SLE in genetically
■■ Genes that affect the accessibility and handling of apoptotic material and ­engineered murine models.
chromatin might also contribute to SLE and/or lupus nephritis
■■ The presence of cognate antigens on the glomerular matrix, together with
Categorizing genes implicated in SLE
intrinsic molecular abnormalities in resident renal cells, could further
accentuate disease progression in lupus nephritis
The identified genes implicated in SLE can be assigned to
■■ Differential involvement of the above-listed mechanisms in patients could one of four functional categories: genes that affect lym­
potentially explain the wide spectrum of clinical phenotypes observed among phocyte activation, particularly B cells; genes that affect
individuals with SLE and lupus nephritis innate immune signalling, notably NF-κB activation and
IFN‑I signalling; genes that might function within the
kidneys, potentially promoting renal tissue damage; and
suitable, we find the following categories to be a useful genes that influence the handling of apoptotic debris,
framework for understanding the genetic contributions chromatin, and immune complexes bearing these anti­
to SLE and lupus nephritis. gens. These categories have been designated on the basis
of a priori information regarding the cell types in which
Gene discovery the identified genes are expressed and their known
Genome-wide association studies molecular function; however, alternative pathways and
Genome-wide association studies (GWAS) that aimed to models cannot be excluded.
identify genetic loci linked with SLE were initiated more
than 6 years ago.17–21 Thus far, >10 GWAS have been con­ Genetic composition of SLE and lupus nephritis
ducted using samples obtained from patients with SLE Although a given patient might harbour mutations in
that encompass multiple ethnic groups, and have collec­ multiple genes from a given functional category, whether
tively identified >50 genes associated with SLE. Although the inheritance of one or more genes from each cat­egory
the focus of these GWAS has not been exclusive to lupus proposed above is required for the development of SLE
nephritis, the inclusion of patients with lupus nephritis and/or lupus nephritis is unclear. Murine models of
in these studies has provided important insights into the SLE and/or lupus nephritis have been insightful in
potential pathogenic pathways that lead to both SLE and this respect as genes from all four categories have been
lupus nephritis. Several genes identified from GWAS implicated through both forward and reverse genetic
and additional candidate genes have been validated in approaches.23–26 Congenic dissection (where multiple
independent patient cohorts as being associated with SLE genes mediating a polygenic disease are separated into a
or lupus nephritis. Table 1 lists some of the key genes that collection of congenic strains) and congenic reconstitu­
have been implicated in the pathogenesis of SLE and/or tion studies (involving genetic crossing of each separate
lupus nephritis; this list is not exhaustive and additional congenic strain) of SLE-associated polymorphic vari­
studies are ongoing. ants have generated three main findings. Firstly, genes
that only affect lymphocyte function might lead to the
Genetic aberrations implicated in SLE production of antinuclear antibodies or IgM polyreac­
Although numerous genes have been implicated in SLE tivity but not lupus nephritis, suggesting that simply the
and/or lupus nephritis (Table 1), questions remain as presence of these antibodies is not sufficient for renal
to their function in disease pathology. Firstly, the spe­ pathology to ensue. Secondly, genes that activate innate
cific causative mutations and subsequent molecular immune signalling in isolation might result in the pro­
alterations that contribute to the disease phenotype duction of inter­mediate levels of anti-DNA antibodies
have not been firmly established for many of the identi­ (compared to polygenic strains with complete SLE) and
fied candidate genes. Coding region single nucleotide non-­proliferative glomerulonephritis. Finally, the epi­
poly­morph­isms (SNPs), polymorphisms that lead to static interaction between genes from multiple categories
differential alternative splicing, polymorphisms in the is required for severe lupus nephritis to develop.27–30 The
3' untranslated region (UTR) that influence gene expres­ emerging concept of genetic interaction is exemplified by
sion, and copy number variants (CNVs) have all been a series of congenic dissection and reconstitution studies
documented. This catalogue of implicated molecular that have been performed using the C57Bl/6 (B6) mouse
vari­ations in each gene is likely to expand as more infor­ strain, as illustrated in Figure 1.27,29–32
mation becomes available from deep sequencing studies Through extrapolation of the genetic data obtained
that are currently in progress. Secondly, the association from murine congenic dissection and reconstitution
between these candidate genes and SLE or lupus nephri­ studies, it could be predicted that genes from mul­
tis has only been inferred from studies using murine tiple functional categories would act in concert to
models that have been engineered to either lack or promote lupus nephritis in human patients. Although
overexpress the gene (using knockouts or transgenics, it is apparent which functional pathways the majority of

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Table 1 | Susceptibility genes implicated in human SLE or LN* Adaptive immune system activation
Modulation of B‑cell receptor signalling
Gene name Association with SLE Association with LN
T cells, B cells and autoantibodies have been shown to
Lymphocyte signalling have an essential function in lupus nephritis, with the
BANK1 Yes168–170 Unknown majority of the evidence originating from mechanistic
BLK Yes169–175 Yes70 studies performed in mice.1,17–20 A conglomerate of SLE-
CD80 Yes 63
Unknown associated genes collectively regulates B-cell signalling
via the B‑cell receptor, BCR (Figure 2). BANK1 is a
CSK Yes50 Unknown
scaffold adaptor protein primarily expressed in B cells
ETS1 Yes169,172,174,175 Unknown
that amplifies B‑cell signalling by linking the activa­
HLA DR Yes 58,59,174
Yes70,71 tion of Src-family kinases, such as LYN, with the acti­
IL-10 Yes 176,177
Unknown vation of the IP3 receptor, leading to calcium influx.
LYN Yes178 Unknown Stimulation of BCR facilitates the association of BANK1
PP2A Yes 74
Unknown
with PLCγ2, resulting in PLCγ2 activation, expression
of IP3 and DAG, and subsequent activation of PRKCB,
PRDM1 (BLIMP1) Yes177,179 Unknown
another gene implicated in SLE.33–36
PRKCB Yes180 Unknown RasGRP3—one of the downstream molecules acti­
PTPN22 Yes 51,53,181–183
Unknown vated by the BCR pathway—has also been implicated
RasGRP3 Yes172,184 Unknown in SLE (Figure 2). RasGRP3 amplifies downstream Ras-
STAT4 Yes 170,172,174,175,185,186
Yes70,72
mediated ERK and MAPK signalling in B cells, and is
associated with B-cell proliferation and antibody pro­
TNFSF4 (OX40L) Yes 169,170,172,175,187
Yes76,77
duction. PRKCB and RasGRP3 are expressed in B cells,
Innate immune signalling T cells, myeloid cells, and endothelial cells, and thus
IFIH1 Yes188,189 Unknown could contribute to the progression of SLE through
IKZF1 Yes172,175,189,190 Yes81 several different pathways.37–41 Although genetic manip­
ILT3 Yes24 Unknown ulation studies of Bank1 and Rasgrp3 are yet to be pub­
lished, the available data suggest that PRKCB might be
IRAK1 Yes 107,191,192
Unknown
necessary for the development of SLE and lupus nephritis
IRF5 Yes23,169,172,175,193–196 Yes70,83 in mice.42
IRF7 Yes197,198 Unknown
IRF8 Yes 189,199,200
Unknown Src-family tyrosine kinases
TLR7 Yes201,202 Unknown Three SLE-associated B-cell genes, LYN, BLK and CSK,
are Src-family tyrosine kinases that might have direct or
TLR9 Yes203 Yes87
indirect inhibitory roles on BCR signalling.42–46 The fact
TNFAIP3 (A20) Yes 21,169,172,174,175,204
Yes101
that Lyn-deficient mice develop B-cell hyperactivity with
TNIP3 (ABIN3) Yes172,177 Yes94 associated autoimmunity is well documented.44–46 The
TYK2 Yes 161,189
Unknown inhibitory effect of LYN on B-cell signalling is mediated
UBE2L3 Yes205,206 Unknown in part by phosphorylation and subsequent activation
of the inhibitory B-cell surface receptors, CD22 and
Intra-renal signalling
FcGR2B. The CD22 and FcGR2B receptors function
ACE Yes125 Yes125
through SHIP and SHP-1 phosphatases and dampen
COL25A1 Yes126 Unknown B-cell activation as a consequence.43
KLK Yes127 Yes127 One function of BLK is to promote the inter­action
LAMC2 Yes 126
Unknown between BANK1 and PLCγ2 (Figure  2). Reduced
Immune complex clearance
expression of BLK is associated with reduced numbers
of pre-B cells and marginal zone B cells. Reduced expres­
ATG5 Yes179 Unknown
sion of BLK can also promote renal disease in B6 mice
DNAse1 Yes207 Unknown that are prone to SLE.47,48
FCGR2A, 3A, 3B Yes95–100,170,186 Yes96 The third Src-family kinase, CSK, can phosphory­
ITGAM Yes 170,186,208–210
Yes77,102,106 late and regulate LYN. 49 Overexpression of CSK is
TREX1 Yes 211
Unknown observed among patients with SLE that carry the CSK
risk allele, and leads to increased phosphorylation of
*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. 2–5 LYN; this effect is associated with elevated production
Abbreviations: LN, lupus nephritis; SLE, systemic lupus erythematosus.
of ­antibodies and transitional B cells.50

SLE-associated genes are most likely to impact, for some PTPN22


genes the functional pathway is unclear. For example, PTPN22 has been implicated in several autoimmune
complement genes and proteins could potentially diseases, including SLE, and the effect of a disease-­
exert effects on several pathways, including chromatin associated variant of Ptpn22 on systemic autoimmun­
­handling and B-cell activation. ity has been verified using murine models.51 PTPN22

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Wild-type a Adaptive b Innate c End-organ


C57Bl/6 Gene 1 immunity immunity disease
Gene 2 Gene 3
e.g. Ly108 e.g. Sle3 e.g. Klk
Ly108 Ly108 Ly108

Sle3 Sle3 Klk

Figure 1 | Stepwise evolution of systemic lupus erythematosus (SLE) as a function of genetic load. The schematic depicts
Nature Reviews | Nephrology
how genetic dissection studies in the mouse have been used to investigate the evolution and pathology of SLE. 27,29–31
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 T-cell the autoantigens that they bind to, and subsequently
receptor signalling threshold and downstream activa­ present autoantigen-derived peptides to T H cells
tion of AKT in both B cells and T cells.32–36,42 In addition through their MHC-II molecules, as demonstrated for
to activating B cells, PTPN22 also modulates the extent nucleosome-­derived histone epitopes.57 MHC-II mol­
of the regulatory T (TREG) cell pool, and affects myeloid ecules, notably HLA-DR2 and HLA-DR3, represent
cell-signalling.52–55 Specifically, the numbers of thymic two of the best characterized genes with the strongest
and TREG cells vary inversely with the levels of PTPN22,54 associ­ation with SLE;58,59 however, the available infor­
whereas PTPN22 deficiency reduces IFN-I production mation with regard to their role in SLE is difficult to
and augments inflammation.55 interpret. Multiple HLA-DR2 and HLA-DR3 alleles, as
At present, it is not fully understood how LYN, BLK, well as several additional HLA alleles, are associated
CSK and PTPN22 interact to fine-tune BCR signalling, or with SLE. The strength of the association and specific
how SNPs in various genes within this axis might impact allele(s) implicated in SLE depends on the ethnic group
the overall strength of the signalling cascade. Given that and clinical presentation being studied.58–60 Different
SNPs in all of the above genes can modulate the extent SLE-associated HLA MHC-II alleles have documented
of BCR signalling, it would be interesting to determine associations with other autoimmune diseases, such as
whether an increasing number of genetic hits in this diabetes mellitus and Sjögren syndrome.60
pathway confer increased risk for SLE or lupus nephritis; Co-stimulatory molecular pairs, such as CD28–
data to support this concept are currently lacking. CD80, CD40–CD40L and OX40–OX40L (also known as
TNFSF4), also have an important function in the bilat­
Interaction of BCRs with Toll-like receptors eral amplification of lymphocyte cross-talk (Figure 2).61
Interaction between the signalling pathways triggered Among these co-stimulatory molecules, OX40L and
by the BCR and Toll-like receptors (TLRs) can serve CD80 have been implicated in susceptibility to SLE
to amplify B-cell signalling. SLE autoantigens, such as (Table 1).17–20,62,63 Interaction between OX40 and CD123
DNA and RNA, can also bind to TLRs such as TLR9 or TNFSF4 on activated T cells might result in the gener­
and TLR7.56 This interaction in turn activates a signal­ ation of IL-10-producing TREG cells.62 These same pairs of
ling pathway that is shared with innate immune cells, co-stimulatory molecules might also regulate the inter­
involving MYD88, IRAK4 and IRAK1, which eventu­ action between specialized antigen-presenting cells, such
ally leads to the activation of NF-κB, IRF5, and IRF7 as dendritic cells, and T cells (Figure 2).
(Figure 2). These transcription factors are responsible for
the increased survival of B cells, autoantibody produc­ Generation of immune effector cells
tion and the production of several cytokines, including The activation of B cells and T cells leads to the gen­
IFN-I. Importantly, several molecules in this pathway eration of effector cells, which can subsequently cause
constitute SLE-associated genes, including TLR7, IRAK1, tissue injury. Such effector cells include plasma cells and
IRF5, IRF7, and molecules that regulate NF-κB activa­ TH17 cells, both of which have been implicated in the
tion such as UBE2L3, TNFAIP3 and TNIP3 (Figure 2). pathogenesis of lupus nephritis.64–67 ETS1 and PRDM1
These genes will be discussed in the analysis of the innate (also known as BLIMP1) are two molecules that can regu­
immune system. late the generation of both plasma cells and TH17 cells.
Evidence suggests that expression of the mRNA transcript
Cross-talk between T cells and B cells for the negative regulator ETS1 is reduced in peripheral
SLE-associated genes might mediate cross-talk between blood mononuclear cells of patients with SLE, and Ets1
lymphocytes. B cells are able to endocytose and process ablation leads to SLE in mice.68,69 Conversely, blockade

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Nuclear antigen

B-cell receptor
T cell B cell
CSK* PTPN22*
B-cell LYN*
receptor
signalling BANK1* Endosome
CD80* CD28 BLK1*

TLR7*

TLR9*
PLCγ2

TLR8
OX40L* OX40
IP3 DAG
CD40 CD40L
Myd88
PRKCB* TRAF6 IRAK4
MHCII* TCR
IRAK1*
PTPN22* RasGRP3* UBE2L3*
CSK* TNFAIP3* NF-κB IRF5* IRF7*
Ras
STAT4* TNIP3*
Antigen- ERK
presenting PP2A*
cell
(dendritic Nucleus
cell)

ETS1*

PRDM1*
Increased survival Cytokine IFN-I
TH17 Plasma antibody production production production
cells cells

Figure 2 | Gene products associated with systemic lupus erythematosus (SLE) that might affect the adaptive
Nature immune
Reviews system.
| Nephrology
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 TH17 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; TH17 cells, T‑helper 17 cells; TLR, Toll-like receptor.

or deficiency of PRDM1 reduces the severity of SLE in HLA DRB1, STAT4 and OX40L. The presence of SNPs in
mice.70,71 Both genetic evidence from human GWAS and OX40L and expression levels of OX40L on the surface of
mechanistic studies in mice, therefore, underscore the peripheral blood mononuclear cells are both associated
importance of the generation of TH17 cells and plasma with lupus nephritis.62,78–84
cells in the pathogenesis of SLE.
Both mouse models of SLE and patients with SLE Activation of innate immune signalling
exhibit increased levels of IL-17 production and increased Modulation of IFN‑I signalling
numbers of circulating TH17 cells that correlate with SLE in both paediatric and adult patients is increas­
disease activity.72 Furthermore, IL-17 deficiency pro­ ingly recognized to have a molecular signature that is
tects mice from the development of SLE-associated glo­ characterized by over-activation of the IFN-I signal­
merulonephritis, although conflicting evidence has also ling pathway.85 IFN-I signalling is important in myeloid
been reported.72,73 Polymorphisms in PPP2A detected in cells, including monocytes and dendritic cells, and might
patients with SLE are associated with elevated expres­ also have important functions in resident renal cells.86,87
sion of the PP2A catalytic subunit (PP2Ac) in T cells and Previous studies suggest a possible genetic basis for the
decreased IL-2 production, which can be regulated by increased expression of IFN-I observed in SLE; SNPs in
miRNA–155.74,75 A transgenic mouse overexpressing Pp2ac several genes in this pathway are associated with SLE
showed increased T-cell production of IL‑17 and high (Table 1). Signalling via the IFN-I receptor is regulated
susceptibility to the development of antibody-mediated by JAK1, TYK2 and various STAT proteins, includ­
nephritis. Blockade of IL‑17 by intraperitoneal antibody ing STAT4. Importantly, SNPs in TYK2 and STAT4 are
administration markedly reduced proteinuria and histo­ associ­ated with SLE (Figure 3). Another SLE-associated
logical damage in this transgenic mouse model.76 PP2Ac gene, IKZF1, regulates the transcription of STAT4, and
has been shown to deregulate the IL-17 locus via enhanced polymorphisms in IKZF1 are also associated with lupus
histone 3 acetylation; this effect was identified in both nephritis (Figure 3).88
T cells of Pp2ac transgenic mice and in patients with SLE.77
Some of the disease genes in this category have already JAK–STAT signalling
shown an association with lupus nephritis, as summa­ Activation of STAT4 occurs not only in lympho­
rized in Table 1. These associations include SNPs in BLK, cytes but also in activated monocytes and dendritic

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IL-12 the most prominent SLE-associated RNA signature.71


FCGR2A*
Immune IL-23 Some of these IFN-I-regulated genes, such as IRF5, IRF7,
complex IFN-I
FCGR3A* ILT3 and IFIH1, are SLE-associated genes, and some
FCGR3B* can in turn regulate the expression of IFN-I and other
ITGAM* IFNAR
disease-associated cytokines.93 Of note, the IRF5 allele
JAK1 TYK2*
Endosome
implicated in SLE is associated with high serum IFN-I
LYN*
STATs activity and the development of anti-dsDNA anti­
IKZF1* STAT4* bodies.23 Similarly, the ILT3 disease-associated allele
Activation Multiple correlates with elevated IFN-I and TNF expression

TLR7*

TLR9*
TLR8
and signalling IFN-I-induced
genes
among patients with SLE.24 The increased production of
phagocytosis pathways
IFN-I that is driven by these disease alleles is expected
IRF5* to initiate a positive feedback loop that rapidly increases
IRF7*
Myd88 IFIH1* IFN-I production (Figure 3). The pathogenic importance
TRAF6 IRAK4 ILT3* of this axis is also underscored by the observation that
IRAK1*
genetic ablation or pharmacological blockade of key
UBE2L3*
molecules in this axis, such as IRF5, suppresses SLE in
TNFAIP3* NF-κB IRF5* IRF7* mice.25 Furthermore, SNPs in IRF5 are associated with
TNIP3* lupus nephritis in patients.26,70 Finally, emerging evi­
dence suggests that genetic aberrations in multiple genes
Nucleus within the IFN‑I pathway might confer increased disease
susceptibility, as exemplified by the genetic interaction
Myeloid cell
between IRF5, IKZF1 and STAT4.94

Increased Cytokine IFN-I Fc receptors for immunoglobulin


survival production production
The Fc receptors (FcRs) for IgG represent another
family of receptors that have a prominent role in the
Figure 3 | Gene products associated with systemic lupus Nature Reviews | Nephrology
erythematosus (SLE)
that might affect innate immune signalling. The schematic illustrates the
activity of myeloid cells. SNPs and CNVs affecting
signalling pathways that occur in myeloid cells that involve genes that could multiple members of this family, including FCGR2A,
influence innate immune cell function (denoted by an asterisk). Three myeloid cell FCGR3A and FCGR3B, have been associ­ated with SLE
surface receptors (ITGAM, FcR family receptors and IFNAR) are illustrated from and LN.95–100 Interestingly, some of the SNPs and CNVs
which signalling cascades are initiated upon presentation of immune complexes. in FcRs associated with lupus nephritis are characterized
The overall response is regulation of gene transcription that results in the by reduced FcR expression on the myeloid cell surface
modulation of cell survival and the production of cytokines and IFN‑I. The black membrane; this observation has led to the hypothesis
arrows represent activation and bar-headed lines represent inhibition of the target
that reduced FcR-mediated immune complex clearance
gene or process. The dashed lines represent the overall response. Abbreviation:
TLR, Toll-like receptor.
might contribute to lupus nephritis.96–98 Total ablation
of FcRs, however, prevents the development of lupus
nephritis despite the presence of anti-DNA antibodies.101
cells; indeed, monocytes from the kidneys of patients These data suggest that myeloid cells are the major cell
with autoimmune diseases also express high levels of type through which FcR ­expression can ­influence the
STAT4.89–90 Although the JAK–STAT pathway has been pathogenesis of lupus nephritis.102
shown to mediate the progression of renal fibrosis, the FcRs not only activate myeloid cells, but also enable
specific disease contributions of TYK2, STAT4 and these cells to endocytose immune complexes.103 Immune
IKZF1 in intrinsic renal cells are currently unknown. complexes present in SLE might harbour nuclear anti­
Interestingly, patients with SLE who harbour SNPs in gens, such as RNA and DNA, allowing the endocytosed
STAT4 develop symptoms of the disease at an earlier immune complexes to activate endosomal TLRs such
age compared to patients who do not carry these as TLR7, TLR8 and TLR9.104 Activation of these TLRs
SNPs; these patients also exhibit high levels of anti- recruit MYD88 and a series of additional molecules,
dsDNA anti­b odies and develop severe lupus nephri­ including IRAK4, IRAK1 and TRAF6, which together
tis.80 Furthermore, Stat4 deficiency in mice aggravates initiate various transcriptional programmes, including
lupus nephritis, as compared to mice that are Stat4- those driven by NF-κB, IRF5 and IRF7 (Figure 3).105
sufficient.81 Given that diverse cell types express STAT4, These transcriptional processes have important func­
dissecting the cellular and molecular mechanisms by tions in augmenting proinflammatory cytokine pro­
which SNPs in this gene contribute to lupus nephritis duction, including IFN-I. Several of these molecules,
poses a considerable challenge. including TLR7, TLR9, IRAK1, IRF5 and IRF7 have
been implicated as SLE-causative genes, among which,
Activation of IFN receptor by interleukins TLR9 and IRF5 have been directly associated with lupus
IL-12 and IL-23 can activate the IFN α/β receptor nephritis in patients.26,106 In addition, genetic ablation or
(IFNAR), which results in increased production of pharmacological blockade in mouse models of SLE have
­IFN-I.91,92 Consequently, a large number of genes that established a pathogenic role for Tlr7, Irak1 and Irf5 in
are regulated by IFN-I become activated, constituting this disease.25,107–109 Enhancing Tlr7 expression through

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Immune have also shown associations with lupus nephritis in


complex
FCGR2A* human patients.114,115
FCGR3A* ITGAM (also known CD11B or MAC‑1) is a myeloid-­
FCGR3B*
FCGR2A*
FCGR3A*

Glomerular
matrix FCGR3B* specific adhesion molecule with multiple ligands, includ­
ing ICAM1, ICAM2, C3bi and FGA. 116–118 ITGAM
TREX1* Endosome exhibits diverse functions under normal physiological
DNAse1*
conditions, including mediating myeloid-cell activation
Fc (leading to production of NF-κB, IL-6 and TNF), phago­
Multiple cytosis, uptake of immune complexes, and facilitating

TLR7*

TLR9*
TLR8
C1* signalling
C2* pathways interactions between myeloid cells, lymphocytes, plate­
C3* lets and endothelial cells.116–118 The ITGAM Arg77His
C4* Myd88
allele has reduced binding efficiency for ICAM1, and
TRAF6 IRAK4 thus has a potential effect on cell adhesion. The Arg77His
IRAK1* allele correlates with severe disease manifestations of
ITGAM* UBE2L3* SLE, including lupus nephritis, as well as h­ aematological
KLK* TNFAIP3* NF-κB IRF5* IRF7* and neurological phenotypes.84,119,120
TNIP3*
ACE* Intra-renal promotion of tissue damage
LAMC2* Nucleus Activation of T cells and B cells in the kidney
Myeloid Resident Genes associated with SLE can contribute to the patho­
cell COL25A1* renal cell 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.
Increased Cytokine IFN-I
survival production production Previous work has documented the existence of struc­
tures reminiscent of germinal centres and other lym­
Figure 4 | Gene products associated with systemic lupus erythematosus
Nature (SLE)
Reviews | Nephrology phocyte clusters within the inflamed kidneys of patients
that might affect intra-renal events leading to lupus nephritis. The schematic with lupus nephritis.65 All of the genes described above
depicts genes associated with SLE that might exert effects on intra-renal events in the adaptive immune system can potentially influence
that lead to lupus nephritis (denoted by an asterisk). Myeloid cells present to
lupus nephritis by activating T cells and B cells, both
resident renal cells via Fc receptors, which act in concert with complement
molecules (C1–C4). Upon stimulation by an immune complex, resident renal cells
­systemically and within the kidneys.
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 Activation of intra-renal myeloid cells
effects on cell survival, cytokine production and expression of IFN-I. The black Cells of the innate immune system, such as macrophages
arrows represent activation and bar-headed lines represent inhibition of the target and neutrophils, are present in large numbers within
gene or process. The dashed lines represent the overall response. Abbreviation: the kidneys of patients with lupus nephritis. All of the
TLR, Toll-like receptor. genes known to affect innate immune signalling, which
were outlined in the section describing the innate
gene duplication confers susceptibility to SLE and lupus immune system, can potentially influence the progres­
nephritis in mice.108,109 Multiple lines of evidence there­ sion of lupus nephritis by activating intra-renal myeloid
fore support the critical importance of this molecular cells.121,122 In addition, some of these genes, notably
axis in the pathogenesis of SLE and lupus nephritis. ITGAM and FcR, could potentially affect the level of
recruitment of myeloid cells to the glomerular matrix
Modulation of NF-κB activation via cognate binding sites on the immune complexes
Activation of NF-κB has been implicated in both SLE and deposited in the glomeruli.122 Polymorphic variants of
lupus nephritis. NF-κB can be negatively regulated by ITGAM and/or FcR that result in increased binding to
TNFAIP3 (also known as A20) and TNIP3 (also known complement components (for example, C3b) or the Fc
as ABIN3), either independently, or in concert.110 TNIP3 fragment of IgG could possibly augment myeloid cell
can bind to TNFAIP3 to facilitate NF‑κB inhibition.110 recruitment and activation (Figure 4); however, the
UBE2L3 is an E2 ubiquitin-conjugating enzyme that biochemical and mechanistic evidence to support this
can regulate the level of NF‑κB activation and result­ hypothesis is currently lacking. Conversely, evidence
ant cell proliferation.111 SNPs in TNFAIP3, TNIP3 and exists to support reduced levels of FcR and reduced FcR
UBE3L3 have shown an association with SLE in human binding ability to IgGs among patients with SLE, as will
patients (Figure 3).112 Whether multiple perturbations be discussed below.
to this pathway have an incremental effect on NF‑κB
activation remains to be explored. Murine studies have Immune complex clearance from the glomeruli
offered further evidence to support the importance Evidence suggests that SLE-associated genetic poly­
of this pathway in SLE progression. Reduced expres­ morph­isms might regulate the clearance of immune
sion of TNFAIP3 in B cells augments the production of complexes from glomerular tissue. SLE-associated SNPs
autoantibodies and germinal centre type B cells, and the in FCGR2A (Arg131) and FCGR3A (Phe158) might
development of renal disease.113 TNFAIP3 and TNIP3 impair affinity for IgG binding.95,96 Likewise, CNVs in

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FCGR3B could reduce the cell surface expression levels Novel lupus nephritis candidate genes
of this receptor.98–100 Both of these effects could act to In addition to the genes discussed above, further molecules
reduce the uptake and clearance of immune complexes might be important in mediating lupus nephritis that have
from the glomerular matrix, not only by the infiltrating not yet been implicated as disease genes in GWAS. One
myeloid cells, but also by resident mesangial cells, which such example is CAMK4. In mice with SLE, inhibition of
are known to upregulate the same FcRs upon stimula­ CAMK4 is associated with decreased IL‑2 production in
tion with IFN-γ. The effect of FcR expression on infil­ T cells, decreased cell proliferation, and decreased IL‑6 pro­
trating myeloid cells seemed to be more important in duction in PDGF-stimulated mesangial cells.144 Ablation of
the pathogenesis of lupus nephritis as compared to the Camk4 in the lupus-prone murine strain MRL/lpr, resulted
effect of expression of FcR on r­ enal-resident cells, in a in reduced glomerulo­nephritis, accompanied by reduced
direct comparison.102 cytokine production by T cells and macrophages. 144
Other murine studies have also been informative in this
Glomerular deposition of nuclear material respect. A series of congenic dissection studies in the New
Genes associated with SLE might augment the amount Zealand mixed strain SLE mouse model (NZM2328)
and accessibility of nucleosomal material available for have facilitated the separation of genes that contribute to
deposition on the glomerular matrix, as will be discussed autoantibody production from those that promote acute
further in the next section. Strong experimental evidence glomerulo­nephritis, chronic glomerulo­nephritis and
supports the notion that nuclear antigens expressed end-stage renal disease.145–147 A 1.34 Mb region containing
within the glomerular matrix can serve as points of inter­ 45 genes at the distal end of chromosome 1 (the Cgnz1
action with anti-nuclear antibodies (Figure 4).123 Genes locus) was associated with chronic glomerulo­nephritis,
that regulate DNA turnover (for example, DNASE1 and whereas the corresponding allele from non-­autoimmune
TREX1), autophagy, and complement levels, therefore, mice conferred resistance to end-organ damage. Although
might regulate the amount of nuclear material that the exact gene within the Cgnz1 locus is yet to be identi­
is deposited on the glomerular matrix, as well as the fied, this genomic region contains several potentially
subsequent accumulation of immune complexes and interesting candidate genes that influence metabolism
leucocyte recruitment.124 and cell survival. These congenic dissection studies
are important for two reasons. Firstly, the separation
Genetic regulation of resident renal cells between autoantibodies and nephritis can explain the rare
SLE-associated genetic polymorphisms might regu­ clinical situation of kidney disease in patients with SLE
late specific disease pathways within resident renal without appreciable autoantibody titres. Secondly, the
cells, including mesangial cells, podocytes, glomerular concept of genes that afford protection from target organ
endothelial cells and tubular epithelial cells. Potential damage changes some of our long-held notions regard­
SLE genes in this category include ACE,125 extracellular ing the pathogenesis of lupus nephritis, clari­fies the large
matrix molecules (COL25A1 and LAMC2),126 KLK127 between-patient variability in disease expression that can
and genes that activate the IFN-I, TLR and NF-κB be observed, and has important p ­ otential implications for
signalling pathways (Figure 4). Kidneys damaged by treatment recommendations.146,147
nephritis express multiple TLRs; 128,129 furthermore,
renal cells grown in culture, such as mesangial cells, Accessibility of apoptotic debris
podocytes, glomerular endothelial cells and tubular epi­ The final category of molecules that contribute to the
thelial cells, express multiple TLRs and are responsive pathology of SLE comprises genes that could impact
to cognate TLR ligands.129–135 Expression of the innate the circulating or local tissue levels of accessible chro­
signalling axes downstream of TLR activation, including matin, which is predominantly generated from apop­
MYD88, TRAF6 and TNFAIP3, has been documented in totic cells and immune complexes. These genes include
renal cells.136–139 DNASE1, TREX1, FcR, ITGAM, C1Q (and related comple­
SLE genes that influence immune signalling could ment components) and ATG5.148–150 Although deficien­
impact disease in two ways: firstly, by affecting the cies of many of these genes are associated with SLE, the
infiltration of leucocytes, and secondly, by affecting underlying mechanisms contributing to disease pathology
the intrinsic properties of renal cells. Another possi­ remain unclear.148 In particular, ATG5 might serve a key
bility is that some SLE genes might produce differen­ function in podocyte biology, as multiple nephropathies
tial effects systemically and intra-renally, as illustrated can be induced when ATG5 gene function is impaired.151
by CD80. CD80 usually mediates leucocyte cross-talk Importantly, podocyte-specific deletion of Atg5 in a
in the immune system but has a dramatically different murine model resulted in the accumulation of ubiqui­
function within podocytes.140–142 Specifically, stimula­ tinated and oxidized proteins, endoplasmic reticulum
tion of TLR3 and TLR4 results in upregulation of CD80 stress, and proteinuria, indicating that autophagy is an
in podocytes in an NF-κB-dependent manner, which important homeostatic mechanism for maintaining
leads to abrogation of the glomerular filtration barrier ­podocyte function and preventing glomerular injury.151
and consequent proteinuria.141 Nephropathies charac­
terized by this molecular feature could be treated with Exposure of nuclear autoantigens
selected biologic therapies,143 although the underlying Previous research has established that nuclear antigens
mechanisms require further exploration. are targeted in SLE, which is characterized by a strong

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serological response to DNA, histones and ribonuclear in patients.149,150 Whether any of the genes associated
proteins.152,153 These nuclear antigens are not usually with susceptibility to SLE or lupus nephritis have an
exposed to the immune system as they are sequestered impact on NETosis remains to be established.
within cellular and nuclear membranes. Consequently,
numerous studies have aimed to uncover the processes Opsonization
by which nuclear autoantigens become exposed and Opsonization of apoptotic cells by serum proteins has a
drive SLE-associated autoimmune responses.149,150,154 pivotal role in cell clearance. The opsonin C1Q is addi­
Although several known pathways can lead to cell death tionally involved in the clearance of NETs and has been
(with more being discovered), apoptosis remains the closely linked with SLE.161,162 C1q-deficient mice develop
dominant mechanism by which cells die. Rapid clearance antinuclear autoimmunity, and almost all patients with
of apoptotic cells prevents immunogenicity or the ability C1Q deficiency develop SLE. Moreover, anti-C1Q anti­
to initiate an inflammatory response. Experimental evi­ bodies are frequently found in patients with SLE, which
dence suggests that accumulation of apoptotic debris, can induce a functional state of C1Q deficiency and
which can occur as a result of failure of this clearance hinder the clearance of apoptotic cells.163 Other comple­
machinery, is an important contributor to ­autoimmunity ment proteins, such as C2, C3, and C4, might be neces­
in SLE.155,156 sary for phagocytosis; indeed, genetic associations with
SLE have been described not only for C1Q, but also
Clearance of apoptotic cells with mutations in C2, C4, CR3 and complement inhibi­
Multiple ligands, receptors, opsonins, and other mol­ tors.163 Finally, although the association between C1Q
ecule classes are involved in the clearance of apoptotic and SLE has been attributed to the clearance of dying
cells and other debris associated with the processes cells, findings from some studies have suggested a role
of cell death. Genetic knockout and pharmacological of complement proteins in several other areas perti­
studies in mice have demonstrated how genes affecting nent to the pathogenesis of SLE, including regulation of
autoantigen clearance could promote the production of ­lymphocytes and expression of IFN-I.163
anti-nuclear autoantibodies and trigger other features
of SLE.149 Nevertheless, few of these genes have thus far Conclusions
been implicated in SLE among human patients. Some Genetic studies of SLE and lupus nephritis have already
illustrative examples in murine models include defi­ highlighted more than 50 potential candidate genes that
ciency of Tyro‑3, Axl and Mertk (also known as Tam)— contribute to disease pathology, many of which can be
receptors that are important for binding to apoptotic subdivided into one of four key molecular pathways.
cells and their subsequent engulfment—that results Although many more genes are likely to be identified in
in the development of autoantibodies, arthritis, skin the coming years, the molecular pathways implicated by
rashes and glomerular immune complex deposition.157 these disease genes yield insights into some of the key
Mice deficient in T-cell IgG4 (TIM-4), which binds the steps that might be important for the pathogenesis of
phosphatidyl serine residues exposed on the surface lupus nephritis. Genes that breach immune tolerance
of apoptotic cells, exhibit anti-dsDNA antibodies and and promote autoantibody production, notably anti-
elevated B‑cell and T‑cell activation.158 Other proteins dsDNA, might act in concert with genes that augment
that regulate apoptotic cell clearance include MFGE8, innate immune signalling and IFN-I production to gen­
MBL2, APCS, and CRP.149,150 erate waves of effector leucocyte secretion and release
of inflammatory mediators and autoantibodies that
NETosis together initiate renal assault.164–166 The presence of
NETosis is a specialized form of cell death that occurs cognate antigens in the glomerular matrix, together with
primarily in neutrophils, during which neutrophil intrinsic molecular abnormalities in resident renal cells,
extracellular traps (NETs) are released. NETs comprise might further accentuate the progression of the disease
a mesh of DNA and histones, as well as the content of among patients with lupus nephritis.164,167 Differential
cytoplasmic granules and other key mediators, such as activation of the various molecular pathways discussed
HMGB1.159 NETs are becoming increasingly recognized in this Review could conceivably lead to the diverse clini­
as a major source of nuclear antigens and other inflam­ cal presentations of SLE and lupus nephritis. Deciphering
matory stimuli that can help drive autoimmunity in the molecular basis of disease in each patient would
SLE.159,160 NETs form more easily in patients with SLE help physicians to tailor therapy accordingly. Patients
as compared to healthy controls, and NET clearance is with genetic polymorphisms that lead to activation of
impaired in patients with SLE,159 perhaps owing to the B cells or T cells might, for example, benefit from thera­
presence of anti-DNASE1 or anti-NET antibodies.154 peutics that target specific signalling molecules or co-­
NETs can stimulate dendritic cells to secrete IFN‑I, and stimulatory pathways encoded by the disease genes.
might also cause direct damage to tissues.159 DNASE1 Patients with SLE risk alleles that promote end-organ
is essential for the degradation of NETs and hence is inflammation might benefit from therapeutics that target
pivotal to their clearance. Mice deficient in Dnase1 the implicated pathways within the kidneys.
develop an SLE-like syndrome, and many patients with The field is yet to arrive at such a level of sophisti­
SLE exhibit decreased DNASE1 activity. Furthermore, cation, where therapies can potentially be tailored to
genetic mutations in DNASE1 have been linked to SLE the genotype of the patient. Firstly, the spectrum of

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genes responsible for SLE is still evolving, and the spe­ Review criteria
cific genetic aberrations responsible for disease within
The articles for this Review were selected as follows: we
each implicated gene are only starting to be elucidated.
first identified all genes that have been implicated in SLE
Secondly, better biomarkers are required to rapidly clas­ and/or lupus nephritis and validated by further analytical
sify patients according to the molecular disease pathways techniques. Publications relating to these genes and
they might harbour. Thirdly, a better armamentarium of their reported functions were gathered from PubMed
therapeutics is warranted, targeting the respective disease and Google Scholar using the gene name as a search
pathways. Finally, clinical trials need to be conducted to term. Additional search terms included “lupus”, “SLE”,
evaluate if pathway-tailored therapy does indeed reduce “nephritis”, “genetics” and “GWAS”. Further articles were
long-term morbidity and mortality in patients with SLE. identified from the reference lists of these publications.
The search was confined to articles published in English,
Clearly, the next decade will witness intense activity in
and all years of publication were included.
all of these quarters.

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erythematosus. Nat. Genet. 41, 1228–1233 lupus erythematosus. Hum. Mol. Genet. 17, The authors would like to acknowledge the editorial
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