REVIEWS

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
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 intra-renal events
are important in the pathogenesis of lupus nephritis.1–4
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.2–6 B cells are pathogenic
in SLE because of the autoantibodies (for example, anti-
Department of
DNA antibodies and anti-nucleosome anti­bodies) and
Bioengineering, cytokines that they produce.7,8 T cells drive the systemic
University of Houston, and intra-renal activation of B cells. Subtypes of T cells,
3605 Cullen Boulevard,
Houston, TX 77204, including type 1 T‑helper (TH1) cells, type 17 T-helper
USA (C.M.). Division of (T H17) cells, and CD3 +CD4 –CD8 – ‘double negative’
Rheumatology, Albert
Einstein College of
TH cells, have been implicated in the pathogenesis of
Medicine, 1300 Morris lupus nephritis.9–11 The innate immune system contrib­
Park Avenue, Bronx, utes to the pathogenesis of SLE in multiple ways. In the
NY 10461, USA (C.P.).
early stages of disease, dendritic and other myeloid cells
Correspondence to:
C.M.
cmohan@ Competing interests
central.uh.edu The authors declare no competing interests.
activate T cells, and produce key mediators such as B-cell
activating factor; this effect results in the activation of
the adaptive immune system.12–14 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 intra-renal
events in the pathogenesis of lupus nephritis have been
reviewed elsewhere.6,13,15–20
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 intra-renal processes that
promote tissue damage. We conclude by discussing the
potential mol­e cules 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

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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
Genome-wide association studies (GWAS) that aimed to
identify genetic loci linked with SLE were initiated more
than 6 years ago.17–21 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,
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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 NF-κB activation and
IFN‑I 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.23–26 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 SLE-associated 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 anti-DNA antibodies
(compared to polygenic strains with complete SLE) and
non-­proliferative glomerulonephritis. Finally, the epi­
static interaction between genes from multiple categories
is required for severe lupus nephritis to develop.27–30 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 1.27,29–32
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
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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
receptor signalling threshold and downstream activa­
tion of AKT in both B cells and T cells.32–36,42 In addition
to activating B cells, PTPN22 also modulates the extent
of the regulatory T (TREG) cell pool, and affects myeloid
cell-signalling.52–55 Specifically, the numbers of thymic
and TREG cells vary inversely with the levels of PTPN22,54
whereas PTPN22 deficiency reduces IFN-I production
and augments inflammation.55
At present, it is not fully understood how LYN, BLK,
CSK and PTPN22 interact to fine-tune 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 Toll-like receptors (TLRs) can serve
to amplify B-cell 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 NF-κB, 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
IFN-I. Importantly, several molecules in this pathway
constitute SLE-associated genes, including TLR7, IRAK1,
IRF5, IRF7, and molecules that regulate NF-κB 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
SLE-associated genes might mediate cross-talk between
lymphocytes. B cells are able to endocytose and process
the autoantigens that they bind to, and subsequently
present autoantigen-derived peptides to T H cells
through their MHC-II molecules, as demonstrated for
nucleosome-­derived histone epitopes.57 MHC-II mol­
ecules, notably HLA-DR2 and HLA-DR3, 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.58–60 Different
SLE-associated HLA MHC-II alleles have documented
associations with other autoimmune diseases, such as
diabetes mellitus and Sjögren syndrome.60
Co-stimulatory 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 cross-talk (Figure 2).61
Among these co-stimulatory molecules, OX40L and
CD80 have been implicated in susceptibility to SLE
(Table 1).17–20,62,63 Interaction between OX40 and CD123
or TNFSF4 on activated T cells might result in the gener­
ation of IL-10-producing TREG cells.62 These same pairs of
co-stimulatory molecules might also regulate the inter­
action between specialized antigen-presenting 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
TH17 cells, both of which have been implicated in the
pathogenesis of lupus nephritis.64–67 ETS1 and PRDM1
(also known as BLIMP1) are two molecules that can regu­
late the generation of both plasma cells and TH17 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

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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
mice.70,71 Both genetic evidence from human GWAS and
mechanistic studies in mice, therefore, underscore the
importance of the generation of TH17 cells and plasma
cells in the pathogenesis of SLE.
Both mouse models of SLE and patients with SLE
exhibit increased levels of IL-17 production and increased
numbers of circulating TH17 cells that correlate with
disease activity.72 Furthermore, IL-17 deficiency pro­
tects mice from the development of SLE-associated 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 IL-2 production, which can be regulated by
miRNA–155.74,75 A transgenic mouse overexpressing Pp2ac
showed increased T-cell production of IL‑17 and high
susceptibility to the development of antibody-mediated
nephritis. Blockade of IL‑17 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.62,78–84
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 over-activation of the IFN-I signal­
ling pathway.85 IFN-I 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 IFN-I 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 SLE-associated
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

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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
Figure 3 | Gene products associated with systemic lupus Nature Reviews | Nephrology
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
STAT4.89–90 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 anti­b odies 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
IL-12 and IL-23 can activate the IFN α/β receptor
(IFNAR), which results in increased production of
­IFN-I.91,92 Consequently, a large number of genes that
are regulated by IFN-I become activated, constituting
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.95–100 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 FcR-mediated immune complex clearance
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
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 NF-κB, IRF5 and IRF7 (Figure 3).105
These transcriptional processes have important func­
tions in augmenting proinflammatory cytokine pro­
duction, including IFN-I. Several of these molecules,
including TLR7, TLR9, IRAK1, IRF5 and IRF7 have
been implicated as SLE-causative 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.25,107–109 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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 REVIEWS
FCGR3B could reduce the cell surface expression levels
of this receptor.98–100 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 IFN-γ. 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 r­ enal-resident 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 anti-nuclear 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
SLE-associated 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 KLK127
and genes that activate the IFN-I, TLR and NF-κB
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.129–135 Expression of the innate
signalling axes downstream of TLR activation, including
MYD88, TRAF6 and TNFAIP3, has been documented in
renal cells.136–139
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 intra-renally, as illustrated
by CD80. CD80 usually mediates leucocyte cross-talk
in the immune system but has a dramatically different
function within podocytes.140–142 Specifically, stimula­
tion of TLR3 and TLR4 results in upregulation of CD80
in podocytes in an NF-κB-dependent 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.
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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 IL‑2 production in
T cells, decreased cell proliferation, and decreased IL‑6 pro­
duction in PDGF-stimulated mesangial cells.144 Ablation of
Camk4 in the lupus-prone 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
end-stage renal disease.145–147 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 non-­autoimmune
mice conferred resistance to end-organ 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 long-held notions regard­
ing the pathogenesis of lupus nephritis, clari­fies the large
between-patient variability in disease expression that can
be observed, and has important p ­ otential 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 ATG5.148–150 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, podocyte-specific 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
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 SLE-associated 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
anti-nuclear 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 T-cell IgG4 (TIM-4), which binds the
phosphatidyl serine residues exposed on the surface
of apoptotic cells, exhibit anti-dsDNA antibodies and
elevated B‑cell and T‑cell 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 anti-DNASE1 or anti-NET antibodies.154
NETs can stimulate dendritic cells to secrete IFN‑I, 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 SLE-like syndrome, and many patients with
SLE exhibit decreased DNASE1 activity. Furthermore,
genetic mutations in DNASE1 have been linked to SLE
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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 C1q-deficient mice develop
antinuclear autoimmunity, and almost all patients with
C1Q deficiency develop SLE. Moreover, anti-C1Q 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 IFN-I.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 IFN-I production to gen­
erate waves of effector leucocyte secretion and release
of inflammatory mediators and autoantibodies that
together initiate renal assault.164–166 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 end-organ
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
12/05/2015 16:08
 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 pathway-tailored therapy does indeed reduce
long-term 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.

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Acknowledgements
The authors would like to acknowledge the editorial
assistance of Simanta Pathak, University of Houston,
USA. Relevant studies in Dr. Putterman’s laboratory
were supported by grants from the NIH, DK090319
and AR048692. Dr. Putterman is currently a Weston
Visiting Professor at the Weizmann Institute.
Author contributions
Both authors researched the data for the article,
provided substantial contributions to discussions of
its content, wrote the article, and undertook review
and/or editing of the manuscript before submission.
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