Nature Reviews Nephrology (Formerly Nature Clinical Practice Nephrology) Volume Issue 2015 (Doi 10.1038/nrneph.2015.33) Mohan, Chandra Putterman, Chaim - Genetics and Pathogenesis of Systemic Lupu

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 4070% of patients
with SLE will develop lupus nephritis. Renal assault during SLE is initiated by genes that breach immune
toleranceand promote autoantibody production. These genes might act in concert with other genetic
factorsthat 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 themolecular basis of SLE and/or lupus nephritis in each patient will help physicians to tailor
specifictherapies.
Mohan, C. and Putterman, C. Nat. Rev. Nephrol. advance online publication 31 March 2015; doi:10.1038/nrneph.2015.33
Introduction
Department of
Bioengineering,
University of Houston,
3605 Cullen Boulevard,
Houston, TX 77204,
USA (C.M.). Division of
Rheumatology, Albert
Einstein College of
Medicine, 1300 Morris
Park Avenue, Bronx,
NY10461, USA (C.P.).
Correspondence to:
C.M.
cmohan@
central.uh.edu
Systemic lupus erythematosus (SLE) is a chronic auto

immune inflammatory disease that can affect the major
ity of organs and tissues. The clinical presentations
ofSLE 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
inSLE. Lupus nephritis affects ~4070% 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.14
At the systemic level, both the adaptive and innate
branches of the immune system contribute to the devel
opment of SLE. The two predominant cell types involved
in the adaptive immune system, B lymphocytes (Bcells)
and T lymphocytes (Tcells), are both essential for the
development of lupus nephritis.26 Bcells are pathogenic
in SLE because of the autoantibodies (for example, antiDNA antibodies and anti-nucleosome antibodies) and
cytokines that they produce.7,8 Tcells drive the systemic
and intra-renal activation of Bcells. Subtypes of Tcells,
including type1 Thelper (TH1) cells, type17 T-helper
(T H17) cells, and CD3 +CD4 CD8 double negative
THcells, have been implicated in the pathogenesis of
lupus nephritis.911 The innate immune system contrib
utes to the pathogenesis of SLE in multiple ways. In the
early stages of disease, dendritic and other myeloid cells
Competing interests
The authors declare no competing interests.
activate Tcells, and produce key mediators such as B-cell

activating factor; this effect results in the activation of
the adaptive immune system.1214 Activation ofthe sys
temic immune system leads to the generation of effec
tor Tcells 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
reviewedelsewhere.6,13,1520
The present Review categorizes the genes implicated
in SLE according to the cell types and molecular path
ways in which they are expressed, to gain insight into the
key pathogenic contributors that lead to lupus nephritis.
We first introduce the methods by which novel genetic
loci have been identified and the functional studies
performed to characterize candidate genes. Next, we
discuss the genes that are implicated in the activation
of the adaptive and innate immune systems, as well as
those that are involved in the 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 6years ago.1721 Thus far, >10GWAS have been con
ducted using samples obtained from patients with SLE
that encompass multiple ethnic groups, and have collec
tively identified >50genes 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
andadditional candidate genes have been validated in
independent patient cohorts as being associated with SLE
or lupus nephritis. Table1 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 (Table1), questions remain as
to their function in disease pathology. Firstly, the spe
cific causative mutations and subsequent molecular
alterations that contribute to the disease phenotype
have not been firmly established for many of the identi
fied candidate genes. Coding region single nucleotide
polymorphisms (SNPs), polymorphisms that lead to
differential alternative splicing, polymorphisms in the
3'untranslated region (UTR) that influence gene expres
sion, and copy number variants (CNVs) have all been
documented. This catalogue of implicated molecular
variations in each gene is likely to expand as more infor
mation becomes available from deep sequencing studies
that are currently in progress. Secondly, the association
between these candidate genes and SLE or lupus nephri
tis has only been inferred from studies using murine
models that have been engineered to either lack or
overexpress the gene (using knockouts or transgenics,
respectively); some of these associations have been

reviewed elsewhere.22 Additional murine models should
be generated that mimic more closely the type of genetic
mutations that are observed among human patients with
SLE and lupus nephritis; these specific mutations (SNPs,
CNVs and splice isoforms) should be subsequently
validated for their ability to promote SLE in genetically
engineered murine models.
Categorizing genes implicated in SLE
The identified genes implicated in SLE can be assigned to
one of four functional categories: genes that affect lym
phocyte activation, particularly Bcells; genes that affect
innate immune signalling, notably NF-B activation and
IFNI signalling; genes that might function within the
kidneys, potentially promoting renal tissue damage; and
genes that influence the handling of apoptotic debris,
chromatin, and immune complexes bearing these anti
gens. These categories have been designated on the basis
of apriori 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 modelsof
SLE and/or lupus nephritis have been insightful in
this respect as genes from all four categories have been
implicated through both forward and reverse genetic
approaches.2326 Congenic dissection (where multiple
genes mediating a polygenic disease are separated into a
collection of congenic strains) and congenic reconstitu
tion studies (involving genetic crossing of each separate
congenic strain) of 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.2730 The
emerging concept of genetic interaction is exemplified by
a series of congenic dissection and reconstitution studies
that have been performed using the C57Bl/6 (B6) mouse
strain, as illustrated inFigure1.27,2932
Through extrapolation of the genetic data obtained
from murine congenic dissection and reconstitution
studies, it could be predicted that genes from mul
tiple functional categories would act in concert to
promote lupus nephritis in human patients. Although
it is apparent which functional pathways the majority of
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Table 1 | Susceptibility genes implicated in human SLE or LN*
Gene name
Association with SLE
Association with LN
BANK1
Yes168170
Unknown
BLK
Yes169175
Yes70
CD80
Yes63
Unknown
CSK
Yes
Unknown
ETS1
Yes169,172,174,175
Unknown
HLA DR
Yes
Yes70,71
IL-10
Yes
Unknown
LYN
Yes178
Unknown
PP2A
74
Yes
Unknown
PRDM1 (BLIMP1)
Yes177,179
Unknown
PRKCB
Yes180
Unknown
PTPN22
Yes
Unknown
RasGRP3
Yes172,184
Unknown
STAT4
Yes170,172,174,175,185,186
Yes70,72
TNFSF4 (OX40L)
Yes
Yes76,77
IFIH1
Yes188,189
Unknown
IKZF1
Yes172,175,189,190
Yes81
ILT3
Yes24
Unknown
IRAK1
Yes
Unknown
IRF5
Yes23,169,172,175,193196
Yes70,83
IRF7
Yes197,198
Unknown
IRF8
Yes
Unknown
TLR7
Yes201,202
Unknown
TLR9
Yes203
Yes87
TNFAIP3 (A20)
Yes
Yes101
TNIP3 (ABIN3)
Yes172,177
Yes94
TYK2
161,189
Yes
Unknown
UBE2L3
Yes205,206
Unknown
ACE
Yes125
Yes125
COL25A1
Yes
Unknown
KLK
Yes127
Yes127
LAMC2
126
Yes
Unknown
ATG5
Yes179
Unknown
DNAse1
Yes
Unknown
FCGR2A, 3A, 3B
Yes95100,170,186
Yes96
ITGAM
Yes
Yes77,102,106
TREX1
Yes
Unknown
Lymphocyte signalling
50
58,59,174
176,177
51,53,181183
169,170,172,175,187
Innate immune signalling
107,191,192
189,199,200
21,169,172,174,175,204
Intra-renal signalling
126
Immune complex clearance
207
170,186,208210
211
*Susceptibility genes implicated in SLE or LN have been functionally organized into four pathogenic
cascades. Additional genes associated with SLE have not been listed but are reviewed elsewhere. 25
Abbreviations: LN, lupus nephritis; SLE, systemic lupus erythematosus.
SLE-associated genes are most likely to impact, for some

genes the functional pathway is unclear. For example,
complement genes and proteins could potentially
exert effects on several pathways, including chromatin
handling and B-cell activation.
Adaptive immune system activation

Modulation of Bcell receptor signalling
Tcells, Bcells and autoantibodies have been shown to
have an essential function in lupus nephritis, with the
majority of the evidence originating from mechanistic
studies performed in mice.1,1720 A conglomerate of SLEassociated genes collectively regulates B-cell signalling
via the Bcell receptor, BCR (Figure2). BANK1 is a
scaffold adaptor protein primarily expressed in Bcells
that amplifies Bcell signalling by linking the activa
tionof Src-family kinases, such as LYN, with the acti
vation ofthe IP3 receptor, leading to calcium influx.
Stimulationof BCR facilitates the association of BANK1
with PLC2, resulting in PLC2 activation, expression
of IP3 and DAG, and subsequent activation of PRKCB,
another gene implicated in SLE.3336
RasGRP3one of the downstream molecules acti
vated by the BCR pathwayhas also been implicated
in SLE (Figure2). RasGRP3 amplifies downstream Rasmediated ERK and MAPK signalling in Bcells, and is
associated with B-cell proliferation and antibody pro
duction. PRKCB and RasGRP3 are expressed in Bcells,
Tcells, myeloid cells, and endothelial cells, and thus
could contribute to the progression of SLE through
several different pathways.3741 Although genetic manip
ulation studies of Bank1 and Rasgrp3 are yet to be pub
lished, the available data suggest that PRKCB might be
necessary for the development of SLE and lupus nephritis
in mice.42
Src-family tyrosine kinases
Three SLE-associated B-cell genes, LYN, BLK and CSK,
are Src-family tyrosine kinases that might have direct or
indirect inhibitory roles on BCR signalling.4246 The fact
that Lyn-deficient mice develop B-cell hyperactivity with
associated autoimmunity is well documented.4446 The
inhibitory effect of LYN on B-cell signalling is mediated
in part by phosphorylation and subsequent activation
of the inhibitory B-cell surface receptors, CD22 and
FcGR2B. The CD22 and FcGR2B receptors function
through SHIP and SHP-1 phosphatases and dampen
B-cell activation as a consequence.43
One function of BLK is to promote the interaction
between BANK1 and PLC2 (Figure 2). Reduced
expression of BLK is associated with reduced numbers
of pre-Bcells and marginal zone Bcells. Reduced expres
sion of BLK can also promote renal disease in B6 mice
that are prone to SLE.47,48
The third Src-family kinase, CSK, can phosphory
late and regulate LYN. 49 Overexpression of CSK is
observed among patients with SLE that carry the CSK
risk allele, and leads to increased phosphorylation of
LYN; this effect is associated with elevated production
of antibodies and transitional Bcells.50
PTPN22
PTPN22 has been implicated in several autoimmune
diseases, including SLE, and the effect of a disease-
associated variant of Ptpn22 on systemic autoimmun
ity has been verified using murine models.51 PTPN22

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Wild-type
C57Bl/6
a
Gene 1
e.g. Ly108
Adaptive
immunity
b
Gene 2
e.g. Sle3
Ly108
Innate
immunity
Ly108
Sle3
c
Gene 3
e.g. Klk
End-organ
disease
Ly108
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. 27,2931
Thegenetic 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
asthe 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 Bcells and Tcells.3236,42 In addition
to activating Bcells, PTPN22 also modulates the extent
of the regulatory T (TREG) cell pool, and affects myeloid
cell-signalling.5255 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 currentlylacking.
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-B, IRF5, and IRF7
(Figure2). These transcription factors are responsible for
the increased survival of Bcells, 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-B activa
tion such as UBE2L3, TNFAIP3 and TNIP3 (Figure2).
These genes will be discussed in the analysis of the innate
immunesystem.
Cross-talk between Tcells and Bcells

SLE-associated genes might mediate cross-talk between
lymphocytes. Bcells 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.5860 Different
SLE-associated HLA MHC-II alleles have documented
associations with other autoimmune diseases, such as
diabetes mellitus and Sjgren syndrome.60
Co-stimulatory molecular pairs, such as CD28
CD80, CD40CD40L and OX40OX40L (also known as
TNFSF4), also have an important function in the bilat
eral amplification of lymphocyte cross-talk (Figure2).61
Among these co-stimulatory molecules, OX40L and
CD80 have been implicated in susceptibility to SLE
(Table1).1720,62,63 Interaction between OX40 and CD123
or TNFSF4 on activated Tcells might result in the gener
ation of IL-10-producing TREGcells.62 These same pairs of
co-stimulatory molecules might also regulate the inter
action between specialized antigen-presenting cells, such
as dendritic cells, and Tcells (Figure2).
Generation of immune effector cells

The activation of Bcells and Tcells leads to the gen
eration of effector cells, which can subsequently cause
tissue injury. Such effector cells include plasma cells and
TH17cells, both of which have been implicated in the
pathogenesis of lupus nephritis.6467 ETS1 and PRDM1
(also known as BLIMP1) are two molecules that can regu
late the generation of both plasma cells and TH17cells.
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
REVIEWS
Nuclear antigen
B-cell receptor
OX40L*
OX40
BANK1*
BLK1*
PLC2
IP3
CD40
MHCII*
DAG
CD40L
Myd88
TRAF6
IRAK4
IRAK1*
PRKCB*
TCR
PTPN22*
RasGRP3*
CSK*
Antigenpresenting
cell
(dendritic
cell)
Endosome
TLR8
CD28
B cell
PTPN22*
TLR9*
CD80*
CSK*
LYN*
B-cell
receptor
signalling
TLR7*
T cell
Ras
STAT4*
ERK
PP2A*
UBE2L3*
TNFAIP3*
NF-B
IRF5*
IRF7*
TNIP3*
Nucleus
ETS1*
PRDM1*
TH17
cells
Increased survival
antibody production
Plasma
cells
Cytokine
production
IFN-I
production
Figure 2 | Gene products associated with systemic lupus erythematosus (SLE) that might affect the
adaptive
immune
system.
Nature
Reviews
| 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), Tcells, and Bcells. The overall result of
signalling pathways in these three cell types is the production of effector cells, including TH17cells 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, Thelper 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 TH17cells 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 Tcells and
decreased IL-2 production, which can be regulated by
miRNA155.74,75 A transgenic mouse overexpressing Pp2ac
showed increased T-cell production of IL17 and high
susceptibility to the development of antibody-mediated
nephritis. Blockade of IL17by 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
Tcells 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 Table1. These associations include SNPs in BLK,
HLA DRB1, STAT4 and OX40L. The presence of SNPs in

OX40L and expression levels of OX40L on the surface of
peripheral blood mononuclear cells are both associated
with lupus nephritis.62,7884
Activation of innate immune signalling

Modulation of IFNI 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
(Table1). 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 (Figure3). Another SLE-associated
gene, IKZF1, regulates the transcription of STAT4, and
polymorphisms in IKZF1 are also associated with lupus
nephritis (Figure3).88
JAKSTAT signalling
Activation of STAT4 occurs not only in lympho
cytes but also in activated monocytes and dendritic

REVIEWS
Immune
complex
FCGR2A*
IL-12
IL-23
IFN-I
FCGR3A*
FCGR3B*
ITGAM*
IFNAR
JAK1
Endosome
LYN*
TLR9*
TLR7*
Multiple
signalling
pathways
TLR8
IKZF1*
Activation
and
phagocytosis
TYK2*
STATs
STAT4*
IFN-I-induced
genes
IRF5*
IRF7*
IFIH1*
ILT3*
Myd88
TRAF6
IRAK4
IRAK1*
UBE2L3*
TNFAIP3*
NF-B
IRF5*
IRF7*
TNIP3*
Nucleus
Myeloid cell
Increased
survival
Cytokine
production
IFN-I
production
Nature
Reviews | Nephrology
Figure 3 | Gene products associated with systemic lupus
erythematosus
(SLE)
that might affect innate immune signalling. The schematic illustrates the
signalling pathways that occur in myeloid cells that involve genes that could
influence innate immune cell function (denoted by an asterisk). Three myeloid cell
surface receptors (ITGAM, FcR family receptors and IFNAR) are illustrated from
which signalling cascades are initiated upon presentation of immune complexes.
The overall response is regulation of gene transcription that results in the
modulation of cell survival and the production of cytokines and IFNI. 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-likereceptor.
cells; indeed, monocytes from the kidneys of patients

with autoimmune diseases also express high levels of
STAT4.8990 Although the JAKSTAT 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 antidsDNA antib odies and develop severe lupus nephri
tis.80 Furthermore, Stat4 deficiency in mice aggravates
lupus nephritis, as compared to mice that are Stat4sufficient.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 considerablechallenge.
Activation of IFN receptor by interleukins
IL-12 and IL-23 can activate the IFN / 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 most prominent SLE-associated RNA signature.71

Some of these IFN-I-regulated genes, such as IRF5, IRF7,
ILT3 and IFIH1, are SLE-associated genes, andsome
can in turn regulate the expression of IFN-I and other
disease-associated cytokines.93 Of note, the IRF5 allele
implicated in SLE is associated with high serum IFN-I
activity and the development of anti-dsDNA anti
bodies.23 Similarly,the ILT3 disease-associated allele
correlateswith elevated IFN-I and TNF expression
among patients with SLE.24 The increased production of
IFN-I that is driven by these disease alleles is expected
to initiate a positive feedback loop that rapidly increases
IFN-I production (Figure3). The pathogenic importance
of this axis is also underscored by the observation that
genetic ablation or pharmacological blockade of key
molecules in this axis, such as IRF5, suppresses SLE in
mice.25 Furthermore, SNPs in IRF5 are associated with
lupus nephritis in patients.26,70 Finally, emerging evi
dence suggests that genetic aberrations in multiple genes
within the IFNI pathway might confer increased disease
susceptibility, as exemplified by the genetic interaction
between IRF5, IKZF1 andSTAT4.94
Fc receptors for immunoglobulin

The Fc receptors (FcRs) for IgG represent another
family of receptors that have a prominent role in the
activityof myeloid cells. SNPs and CNVs affecting
multiple members of this family, including FCGR2A,
FCGR3A and FCGR3B, have been associated with SLE
and LN.95100 Interestingly, some of the SNPs and CNVs
in FcRs associated with lupus nephritis are characterized
by reduced FcR expression on the myeloid cell surface
membrane; this observation has led to the hypothesis
that reduced FcR-mediated immune complex clearance
might contribute to lupus nephritis.9698 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 lupusnephritis.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-B, IRF5 and IRF7 (Figure3).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.25,107109 Enhancing Tlr7 expression through
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Immune
complex
FCGR3A*
FCGR3B*
FCGR2A*
FCGR2A*
FCGR3A*
Glomerular
matrix
FCGR3B*
TREX1*
Endosome
Myd88
TRAF6
IRAK4
IRAK1*
ITGAM*
UBE2L3*
TNFAIP3*
KLK*
NF-B
IRF5*
IRF7*
TNIP3*
ACE*
COL25A1*
Intra-renal promotion of tissue damage
Nucleus
LAMC2*
Myeloid
cell
TLR7*
Multiple
signalling
pathways
C1*
C2*
C3*
C4*
TLR8
Fc
TLR9*
DNAse1*
have also shown associations with lupus nephritis in

humanpatients.114,115
ITGAM (also known CD11B or MAC1) is a myeloid-
specific adhesion molecule with multiple ligands, includ
ing ICAM1, ICAM2, C3bi and FGA. 116118 ITGAM
exhibits diverse functions under normal physiological
conditions, including mediating myeloid-cell activation
(leading to production of NF-B, IL-6 and TNF), phago
cytosis, uptake of immune complexes, and facilitating
interactions between myeloid cells, lymphocytes, plate
lets and endothelial cells.116118 The ITGAM Arg77His
allele has reduced binding efficiency for ICAM1, and
thus has a potential effect on cell adhesion. The Arg77His
allele correlates with severe disease manifestations of
SLE, including lupus nephritis, as well as h
aematological
and neurological phenotypes.84,119,120
Resident
renal cell
Increased
survival
Cytokine
production
IFN-I
production
Figure 4 | Gene products associated with systemic lupus

erythematosus
(SLE)
Nature
Reviews | Nephrology
that might affect intra-renal events leading to lupus nephritis. The schematic
depicts genes associated with SLE that might exert effects on intra-renal events
that lead to lupus nephritis (denoted by an asterisk). Myeloid cells present to
resident renal cells via Fc receptors, which act in concert with complement
molecules (C1C4). Upon stimulation by an immune complex, resident renal cells
can initiate multiple signalling pathways that culminate in the activation of NF-B,
IRF5 and IRF7. In this way, gene transcription can be modulated, with subsequent
effects on cell survival, cytokine production and expression of IFN-I. The black
arrows represent activation and bar-headed lines represent inhibition of the target
gene or process. The dashed lines represent the overall response. Abbreviation:
TLR, Toll-like receptor.
gene duplication confers susceptibility to SLE and lupus

nephritis in mice.108,109 Multiple lines of evidence there
fore support the critical importance of this molecular
axis in the pathogenesis of SLE and lupusnephritis.
Modulation of NF-B activation

Activation of NF-B has been implicated in both SLE and
lupus nephritis. NF-B can be negatively regulated by
TNFAIP3 (also known as A20) and TNIP3 (also known
as ABIN3), either independently, or in concert.110 TNIP3
can bind to TNFAIP3 to facilitate NFB inhibition.110
UBE2L3 is an E2 ubiquitin-conjugating enzyme that
can regulate the level of NFB activation and result
ant cell proliferation.111 SNPs in TNFAIP3, TNIP3 and
UBE3L3 have shown an association with SLE in human
patients (Figure3).112 Whether multiple perturbations
to this pathway have an incremental effect on NFB
activation remains to be explored. Murine studies have
offered further evidence to support the importance
of this pathway in SLE progression. Reduced expres
sion of TNFAIP3 in Bcells augments the production of
autoantibodies and germinal centre type Bcells, and the
development of renal disease.113 TNFAIP3 and TNIP3
Activation of Tcells and Bcells in the kidney

Genes associated with SLE can contribute to the patho
genesis of lupus nephritis either directly or indirectly.
Cells involved in the adaptive arm of the immune system
(Bcells and Tcells) are known to infiltrate the kidneys.
Previous work has documented the existence of struc
tures reminiscent of germinal centres and other lym
phocyte clusters within the inflamed kidneys of patients
with lupus nephritis.65 All of the genes described above
in the adaptive immune system can potentially influence
lupus nephritis by activating Tcells and Bcells, both
systemically and within the kidneys.
Activation of intra-renal myeloid cells
Cells of the innate immune system, such as macrophages
and neutrophils, are present in large numbers within
the kidneys of patients with lupus nephritis. All of the
genes known to affect innate immune signalling, which
were outlined in the section describing the innate
immune system, can potentially influence the progres
sion of lupus nephritis by activating intra-renal myeloid
cells.121,122 In addition, some of these genes, notably
ITGAM and FcR, could potentially affect the level of
recruitment of myeloid cells to the glomerular matrix
via cognate binding sites on the immune complexes
deposited in the glomeruli.122 Polymorphic variants of
ITGAM and/or FcR that result in increased binding to
complement components (for example, C3b) or the Fc
fragment of IgG could possibly augment myeloid cell
recruitment and activation (Figure4); however, the
biochemical and mechanistic evidence to support this
hypothesis is currently lacking. Conversely, evidence
exists to support reduced levels of FcR and reduced FcR
binding ability to IgGs among patients with SLE, as will
be discussedbelow.
Immune complex clearance from the glomeruli
Evidence suggests that SLE-associated genetic poly
morphisms might regulate the clearance of immune
complexes from glomerular tissue. SLE-associated SNPs
in FCGR2A (Arg131) and FCGR3A (Phe158) might
impair affinity for IgG binding.95,96 Likewise, CNVs in

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FCGR3B could reduce the cell surface expression levels
of this receptor.98100 Both of these effects could act to
reduce the uptake and clearance of immune complexes
from the glomerular matrix, not only by the infiltrating
myeloid cells, but also by resident mesangial cells, which
are known to upregulate the same FcRs upon stimula
tion with IFN-. 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 (Figure4).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
leucocyterecruitment.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-B
signalling pathways (Figure4). Kidneys damaged by
nephritis express multiple TLRs; 128,129 furthermore,
renal cells grown in culture, such as mesangial cells,
podocytes, glomerular endothelial cells and tubular epi
thelial cells, express multiple TLRs and are responsive
to cognate TLR ligands.129135 Expression of the innate
signalling axes downstream of TLR activation, including
MYD88, TRAF6 and TNFAIP3, has been documented in
renalcells.136139
SLE genes that influence immune signalling could
impact disease in two ways: firstly, by affecting the
infiltration of leucocytes, and secondly, by affecting
the intrinsic properties of renal cells. Another possi
bility is that some SLE genes might produce differen
tial effects systemically and intra-renally, as illustrated
by CD80. CD80 usually mediates leucocyte cross-talk
in the immune system but has a dramatically different
function within podocytes.140142 Specifically, stimula
tion of TLR3 and TLR4 results in upregulation of CD80
in podocytes in an NF-B-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.
Novel lupus nephritis candidate genes

In addition to the genes discussed above, further mol
ecules might be important in mediating lupus nephri
tis that have not yet been implicated as disease genes in
GWAS. One such example is CAMK4. In mice with SLE,
inhibition of CAMK4 is associated with decreased IL2
production in Tcells, decreased cell proliferation, and
decreased IL6 production in PDGF-stimulated mesan
gial cells.144 Ablation of Camk4 in the lupus-prone murine
strain MRL/lpr, resulted in reduced glomerulonephritis,
accompanied by reduced cytokine production by Tcells
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 glomerulo
nephritis and end-stage renal disease.145147 A 1.34Mb
region containing 45 genes at the distal end of chromo
some 1 (the Cgnz1 locus) was associated with chronic glo
merulonephritis, 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 identified, 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 separa
tion 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 potential implications for
treatmentrecommendations.146,147
Accessibility of apoptotic debris
The final category of molecules that contribute to the

pathology of SLE comprises genes that could impact
thecirculating or local tissue levels of accessible chro
matin, which is predominantly generated from apop
totic cells and immune complexes. These genes include
DNASE1, TREX1, FcR, ITGAM, C1Q (and related comple
ment components) and ATG5.148150 Although deficien
cies of many of these genes are associated with SLE, the
underlying mechanisms contributing to disease pathology
remain unclear.148 In particular, ATG5 might serve a key
function in podocyte biology, as multiple nephropathies
can be induced when ATG5 gene function is impaired.151
Importantly, podocyte-specific deletion of Atg5 in a
murine model resulted in the accumulation ofubiqui
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
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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 Tyro3, Axl and Mertk (also known as Tam)
receptors that are important for binding to apoptotic
cells and their subsequent engulfmentthat 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 Bcell and Tcell activation.158 Other proteins
that regulate apoptotic cell clearance include MFGE8,
MBL2, APCS, and CRP.149,150
NETosis
NETosis is a specialized form of cell death that occurs
primarily in neutrophils, during which neutrophil
extracellular traps (NETs) are released. NETs comprise
a mesh of DNA and histones, as well as the content of
cytoplasmic granules and other key mediators, such as
HMGB1.159 NETs are becoming increasingly recognized
as a major source of nuclear antigens and other inflam
matory stimuli that can help drive autoimmunity in
SLE.159,160 NETs form more easily in patients with SLE
as compared to healthy controls, and NET clearance is
impaired in patients with SLE,159 perhaps owing to the
presence of anti-DNASE1 or anti-NET antibodies.154
NETs can stimulate dendritic cells to secrete IFNI, and
might also cause direct damage to tissues.159 DNASE1
is essential for the degradation of NETs and hence is
pivotal to their clearance. Mice deficient in Dnase1
develop an SLE-like syndrome, and many patients with
SLE exhibit decreased DNASE1 activity. Furthermore,
genetic mutations in DNASE1 have been linked to SLE
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
withmutations 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 antidsDNA, 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.164166 The presence of
cognate antigens in the glomerular matrix, together with
intrinsic molecular abnormalities in resident renal cells,
might further accentuate the progression of the disease
among patients with lupus nephritis.164,167 Differential
activation of the various molecular pathways discussed
in this Review could conceivably lead to the diverse clini
cal presentations of SLE and lupus nephritis. Deciphering
the molecular basis of disease in each patient would
help physicians to tailor therapy accordingly. Patients
with genetic polymorphisms that lead to activation of
Bcells or Tcells 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

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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.
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and Google Scholar using the gene name as a search
term. Additional search terms included lupus, SLE,
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The search was confined to articles published in English,
and all years of publication were included.
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48. Samuelson, E.M. etal. Reduced B lymphoid
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50. Manjarrez-Orduno, N. etal. CSK regulatory
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52. Bayley, R. etal. The autoimmune-associated
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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. Puttermans 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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REVIEWS

Genetics and pathogenesis of systemic lupus

Systemic lupus erythematosus (SLE) is a chronic auto

activate Tcells, and produce key mediators such as B-cell

NATURE REVIEWS | NEPHROLOGY

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suitable, we find the following categories to be a useful

respectively); some of these associations have been

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Association with SLE

Innate immune signalling

Immune complex clearance

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

Adaptive immune system activation

NATURE REVIEWS | NEPHROLOGY

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regulates CSK and can modulate the BCR and T-cell

Cross-talk between Tcells and Bcells

the autoantigens that they bind to, and subsequently

Generation of immune effector cells

4 | ADVANCE ONLINE PUBLICATION

or deficiency of PRDM1 reduces the severity of SLE in

HLA DRB1, STAT4 and OX40L. The presence of SNPs in

Activation of innate immune signalling

NATURE REVIEWS | NEPHROLOGY

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cells; indeed, monocytes from the kidneys of patients

the most prominent SLE-associated RNA signature.71

Fc receptors for immunoglobulin

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Intra-renal promotion of tissue damage

have also shown associations with lupus nephritis in

Figure 4 | Gene products associated with systemic lupus

gene duplication confers susceptibility to SLE and lupus

Modulation of NF-B activation

Activation of Tcells and Bcells in the kidney

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Glomerular deposition of nuclear material

Novel lupus nephritis candidate genes

Accessibility of apoptotic debris

The final category of molecules that contribute to the

Exposure of nuclear autoantigens

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Clearance of apoptotic cells

in patients.149,150 Whether any of the genes associated

Genetic studies of SLE and lupus nephritis have already

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Feldman, C. H. et al. Epidemiology and

in the genetics of systemic lupus erythematosus.

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

erythematosus. Arthritis Rheum. 48, 13321342

NATURE REVIEWS | NEPHROLOGY

86. Fairhurst, A.M. etal. TypeI interferons

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125. Zhou, T.B. etal. Relationship between

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143. Yu, C.C. etal. Abatacept in B71positive

systemic lupus erythematosus. Rheumatology

NATURE REVIEWS | NEPHROLOGY

198. Salloum, R. etal. Genetic variation at the IRF7/

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