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The Pathogenesis of Lupus Nephritis


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

ABSTRACT
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 www.jasn.org.
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: hjanders@med.uni-muenchen.de
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


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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
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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


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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-
vasculature.61,62

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
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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

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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-
DISCLOSURES.
harbor the long-term memory of hu- bination therapy of the CCL2 chemokine
None.
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
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