the pathogenesis of lupus nephritis - nephrology now

BRIEF REVIEW www.jasn.org

The Pathogenesis of Lupus Nephritis

Maciej Lech and Hans-Joachim Anders

Department of Nephrology, Medical Clinic and Polyclinic IV, University of Munich, Munich, Germany

ABSTRACTLupus nephritis is an immune complex GN that develops as a frequent complication ofSLE. The pathogenesis of lupus nephritis involves a variety of pathogenic mechanisms.The extrarenal etiology of systemic lupus is based on multiple combinations of geneticvariants that compromise those mechanisms normally assuring immune tolerance to nu-clear autoantigens. This lossof tolerancebecomesclinicallydetectableby thepresenceofantinuclear antibodies. In addition, nucleic acids released from netting or apoptotic neu-trophils activate innateandadaptive immunityvia viral nucleic acid-specificToll-like recep-tors. Therefore, many clinical manifestations of systemic lupus resemble those of viralinfection. In lupus, endogenous nuclear particles trigger IFN-a signaling just like viralparticles during viral infection. As such, dendritic cells, T helper cells, B cells, and plasmacells all contribute to the aberrant polyclonal autoimmunity. The intrarenal etiology oflupus nephritis involves antibody binding to multiple intrarenal autoantigens rather thanthe deposition of circulating immune complexes. Tertiary lymphoid tissue formation andlocal antibody production add to intrarenal complement activation as renal immunopa-thology progresses.Hereweprovide an update on thepathogenicmechanisms that leadto lupus nephritis and provide the rationale for the latest and novel treatment strategies.

J Am Soc Nephrol 24: 1357–1366, 2013. doi: 10.1681/ASN.2013010026

SLE is a chronic autoimmune diseasecharacterized by loss of tolerance againstnuclear autoantigens, lymphoprolifera-tion, polyclonal autoantibody produc-tion, immune complex disease, andmultiorgan tissue inflammation.1,2 SLEused to be referred to as a complex au-toimmune disease of unknown etiology;however, during the last decade, a multi-disciplinary approach to SLE researchhas built a more concise view of its path-ogenesis and for lupus nephritis (LN).Here we briefly summarize an updatedworking model of SLE and LN, whichprovides a rationale for novel therapies.

EXTRARENAL PATHOGENICMECHANISMS OF LN

Cell Death and Dead Cell HandlingSLE develops froma loss of self-toleranceto ubiquitous nuclear autoantigens,

which is a result of an immunizationprocess. This observation implies twonotions (Figure 1 and Table 1). First, au-toreactive, long-lived plasma cells, andmemory T cells memorize their immu-nization against nuclei. These cellscannot be deleted by current immuno-suppressive therapies; hence, currenttreatments may suppress disease activitybut do not cure SLE.2,3 Second, the nu-clear antigens used for immunizationhad to be accessible to antigen-presentingcells, a process that is normally avoidedby the homeostatic mechanism of rapiddead cell clearance. In fact, SLE developsin individuals with unfortunate combi-nations of genetic variants that, amongother immunoregulatory defects, com-promise those mechanisms that nor-mally assure low levels of chromatin inextracellular compartments, particularlymutations that alter apoptosis,4,5 the

opsonization of dead cells by comple-ment, or their removal by phagocytes.6

Neutrophils undergo NETosis, which re-leases nucleosomes into the extracellularextracellular space.7–10 This finding re-cently revealed an unexpected role ofneutrophils in SLE.11 But how do deadcell clearance defects lead to SLE?

Induction of Antiviral ImmunityA delay of dead cell removal leads todegeneration of its components, whichcompromises those elements that nor-mally distinguish self-nucleic acids fromviral nucleic acids.12,13 For example, na-ture developed the methylation of DNAand RNA as a way to inhibit RNA andDNA recognition by Toll-like receptors(TLRs) 3, 7, and 9, a set of endosomalviral nucleic acid recognition receptorsthat trigger antiviral immunity duringviral infection.14 Therefore, in SLE pa-tients, nuclear particles are taken as viralparticles that contain some protein com-ponent (antigen) as well as some immu-nostimulatory nucleic acid (immuneadjuvant; Figure 1).

During evolution, our immune sys-tem was primed to mount potent anti-viral immunity upon the recognition ofviral particles, a response that is initiatedagainst the components of virus-likenuclear particles in SLE patients. For

Published online ahead of print. Publication dateavailable at www.jasn.org.

Correspondence: Dr. Hans-Joachim Anders, De-partment of Nephrology, Medical Clinic and PolyclinicIV, University of Munich, Ziemssenstr. 1, D-80336 Mu-nich, Germany. Email: [email protected]

Copyright © 2013 by the American Society ofNephrology

J Am Soc Nephrol 24: 1357–1366, 2013 ISSN : 1046-6673/2409-1357 1357

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example, ribonucleoprotein, U1snRNP,ligatesTLR7to induce type I IFNrelease inplasmacytoid dendritic cells,15 a processthat is tightly controlled by IL-1 receptor–associated kinase-M.16 RNA immunecomplexes activate B cells to produce an-tinuclear antibodies,17 which is con-trolled by the TIR8 gene encoding forthe SIGIRR protein.18,19 NucleosomalDNA or DNAwithin immune complexescan 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 LNin mice.21–23 This (pseudo)antiviral im-mune response involves all antigen-pre-senting cells, particularly dendritic cellsand B cells, but only plasmacytoid den-dritic cells secrete large amounts of type IIFNs to set off an antiviral immuneresponse.5,24 The signature for IFNreceptor–dependent secondary gene ex-pression includes multiple antiviral andproliferative genes such as IFIT1, MX1,MX2, ISG15, and the OAS gene family,the IFN regulatory factors IRF7 andIRF5, as well as proinflammatory che-mokines CXCL10 and CXCL5, which al-together account for the nonspecificsymptoms shared by viral infectionsand SLE, such as fever, fatigue, arthralgia,and myalgia (Figure 2).25

Aberrant Lymphocyte ProliferationDendritic cells and B cells both have thecapacity to process antigens and presentantigens to T cells and they can substituteeach other for this purpose.26 Dendriticcells have a limited life span but their per-sistent activation by lupus autoantigensby TLR7 and TLR9 enhances their sur-vival and renders them resistant to gluco-corticoid-induced death.21 Persistentactivation of antigen-presenting cellsturns the interpretation of autoantigensfrom immune ignorance and lymphocyteanergy into lymphocyte activation andproliferation, which can overcome thefunctional unresponsiveness or anergyof mature autoreactive B cells.27 Murinedouble minute-2 is one of these mito-genic factors that is specifically inducedby DNA recognition.28 Murine doubleminute-2 neutralizes p53-dependent cellcycle arrest, which explains themitogenic

Figure 1. Pathomechanisms of LN outside the kidney. (A) Genetic variants of homeostaticcell death (i.e., Fas variants) and the rapid clearance of dead cell corpses (e.g., C3/4variants or DNAses variants) result either in secondary necrosis or incomplete chromatindigestion, which both promote the exposure of nuclear particles to the immune system.(B) Nuclear particles resemble viral particles and activate the same viral nucleic acidrecognition receptors on antigen-presenting cells. Genetic variants of those signalingelements are recognized to be risk factors for SLE. The activation of antigen-presentingcells changes (by costimulation) the immune interpretation of concomitantly presentedantigens of the same particle. (C) Polyclonal lymphocyte expansion hasmultiple effects onthe disease process and genetic variants further affect the differentiation of T helper cells.The complex regulation of lymphocyte activation and expansion is affected by multiplegenetic variants. The susceptibility genes and genes/molecules that are involved withineach biologic pathway are listed to the right: C1q, C2, C4A/B, C-reactive protein (CRP),a-glucoside transporter 5 (ATG5), three prime repair exonuclease 1 (TREX1), B cell CLL/lymphoma 2 (Bcl-2), IL-2 receptor a (IL-2Ra), tyrosine-protein kinase receptor 3 (TYRO3),mast/stem cell growth factor (MGF), Fcg receptor (FcGR), HLA IL-1 receptor–associatedkinase (HLA IRAK), IFN regulatory factor (IRF), signal transducer and activator of tran-scription (STAT), integrin aM (ITGAM), TNF a-induced protein 3 (TNFAIP3), zinc fingerprotein 36 (Zfp-36), IL-4, IFN-g, MHCI, MHCII, TNF, TLR7, single Ig and Toll-IL 1 receptor(SIGIRR), B cell scaffold protein with ankyrin repeats 1 (BANK1), B lymphoid tyrosine ki-nase (BLK), IKAROS family zinc finger 1 (IKZF1), protein tyrosine phosphatase, non-receptor type 22 (PTPN22), pituitary tumor-transforming 1 (PTTG1), RAS guanyl releasingprotein 3 (RASGRP3), TNF (ligand) superfamily, member 4 (TNFSF4), TNFAIP3-interactingprotein 1 (TNIP1), transmembrane activator and calcium-modulator and cyclophilin ligandinteractor (TACI), BAFF/BLyS, cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmedcell death protein 1 (PD-1/PDCD-1), and Gadd45 (activated by the stress-inducibleGADD45).

1358 Journal of the American Society of Nephrology J Am Soc Nephrol 24: 1357–1366, 2013


effect of endogenous DNA or DNA vi-ruses on autoreactive lymphocytes inSLE. Other lymphocyte mitogens are Blymphocyte stimulator (BlyS, also namedB cell activating factor [BAFF]) and aproliferation-inducing ligand (APRIL),which regulate B cell differentiation andIg class switching.29 The two APRIL/BLyS receptors transmembrane activatorand CAML-interactor (TACI) and B cellmaturation protein promote plasma cellsurvival; therefore, they are currentlyconsidered as potential therapeutic targetsin SLE.30

Furthermore, TNF-like weak inducerof apoptosis, a proinflammatory cyto-kine of the TNF superfamily, regulatesmultiple processes in autoimmunity andtissue inflammation through activationof the fibroblast growth factor–inducible14 receptor. B cell maturation towardautoantibody-producing plasma cellsinvolves IFN-related factor-4.31

Environmental Triggers of SLEActivityViral infections induce IFN-a release,which triggers antiviral immunity aswell as lupus disease activity.25 Bacterialinfections have a nonspecific immunos-timulatory effect, which involves atransient expansion of autoreactive lym-phocyte clones. Furthermore, bacterial

products stimulate intrarenal immunecells and renal cells, which can trigger atransient aggravation of proteinuria andkidney damage. Another environmentaltrigger of SLE activity is ultraviolet light,which induces an increase in the load ofdead cells by causing keratinocytedeath.32 In patients with a significantdead cell clearance defect, this processwill lead to increased levels of extracel-lular nuclear material, and additionalexposure of autoantigens and autoadju-vants to the immune system.1 Drug-induced SLE involves inhibition ofmethyl-transferases, a process that enhancesthe unmasking of endogenous nucleic acidsand the activation of TLR7 and TLR9.33,34

Progesterone and estrogens stimulate thesex hormone–dependent immunoregu-latory pathways.35

Together, SLE develops from a pecu-liar combination of genetic variants thatimpair those mechanisms that normallyprevent the exposure of nuclear particlesto the immune system and their capacityto activate viral recognition nucleic acidreceptors (Figure 1). Therefore, an IFN-a–dependent (pseudo)antiviral im-mune response accounts for thosenonspecific SLE symptoms that areshared with viral infections. The autoad-juvant activity of endogenous nucleicacids promotes an adaptive immune

response against the components of thenuclear particle, a process identical tovaccination. This implies the expansionof T and B cell clones with specificitiesfor predominantly nuclear autoantigensthat account for the production of anti-nuclear antibodies, immune complexdisease, and T cell–dependent tissuedamage. Hormonal and environmentalstimuli can enhance these processes atdifferent levels.

INTRARENAL PATHOGENICMECHANISMS OF LN

Immune Complex-Mediated RenalImmunopathologyThe nonspecific activation of autoreactiveB cells explains the polyclonal autoanti-body response leading to the diagnostichallmark of LN, the full house pattern ofIgM, IgA, and IgG deposits.36 However,antibody-deficient mice still develop LN;therefore, B cells have pathogenic effectsbeyond antibody production,37 includ-ing autoantigen presentation to activateautoreactive T cells and local proinflam-matory effects.26 Immune complexesdeposit in the mesangium or the suben-dothelial and subepithelial spaces or inperitubular capillaries depending on thequality of the autoantibodies, the dura-tion, and severity of LN.38 This impliesthat immune complex formation in themesangium causes class I and II lesions,subendothelial immune complex forma-tion in class III and IV lesions, and sub-epithelial immune complexes in class Vlesions as well as the overlapping formsIII/IV and IV/V.39 The traditional con-cept that circulating immune complexesin lupus passively deposit in the kidneyhas been challenged by novel data.40,41

Glomerular immune complexes ratherform in situ by secondary binding to nu-cleosomes from renal cells.42 Anotherpotential intrarenal source of nucleo-somes are neutrophils upon NETosis,11

due to the release of neutrophil extracel-lular traps that is initiated by anti-LL37antibodies.7–10 Heparin modulates theintrarenal effect of chromatin either byenhancing the DNA-I–dependent chro-matin degradation or by preventing

Table 1. Pathomechanisms of LN inside the kidney

Glomerular Pathology Tubulointerstitial Pathology

Mesangial and subendothelial, immunecomplex deposits, complement activation

Immune complex deposits inperiglomerular vessels

Fc, Toll-like, and complement receptor activation Complement activationActivation of renal cells and infiltrating leukocytes(subepithelial IC causes LN class V andpodocyte injury with massive proteinuria)

Activation of endothelial cells, luminaladhesion molecules

Local cytokine expression Leukocyte recruitmentRecruitment of leukocytes Local antibody production by B cells including

tertiary lymphoid organ formationProliferation of endothelial and mesangial cells Cytotoxic and Th17 T cellsFiltration barrier damage causing proteinuriaand hematuria

Proapoptotic cytokines

Renal cell necrosis causing focal scaring Proximal tubular cell damage causingproteinuria

Proliferation of parietal epithelial cells andcrescent formation

Tubular/vascular atrophy

Periglomerular inflammation Hypoxia → inflammationGlobal glomerulosclerosis Insufficient tubular and vascular repair plus

ischemia promotes interstitial fibrosis

J Am Soc Nephrol 24: 1357–1366, 2013 Pathogenesis of Lupus Nephritis 1359

www.jasn.org BRIEF REVIEW

chromatin binding to the glomerularbasement membrane.43 Anti-DNA anti-bodies activate endothelial and mesangialcells through different mechanisms. Forexample, antibodies are directly taken upinside renal cells.41 This process involvescross-reactivity with a-actinin or annexinII on mesangial cells,44,45 but this conceptcould not be confirmed by recent stud-ies.46,47 In addition, intrarenal immune

complex deposits activate comple-ment,36 which demonstrates the dualrole of complement factors in LN.48Com-plement deficiency impairs opsonizationand removal of lupus autoantigens fromthe extracellular space, whereas comple-ment factors also directly cause immunecomplex–related renal inflammation andimmunopathology.49,50 That immunecomplexes activate glomerular cells by

Fc receptor (FcR) ligation is also well es-tablished even though the data accumu-lated over the last few decades remaincomplex.51 Subepithelial immune com-plex deposits lead to secondary membra-nous GN and nephrotic syndrome bydamaging podocytes.

Intrarenal Activation of TLRs andIFN SignalingThe nucleic acid component of immunecomplexes also activates intrarenal in-flammation by TLRs in intrarenal mac-rophages and dendritic cells.52 Inaddition, immunostimulatory nucleicacids activate glomerular endothelium,mesangial cells, and macrophages toproduce large amounts of proinflamma-tory cytokines and IFN-a and IFN-b.53–59

The functional significance of thisintraglomerular IFN signaling is poorlyunderstood but seems to contribute torenal damage in LN and should triggerthe formation of tubuloreticular struc-tures or inclusions that represent anultrastructural characteristic of IFNsignaling.56,60 Together, the ligation ofTLRs, complement receptors, and FcRsactivates renal cells to release proinflam-matory cytokines and chemokines, andinduces the luminal expression of selectinsand adhesion molecules inside the micro-vasculature.61,62

Chemokine-Mediated Recruitmentof Different Leukocyte SubsetsCytotoxicTcells, Th17Tcells, aswell asBcells infiltrate the kidney in LN.24 Themembers of the chemokine family spe-cifically direct different leukocyte sub-sets by distinct chemokine receptorsinto different renal compartments.63

For example, the chemokine CCL2 re-cruits CCR2+ proinflammatory macro-phages and T cells into the glomerulusand the tubulointerstitium,64,65 whereasCCR1+ cells only recruit to the intersti-tial compartment and not to the glomer-ulus in LN.66 Other leukocyte subsetsinvolve other chemokines and chemo-kine receptors for their recruitmentinto the kidney.63,67 Leukocyte recruit-ment is tightly regulated. For example,renal cells produce pentraxin-3, whichhas the potential to directly inhibit

Figure2. Therapeutic targets for LN.Aberrant immunity in SLE involvesmanydifferent celltypes and cytokine mediators, which could be suitable therapeutic targets. MCP-1,monocyte chemotactic protein-1; CCR, CC chemokine receptor; CXCR, C-X-C chemokinereceptor.



leukocyte recruitment by interferingwith P-selectin on the surface of acti-vated endothelial cells.68,69 In lupus-like autoimmunity of C57BL/6lpr/lpr

mice, the role of pentraxin-3 seems tobe organ specific, because it suppresseslymphocyte recruitment to the lungs butnot to the kidney.70 Infiltrating leuko-cytes form de novo perivascular tertiarylymphoid organs inside the kidney,which involve the clonal expansion andongoing somatic hypermutation of Bcells in proximity to T cell aggregates.71

Such B cells undergo intrarenal prolifera-tion and activation, which contributes tolocal inflammation and tissue pathologyin addition to their role for systemic andintrarenal autoantibody production.26,72,73

These data provide a rationale for B cell–targeted therapies in LN.74,75 T cellinfiltrates also contribute to immunopa-thology in LN, particularly IL-17 produc-ing CD3+/CD4+ or CD3+CD4/82/2

T cells.76 Macrophages also contributeto renal damage, particularly F4/80(hi)/CD11c(int)Gr1(lo)/Ly6C(lo)/VLA4(lo)/MHCII(hi)/CD43(lo)/CD62L(lo) mac-rophages.77,78

Maladaptive Tissue RepairContributes to CKD ProgressionDamage to renal parenchymal cells trig-gers healing responses that contribute torenal pathology. Focal tuft necrosis isfollowed by a migration of parietal epi-thelial cells in the glomerular tuft, wherethey produce extracellular matrix con-tributing to FSGS progressing to globalglomerulosclerosis.79 During this pro-cess, the parietal cells maintain their po-larized epithelial phenotype and laydown extracellular matrix on top of thepodocytes.79 In addition, cellular glo-merular crescent formation resultsfrom activation of parietal epithelial cellsthat fill the urinary space by uncoordi-nated proliferation.80,81 This process canbe triggered by glomerular basementmembrane breaks that allow plasmaleakage into Bowman’s space, where mi-togenic plasma components such as fi-brinogen trigger hyperproliferation ofthe parietal epithelial cells.82 At laterstages, the parietal epithelial cells losetheir polarity and produce matrix all

around themselves, which creates hon-eycomb matrix deposits in Bowman’sspace that turn cellular crescents into fi-brocellular crescents with glomerulo-sclerosis, also referred to as class VI LN.

THE PRESENT AND FUTURE OF LNTHERAPY

Nonselective ImmunosuppressantsSteroids, cyclophosphamide, azathio-prine, andmycophenolate mofetil remainfirst-line therapeutics for treatment ofLN. These nonselective immunosuppres-sants have much improved the responserates of acute manifestations and theoverall mortality of SLE; however, thelong-term outcomes of LN have notfurther improved during the last 30years.83 High-dose steroids and cyclo-phosphamide are frequently associatedwith severe side effects, and infectionscontribute to the overall mortality inSLE. The same applies to the other non-selective immunosuppressants. Forexample, in the ALMS (Apreva LupusManagement) trial, infection-relatedmortality was even higher in patientstreated with mycophenolate mofetilthan in the group treated with high-dose cyclophosphamide. Reducing thedrug dose was the first strategy to limitside effects, and some researchers won-der whether oral cyclophosphamidetherapy is no longer needed.84 In addi-tion, some studies suggest that Caucasianpatients may no longer need high-dosecyclophosphamide, because the Euro-Lupus trial demonstrated favorablelong-term outcomes with much lowerdoses of cyclophosphamide.85 Otherimmunosuppressants like dihydrooro-tate dehydrogenase inhibitors add tothe current choices but are still nonspe-cific.86,87 However, lupus drug develop-ers continue to search for new drugsthat more specifically modulate the ab-errant immunity in SLE with fewer sideeffects.

Novel Moieties that Target SpecificLeukocyte SubsetsOne of the current strategies to specificallyinterfere with systemic autoimmunity in

SLE is to use cell type–specific drugs. Forexample, great hope was put into thestrategy of B cell–directed therapy as Bcells are the source of autoantibody pro-duction.88 Meanwhile, it is clear that Bcells in SLE also contribute to autoimmu-nity and tissue inflammation in manyother ways, which increases the hopethat depleting or modulating B cellswould result in major benefits in SLEand LN.89 This led to the developmentof the fully humanized anti-CD20 anti-body (rituximab), the anti-CD22 anti-body (epratuzumab), and to anti-BlyS(belimumab). Because the randomizedplacebo-controlled Lupus Nephritis As-sessment with Rituximab trial failed todemonstrate a benefit of add-on rituximabfor the induction therapy of incident LNclass III/IV/V, this approach to B cell de-pletion still has questions.90,91 At about thesame time, the Exploratory Phase II/IIISLE Evaluation of Rituximab trial alsofailed to demonstrate benefits on nonrenallupus.91 However, uncontrolled studies onrefractory LN still document 75% re-sponder rates and many specialists con-tinue using rituximab successfully forthese patients.92

BLyS blockade is another promisingstrategy to target B cell proliferation. Alarge randomizedplacebo-controlled tri-al suggested that add-on belimumab ontop of standardmaintenance therapy cansignificantly improve persistent diseaseactivity up to 72 weeks.93 This study ledto the US Food and Drug Administra-tion and European Medicines Agencyapproval of belimumab for nonrenal lu-pus in the United States and Europe. Pa-tients with severe LN were excludedfrom the BLISS-56 and BLISS-76 trials,but data from those patients with mod-erate nephritis raise hope that belimumabcould also be efficient in severe LN.94

Such a trial is currently underway. OtherB cell–directed strategies include atacicept(TACI-Ig), LY2127399 (anti-BAFF), andanti-BR3 (anti-BAFF-R).89

Dendritic cell–T cell interaction is atarget of costimulatory ligand/receptorblockers such as CTLA-4-Ig (abatacept).This drug blocks the interaction of CD80and CD86 on antigen-presenting cellswith CD28 on T cells, which suppresses



T cell activation.95 Abatacept suppressedlupus in mice but did not prevent flaresin SLE patients.96 Three trials with anti-CD40L failed to demonstrate efficacy.Abetimus is a drug that modulates auto-immunity by altering antigen recogni-tion by T cells. Abetimus is composedof a series of linked oligonucleotides,which block the binding of anti-dsDNAantibodies to their autoimmune targetsand tolerize B cells with antigen specific-ity for DNA. Unfortunately, the resultsin clinical trials have been very modest.A similar approach is followed byedratide, a peptide derived from theantigen-binding region of a humanmonoclonal anti-dsDNA antibody. It hasbeen proposed that this molecule canmodulate the function of DNA-reactiveB cells through idiotype–anti-idiotype in-teractions but again, the convincing dataon efficacy are still lacking.

The concept of anti-dsDNA–specifictherapeutic interventions is no longerpreferred because it targets only a verysmall subset of B cells, and no longerseems sufficient in view of the failing Bcell depletion trials and the fact thatdsDNA antibodies certainly contributeto SLE but remain only one of many dif-ferent pathogenic elements. Finally,plasma cells now appear as an attractivetherapeutic target in SLE because theyharbor the long-term memory of hu-moral immunity and produce the lupusautoantibodies.97 Rituximab does notdeplete plasma cells, because these arenegative for CD20.97 Massive antibodyproduction in plasma cells involves theintracellular proteasome complex forprotein processing. The proteasome in-hibitor bortezomib was proven to be ef-fective in mouse models of LN,98,99 butclinical trials with bortezomib in humanLN is still pending.

Additional Innovative TherapeuticStrategiesThe pseudo-antiviral immunity conceptis based on the molecular mimicry ofendogenous nucleic acids at the viral nu-cleic acid recognition receptors TLR7 andTLR9.100 Hence, blocking these TLRs andthe subsequent IFN signaling are additiveto established therapeutic targets in

SLE.101 Current treatment guidelinesrecommend hydroxychloroquine treat-ment for all SLE patients, including allpatients with LN.102–104 Antimalarialdrugs like hydroxychloroquine inhibitlysosomal acidification, which blocksthe adjuvant effect of endogenous nu-cleic acids by TLR7 and TLR9 duringthe lysosomal processing of nuclear par-ticles in endolysosomal compartmentsof antigen-presenting cells.20 Mean-while, more specific TLR7 and TLR9agents have been developed that effec-tively suppressed LN in murine SLEmodels and are now being tested in clin-ical trials.21–23,105 Antagonism of IFN-ais feasible with IFN-a antibodies. Adouble-blind randomized study withsifalimumab, a fully human anti-IFN-amAb, demonstrated that IFNa drivesthe overexpression of IFN-dependentgenes in human SLE, which is reversedby sifalimumab.106 Other cytokine-directed innovative therapies includeanti-Tweak (ATLAS trial) as well as anti-IL6R (tocilizumab). The current status foroff-label use of these drugs was recentlysummarized.30,107 Finally, it remains an at-tractive notion to add anti-inflammatoryagents to immunosuppressive drugs to re-duce the degree of therapeutic immuno-suppression and the risk of therapy-relatedinfections. As a proof of concept, the com-bination therapy of the CCL2 chemokineantagonistic Spiegelmer,mNOX-E36, and25% of full-dose cyclophosphamide wasshown to be as effective as 100% cyclophos-phamide to control severe SLE in MRLlpr/lprmice108; thus, the cyclophosphamide-related T cell ablation and myelosuppres-sion couldbeprevented,whilemaintainingtreatment efficacy.108

SUMMARY

The pathogenesis of LN involves extrare-nal and intrarenalpathogenicmechanisms.The extrarenal factors include complexcombinations of genetic variants thatare different in each patient, which ex-plains the variability of clinical mani-festations. SLE develops when geneticvariants compromise those mechanismsthat normally assure immune tolerance

for nuclear autoantigens. Loss of toler-ance becomes clinically evident by thepresence of antinuclear antibodies. Thenucleic acid content of nuclear particlesfrom netting or apoptotic neutrophilsactivates innate and adaptive immunityby TLR7 and TLR9, which triggers anIFN-a–mediated antiviral host defenseprogram that accounts for many of thenonspecific SLE symptoms. As such,dendritic cells, T helper cells, B cells,and plasma cells all contribute to the ab-errant polyclonal autoimmunity. The in-trarenal etiology of LN involves antibodybinding to intrarenal nuclear autoanti-gens, local complement, and FcR activa-tion. Tertiary lymph follicles, to somedegree, form inside the kidney, which in-clude B cells with local proinflammatoryeffects as well as plasma cells that secreteautoantibody inside the kidney. These in-sights into the pathogenesis of lupus pro-vide the rationale for a number of noveltherapeutic targets.

ACKNOWLEDGMENTS

This work was supported by the German

Research Foundation (grants AN372/11-1

and GRK 1202).

DISCLOSURES.None.

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