Está en la página 1de 10

BRIEF REVIEW www.jasn.


The Pathogenesis of Lupus Nephritis

Maciej Lech and Hans-Joachim Anders
Department of Nephrology, Medical Clinic and Polyclinic IV, University of Munich, Munich, Germany

Lupus nephritis is an immune complex GN that develops as a frequent complication of opsonization of dead cells by comple-
SLE. The pathogenesis of lupus nephritis involves a variety of pathogenic mechanisms. ment, or their removal by phagocytes.6
The extrarenal etiology of systemic lupus is based on multiple combinations of genetic Neutrophils undergo NETosis, which re-
variants that compromise those mechanisms normally assuring immune tolerance to nu- leases nucleosomes into the extracellular
clear autoantigens. This loss of tolerance becomes clinically detectable by the presence of extracellular space.7–10 This finding re-
antinuclear antibodies. In addition, nucleic acids released from netting or apoptotic neu- cently revealed an unexpected role of
trophils activate innate and adaptive immunity via viral nucleic acid-specific Toll-like recep- neutrophils in SLE.11 But how do dead
tors. Therefore, many clinical manifestations of systemic lupus resemble those of viral cell clearance defects lead to SLE?
infection. In lupus, endogenous nuclear particles trigger IFN-a signaling just like viral
particles during viral infection. As such, dendritic cells, T helper cells, B cells, and plasma Induction of Antiviral Immunity
cells all contribute to the aberrant polyclonal autoimmunity. The intrarenal etiology of A delay of dead cell removal leads to
lupus nephritis involves antibody binding to multiple intrarenal autoantigens rather than degeneration of its components, which
the deposition of circulating immune complexes. Tertiary lymphoid tissue formation and compromises those elements that nor-
local antibody production add to intrarenal complement activation as renal immunopa- mally distinguish self-nucleic acids from
thology progresses. Here we provide an update on the pathogenic mechanisms that lead viral nucleic acids.12,13 For example, na-
to lupus nephritis and provide the rationale for the latest and novel treatment strategies. ture developed the methylation of DNA
and RNA as a way to inhibit RNA and
J Am Soc Nephrol 24: ccc–ccc, 2013. doi: 10.1681/ASN.2013010026
DNA recognition by Toll-like receptors
(TLRs) 3, 7, and 9, a set of endosomal
viral nucleic acid recognition receptors
SLE is a chronic autoimmune disease which is a result of an immunization that trigger antiviral immunity during
characterized by loss of tolerance against process. This observation implies two viral infection.14 Therefore, in SLE pa-
nuclear autoantigens, lymphoprolifera- notions (Figure 1 and Table 1). First, au- tients, nuclear particles are taken as viral
tion, polyclonal autoantibody produc- toreactive, long-lived plasma cells, and particles that contain some protein com-
tion, immune complex disease, and memory T cells memorize their immu- ponent (antigen) as well as some immu-
multiorgan tissue inflammation.1,2 SLE nization against nuclei. These cells nostimulatory nucleic acid (immune
used to be referred to as a complex au- cannot be deleted by current immuno- adjuvant; Figure 1).
toimmune disease of unknown etiology; suppressive therapies; hence, current During evolution, our immune sys-
however, during the last decade, a multi- treatments may suppress disease activity tem was primed to mount potent anti-
disciplinary approach to SLE research but do not cure SLE.2,3 Second, the nu- viral immunity upon the recognition of
has built a more concise view of its path- clear antigens used for immunization viral particles, a response that is initiated
ogenesis and for lupus nephritis (LN). had to be accessible to antigen-presenting against the components of virus-like
Here we briefly summarize an updated cells, a process that is normally avoided nuclear particles in SLE patients. For
working model of SLE and LN, which by the homeostatic mechanism of rapid
provides a rationale for novel therapies. dead cell clearance. In fact, SLE develops
Published online ahead of print. Publication date
in individuals with unfortunate combi- available at
EXTRARENAL PATHOGENIC nations of genetic variants that, among
Correspondence: Dr. Hans-Joachim Anders, De-
MECHANISMS OF LN other immunoregulatory defects, com-
partment of Nephrology, Medical Clinic and Polyclinic
promise those mechanisms that nor- IV, University of Munich, Ziemssenstr. 1, D-80336 Mu-
Cell Death and Dead Cell Handling mally assure low levels of chromatin in nich, Germany. Email:
SLE develops from a loss of self-tolerance extracellular compartments, particularly Copyright © 2013 by the American Society of
to ubiquitous nuclear autoantigens, mutations that alter apoptosis, 4,5 the Nephrology

J Am Soc Nephrol 24: ccc–ccc, 2013 ISSN : 1046-6673/2409-ccc 1


example, ribonucleoprotein, U1snRNP,

ligates TLR7 to induce type I IFN release in
plasmacytoid dendritic cells,15 a process
that is tightly controlled by IL-1 receptor–
associated kinase-M.16 RNA immune
complexes activate B cells to produce an-
tinuclear antibodies, 17 which is con-
trolled by the TIR8 gene encoding for
the SIGIRR protein.18,19 Nucleosomal
DNA or DNA within immune complexes
can activate TLR9 on plasmacytoid den-
dritic cells and drive B cell proliferation.20
Blockade of TLR7, TLR9, or both abro-
gates type I IFN induction, SLE, and LN
in mice.21–23 This (pseudo)antiviral im-
mune response involves all antigen-pre-
senting cells, particularly dendritic cells
and B cells, but only plasmacytoid den-
dritic cells secrete large amounts of type I
IFNs to set off an antiviral immune
response. 5,24 The signature for IFN
receptor–dependent secondary gene ex-
pression includes multiple antiviral and
proliferative genes such as IFIT1, MX1,
MX2, ISG15, and the OAS gene family,
the IFN regulatory factors IRF7 and
IRF5, as well as proinflammatory che-
mokines CXCL10 and CXCL5, which al-
together account for the nonspecific
symptoms shared by viral infections
Figure 1. Pathomechanisms of LN outside the kidney. (A) Genetic variants of homeostatic and SLE, such as fever, fatigue, arthralgia,
cell death (i.e., Fas variants) and the rapid clearance of dead cell corpses (e.g., C3/4 and myalgia (Figure 2).25
variants or DNAses variants) result either in secondary necrosis or incomplete chromatin
digestion, which both promote the exposure of nuclear particles to the immune system. Aberrant Lymphocyte Proliferation
(B) Nuclear particles resemble viral particles and activate the same viral nucleic acid Dendritic cells and B cells both have the
recognition receptors on antigen-presenting cells. Genetic variants of those signaling capacity to process antigens and present
elements are recognized to be risk factors for SLE. The activation of antigen-presenting antigens to T cells and they can substitute
cells changes (by costimulation) the immune interpretation of concomitantly presented
each other for this purpose.26 Dendritic
antigens of the same particle. (C) Polyclonal lymphocyte expansion has multiple effects on
the disease process and genetic variants further affect the differentiation of T helper cells.
cells have a limited life span but their per-
The complex regulation of lymphocyte activation and expansion is affected by multiple sistent activation by lupus autoantigens
genetic variants. The susceptibility genes and genes/molecules that are involved within by TLR7 and TLR9 enhances their sur-
each biologic pathway are listed to the right: C1q, C2, C4A/B, C-reactive protein (CRP), vival and renders them resistant to gluco-
a-glucoside transporter 5 (ATG5), three prime repair exonuclease 1 (TREX1), B cell CLL/ corticoid-induced death. 21 Persistent
lymphoma 2 (Bcl-2), IL-2 receptor a (IL-2Ra), tyrosine-protein kinase receptor 3 (TYRO3), activation of antigen-presenting cells
mast/stem cell growth factor (MGF), Fcg receptor (FcGR), HLA IL-1 receptor–associated turns the interpretation of autoantigens
kinase (HLA IRAK), IFN regulatory factor (IRF), signal transducer and activator of tran- from immune ignorance and lymphocyte
scription (STAT), integrin aM (ITGAM), TNF a-induced protein 3 (TNFAIP3), zinc finger anergy into lymphocyte activation and
protein 36 (Zfp-36), IL-4, IFN-g, MHCI, MHCII, TNF, TLR7, single Ig and Toll-IL 1 receptor proliferation, which can overcome the
(SIGIRR), B cell scaffold protein with ankyrin repeats 1 (BANK1), B lymphoid tyrosine ki-
functional unresponsiveness or anergy
nase (BLK), IKAROS family zinc finger 1 (IKZF1), protein tyrosine phosphatase, non-
receptor type 22 (PTPN22), pituitary tumor-transforming 1 (PTTG1), RAS guanyl releasing
of mature autoreactive B cells.27 Murine
protein 3 (RASGRP3), TNF (ligand) superfamily, member 4 (TNFSF4), TNFAIP3-interacting double minute-2 is one of these mito-
protein 1 (TNIP1), transmembrane activator and calcium-modulator and cyclophilin ligand genic factors that is specifically induced
interactor (TACI), BAFF/BLyS, cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed by DNA recognition.28 Murine double
cell death protein 1 (PD-1/PDCD-1), and Gadd45 (activated by the stress-inducible minute-2 neutralizes p53-dependent cell
GADD45). cycle arrest, which explains the mitogenic

2 Journal of the American Society of Nephrology J Am Soc Nephrol 24: ccc–ccc, 2013 BRIEF REVIEW

Table 1. Pathomechanisms of LN inside the kidney response against the components of the
Glomerular Pathology Tubulointerstitial Pathology nuclear particle, a process identical to
Mesangial and subendothelial, immune Immune complex deposits in vaccination. This implies the expansion
complex deposits, complement activation periglomerular vessels of T and B cell clones with specificities
Fc, Toll-like, and complement receptor activation Complement activation for predominantly nuclear autoantigens
Activation of renal cells and infiltrating leukocytes Activation of endothelial cells, luminal that account for the production of anti-
(subepithelial IC causes LN class V and adhesion molecules nuclear antibodies, immune complex
podocyte injury with massive proteinuria) disease, and T cell–dependent tissue
Local cytokine expression Leukocyte recruitment damage. Hormonal and environmental
Recruitment of leukocytes Local antibody production by B cells including stimuli can enhance these processes at
tertiary lymphoid organ formation
different levels.
Proliferation of endothelial and mesangial cells Cytotoxic and Th17 T cells
Filtration barrier damage causing proteinuria Proapoptotic cytokines
and hematuria
Renal cell necrosis causing focal scaring Proximal tubular cell damage causing INTRARENAL PATHOGENIC
proteinuria MECHANISMS OF LN
Proliferation of parietal epithelial cells and Tubular/vascular atrophy
crescent formation Immune Complex-Mediated Renal
Periglomerular inflammation Hypoxia → inflammation Immunopathology
Global glomerulosclerosis Insufficient tubular and vascular repair plus The nonspecific activation of autoreactive
ischemia promotes interstitial fibrosis B cells explains the polyclonal autoanti-
body response leading to the diagnostic
hallmark of LN, the full house pattern of
effect of endogenous DNA or DNA vi- products stimulate intrarenal immune IgM, IgA, and IgG deposits.36 However,
ruses on autoreactive lymphocytes in cells and renal cells, which can trigger a antibody-deficient mice still develop LN;
SLE. Other lymphocyte mitogens are B transient aggravation of proteinuria and therefore, B cells have pathogenic effects
lymphocyte stimulator (BlyS, also named kidney damage. Another environmental beyond antibody production,37 includ-
B cell activating factor [BAFF]) and a trigger of SLE activity is ultraviolet light, ing autoantigen presentation to activate
proliferation-inducing ligand (APRIL), which induces an increase in the load of autoreactive T cells and local proinflam-
which regulate B cell differentiation and dead cells by causing keratinocyte matory effects. 26 Immune complexes
Ig class switching.29 The two APRIL/ death.32 In patients with a significant deposit in the mesangium or the suben-
BLyS receptors transmembrane activator dead cell clearance defect, this process dothelial and subepithelial spaces or in
and CAML-interactor (TACI) and B cell will lead to increased levels of extracel- peritubular capillaries depending on the
maturation protein promote plasma cell lular nuclear material, and additional quality of the autoantibodies, the dura-
survival; therefore, they are currently exposure of autoantigens and autoadju- tion, and severity of LN.38 This implies
considered as potential therapeutic targets vants to the immune system. 1 Drug- that immune complex formation in the
in SLE.30 induced SLE involves inhibition of mesangium causes class I and II lesions,
Furthermore, TNF-like weak inducer methyl-transferases, a process that enhances subendothelial immune complex forma-
of apoptosis, a proinflammatory cyto- the unmasking of endogenous nucleic acids tion in class III and IV lesions, and sub-
kine of the TNF superfamily, regulates and the activation of TLR7 and TLR9.33,34 epithelial immune complexes in class V
multiple processes in autoimmunity and Progesterone and estrogens stimulate the lesions as well as the overlapping forms
tissue inflammation through activation sex hormone–dependent immunoregu- III/IV and IV/V.39 The traditional con-
of the fibroblast growth factor–inducible latory pathways.35 cept that circulating immune complexes
14 receptor. B cell maturation toward Together, SLE develops from a pecu- in lupus passively deposit in the kidney
autoantibody-producing plasma cells liar combination of genetic variants that has been challenged by novel data.40,41
involves IFN-related factor-4.31 impair those mechanisms that normally Glomerular immune complexes rather
prevent the exposure of nuclear particles form in situ by secondary binding to nu-
Environmental Triggers of SLE to the immune system and their capacity cleosomes from renal cells.42 Another
Activity to activate viral recognition nucleic acid potential intrarenal source of nucleo-
Viral infections induce IFN-a release, receptors (Figure 1). Therefore, an IFN- somes are neutrophils upon NETosis,11
which triggers antiviral immunity as a–dependent (pseudo)antiviral im- due to the release of neutrophil extracel-
well as lupus disease activity.25 Bacterial mune response accounts for those lular traps that is initiated by anti-LL37
infections have a nonspecific immunos- nonspecific SLE symptoms that are antibodies.7–10 Heparin modulates the
timulatory effect, which involves a shared with viral infections. The autoad- intrarenal effect of chromatin either by
transient expansion of autoreactive lym- juvant activity of endogenous nucleic enhancing the DNA-I–dependent chro-
phocyte clones. Furthermore, bacterial acids promotes an adaptive immune matin degradation or by preventing

J Am Soc Nephrol 24: ccc–ccc, 2013 Pathogenesis of Lupus Nephritis 3


Fc receptor (FcR) ligation is also well es-

tablished even though the data accumu-
lated over the last few decades remain
complex.51 Subepithelial immune com-
plex deposits lead to secondary membra-
nous GN and nephrotic syndrome by
damaging podocytes.

Intrarenal Activation of TLRs and

IFN Signaling
The nucleic acid component of immune
complexes also activates intrarenal in-
flammation by TLRs in intrarenal mac-
rophages and dendritic cells. 5 2 In
addition, immunostimulatory nucleic
acids activate glomerular endothelium,
mesangial cells, and macrophages to
produce large amounts of proinflamma-
tory cytokines and IFN-a and IFN-b.53–59
The functional significance of this
intraglomerular IFN signaling is poorly
understood but seems to contribute to
renal damage in LN and should trigger
the formation of tubuloreticular struc-
tures or inclusions that represent an
ultrastructural characteristic of IFN
signaling.56,60 Together, the ligation of
TLRs, complement receptors, and FcRs
activates renal cells to release proinflam-
matory cytokines and chemokines, and
induces the luminal expression of selectins
and adhesion molecules inside the micro-

Chemokine-Mediated Recruitment
of Different Leukocyte Subsets
Cytotoxic T cells, Th17 T cells, as well as B
cells infiltrate the kidney in LN.24 The
members of the chemokine family spe-
Figure 2. Therapeutic targets for LN. Aberrant immunity in SLE involves many different cell cifically direct different leukocyte sub-
types and cytokine mediators, which could be suitable therapeutic targets. MCP-1, sets by distinct chemokine receptors
monocyte chemotactic protein-1; CCR, CC chemokine receptor; CXCR, C-X-C chemokine into different renal compartments. 63
receptor. For example, the chemokine CCL2 re-
cruits CCR2+ proinflammatory macro-
phages and T cells into the glomerulus
chromatin binding to the glomerular complex deposits activate comple- and the tubulointerstitium,64,65 whereas
basement membrane.43 Anti-DNA anti- ment,36 which demonstrates the dual CCR1+ cells only recruit to the intersti-
bodies activate endothelial and mesangial role of complement factors in LN.48 Com- tial compartment and not to the glomer-
cells through different mechanisms. For plement deficiency impairs opsonization ulus in LN.66 Other leukocyte subsets
example, antibodies are directly taken up and removal of lupus autoantigens from involve other chemokines and chemo-
inside renal cells.41 This process involves the extracellular space, whereas comple- kine receptors for their recruitment
cross-reactivity with a-actinin or annexin ment factors also directly cause immune into the kidney.63,67 Leukocyte recruit-
II on mesangial cells,44,45 but this concept complex–related renal inflammation and ment is tightly regulated. For example,
could not be confirmed by recent stud- immunopathology.49,50 That immune renal cells produce pentraxin-3, which
ies.46,47 In addition, intrarenal immune complexes activate glomerular cells by has the potential to directly inhibit

4 Journal of the American Society of Nephrology J Am Soc Nephrol 24: ccc–ccc, 2013 BRIEF REVIEW

leukocyte recruitment by interfering around themselves, which creates hon- SLE is to use cell type–specific drugs. For
with P-selectin on the surface of acti- eycomb matrix deposits in Bowman’s example, great hope was put into the
vated endothelial cells. 68,69 In lupus- space that turn cellular crescents into fi- strategy of B cell–directed therapy as B
like autoimmunity of C57BL/6 lpr/lpr brocellular crescents with glomerulo- cells are the source of autoantibody pro-
mice, the role of pentraxin-3 seems to sclerosis, also referred to as class VI LN. duction.88 Meanwhile, it is clear that B
be organ specific, because it suppresses cells in SLE also contribute to autoimmu-
lymphocyte recruitment to the lungs but nity and tissue inflammation in many
not to the kidney.70 Infiltrating leuko- THE PRESENT AND FUTURE OF LN other ways, which increases the hope
cytes form de novo perivascular tertiary THERAPY that depleting or modulating B cells
lymphoid organs inside the kidney, would result in major benefits in SLE
which involve the clonal expansion and Nonselective Immunosuppressants and LN.89 This led to the development
ongoing somatic hypermutation of B Steroids, cyclophosphamide, azathio- of the fully humanized anti-CD20 anti-
cells in proximity to T cell aggregates.71 prine, and mycophenolate mofetil remain body (rituximab), the anti-CD22 anti-
Such B cells undergo intrarenal prolifera- first-line therapeutics for treatment of body (epratuzumab), and to anti-BlyS
tion and activation, which contributes to LN. These nonselective immunosuppres- (belimumab). Because the randomized
local inflammation and tissue pathology sants have much improved the response placebo-controlled Lupus Nephritis As-
in addition to their role for systemic and rates of acute manifestations and the sessment with Rituximab trial failed to
intrarenal autoantibody production.26,72,73 overall mortality of SLE; however, the demonstrate a benefit of add-on rituximab
These data provide a rationale for B cell– long-term outcomes of LN have not for the induction therapy of incident LN
targeted therapies in LN. 74,75 T cell further improved during the last 30 class III/IV/V, this approach to B cell de-
infiltrates also contribute to immunopa- years.83 High-dose steroids and cyclo- pletion still has questions.90,91 At about the
thology in LN, particularly IL-17 produc- phosphamide are frequently associated same time, the Exploratory Phase II/III
ing CD3+/CD4+ or CD3 + CD4/8 2/2 with severe side effects, and infections SLE Evaluation of Rituximab trial also
T cells. 76 Macrophages also contribute contribute to the overall mortality in failed to demonstrate benefits on nonrenal
to renal damage, particularly F4/80(hi)/ SLE. The same applies to the other non- lupus.91 However, uncontrolled studies on
CD11c(int)Gr1(lo)/Ly6C(lo)/VLA4(lo)/ selective immunosuppressants. For refractory LN still document 75% re-
MHCII(hi)/CD43(lo)/CD62L(lo) mac- example, in the ALMS (Apreva Lupus sponder rates and many specialists con-
rophages.77,78 Management) trial, infection-related tinue using rituximab successfully for
mortality was even higher in patients these patients.92
Maladaptive Tissue Repair treated with mycophenolate mofetil BLyS blockade is another promising
Contributes to CKD Progression than in the group treated with high- strategy to target B cell proliferation. A
Damage to renal parenchymal cells trig- dose cyclophosphamide. Reducing the large randomized placebo-controlled tri-
gers healing responses that contribute to drug dose was the first strategy to limit al suggested that add-on belimumab on
renal pathology. Focal tuft necrosis is side effects, and some researchers won- top of standard maintenance therapy can
followed by a migration of parietal epi- der whether oral cyclophosphamide significantly improve persistent disease
thelial cells in the glomerular tuft, where therapy is no longer needed.84 In addi- activity up to 72 weeks.93 This study led
they produce extracellular matrix con- tion, some studies suggest that Caucasian to the US Food and Drug Administra-
tributing to FSGS progressing to global patients may no longer need high-dose tion and European Medicines Agency
glomerulosclerosis.79 During this pro- cyclophosphamide, because the Euro- approval of belimumab for nonrenal lu-
cess, the parietal cells maintain their po- Lupus trial demonstrated favorable pus in the United States and Europe. Pa-
larized epithelial phenotype and lay long-term outcomes with much lower tients with severe LN were excluded
down extracellular matrix on top of the doses of cyclophosphamide. 85 Other from the BLISS-56 and BLISS-76 trials,
podocytes.79 In addition, cellular glo- immunosuppressants like dihydrooro- but data from those patients with mod-
merular crescent formation results tate dehydrogenase inhibitors add to erate nephritis raise hope that belimumab
from activation of parietal epithelial cells the current choices but are still nonspe- could also be efficient in severe LN.94
that fill the urinary space by uncoordi- cific.86,87 However, lupus drug develop- Such a trial is currently underway. Other
nated proliferation.80,81 This process can ers continue to search for new drugs B cell–directed strategies include atacicept
be triggered by glomerular basement that more specifically modulate the ab- (TACI-Ig), LY2127399 (anti-BAFF), and
membrane breaks that allow plasma errant immunity in SLE with fewer side anti-BR3 (anti-BAFF-R).89
leakage into Bowman’s space, where mi- effects. Dendritic cell–T cell interaction is a
togenic plasma components such as fi- target of costimulatory ligand/receptor
brinogen trigger hyperproliferation of Novel Moieties that Target Specific blockers such as CTLA-4-Ig (abatacept).
the parietal epithelial cells. 82 At later Leukocyte Subsets This drug blocks the interaction of CD80
stages, the parietal epithelial cells lose One of the current strategies to specifically and CD86 on antigen-presenting cells
their polarity and produce matrix all interfere with systemic autoimmunity in with CD28 on T cells, which suppresses

J Am Soc Nephrol 24: ccc–ccc, 2013 Pathogenesis of Lupus Nephritis 5


T cell activation.95 Abatacept suppressed SLE. 101 Current treatment guidelines for nuclear autoantigens. Loss of toler-
lupus in mice but did not prevent flares recommend hydroxychloroquine treat- ance becomes clinically evident by the
in SLE patients.96 Three trials with anti- ment for all SLE patients, including all presence of antinuclear antibodies. The
CD40L failed to demonstrate efficacy. patients with LN. 102–104 Antimalarial nucleic acid content of nuclear particles
Abetimus is a drug that modulates auto- drugs like hydroxychloroquine inhibit from netting or apoptotic neutrophils
immunity by altering antigen recogni- lysosomal acidification, which blocks activates innate and adaptive immunity
tion by T cells. Abetimus is composed the adjuvant effect of endogenous nu- by TLR7 and TLR9, which triggers an
of a series of linked oligonucleotides, cleic acids by TLR7 and TLR9 during IFN-a–mediated antiviral host defense
which block the binding of anti-dsDNA the lysosomal processing of nuclear par- program that accounts for many of the
antibodies to their autoimmune targets ticles in endolysosomal compartments nonspecific SLE symptoms. As such,
and tolerize B cells with antigen specific- of antigen-presenting cells. 20 Mean- dendritic cells, T helper cells, B cells,
ity for DNA. Unfortunately, the results while, more specific TLR7 and TLR9 and plasma cells all contribute to the ab-
in clinical trials have been very modest. agents have been developed that effec- errant polyclonal autoimmunity. The in-
A similar approach is followed by tively suppressed LN in murine SLE trarenal etiology of LN involves antibody
edratide, a peptide derived from the models and are now being tested in clin- binding to intrarenal nuclear autoanti-
antigen-binding region of a human ical trials.21–23,105 Antagonism of IFN-a gens, local complement, and FcR activa-
monoclonal anti-dsDNA antibody. It has is feasible with IFN-a antibodies. A tion. Tertiary lymph follicles, to some
been proposed that this molecule can double-blind randomized study with degree, form inside the kidney, which in-
modulate the function of DNA-reactive sifalimumab, a fully human anti-IFN-a clude B cells with local proinflammatory
B cells through idiotype–anti-idiotype in- mAb, demonstrated that IFNa drives effects as well as plasma cells that secrete
teractions but again, the convincing data the overexpression of IFN-dependent autoantibody inside the kidney. These in-
on efficacy are still lacking. genes in human SLE, which is reversed sights into the pathogenesis of lupus pro-
The concept of anti-dsDNA–specific by sifalimumab. 106 Other cytokine- vide the rationale for a number of novel
therapeutic interventions is no longer directed innovative therapies include therapeutic targets.
preferred because it targets only a very anti-Tweak (ATLAS trial) as well as anti-
small subset of B cells, and no longer IL6R (tocilizumab). The current status for
seems sufficient in view of the failing B off-label use of these drugs was recently ACKNOWLEDGMENTS
cell depletion trials and the fact that summarized.30,107 Finally, it remains an at-
dsDNA antibodies certainly contribute tractive notion to add anti-inflammatory This work was supported by the German
to SLE but remain only one of many dif- agents to immunosuppressive drugs to re- Research Foundation (grants AN372/11-1
ferent pathogenic elements. Finally, duce the degree of therapeutic immuno- and GRK 1202).
plasma cells now appear as an attractive suppression and the risk of therapy-related
therapeutic target in SLE because they infections. As a proof of concept, the com-
harbor the long-term memory of hu- bination therapy of the CCL2 chemokine
moral immunity and produce the lupus antagonistic Spiegelmer, mNOX-E36, and
autoantibodies.97 Rituximab does not 25% of full-dose cyclophosphamide was
deplete plasma cells, because these are shown to be as effective as 100% cyclophos- REFERENCES
negative for CD20.97 Massive antibody phamide to control severe SLE in MRLlpr/
production in plasma cells involves the lpr mice108; thus, the cyclophosphamide- 1. Liu Z, Davidson A: Taming lupus-a new un-
intracellular proteasome complex for related T cell ablation and myelosuppres- derstanding of pathogenesis is leading to
protein processing. The proteasome in- sion could be prevented, while maintaining clinical advances. Nat Med 18: 871–882,
hibitor bortezomib was proven to be ef- treatment efficacy.108
2. Tsokos GC: Systemic lupus erythematosus.
fective in mouse models of LN,98,99 but N Engl J Med 365: 2110–2121, 2011
clinical trials with bortezomib in human 3. Goodnow CC: Multistep pathogenesis of
LN is still pending. SUMMARY autoimmune disease. Cell 130: 25–35, 2007
4. Saxena R, Mahajan T, Mohan C: Lupus ne-
phritis: Current update. Arthritis Res Ther
Additional Innovative Therapeutic The pathogenesis of LN involves extrare-
13: 240, 2011
Strategies nal and intrarenal pathogenic mechanisms. 5. Migliorini A, Anders HJ: A novel pathoge-
The pseudo-antiviral immunity concept The extrarenal factors include complex netic concept-antiviral immunity in lupus
is based on the molecular mimicry of combinations of genetic variants that nephritis. Nat Rev Nephrol 8: 183–189,
endogenous nucleic acids at the viral nu- are different in each patient, which ex- 2012
6. Muñoz LE, Lauber K, Schiller M, Manfredi
cleic acid recognition receptors TLR7 and plains the variability of clinical mani-
AA, Herrmann M: The role of defective
TLR9.100 Hence, blocking these TLRs and festations. SLE develops when genetic clearance of apoptotic cells in systemic au-
the subsequent IFN signaling are additive variants compromise those mechanisms toimmunity. Nat Rev Rheumatol 6: 280–
to established therapeutic targets in that normally assure immune tolerance 289, 2010

6 Journal of the American Society of Nephrology J Am Soc Nephrol 24: ccc–ccc, 2013 BRIEF REVIEW

7. Hakkim A, Fürnrohr BG, Amann K, Laube B, 18. Lech M, Kulkarni OP, Pfeiffer S, Savarese E, HW, Mak TW, Anders HJ: IRF4 deficiency
Abed UA, Brinkmann V, Herrmann M, Voll Krug A, Garlanda C, Mantovani A, Anders abrogates lupus nephritis despite enhanc-
RE, Zychlinsky A: Impairment of neutrophil HJ: Tir8/Sigirr prevents murine lupus by ing systemic cytokine production. J Am Soc
extracellular trap degradation is associated suppressing the immunostimulatory effects Nephrol 22: 1443–1452, 2011
with lupus nephritis. Proc Natl Acad Sci U S of lupus autoantigens. J Exp Med 205: 32. Caricchio R, McPhie L, Cohen PL: Ultraviolet
A 107: 9813–9818, 2010 1879–1888, 2008 B radiation-induced cell death: Critical role
8. Villanueva E, Yalavarthi S, Berthier CC, 19. Lech M, Skuginna V, Kulkarni OP, Gong J, of ultraviolet dose in inflammation and lu-
Hodgin JB, Khandpur R, Lin AM, Rubin CJ, Wei T, Stark RW, Garlanda C, Mantovani A, pus autoantigen redistribution. J Immunol
Zhao W, Olsen SH, Klinker M, Shealy D, Anders HJ: Lack of SIGIRR/TIR8 aggravates 171: 5778–5786, 2003
Denny MF, Plumas J, Chaperot L, Kretzler hydrocarbon oil-induced lupus nephritis. 33. Cornacchia E, Golbus J, Maybaum J,
M, Bruce AT, Kaplan MJ: Netting neutrophils J Pathol 220: 596–607, 2010 Strahler J, Hanash S, Richardson B: Hydral-
induce endothelial damage, infiltrate tissues, 20. Leadbetter EA, Rifkin IR, Hohlbaum AM, azine and procainamide inhibit T cell DNA
and expose immunostimulatory molecules in Beaudette BC, Shlomchik MJ, Marshak- methylation and induce autoreactivity.
systemic lupus erythematosus. J Immunol Rothstein A: Chromatin-IgG complexes acti- J Immunol 140: 2197–2200, 1988
187: 538–552, 2011 vate B cells by dual engagement of IgM and 34. Richardson B, Scheinbart L, Strahler J, Gross
9. Garcia-Romo GS, Caielli S, Vega B, Toll-like receptors. Nature 416: 603–607, 2002 L, Hanash S, Johnson M: Evidence for
Connolly J, Allantaz F, Xu Z, Punaro M, 21. Guiducci C, Gong M, Xu Z, Gill M, impaired T cell DNA methylation in sys-
Baisch J, Guiducci C, Coffman RL, Barrat FJ, Chaussabel D, Meeker T, Chan JH, Wright temic lupus erythematosus and rheumatoid
Banchereau J, Pascual V: Netting neutrophils T, Punaro M, Bolland S, Soumelis V, Banchereau arthritis. Arthritis Rheum 33: 1665–1673,
are major inducers of type I IFN production in J, Coffman RL, Pascual V, Barrat FJ: TLR re- 1990
pediatric systemic lupus erythematosus. Sci cognition of self nucleic acids hampers glu- 35. Hughes GC: Progesterone and autoim-
Transl Med 3: 73ra20, 2011 cocorticoid activity in lupus. Nature 465: mune disease. Autoimmun Rev 11: A502–
10. Lande R, Ganguly D, Facchinetti V, Frasca L, 937–941, 2010 A514, 2012
Conrad C, Gregorio J, Meller S, Chamilos G, 22. Patole PS, Zecher D, Pawar RD, Gröne HJ, 36. Tojo T, Friou GJ: Lupus nephritis: Varying
Sebasigari R, Riccieri V, Bassett R, Amuro H, Schlöndorff D, Anders HJ: G-rich DNA complement-fixing properties of immuno-
Fukuhara S, Ito T, Liu YJ, Gilliet M: Neu- suppresses systemic lupus. J Am Soc globulin G antibodies to antigens of cell
trophils activate plasmacytoid dendritic Nephrol 16: 3273–3280, 2005 nuclei. Science 161: 904–906, 1968
cells by releasing self-DNA-peptide com- 23. Pawar RD, Ramanjaneyulu A, Kulkarni OP, 37. Jacob N, Stohl W: Autoantibody-dependent
plexes in systemic lupus erythematosus. Sci Lech M, Segerer S, Anders HJ: Inhibition of and autoantibody-independent roles for B
Transl Med 3: 73ra19, 2011 Toll-like receptor-7 (TLR-7) or TLR-7 plus cells in systemic lupus erythematosus: Past,
11. Bosch X: Systemic lupus erythematosus and TLR-9 attenuates glomerulonephritis and present, and future. Autoimmunity 43: 84–
the neutrophil. N Engl J Med 365: 758–760, lung injury in experimental lupus. J Am Soc 97, 2010
2011 Nephrol 18: 1721–1731, 2007 38. Yu F, Wu LH, Tan Y, Li LH, Wang CL, Wang
12. Hof D, Raats JM, Pruijn GJ: Apoptotic mod- 24. Teichmann LL, Ols ML, Kashgarian M, Reizis WK, Qu Z, Chen MH, Gao JJ, Li ZY, Zheng X,
ifications affect the autoreactivity of the U1 B, Kaplan DH, Shlomchik MJ: Dendritic cells Ao J, Zhu SN, Wang SX, Zhao MH, Zou WZ,
snRNP autoantigen. Autoimmun Rev 4: 380– in lupus are not required for activation of T Liu G: Tubulointerstitial lesions of patients
388, 2005 and B cells but promote their expansion, with lupus nephritis classified by the 2003
13. Huck S, Deveaud E, Namane A, Zouali M: Ab- resulting in tissue damage. Immunity 33: International Society of Nephrology and
normal DNA methylation and deoxycytosine- 967–978, 2010 Renal Pathology Society system. Kidney Int
deoxyguanine content in nucleosomes from 25. Theofilopoulos AN, Baccala R, Beutler B, 77: 820–829, 2010
lymphocytes undergoing apoptosis. FASEB Kono DH: Type I interferons (alpha/beta) in 39. Weening JJ, D’Agati VD, Schwartz MM,
J 13: 1415–1422, 1999 immunity and autoimmunity. Annu Rev Im- Seshan SV, Alpers CE, Appel GB, Balow JE,
14. Karikó K, Ni H, Capodici J, Lamphier M, munol 23: 307–336, 2005 Bruijn JA, Cook T, Ferrario F, Fogo AB,
Weissman D: mRNA is an endogenous li- 26. Chan OT, Hannum LG, Haberman AM, Ginzler EM, Hebert L, Hill G, Hill P, Jennette
gand for Toll-like receptor 3. J Biol Chem Madaio MP, Shlomchik MJ: A novel mouse JC, Kong NC, Lesavre P, Lockshin M, Looi
279: 12542–12550, 2004 with B cells but lacking serum antibody re- LM, Makino H, Moura LA, Nagata M; In-
15. Savarese E, Chae OW, Trowitzsch S, Weber veals an antibody-independent role for B ternational Society of Nephrology Working
G, Kastner B, Akira S, Wagner H, Schmid cells in murine lupus. J Exp Med 189: 1639– Group on the Classification of Lupus Nephritis
RM, Bauer S, Krug A: U1 small nuclear ribo- 1648, 1999 Renal Pathology Society Working Group
nucleoprotein immune complexes induce 27. Zikherman J, Parameswaran R, Weiss A: on the Classification of Lupus Nephritis: The
type I interferon in plasmacytoid dendritic Endogenous antigen tunes the responsiveness classification of glomerulonephritis in syste-
cells through TLR7. Blood 107: 3229–3234, of naive B cells but not T cells. Nature 489: mic lupus erythematosus revisited. Kidney Int
2006 160–164, 2012 65: 521–530, 2004
16. Savarese E, Steinberg C, Pawar RD, Reindl 28. Allam R, Sayyed SG, Kulkarni O, Lichtnekert 40. Nowling TK, Gilkeson GS: Mechanisms of
W, Akira S, Anders HJ, Krug A: Requirement J, Anders HJ: Murine double minute-2 tissue injury in lupus nephritis. Arthritis Res
of Toll-like receptor 7 for pristane-induced drives systemic lupus erythematosus and Ther 13: 250, 2011
production of autoantibodies and develop- lupus nephritis. J Am Soc Nephrol 22: 41. Yung S, Chan TM: Autoantibodies and res-
ment of murine lupus nephritis. Arthritis Rheum 2016–2027, 2011 ident renal cells in the pathogenesis of lupus
58: 1107–1115, 2008 29. Liu Z, Davidson A: BAFF and selection of nephritis: Getting to know the unknown. Clin
17. Lau CM, Broughton C, Tabor AS, Akira S, autoreactive B cells. Trends Immunol 32: Dev Immunol 2012: 139365, 2012
Flavell RA, Mamula MJ, Christensen SR, 388–394, 2011 42. Mortensen ES, Rekvig OP: Nephritogenic
Shlomchik MJ, Viglianti GA, Rifkin IR, 30. Gayed M, Gordon C: Novel treatments for potential of anti-DNA antibodies against
Marshak-Rothstein A: RNA-associated auto- systemic lupus erythematosus. Curr Opin necrotic nucleosomes. J Am Soc Nephrol
antigens activate B cells by combined B cell Investig Drugs 11: 1256–1264, 2010 20: 696–704, 2009
antigen receptor/Toll-like receptor 7 engage- 31. Lech M, Weidenbusch M, Kulkarni OP, Ryu 43. Hedberg A, Fismen S, Fenton KA, Fenton C,
ment. J Exp Med 202: 1171–1177, 2005 M, Darisipudi MN, Susanti HE, Mittruecker Osterud B, Mortensen ES, Rekvig OP:

J Am Soc Nephrol 24: ccc–ccc, 2013 Pathogenesis of Lupus Nephritis 7


Heparin exerts a dual effect on murine lupus DNA activates glomerular endothelial cells Expert Opin Ther Targets 13: 1147–1153,
nephritis by enhancing enzymatic chroma- and enhances albumin permeability via a 2009
tin degradation and preventing chromatin toll-like receptor-independent cytosolic DNA 68. Bussolati B, Peri G, Salvidio G, Verzola D,
binding in glomerular membranes. Arthritis recognition pathway. Am J Pathol 175: 1896– Mantovani A, Camussi G: The long pen-
Rheum 63: 1065–1075, 2011 1904, 2009 traxin PTX3 is synthesized in IgA glomeru-
44. Yung S, Cheung KF, Zhang Q, Chan TM: 56. Fairhurst AM, Xie C, Fu Y, Wang A, lonephritis and activates mesangial cells. J
Anti-dsDNA antibodies bind to mesangial Boudreaux C, Zhou XJ, Cibotti R, Coyle A, Immunol 170: 1466–1472, 2003
annexin II in lupus nephritis. J Am Soc Connolly JE, Wakeland EK, Mohan C: Type 69. Deban L, Russo RC, Sironi M, Moalli F,
Nephrol 21: 1912–1927, 2010 I interferons produced by resident renal Scanziani M, Zambelli V, Cuccovillo I,
45. Zhao Z, Deocharan B, Scherer PE, Ozelius cells may promote end-organ disease in Bastone A, Gobbi M, Valentino S, Doni A,
LJ, Putterman C: Differential binding of autoantibody-mediated glomerulonephri- Garlanda C, Danese S, Salvatori G, Sassano
cross-reactive anti-DNA antibodies to me- tis. J Immunol 183: 6831–6838, 2009 M, Evangelista V, Rossi B, Zenaro E, Constantin
sangial cells: The role of alpha-actinin. 57. Anders HJ, Lichtnekert J, Allam R: Interferon- G, Laudanna C, Bottazzi B, Mantovani A: Re-
J Immunol 176: 7704–7714, 2006 alpha and -beta in kidney inflammation. gulation of leukocyte recruitment by the long
46. Mjelle JE, Rekvig OP, Van Der Vlag J, Kidney Int 77: 848–854, 2010 pentraxin PTX3. Nat Immunol 11: 328–334,
Fenton KA: Nephritogenic antibodies bind 58. Triantafyllopoulou A, Franzke CW, Seshan 2010
in glomeruli through interaction with ex- SV, Perino G, Kalliolias GD, Ramanujam M, 70. Lech M, Römmele C, Kulkarni OP, Susanti
posed chromatin fragments and not with van Rooijen N, Davidson A, Ivashkiv LB: HE, Migliorini A, Garlanda C, Mantovani A,
renal cross-reactive antigens. Autoimmu- Proliferative lesions and metalloproteinase Anders HJ: Lack of the long pentraxin PTX3
nity 44: 373–383, 2011 activity in murine lupus nephritis mediated promotes autoimmune lung disease but not
47. Fenton KA, Tømmerås B, Marion TN, Rekvig by type I interferons and macrophages. glomerulonephritis in murine systemic lu-
OP: Pure anti-dsDNA mAbs need chromatin Proc Natl Acad Sci U S A 107: 3012–3017, pus erythematosus. PLoS ONE 6: e20118,
structures to promote glomerular me- 2010 2011
sangial deposits in BALB/c mice. Autoim- 59. Anders HJ, Vielhauer V, Eis V, Linde Y, 71. Chang A, Henderson SG, Brandt D, Liu N,
munity 43: 179–188, 2010 Kretzler M, Perez de Lema G, Strutz F, Bauer Guttikonda R, Hsieh C, Kaverina N, Utset
48. Sekine H, Ruiz P, Gilkeson GS, Tomlinson S: S, Rutz M, Wagner H, Gröne HJ, Schlöndorff TO, Meehan SM, Quigg RJ, Meffre E, Clark
The dual role of complement in the pro- D: Activation of toll-like receptor-9 induces MR: In situ B cell-mediated immune re-
gression of renal disease in NZB/W F(1) progression of renal disease in MRL-Fas(lpr) sponses and tubulointerstitial inflammation
mice and alternative pathway inhibition. mice. FASEB J 18: 534–536, 2004 in human lupus nephritis. J Immunol 186:
Mol Immunol 49: 317–323, 2011 60. Rich SA: Human lupus inclusions and in- 1849–1860, 2011
49. Sekine H, Kinser TT, Qiao F, Martinez E, terferon. Science 213: 772–775, 1981 72. Neusser MA, Lindenmeyer MT, Edenhofer I,
Paulling E, Ruiz P, Gilkeson GS, Tomlinson 61. Allam R, Anders HJ: The role of innate im- Gaiser S, Kretzler M, Regele H, Segerer S,
S: The benefit of targeted and selective in- munity in autoimmune tissue injury. Curr Cohen CD: Intrarenal production of B-cell
hibition of the alternative complement Opin Rheumatol 20: 538–544, 2008 survival factors in human lupus nephritis.
pathway for modulating autoimmunity and 62. Wang Y, Ito S, Chino Y, Goto D, Matsumoto Mod Pathol 24: 98–107, 2011
renal disease in MRL/lpr mice. Arthritis I, Murata H, Tsutsumi A, Hayashi T, Uchida 73. Espeli M, Bökers S, Giannico G, Dickinson
Rheum 63: 1076–1085, 2011 K, Usui J, Yamagata K, Sumida T: Laser HA, Bardsley V, Fogo AB, Smith KG: Local
50. Bao L, Haas M, Quigg RJ: Complement microdissection-based analysis of cytokine renal autoantibody production in lupus ne-
factor H deficiency accelerates development balance in the kidneys of patients with lupus phritis. J Am Soc Nephrol 22: 296–305,
of lupus nephritis. J Am Soc Nephrol 22: nephritis. Clin Exp Immunol 159: 1–10, 2010 2011
285–295, 2011 63. Kulkarni O, Anders HJ: Chemokines in lupus 74. Bekar KW, Owen T, Dunn R, Ichikawa T,
51. Niederer HA, Clatworthy MR, Willcocks LC, nephritis. Front Biosci 13: 3312–3320, 2008 Wang W, Wang R, Barnard J, Brady S,
Smith KG: FcgammaRIIB, FcgammaRIIIB, 64. Kulkarni O, Pawar RD, Purschke W, Eulberg Nevarez S, Goldman BI, Kehry M, Anolik JH:
and systemic lupus erythematosus. Ann N Y D, Selve N, Buchner K, Ninichuk V, Segerer Prolonged effects of short-term anti-CD20
Acad Sci 1183: 69–88, 2010 S, Vielhauer V, Klussmann S, Anders HJ: B cell depletion therapy in murine systemic
52. Allam R, Lichtnekert J, Moll A, Taubitz A, Spiegelmer inhibition of CCL2/MCP-1 ame- lupus erythematosus. Arthritis Rheum 62:
Vielhauer V, Anders HJ: Viral RNA and DNA liorates lupus nephritis in MRL-(Fas)lpr mice. 2443–2457, 2010
trigger common antiviral responses in me- J Am Soc Nephrol 18: 2350–2358, 2007 75. Ramanujam M, Bethunaickan R, Huang W,
sangial cells. J Am Soc Nephrol 20: 1986– 65. Pérez de Lema G, Maier H, Franz TJ, Tao H, Madaio MP, Davidson A: Selective
1996, 2009 Escribese M, Chilla S, Segerer S, Camarasa blockade of BAFF for the prevention and
53. Fluer K, Allam R, Zecher D, Kulkarni O, N, Schmid H, Banas B, Kalaydjiev S, Busch treatment of systemic lupus erythematosus
Lichtnekert J, Schwarz M, Beutler B, DH, Pfeffer K, Mampaso F, Schlöndorff D, nephritis in NZM2410 mice. Arthritis Rheum
Vielhauer V, Anders HJ: Viral RNA induces Luckow B: Chemokine receptor Ccr2 de- 62: 1457–1468, 2010
type I interferon-dependent cytokine re- ficiency reduces renal disease and prolongs 76. Apostolidis SA, Crispín JC, Tsokos GC: IL-
lease and cell death in mesangial cells via survival in MRL/lpr lupus-prone mice. J Am 17-producing T cells in lupus nephritis. Lu-
melanoma-differentiation-associated gene- Soc Nephrol 16: 3592–3601, 2005 pus 20: 120–124, 2011
5: Implications for viral infection-associated 66. Anders HJ, Belemezova E, Eis V, Segerer S, 77. Bethunaickan R, Berthier CC, Ramanujam
glomerulonephritis. Am J Pathol 175: 2014– Vielhauer V, Perez de Lema G, Kretzler M, M, Sahu R, Zhang W, Sun Y, Bottinger EP,
2022, 2009 Cohen CD, Frink M, Horuk R, Hudkins KL, Ivashkiv L, Kretzler M, Davidson A: A unique
54. Hägele H, Allam R, Pawar RD, Anders HJ: Alpers CE, Mampaso F, Schlöndorff D: Late hybrid renal mononuclear phagocyte acti-
Double-stranded RNA activates type I inter- onset of treatment with a chemokine re- vation phenotype in murine systemic lupus
feron secretion in glomerular endothelial ceptor CCR1 antagonist prevents progres- erythematosus nephritis. J Immunol 186:
cells via retinoic acid-inducible gene (RIG)-1. sion of lupus nephritis in MRL-Fas(lpr) mice. 4994–5003, 2011
Nephrol Dial Transplant 24: 3312–3318, 2009 J Am Soc Nephrol 15: 1504–1513, 2004 78. Katsiari CG, Liossis SN, Sfikakis PP: The
55. Hägele H, Allam R, Pawar RD, Reichel CA, 67. Chong BF, Mohan C: Targeting the CXCR4/ pathophysiologic role of monocytes and mac-
Krombach F, Anders HJ: Double-stranded CXCL12 axis in systemic lupus erythematosus. rophages in systemic lupus erythematosus:

8 Journal of the American Society of Nephrology J Am Soc Nephrol 24: ccc–ccc, 2013 BRIEF REVIEW

A reappraisal. Semin Arthritis Rheum 39: combined with prednisone: A prospective placebo-controlled trial. Arthritis Rheum 62:
491–503, 2010 multi-centre observational study. Lupus 17: 3077–3087, 2010
79. Smeets B, Kuppe C, Sicking EM, Fuss A, 638–644, 2008 97. Hiepe F, Dörner T, Hauser AE, Hoyer BF,
Jirak P, van Kuppevelt TH, Endlich K, 88. Chan OT, Madaio MP, Shlomchik MJ: The Mei H, Radbruch A: Long-lived autoreactive
Wetzels JF, Gröne HJ, Floege J, Moeller central and multiple roles of B cells in lupus plasma cells drive persistent autoimmune
MJ: Parietal epithelial cells participate in the pathogenesis. Immunol Rev 169: 107–121, inflammation. Nat Rev Rheumatol 7: 170–
formation of sclerotic lesions in focal seg- 1999 178, 2011
mental glomerulosclerosis. J Am Soc 89. Gregersen JW, Jayne DR: B-cell depletion 98. Ichikawa HT, Conley T, Muchamuel T, Jiang
Nephrol 22: 1262–1274, 2011 in the treatment of lupus nephritis. Nat Rev J, Lee S, Owen T, Barnard J, Nevarez S,
80. Smeets B, Angelotti ML, Rizzo P, Dijkman H, Nephrol 8: 505–514, 2012 Goldman BI, Kirk CJ, Looney RJ, Anolik JH:
Lazzeri E, Mooren F, Ballerini L, Parente E, 90. Rovin BH, Furie R, Latinis K, Looney RJ, Beneficial effect of novel proteasome in-
Sagrinati C, Mazzinghi B, Ronconi E, Becherucci Fervenza FC, Sanchez-Guerrero J, Maciuca hibitors in murine lupus via dual inhibition of
F, Benigni A, Steenbergen E, Lasagni L, R, Zhang D, Garg JP, Brunetta P, Appel G; type I interferon and autoantibody-secreting
Remuzzi G, Wetzels J, Romagnani P: Renal LUNAR Investigator Group: Efficacy and cells. Arthritis Rheum 64: 493–503, 2012
progenitor cells contribute to hyperplastic safety of rituximab in patients with ac- 99. Neubert K, Meister S, Moser K, Weisel F,
lesions of podocytopathies and crescentic tive proliferative lupus nephritis: The Lu- Maseda D, Amann K, Wiethe C, Winkler TH,
glomerulonephritis. J Am Soc Nephrol 20: pus Nephritis Assessment with Rituximab Kalden JR, Manz RA, Voll RE: The protea-
2593–2603, 2009 study. Arthritis Rheum 64: 1215–1226, some inhibitor bortezomib depletes plasma
81. Smeets B, Uhlig S, Fuss A, Mooren F, 2012 cells and protects mice with lupus-like dis-
Wetzels JF, Floege J, Moeller MJ: Tracing 91. Merrill JT, Neuwelt CM, Wallace DJ, ease from nephritis. Nat Med 14: 748–755,
the origin of glomerular extracapillary le- Shanahan JC, Latinis KM, Oates JC, Utset 2008
sions from parietal epithelial cells. J Am Soc TO, Gordon C, Isenberg DA, Hsieh HJ, 100. Anders HJ: Pseudoviral immunity - a novel
Nephrol 20: 2604–2615, 2009 Zhang D, Brunetta PG: Efficacy and safety of concept for lupus. Trends Mol Med 15:
82. Ryu M, Migliorini A, Miosge N, Gross O, rituximab in moderately-to-severely active 553–561, 2009
Shankland S, Brinkkoetter PT, Hagmann H, systemic lupus erythematosus: The ran- 101. Barrat FJ, Coffman RL: Development of TLR
Romagnani P, Liapis H, Anders HJ: Plasma domized, double-blind, phase II/III systemic inhibitors for the treatment of autoimmune
leakage through glomerular basement lupus erythematosus evaluation of ritux- diseases. Immunol Rev 223: 271–283, 2008
membrane ruptures triggers the pro- imab trial. Arthritis Rheum 62: 222–233, 102. Hahn BH, McMahon MA, Wilkinson A,
liferation of parietal epithelial cells and 2010 Wallace WD, Daikh DI, Fitzgerald JD,
crescent formation in non-inflammatory 92. Weidenbusch M, Römmele C, Schröttle A, Karpouzas GA, Merrill JT, Wallace DJ,
glomerular injury [published online ahead Anders HJ: Beyond the LUNAR trial. Ef- Yazdany J, Ramsey-Goldman R, Singh K,
of print May 3, 2012]. J Pathol doi:10.1002/ ficacy of rituximab in refractory lupus Khalighi M, Choi SI, Gogia M, Kafaja S,
path.4046 nephritis. Nephrol Dial Transplant 28: 106– Kamgar M, Lau C, Martin WJ, Parikh S, Peng
83. Croca SC, Rodrigues T, Isenberg DA: As- 111, 2013 J, Rastogi A, Chen W, Grossman JM; Amer-
sessment of a lupus nephritis cohort over a 93. Navarra SV, Guzmán RM, Gallacher AE, Hall ican College of Rheumatology: American
30-year period. Rheumatology (Oxford) 50: S, Levy RA, Jimenez RE, Li EK, Thomas M, College of Rheumatology guidelines for
1424–1430, 2011 Kim HY, León MG, Tanasescu C, Nasonov E, screening, treatment, and management of
84. Houssiau F: Thirty years of cyclophospha- Lan JL, Pineda L, Zhong ZJ, Freimuth W, lupus nephritis. Arthritis Care Res (Hoboken)
mide: Assessing the evidence. Lupus 16: Petri MA; BLISS-52 Study Group: Efficacy 64: 797–808, 2012
212–216, 2007 and safety of belimumab in patients with 103. Clowse ME, Magder L, Witter F, Petri M:
85. Houssiau FA, Vasconcelos C, D’Cruz D, active systemic lupus erythematosus: A Hydroxychloroquine in lupus pregnancy.
Sebastiani GD, de Ramon Garrido E, Danieli randomised, placebo-controlled, phase 3 Arthritis Rheum 54: 3640–3647, 2006
MG, Abramovicz D, Blockmans D, Cauli A, trial. Lancet 377: 721–731, 2011 104. Pons-Estel GJ, Alarcón GS, McGwin G Jr,
Direskeneli H, Galeazzi M, Gül A, Levy Y, 94. Manzi S, Sánchez-Guerrero J, Merrill JT, Danila MI, Zhang J, Bastian HM, Reveille
Petera P, Popovic R, Petrovic R, Sinico RA, Furie R, Gladman D, Navarra SV, Ginzler JD, Vilá LM; Lumina Study Group: Pro-
Cattaneo R, Font J, Depresseux G, Cosyns EM, D’Cruz DP, Doria A, Cooper S, Zhong tective effect of hydroxychloroquine on re-
JP, Cervera R: The 10-year follow-up data of ZJ, Hough D, Freimuth W, Petri MA; BLISS- nal damage in patients with lupus nephritis:
the Euro-Lupus Nephritis Trial comparing 52 and BLISS-76 Study Groups: Effects of LXV, data from a multiethnic US cohort.
low-dose and high-dose intravenous cyclo- belimumab, a B lymphocyte stimulator- Arthritis Rheum 61: 830–839, 2009
phosphamide. Ann Rheum Dis 69: 61–64, specific inhibitor, on disease activity across 105. Barrat FJ, Meeker T, Chan JH, Guiducci C,
2010 multiple organ domains in patients with Coffman RL: Treatment of lupus-prone mice
86. Kulkarni OP, Sayyed SG, Kantner C, Ryu M, systemic lupus erythematosus: Combined with a dual inhibitor of TLR7 and TLR9 leads
Schnurr M, Sárdy M, Leban J, Jankowsky R, results from two phase III trials. Ann Rheum to reduction of autoantibody production
Ammendola A, Doblhofer R, Anders HJ: Dis 71: 1833–1838, 2012 and amelioration of disease symptoms. Eur
4SC-101, a novel small molecule dihy- 95. Mok CC: Abatacept for systemic lupus J Immunol 37: 3582–3586, 2007
droorotate dehydrogenase inhibitor, sup- erythematosus: The outlook. Expert Opin 106. Merrill JT, Wallace DJ, Petri M, Kirou KA,
presses systemic lupus erythematosus in Biol Ther 12: 1559–1561, 2012 Yao Y, White WI, Robbie G, Levin R, Berney
MRL-(Fas)lpr mice. Am J Pathol 176: 2840– 96. Merrill JT, Burgos-Vargas R, Westhovens R, SM, Chindalore V, Olsen N, Richman L, Le
2847, 2010 Chalmers A, D’Cruz D, Wallace DJ, Bae SC, C, Jallal B, White B; Lupus Interferon Skin
87. Wang HY, Cui TG, Hou FF, Ni ZH, Chen XM, Sigal L, Becker JC, Kelly S, Raghupathi K, Li Activity (LISA) Study Investigators: Safety
Lu FM, Xu FF, Yu XQ, Zhang FS, Zhao XZ, T, Peng Y, Kinaszczuk M, Nash P: The effi- profile and clinical activity of sifalimumab, a
Zhao MH, Wang GB, Qian JQ, Cai GY, Zhu cacy and safety of abatacept in patients fully human anti-interferon a monoclonal
TY, Wang YH, Jiang ZP, Li YN, Mei CL, Zou with non-life-threatening manifestations antibody, in systemic lupus erythematosus:
WZ; China Leflunomide Lupus Nephritis of systemic lupus erythematosus: Results A phase I, multicentre, double-blind ran-
Study Group: Induction treatment of pro- of a twelve-month, multicenter, explor- domised study. Ann Rheum Dis 70: 1905–
liferative lupus nephritis with leflunomide atory, phase IIb, randomized, double-blind, 1913, 2011

J Am Soc Nephrol 24: ccc–ccc, 2013 Pathogenesis of Lupus Nephritis 9


107. Aringer M, Burkhardt H, Burmester GR, Dörner T: Current state of evidence on 108. Kulkarni O, Eulberg D, Selve N, Zöllner S,
Fischer-Betz R, Fleck M, Graninger W, ‘off-label’ therapeutic options for sys- Allam R, Pawar RD, Pfeiffer S, Segerer S,
Hiepe F, Jacobi AM, Kötter I, Lakomek HJ, temic lupus erythematosus, including Klussmann S, Anders HJ: Anti-Ccl2 Spiegelmer
Lorenz HM, Manger B, Schett G, Schmidt biological immunosuppressive agents, permits 75% dose reduction of cyclophos-
RE, Schneider M, Schulze-Koops H, in Germany, Austria and Switzerland— phamide to control diffuse proliferative lupus
Smolen JS, Specker C, Stoll T, Strangfeld a consensus report. Lupus 21: 386–401, nephritis and pneumonitis in MRL-Fas(lpr) mice.
A, Tony HP, Villiger PM, Voll R, Witte T, 2012 J Pharmacol Exp Ther 328: 371–377, 2009

10 Journal of the American Society of Nephrology J Am Soc Nephrol 24: ccc–ccc, 2013