t cells and b cells in lupus nephritis - 영남대학교의학...
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T Cells and B Cells in Lupus Nephritis
Mary H. Foster
Summary: T and B lymphocytes play diverse roles at multiple stages in the developmentand progression of lupus nephritis. Disruption of T- and B-cell regulatory functions byenvironmental and genetic influences permits pathogenic effectors to emerge in disease.New insights into the biology of these multifunctional cells offer novel targets forintervention in lupus nephritis and systemic autoimmunity.Semin Nephrol 27:47-58 © 2007 Elsevier Inc. All rights reserved.Keywords: Lupus nephritis, autoimmunity, tolerance, immune regulation, immuno-therapy
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he immune system plays a central rolein the pathogenesis of systemic lupuserythematosus. This review focuses on
and T lymphocytes, 2 pivotal cellular com-onents of adaptive immunity and key cul-rits in mediation of glomerulonephritis, aommon and serious complication of lupus.lomerular immunoglobulin (Ig) depositionnd renal lymphocyte and macrophage infil-ration lead to clinical renal involvement atome point in the clinical course of up to 75%f lupus patients. Lymphocytes and their sol-ble mediators participate at all levels in dis-ase pathogenesis: initiation, perpetuation,mplification, regulation, tissue and organ de-truction, and disease relapse. They thus poserime targets for novel interventions. Intense
aboratory and clinical investigation over theast decade has brought important insights
nto cellular subsets, signaling, mediators andegulatory pathways, and introduced promis-ng new immunotherapies.
epartment of Medicine, Division of Nephrology, Duke University MedicalCenter, Durham, NC.
upported by a Department of Veterans Affairs Merit Review grant andNational Institutes of Health grant DK47424.
he author apologizes to colleagues for the inability to cite many primaryreferences owing to space constraints.
ddress reprint requests to Dr. Mary H. Foster, Department of Medicine,Division of Nephrology, Box 3014, Duke University Medical Center,Durham, NC 27710. E-mail: [email protected]
270-9295/07/$ - see front matter
t2007 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2006.09.007eminars in Nephrology, Vol 27, No 1, January 2007, pp 47-58
NITIATION OF NEPHRITOGENICUTOIMMUNE RESPONSES
olerance andutoimmune Susceptibility
upus is a disease of failed immune tolerance toelf. The repertoire of Ig and T-cell receptors isast and self-recognition is common, generatedy gene recombinatorial and somatic events inhe thymus and bone marrow and, in the casef mature B cells, by somatic mutation in theeripheral lymphoid organs. It is estimated thatp to 75% of newly formed, and up to 40% ofature germinal center, B cells recognize self-
ntigens.1,2 This autoreactivity normally is heldn check by regulatory mechanisms that oper-te on developing lymphocytes in the centralymphoid organs and on mature cells in thepleen and lymph nodes (Table 1).3
Specific tolerance is induced by interactionf the lymphocyte antigen receptor with self-ntigen, either in native conformation for rec-gnition by B cells or as peptide antigen pre-ented by cell-bound major histocompatibilityomplex (MHC) molecules for recognition by-cell receptor (TCR)-�/�–expressing T cellsFig. 1). The strength of this signal may influ-nce the type of tolerance induced (deletion ornergy). Induction of tolerance by antigen con-act requires an appropriate microenvironmentnd noninflammatory milieu that limits lympho-yte signaling to that initiated by antigen alone,lso referred to as signal 1. Delivery of signal 2
o an autoreactive lymphocyte converts a47
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olerogenic signal into an activating one, trig-ering an autoimmune response. Signal 2 typi-ally is delivered by costimulatory moleculesxpressed on activated antigen-presenting cellsAPCs) and lymphocytes. Major costimulatorsnvolved in T- and B-cell collaboration areD40/CD40L and members of the B7/CD28
amily (B7/CD28, inducible costimulator ligandICOSL]/inducible costimulator [ICOS]).4 In ad-ition, potent mitogens or microbial productsan trigger danger signals that permit bypass ofolerance by binding Toll-like receptors (TLRs)n B cells and APCs.5
Failure or bypass of one or more regulatoryechanisms permits autoreactive lymphocytes to
urvive and expand (Table 2, Fig. 2). Dysregula-ion of sufficient magnitude or at a sufficient num-er of checkpoints in combination with lympho-yte activation, antigen exposure, and aermissive end-organ microenvironment ulti-ately leads to tissue destruction and disease.ysregulation results from environmental expo-
ures and inherited autoimmune susceptibility,ften acting in concert.6,7 Considerable data sug-est that different influences alter different path-ays, and that different regulatory mechanisms
Table 1. Mechanisms Regulating Autoim-munity
DeletionAnergyReceptor editingDual-receptor expressionClonal ignorancePeritoneal homingFollicular exclusionCompetition for survival factors or cognate cell
helpRegulatory B- and T-cell subsets*Th1, Th2, and Th17 skewingImmune-suppressive cytokines (TGF-�, IL-10)Receptor and coreceptor modulationIdiotypic networksAntigen sequestration*IL-10– or TGF-�–producing B cells, prototypic
CD4�CD25� Treg, T-helper-3 (Th3) T cells, T regula-tory type 1 (Tr1) T cells, and inhibitory CD8�, TCR-�/�,or NK T cells.
re breached in different individuals. It is evident m
rom animal models that a wide variety of im-une abnormalities can lead to a similar lupus-
ike disease.Exogenous agents can provoke acquired de-
ects in immune tolerance leading to a lupushenotype. Procainamide and hydralazine in-uce systemic autoimmunity in human beingsnd rodents. In vitro they inhibit DNA methyl-tion and upregulate T-cell lymphocyte func-ion-associated antigen-1 (LFA-1) costimulatorxpression to promote T-cell autoreactivity.doptive transfer of T cells overexpressingFA-1 induces lupus-like disease including glo-erulonephritis in naive recipient mice.8 Pro-
ainamide also has been shown to alter T-cellhymic selection and signaling thresholds.9 Mer-uric chloride and gold induce Th2-type auto-eactive CD4� T cells, interleukin (IL) 4 pro-uction, and an interferon (IFN)-�–dependent
upus nephritis in rodents.10,11 A similar pheno-ype is reported in allogeneic reactions. Heavyetals, hydrocarbon oil (pristane), and micro-
ial products are potent B-cell mitogens, withhe potential to activate nontolerant (ignorant)utoreactive cells or reverse anergy.
Autoimmune susceptibility arises from allelicariants or mutations in genes encoding a varietyf immune-relevant proteins of diverse function.7
ransgenic overexpression or targeted disruptionf molecules involved in B- and T-cell signaling,
ymphocyte selection, adhesion, activation, andurvival can lead to spontaneous lupus-like dis-ase and nephritis. Genetic mapping in murineupus strains (MRL/lpr, [NZBxNZW]F1, BXSB,ZM2410) and their congenic variants has iden-
ified loci that modify tolerance. Autoreactive B-nd T-cell–receptor transgenes established on lu-us-prone backgrounds reveal defects in B-cellolerance, induction of T-cell anergy, and defectsn central T-cell deletion.12,13 Studies in humanupus reveal associations with MHC class II alleles,
olecules critical to antigen presentation, com-lement components that regulate B-cell activa-ion, tolerance and effector functions, and anti-ody constant region fragment (Fc)-� receptorshat regulate APC activation.7
- and B-Cell Abnormalities andnteractions in Induction of Lupus
bnormalities in B and T cells characterize
urine and human lupus, reflecting both lympho-
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yte-intrinsic defects and extrinsic influences.14-17
upus T cells manifest decreased DNA methyl-tion; defective TCR signaling; heightened cal-ium responses; decreased activation thresh-ld; upregulated expression of costimulatoryolecules CD40L, ICOS, �2 integrins CD11a/D18 (LFA-1), and CD11c/CD18 (Mac-1); up-
egulated focal adhesion kinase pp125FAK; de-reased expression of TCR-� chain; increasedntracellular phosphorylation; upregulated Fc-�eceptor chain expression; mutations in type Irotein kinase A regulatory subunit �; deficientctivation-induced death; deficient IL-2 produc-ion; upregulated cyclooxygenase-2; mitochon-rial dysfunction; overexpression of perforin;nd regulatory defects in cbl and extracellularignal-related kinase pathways. Paradoxic con-urrent spontaneous T-cell hyperresponsive-ess and defective in vivo and ex vivo T-cell
igure 1. Antigen regulation of autoimmunity. Self-antolerance or activation in the responding lymphocyte. Tent and whether an inflammatory milieu upregulates c
egulatory T cell; PC, plasma cell; CTL, cytotoxic T lymp
roliferative responses are reported. Lupus B e
ells are hyperactive and show enhanced phos-horylation of mitogen-activated protein kinaseathways, altered Lyn expression, upregulatedcl2, upregulated CD40L, and defective B-celleceptor (BCR)-induced apoptosis.18-20 Circulat-ng B-cell–activating factor (BAFF, or BLyS), a-cell survival factor, is increased in a significantroportion of lupus patients, and mice overex-ressing BAFF develop a lupus-like disease.21
AFF rescues autoreactive B cells from periph-ral deletion and initiates CD40L-independentgG isotype class switch.22 Circulating plasma-lasts and cells bearing germinal center markersre reported in lupus patients, and plasmablastsnd ectopic germinal centers and follicles pop-late murine lupus kidneys.18,23
ocal Regulation of Immune Responses
enal parenchymal cells, and proximal tubular
ontact with the T or B cell receptor can induce specifictcome of the interaction depends on the microenviron-latory signals. Ag, antigen; Breg, regulatory B cell; Treg,e.
igen che ouostimu
pithelial cells (TECs) in particular, may play a
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ey role in modulating nephritogenic immuneesponses in lupus.24,25 IFN-�–stimulated TECsownregulate proliferation in autoreactive T-ell clones derived from MRL/lpr kidneys. Mu-ine lupus TEC express MHC molecules andresent antigens ex vivo for recognition byD4� T cells. This interaction can lead to ei-
her anergy or activation of responding T cells,epending on whether antigen-presenting TECs
Table 2. Initiation and Amplification ofNephritogenic Autoimmune Responses inLupus
Altered DNA methylation or histoneacetylation*
Dendritic cell activation†Antigenic mimicry caused by foreign/self-
homologyExposure of cryptic or neo- (modified) self-
antigenExpression of dormant self-antigen (heat shock
protein)Imbalance or defect in T- or B-cell regulatory
subsetsBystander activationPolyclonal activation (mitogens, superantigens,
lectins)Biased T-helper subset expansion (Th1/Th2/
Th17 shift)Defective, abnormal, or excessive apoptosis‡Altered antigen receptor signaling (BCR, TCR)Decreased inhibitory receptor signaling
(FcgRIIB, CD21, CD22, CD5)Enhanced accessory receptor signaling (TLR,
costimulators, activating FcgR, adhesionmolecules)
Enhanced lymphocyte survival (increased BlyS/BAFF, mutated Fas)
Epitope spreading*A given type of environmental challenge (infectious
agents, chemicals, drugs, pharmacologic agents, ultra-violet light) may induce acquired defects by multiplemechanisms shown here.
†Activation of IFN-�/�–producing dendritic cells by vi-ruses, nucleic acid–IgG immune complexes, or micro-bial products may be a major cause of loss of peripheraltolerance.
‡Apoptosis defects may contribute to autoimmunity atmultiple levels. Apoptosis is crucial for autoreactive B-and T-cell deletion, and apoptotic cells expose a varietyof lupus self-antigens that can either tolerize or immu-nize, depending on the context.
oncomitantly upregulate costimulatory or in- a
ibitory molecules. The reported tissue distri-ution of the costimulatory family moleculesuggest that the pathways most likely engagedn parenchymal cell regulation of T lympho-ytes are ICOS/ICOS-L and inhibitory pro-rammed death (PD)-1/PD-L interactions. Col-ectively, these findings suggest that TEC–T-cellnteractions in the kidney are primarily regula-ory and maintain tolerance to self-antigen. Aimilar role may apply to other parenchymalells, such as mesangial cells, glomerular podo-ytes, and endothelium, which have induciblentigen-presenting functions.
CELLS AND CELLULARMMUNITY IN LUPUS NEPHRITIS
egulation by T-Cell Subsets
cells play central and multiple roles in theathogenesis of lupus nephritis (Fig. 2). Theyrovide help for B-cell production of nephrito-enic autoantibodies, regulate B-cell responses,nd modulate T-helper (Th) and effector func-ions and expansion. T cells infiltrate the kidneyo injure renal parenchymal cells directly viaytotoxicity or indirectly through activationnd recruitment of macrophages and naturaliller (NK) cells.
The importance of T cells in lupus is wellocumented.15,26 Oligoclonally expanded IFN-–producing T cells autoreactive to classic lu-us-associated autoantigens can be isolated
rom peripheral blood of lupus patients androm lupus mice. Most lines or clones isolatedo date are CD4� TCR-�/� phenotype, al-hough recovery of CD8� and TCR-�/� T cellsas been reported. An imbalance in the numbernd function of T-cell subsets has been re-orted, including an increase in CD4� relativeo CD8� T cells, increased frequency of circu-ating double-negative CD4-CD8- T cells, andltered Th1 and Th2 cytokine production. Pa-ient and murine lupus �/�, �/� and CD4-CD8-
cells facilitate autoantibody production by Bells. Chromatin-reactive CD4� T cells isolatedrom lupus patients and mice augment produc-ion of anti-DNA and antichromatin antibod-es.27 Evidence of T-cell help is found in the lupusutoantibodies themselves; IgG isotype switch
nd accumulation of replacement mutations sug-
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T cells and B cells 51
est that they are products of an antigen-driven-cell–dependent immune response.Definitive evidence of the requirement for T
ells comes from rodent lupus models, inhich T-cell helper and effector subsets haveeen depleted and costimulatory pathways in-errupted using monoclonal antibodies, fusionroteins, and gene-targeted deletion.28 In gen-ral, murine lupus nephritis is delayed and ame-iorated by depletion of CD4� and �/� T-cellubsets and antagonism of CD28/B7, CD40/D40L, and intercellular adhesion molecule-1/FA-1 costimulatory interactions. Each strategyan delay nephritis and variably decrease pro-einuria, improve urea and creatinine clear-nces, decrease renal histopathologic injury
igure 2. Diverse roles for B cells, T cells and dendritic cupus nephritis.
nd lymphocytic infiltration, and decrease auto- u
ntibody production.29-31 Recent results fromnterruption of the ICOS/ICOSL pathway vary bytrain and experimental strategy; anti-ICOS mono-lonal antibody (mAb) improved nephritis in theWF1 mouse whereas targeted deletion of ICOSad no effect on MRL/lpr nephritis.32,33 Efficacyf T depletion and costimulatory blockade inrolonging survival and ameliorating disease inonrenal organ systems is variable, and the per-istence of some lupus manifestations in miceacking �/� T cells suggests �/�-independent
echanisms.34
Notably, each major T-cell subset has reg-latory and pathogenic effector roles suchhat the net effect of a given interventionppears to be context dependent and may be
C) in the control of autoimmunity and pathogenesis of
ells (Dnpredictable. In this regard, deletion of class
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MHC and CD8� T cells has yielded conflict-ng observations. Targeted deletion of �2-mi-roglobulin, which eliminates both classicnd nonclassic (CD1) MHC class I expressionnd thus eliminates CD8� and NK1 T cells,meliorates kidney injury but accelerates skinisease in MRL/lpr mice.35,36 The effect isttributed to CD8� T-cell depletion, becausesolated CD1 deletion does not alter MRL/lprephritis. Conversely, �2-microglobulin dele-ion in BWF1 mice accelerates disease,37 androlonged anti-CD8 mAb treatment fails tolter disease in MRL/lpr and (NZWxBXSB)F1ice, in contrast to a favorable response in-
uced with anti-CD4 mAb.38,39
TCR-�/� T cells and NKT cells play an equallyomplex role in lupus.40 MRL/lpr mice lackingCR-�/� T cells develop accelerated nephritisnd mortality accompanied by polyclonal ex-ansion of CD4� T cells, suggesting a domi-ant-negative regulatory function for this T-cellubset.41 Conversely, TCR-�/� effectors appearo be responsible for the residual mild autoim-unity and nephritis observed in TCR-�/�-defi-
ient MRL/lpr mice because autoantibody pro-uction and disease are absent in TCR-�/� TCR-/� double-deficient MRL/lpr mice.41 NKT cellsxpress an invariant TCR and NK cell receptorK1.1 and recognize glycolipid presented byD1d. Activated NKT cells produce immuno-odulatory cytokines and mediate cytotoxicity.s noted earlier, CD1 deficiency does not alterRL/lpr nephritis, whereas in vivo activation ofKT cells has variably been associated withxacerbation and amelioration of murine lu-us.42
Collectively these observations support anmportant role for regulatory T-cell subsets inupus. This is consistent with numerous earlyeports of abnormalities of T-cell suppression inupus, including decreased numbers of CD4�D25� T cells in the peripheral blood of SLEatients with active disease.15 The suppressionf autoantibody production and nephritis in
upus mice using tolerogenic peptides to ex-and CD4� CD25� regulatory T cells andransforming growth factors (TGF)-�–produc-ng inhibitory CD8� T-cell subsets has been
eported.43 d-Cell Effector Mechanisms in Lupus
ifferentiated T-cell effectors exert theirunctions by interactions with other cells orhrough overproduction of immunomodula-ory cytokines, such as IFN-�, tumor necrosisactor (TNF)-�, TGF-�, IL-4, and IL-17. Acti-ated CD4� and CD8� T cells, and, in MRL/pr mice, the unique population of B220�lass I–restricted double-negative CD4-CD8-CR-�/� T cells are present in glomerular
esions in murine and human lupus, recruitedy chemokines to exert actions locally.44,45 Inddition to promoting autoantibody re-ponses, T-cell– generated proinflammatoryytokines amplify disease by upregulating ad-esion and MHC class II molecules, recruitacrophages, promote fibrosis, and induce
ntrarenal nephritogenic cytokines colony-timulating factor-1, granulocyte-macrophageolony-stimulating factor, and TNF-�.46,47 Au-oreactive double-negative T-cell clones prop-gated from nephritic lupus mouse kidneysnduce MHC class II and intercellular adhe-ion molecule-1 expression and proliferate inesponse to renal parenchymal cells.48 Auto-eactive cytotoxic CD4� TCR-�/� T cells cane isolated from nephritic kidneys of miceith chronic graft-versus-host disease, a lu-us-like syndrome with glomerulopathy.49
raft-versus-host disease– derived T-cell effec-ors induce glomerular crescents and a focalononuclear infiltration when transferred to
aive syngeneic recipients by renal subcapsu-ar transfer. In nonlupus model systems, ne-hritogenic CD4� and CD8� T-cell clonesave been shown to mediate MHC-restricted,erforin and granzyme-mediated cytotoxicityoward cultured renal proximal tubularells.50 It is notable therefore that T-cell cyto-oxicity in lupus may be predominantly regu-atory, directed toward controlling patho-enic lymphocytes. Cytotoxic responses areediated primarily through Fas, perforin, andNF. Deficiency in each of these pathways
ntroduced in lupus-prone mice by gene-tar-eted deletion of Fas, Fas ligand, perforin, orNF-receptor leads to acceleration, not im-rovement, of autoimmunity and nephritis.51
his may explain in part the association of
rug-induced lupus with anti–TNF-� therapy.
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Cytokines involved in CD4� Th1/Th2-helper cell differentiation received early at-
ention because of their proinflammatoryIFN-�, IL-12, TNF-�/�) or anti-inflammatoryIL-4, IL-10) actions and potential therapeuticfficacy. However, in vivo biologic or geneticodulation of cytokine production or functionas shown inconsistent results in modulating
upus nephritis.52 In vivo administration of ei-her IL-10 or IFN-� accelerates nephritis in lu-us-prone BWF1 mice, whereas antibody block-de of either cytokine delays disease. Nephritisn MRL/lpr mice is ameliorated by targeted dis-uption of either IFN-� or IL-4. Administrationf IL-12 accelerates nephritis and promotes
ntrarenal accumulation of IFN-�–secretingD4�, CD8�, and double-negative T cells in
upus mice. These results fail to implicate dis-ase dependence on a single CD4� T-helperubset. Notably, levels of both Th1 and Th2ytokines are increased in murine lupus, androteinuria and glomerulonephritis in MRL/lpr
upus is ameliorated by histone deacetylase in-ibitors that downregulate transcription ofoth subsets (IL-12, IFN-�, IL-6, and IL-10).53
Recognition that IL-23 and IL-27, additionalembers of the IL-6/IL-12 family, influence Th1
esponses and identification of a third lineage ofD4� T-helper cell, termed Th17 cells, explainome of the previous conflicting findings. Th17ells develop under the influence of IL-6,GF-�, and IL-23 and produce the proinflamma-
ory cytokine IL-17.54 Notably, deficiency forSX-1, a component of the IL-27 receptor, al-
ers the cytokine profile and phenotype of lu-us glomerulonephritis in MRL/lpr lupusice.55 A significant decrease in IFN-� produc-
ion by CD4� T cells accompanies a shift fromiffuse proliferative glomerulonephritis (GN) toclinical and pathologic picture resembling hu-an membranous nephropathy. The impor-
ance and nature of local cytokines that mediateenal immune injury was elucidated using annnovative strategy of implanting genetically
odified cytokine-secreting renal tubular cellsnder the kidney capsule. IL-12, macrophagerowth factors, and the chemokine RANTES,ut not IL-6, elicit autoimmune injury in lupus
ouse kidneys.56 oCELLS AND HUMORALMMUNITY IN LUPUS NEPHRITIS
ultifunctional B Cells
cells serve diverse regulatory functions inmmune biology and lupus (Fig. 2 and Table 3).57,58
lthough best appreciated for antibody release,-cell production of regulatory cytokines andirect interactions with T cells and dendriticells have a profound impact in shaping cellularmmune responses. B cells are highly efficientntigen-presenting cells, capable of capturingntigens via cell-surface Ig receptors for subse-uent internalization, processing, and presenta-ion via class I or II MHC molecules. B-cellresentation of autoantigen peptides directlyctivates autoreactive T cells. B cells modulate-cell memory and regulate dendritic cell devel-pment and activation. Distinct subsets ofifferentiated effector and regulatory B cellsroduce significant amounts of immune modu-
atory cytokines, such as IL-10 and TGF-�.59
L-10 suppresses macrophage activation and cy-okine production and skews T-helper differen-iation toward a Th2 phenotype. Notably, gen-ration of IL-10–producing regulatory B cells
Table 3. Diverse Roles for B Cells in Immu-nity and Lupus
Produce pathogenic autoantibodiesProduce regulatory antibodies (anti-idiotypic,
FcgRIIB-binding, mediator-neutralizing)Produce immunomodulatory cytokines (IL-
10, IL-6, TGF-�, IFN-�, IL-12)Differentiate into polarized B-cell effectorsProcess and present antigen to T cells for
activation or tolerance inductionCoordinate T-cell migration and
differentiationDirectly cross-regulate Th1 and Th2 cell
differentiationInhibit or delete T-cell effectors via direct
contact or TGF-�Recruit CD8� and NKT regulatory T cellsPromote the development of follicular
dendritic cellsRegulate dendritic-cell cytokine productionMaintain secondary lymphoid architecture
ccurs under inflammatory conditions, appears
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o involve a marginal zone B cell precursor,ccurs in human beings, and can be induced byLR signaling. This latter observation is consis-
ent with recent reports of apparent paradoxicmmunosuppressive effects of TLR agonists.GF-� suppresses inflammation, induces apo-tosis in effector T cells, and skews T-helperifferentiation toward a Th17 phenotype. Ex-erimental manipulations suggest multiple ad-itional mechanisms, many of which are listed
n Table 3, by which B cells modulate T-cellxpansion and function, induce T-cell toler-nce, and dampen inflammation. Secreted anti-odies also function in regulation, via protec-ive self-antigen specificities, IgG constantegion engagement of inhibitory FcgRIIB recep-ors on APCs, or within regulatory idiotypicetworks.60 There has been a recent resur-ence of interest in the regulatory role of B cellsnd autoantibodies with the discovery of B-cellependence in autoimmune disease modelsreviously thought to be primarily T-cell medi-ted and, conversely, exacerbation of severalurine autoimmune and inflammatory diseases
n B-cell–deficient mice as compared with their-cell–sufficient counterparts. These diverseoles raise some concern regarding the predict-bility of outcomes with B-cell targeted thera-ies. Nonetheless, B-cell ablation through geneeletion or anti-CD20 monoclonal antibody ad-inistration eliminates early mortality, immune
nfiltrates, and organ injury in murine lupus,nd early reports suggest similar therapeuticfficacy of anti-CD20 therapy in human lupus,uggesting a dominant pathogenic role for Bells in this disease.19,58
B cells serve multiple functions in lupus. Bestharacterized is their production of antinuclearnd polyreactive autoantibodies, the corner-tone of diagnosis and characteristic feature ofupus glomerulonephritis. Autoantibodies de-osit in the kidney and induce injury by a vari-ty of mechanisms. It is clear, however, that the-cell contribution to pathogenicity extends be-ond antibody production.58 Nephritis and vas-ulitis do not develop in B-cell–deficient MRL/pr mice, whereas glomerulonephritis and earlyeath are unaffected in MRL/lpr mice bearingenetically manipulated B cells incapable of se-
reting antibody.61 B-cell–deficient MRL/lpr gice fail to develop the activated CD8 and CD4cells found in B-cell–sufficient mice, a finding
ttributed to loss of B-cell–CD4 T-cell interac-ions because activated CD8 T cells persist inRL/lpr mice lacking MHC class I antigens on B
ells. Tissue infiltrating antibody-secreting Bells and plasma cells are abundant in nephriticWF1 kidneys, and B cells secreting nephro-athic anti-DNA autoantibodies can be isolated
rom nephritic MRL/lpr kidneys.23 BWF1 micectopically express a B-cell chemoattractanthat promotes renal and other organ traffickingf B-1 B cells.62 IL-10–producing regulatory Bells also are present in murine lupus wherehey may play a role in limiting disease. Thisay in part explain the conflicting results ob-
ained from ablation of the marginal zone B-cellopulation, a proposed precursor of regulatorycells, in BWF1 and BXSB lupus-prone mice.57
ephritogenic Autoantibodiesnd Antibody-Mediated Injury
lomerular antibody deposition is a hallmark ofupus glomerulonephritis. Renal bound anti-odies engage cell-bound Fc receptors, activateomplement, mediate thrombosis, and directlylter cell functions. Mechanisms of immuneeposition and injury have been reviewed ex-ensively elsewhere,63,64 and are summarizedriefly here, with emphasis on recent new in-ights. Extensive investigation has revealed mul-iple IgG subclasses and diverse antigen speci-cities, avidity, and charge among Ig elutedrom nephritic lupus kidneys or isolated fromupus serum or monoclonal antibodies. IgG ishe predominant isotype deposited, but IgMnd IgA also typically are present in humanupus nephritis, accompanied by C3, C4, and1q. Specificity for DNA is important for patho-enesis for a subset of lupus Ig, but multiplexperimental models indicate that anti-DNA ac-ivity is neither necessary nor sufficient to in-uce lupus nephritis, and many Ig eluted from
upus kidneys do not bind to DNA.These nephritogenic antibodies localize to
he kidney by multiple mechanisms. In situ for-ation of immune complexes may be a domi-
ant mechanism of renal Ig deposition. Directinding of cross-reactive anti-DNA Ig to purified
lomerular antigens, including �-actinin and
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T cells and B cells 55
-enolase, and to cultured parenchymal cells,an be shown in vitro and in experimentalodels. Nuclear antigens with intrinsic affinity
or glomerular cell or basement membrane sur-aces can serve as planted antigens for subse-uent binding by anti-DNA and antinucleosomentibodies. Collagen, laminin, fibronectin, andome cells have binding sites for DNA, whereasharge interactions attract anionic DNA to cat-onic immune complexes, histones, and nucleo-omes previously captured by anionic sites inlomerular basement membrane or on cellembranes. Rheumatoid factors and anti-C1q
Table 4. Targeted Immunotherapy in Lupus N
B- and T-cell signaling and activation thresholdsUpregulation or stimulation of B-cell inhibitoryB-cell tolerance induction (dsDNA oligomers)*Inhibition of DNA methylation or histone deac
B- and T-cell survival, proliferation, differentiationAnti–B-cell therapy (anti-CD20 and anti-CD19Blockade of BAFF/BAFF-receptor pathway (antiModulate activating or inhibitory surface recepAnti–T-cell subset therapyBlockade of B7/CD28 pathway (CTLA4-Ig, singBlockade of CD40/CD40L (anti-CD40L mAb)Blockade of ICOS/ICOSL pathway (anti-ICOSLBlockade of CD137 (4-1BB)/4-1BBL pathwayStimulation of T-cell inhibitory pathways PD-1Modulation of TLR signaling (inhibitory GpG oModified antigen-presenting cells (dendritic ce
Regulatory cell functionIn vivo or ex vivo induction of regulatory T orAdministration of tolerizing self-antigen–expre
B- and T-effector cell function and inflammationBlockade of Ig productionInhibition of memory or plasma cell differentiaBlockade or adsorption of autoantibody reactivComplement inhibition (anti-C5 mAb, solubleBlockade of activatory FcgRI, FcgRIII, or FcgRIVStimulation of inhibitory FcgRIIBInhibition of secondary mediators (cytokines, c
lipid mediators, and so forth)Antimacrophage or neutrophil therapyT-helper subset skewing
Abbreviations: dsDNA, double-stranded deoxyribonucleic accytotoxic T lymphocyte antigen-4; BTLA, B- and T-lympho
*Selected examples of interventions currently in preclinical o†Some interventions modulate multiple checkpoints; for sim
g can engage previously deposited IgG or C1q. m
urine IgG3 has a unique capacity to formryoglobulins and occlude glomerular capillar-es. Additional mechanisms of renal injury haveeen proposed: disruption of cell functions byutoantibodies that gain intracellular access,isruption of glomerular permeability by mask-
ng anionic sites, thrombus formation caused bynterference with phospholipid-dependent co-gulation, and complement-mediated cytotoxic-ty of renal parenchymal cells.
The ultimate renal disease phenotype is depen-ent on several factors, including antibody speci-city and isotype and effector functions deter-
itis
RIIB
ion†laboration, and costimulations)mAb, TACI–Ig fusion protein)anti-CD22 mAb)
ain Fv CD28 inhibitor)
L, CTLA4, BTLAeoxynucleotides)rapy)
sdendritic or stem cells
or Crry-Fc fusion protein, C5a antagonist)
kines, nitric oxide, reactive oxygen species,
y, complement receptor-1–related gene/protein Y; CTLA-4,ttenuator.al trials are indicated in parentheses.only one category is shown.
ephr
Fc-�
etylat, colmAb-BAFFtors (
le-ch
mAb)
/PD1-ligodll the
B cellssing
tionityCrry
hemo
id; Crrcyte ar clinicplicity,
ined by Ig constant region domains, each
strckmmgHmrriFiinip
tttio(iiiabtactptBsnCim
S
Ttoom
pbncttdaectenaogbvi
R
1
56 M.H. Foster
ubclass of which has a unique profile of interac-ions with complement and multifunctional Fc-�eceptors. Outcomes are regulated in turn by aomplex system of regulatory proteins and cyto-ines. Igs engage activating Fc-� receptors onacrophages, neutrophils, and renal parenchy-al cells to promote leukocyte adhesion and trig-
er release of multiple inflammatory mediators.65
owever, nephritis is variably attenuated in lupusice with targeted deletion of the common Fc
eceptor �-chain gene.66,67 Discordant outcomeseflect in part the importance of Fc receptors inmmune complex clearance; loss of activatingc-� receptors in nonautoimmune mice markedlyncreases immune deposition.65 Loss of the inhib-tory IgG Fc receptor, FcgRIIB, induces lupus-likeephritis in a strain-specific manner in nonauto-
mmune mice and accelerates disease in lupus-rone strains.68
Notably, secreted IgG, autoantibodies, and an-igen–IgG immune complexes also serve regula-ory roles to modulate lupus phenotypes. Autoan-ibodies reactive with phospholipids aremplicated in the clearance of apoptotic bodies,ne source of lupus self-immunogen. Nucleic acidDNA and RNA) and chromatin-containing IgGmmune complexes are potent amplifiers of auto-mmunity. Dendritic cells and B cells capture andnternalize DNA/anti-DNA immune complexes byctivating Fc-� receptors, FcgRIIa and FcgRIII, ory IgG-binding (rheumatoid factor) B-cell recep-ors. This sets the stage for subsequent nucleiccid engagement of TLR9 or TLR7 in cytoplasmicompartments, promoting cell maturation and ac-ivation, and, in autoreactive B cells, switch toathogenic IgG isotypes.65,69 Conversely, inhibi-ory Fc-� RIIB receptors on B cells downmodulate-cell–receptor signaling and plasma cell expan-ion.65 Immune complexes also inhibit B-cell sig-aling by engaging complement-receptor CD21/D35; deficiency of this inhibitory receptor
nterrupts induction of B-cell anergy and, in per-issive backgrounds, promotes lupus nephritis.70
UMMARY AND CONCLUSIONS
and B lymphocytes play diverse roles at mul-iple stages in the development and progressionf lupus nephritis. Disease phenotype dependsn the balance of pathogenic effector and im-
une regulatory cell subsets and their secreted 1roducts. New insights into their biology hasrought the promise of new therapies in lupusephritis (Table 4). Major recent advances in-lude appreciation of a key modulatory func-ion for innate immune elements, novel regula-ory roles for B cells and antibodies, a newlyiscovered T cell subset (Th17), elucidation ofdditional immune regulatory checkpoints, anxpanding list of genetic or acquired lympho-yte abnormalities that predispose to autoreac-ivity, and recognition of new functions offfector molecule cascades, including compo-ents that potently impact both the inductivend effector limbs of disease, sometimes withpposite effects on outcomes. Support for on-oing research in this effort is crucial, toroaden the arsenal of nontoxic targeted inter-entions for lupus nephritis and systemic auto-mmunity.
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