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The Glomerular Responseto IgA Deposition in IgA Nephropathy

Ivan C. Moura, PhD*,† Marc Benhamou, PhD*,† Pierre Launay, PhD*,†

François Vrtovsnik, MD, PhD*,† Ulrich Blank, PhD*,† and Renato C. Monteiro, MD, PhD*,†

Summary: Compelling evidence points to a role for IgA receptors in the pathogenesis of IgAnephropathy. The soluble form of the type I IgA receptor (Fc�RI or CD89) forms complexeswith IgA that can be found in patients’ serum and that initiate the disease in CD89 transgenicmice. A nonclassic IgA receptor, identified as the transferrin receptor (TfR), is highlyexpressed in patients’ mesangium and colocalizes with IgA deposits. TfR preferentially bindspolymeric IgA1 complexes, but not monomeric IgA1 or IgA2. The TfR-IgA1 interaction isdependent on carbohydrate moieties because hypoglycosylated IgA1 has superior binding toTfR than normally glycosylated IgA1. Polymeric IgA1 binding enhances mesangial cell TfRexpression and results in cell proliferation and inflammatory and profibrogenic cytokine andchemokine production, suggesting a pivotal role in mesangial cell proliferation, matrixexpansion, and recruitment of inflammatory cells. We propose that, as a second event,activation of the classic, FcR�-associated transmembrane Fc�RI expressed on circulatingmyeloid leukocytes takes place. Fc�RI/�2 cross-linking in human Fc�RI transgenic animalspromotes disease progression by enhancing leukocyte chemotaxis and cytokine production,and IgA immune complexes from IgA nephropathy patients induce Fc�RI-dependent cellactivation. This review therefore details the functional consequences of IgA/receptor inter-actions and discusses proposed mechanisms to explain the development and chronicity of thedisease.Semin Nephrol 28:88-95 © 2008 Elsevier Inc. All rights reserved.Keywords: IgA, Fc receptor, mesangial cells, transferrin receptor, CD71, CD89

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gA deposition in the mesangium is the hall-mark of IgA nephropathy (IgAN). Early stud-ies examined the type of IgA deposited as

ell as its physicochemical properties. It wasound that mesangial IgA was of the IgA1 sub-lass and contained predominantly, but not ex-lusively, � light chains.1,2 In some cases, IgA2lso has been identified in renal biopsy speci-ens.3 Application of acid-elution techniques

rom renal biopsy specimens indicate that mes-ngial IgA consists mainly of macromoleculargA and IgA complexes.4,5 These studies alsouggest that mesangial IgA predominantly is an-

Inserm U699, Paris, France.

University of Paris 7, Faculty of Medicine Denis Diderot, Bichat Hospital,Paris, France.

ddress reprint requests to Renato C. Monteiro, INSERM U699, 16 rue HenriHuchard, F-75870 Paris Cedex 18, France. E-mail: monteiro@bichat.inserm.fr

270-9295/08/$ - see front matter

d2008 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2007.10.010

Seminar8

onic, consistent with abnormal glycosylationf the deposited IgA.5 More recent studies6,7

ave shown alterations in the O-glycosylation ofluted IgA1 molecules, suggesting such glyco-orms of IgA1 are more likely to deposit in theidney. Underglycosylation of IgA may lead toelf-aggregation and formation of IgA1-IgA1 andgA1-IgG immune complexes.8,9 Interestingly, itecently was shown that dimers and polymersf IgA aggregate more readily than mono-ers,10 which might explain the propensity foracromolecular IgA to aggregate and deposit in

issues. A number of investigators have sug-ested that an altered IgA immune response topecific antigens is responsible for the forma-ion of nephritogenic IgA antibody complexesn IgAN. Although it is possible that specificntigens may contribute to the formation ofacromolecular IgA, there is no direct evi-

ence to support this hypothesis.11 IgA is

s in Nephrology, Vol 28, No 1, January 2008, pp 88-95

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Glomerular response to IgA deposition 89

hought of principally as an anti-inflammatorymmunoglobulin under physiologic conditions,resent predominantly as a monomer in theerum where it interacts with IgA receptors onirculating blood cells.12,13 The formation ofberrant IgA immune complexes in IgAN maymportantly contribute to the inappropriate ac-ivation of circulating IgA receptor–bearingells and resident glomerular cells. In this re-iew we discuss the compelling evidence forhe pathologic contribution of IgA/receptor in-eractions in IgAN.

gA COMPLEXES IN THENITIATION OF THE DISEASE

esides the structural alterations of IgA de-cribed earlier, IgAN is characterized by theresence of high levels of IgA immune com-lexes both in the circulation and within mes-ngial IgA deposits.11,14 IgA immune complexesre thought to develop by at least 3 distinctechanisms: (1) self-aggregation of aberrantly

lycosylated IgA1; (2) formation of complexesith soluble IgA Fc receptor I (Fc�RI), and (3)

nteraction of IgA with other circulating pro-eins. The first of these mechanism is linkedirectly to the abnormal structure of IgA1 (re-iewed by Novak, pp. 78-87).

The second mechanism relies on the bindingf IgA with myeloid cell–expressed Fc�RICD89), which through its � chain binds mo-omeric IgA of both IgA subclasses with lowffinity, whereas multimeric IgA binds withigh avidity.15 In IgAN, soluble Fc�RI can beetected in the serum and the presence oflasma IgA seems essential for this appearance.his was first shown by incubating myeloidells from patients with IgAN with and withoutomologous plasma, and by incubating purifiedolymeric IgA (pIgA) with monocytes from nor-al individuals.16 The mechanism proposed to

xplain this phenomenon involves shedding ofhe extracellular domain of the Fc�RI.14 Studiesith metabolically labeled cells revealed theresence of a glycosylated soluble 50- to 70-kd

orm of Fc�RI with a 24-kd protein core.17 Pro-uction of soluble Fc�RI is induced by poly-eric IgA from Fc�RI-transfected cells. These

ata indicate that cleavage of the Fc�RI extra-

ellular domain may occur, resulting in release a

f IgA/Fc�RI complexes into circulation. Thehedding process involves Fc�RI that are not as-ociated with FcR�.17 Two other types of solublec�RI also have been described, which are re-eased from eosinophils, neutrophils, and mono-ytes,18,19 and differ from the 50- to 70-kd prod-ct. The eosinophil-/neutrophil-derived solubleeceptor is a secreted splice product.18 Interest-ngly, the monocyte-derived soluble Fc�RI is alycosylated 30-kd protein with a 25-kd back-one that is associated covalently with poly-eric IgA.19,20 It circulates in serum of normal

ndividuals but is not increased in IgAN pa-ients.21 In contrast with the 50- to 70-kd solu-le receptor, the shedding process of this 30-kdc�RI is FcR� dependent.19

The detection of circulating complexes con-aining IgA and the 50- to 70-kd form of solublec�RI in IgAN patients serum raise the possibil-ty that these complexes may be involved in theevelopment of this disease. To show this weenerated human Fc�RI transgenic mice,hich serve as a novel animal model of spon-

aneous IgAN.17 In this model, transgenicallyxpressed human Fc�RI binds mouse poly-eric IgA, albeit with very low affinity, to form

omplexes that subsequently are deposited in theesangium of the Fc�RI transgenic mice. Human

c�RI transgenic mice develop mesangial IgAeposition, hematuria, mild proteinuria, and mac-ophage infiltration around the renal glomeruli.17

he disease can be transferred to wild-type re-ipients by infusion of serum IgA/soluble Fc�RIomplexes from these transgenic mice. Re-ently, we also showed that transgenic micexpressing a mutated Fc�RIR209L that is unableo associate with the FcR� adaptor also haveirculating soluble human Fc�RI/mouse IgAomplexes and develop IgA deposits and hema-uria,22 suggesting that the soluble, rather thanhe signal-competent, Fc�RI is important forhe onset of the disease. Nevertheless, othersave failed to induce IgAN in mice after injec-ion of recombinant soluble Fc�RI fused to Fcragment.23 This failure could be the result ofhe short half-life of soluble Fc�RI in transgenicice. To examine the contribution of patient

gA, a model of severe combined immunode-cient (SCID)-Fc�RI transgenic mice was cre-

ted. Although these mice do not develop

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gAN spontaneously, they develop the mani-estations of IgAN when IgA from IgAN pa-ients are injected.17 Interestingly, IgA fromealthy subjects does not induce IgAN inhese mice, implying that aberrant IgA to-ether with Fc�RI participate in the patho-enesis of IgAN.

The third mechanism for formation of IgA com-lexes in IgAN may involve IgA binding to otherirculating proteins such as fibronectin, collagen,nd laminin.24–27 This also raises the possibility ofn additional mechanism by which these IgAomplexes might bind to the mesangium, nothrough IgA receptors but through adhesion toxtracellular matrix proteins. In favor of thisypothesis, when uteroglobin, a serum proteinhat controls circulating fibronectin levels, isnocked out in transgenic mice these mice gon to develop IgAN.28 However, no alterationsf uteroglobin have been found in humangAN.29 Deposition of mannan-binding lectinMBL) and MBL-associated serine protease inssociation with IgA in the mesangial area ofatients with IgAN also have been reported.30,31

ecause IgA is glycosylated aberrantly in IgAN itlso is possible that IgA binding to MBL andBL-associated serine protease may contribute

o the formation of IgA complexes in IgAN.

CTIVATION OF MESANGIALELLS BY ABERRANT COMPLEXED IgA

esangial cell proliferation and matrix expan-ion are characteristic features of IgAN. Thisrocess seems to be dependent on IgA-inducedriggering of mesangial cell activation. Severaltudies have shown that IgA complexes are capa-le of inducing human mesangial cell (HMC) ac-ivation. Binding of IgA1 complexes induces anncrease in intracellular Ca2�, PLC-�1 activation,roduction of inositol trisphosphate, and proteinyrosine phosphorylation.32 As a consequence,esangial cells release cytokines such as interleu-

in (IL)-6, IL-8, and IL-1�, but also profibrogenicransforming growth factor-�.33–35 They alsoroliferate and synthesize extracellular matrixroteins. Furthermore, it has been shown thatbnormally glycosylated IgA is able to modulateuman mesangial integrin expression and vas-ular endothelial growth factor synthesis.36

hese results point to the existence of a mes- t

ngial IgA receptor that could link IgA and HMCctivation.

ESANGIAL IgA RECEPTORS

t has been postulated that HMCs express aumber of different IgA receptors. Many inves-igators have studied direct interactions of se-um IgA with mesangial cells and matrix com-onents. A number of IgA receptors have been

dentified on different cell types: the hepatic asia-oglycoprotein receptor, the myeloid Fc�RI/D89 receptor, the mucosal polymeric Ig recep-

or, the B cell and macrophage Fc�/�R, and theransferrin receptor (TfR).37–41 Studies from sev-ral groups have now excluded the asialoglycop-otein receptor, Fc�RI/CD89, and the pIgR aseing mesangial cell IgA receptors.34,42–45 Al-hough mesangial cells express messenger RNAor Fc�/�R,46 IgA1 binding to mesangial cells wasot inhibited by IgM43 or by recombinant Fc�/R,47 and no expression of the Fc�/�R protein byMC has been reported, indicating a modest role

or this receptor in the glomerulus. By contrast,here is overexpression of TfR in the mesangiumf patients with IgAN and Henoch-Schönlein pur-ura.48 Interestingly, this TfR overexpression isolocalized with IgA deposits, indicating that TfRay be a mesangial IgA receptor involved in the

ormation of IgA1 deposits. Furthermore, TfRverexpression by mesangial cells also has beenbserved in patients with lupus nephritis with IgAeposits, but not in those with no such depos-

ts.48 Expression of TfR messenger RNA (CD71)y proliferating mesangial cells was confirmedecently.42 TfR binds pIgA1 and has a highervidity for underglycosylated IgA1 and for IgA1omplexes than for normal IgA1.47 Several in-estigators agree that the Fc portion of the IgA1olecule mediates binding of IgA1 to mesangial

ells because both intact IgA1 and the Fc por-ion, but not its Fab fragment, inhibit binding ofgA1 to mesangial cells.42,43,47 We have shownhat IgA1 binding to TfR is likely to be mediatedy the IgA1 hinge region and involve the asso-iated carbohydrate moieties.47 By using a vari-ty of mutated recombinant dimeric IgA1 mol-cules we observed that deletion of either N- or-linked glycosylation sites abrogated IgA1inding to TfR, suggesting that sugars are essen-

ial for IgA1 binding. However, sialidase and

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Glomerular response to IgA deposition 91

-galactosidase treatment of IgA1 significantlynhanced IgA1/TfR interaction. These resultsndicate that aberrant glycosylation of IgA1 as

ell as immune complex formation constitutessential factors favoring mesangial TfR-IgA1 in-eraction during the initial phase of IgAN patho-enesis. We recently showed that macromolec-lar IgA1 is a major inducer of TfR expression3- to 4-fold increase) in quiescent HMCs.35 IgA-nduced, but not cytokine-induced, HMC prolif-ration was dependent on TfR engagement be-ause proliferation was inhibited by both TfR1nd TfR2 ectodomains as well as by an anti-TfRonoclonal antibody A24. It is noteworthy thatfR up-regulation is dependent on the contin-ed presence of IgA1 rather than on solubleactors released during IgA1-mediated activa-ion. In addition, pIgA1 induced IL-6 and trans-orming growth factor-� production fromMCs was inhibited specifically by the mono-lonal antibody A24, confirming that pIgA1 trig-ers TfR-dependent HMC activation. In thistudy, up-regulation of TfR expression inducedy sera from patients with IgAN, but not fromealthy individuals, was dependent on IgA.35

e propose that deposited pIgA1 or IgA1 im-une complexes initiate a process of auto-am-lification involving overexpression of TfR byMCs promoting increased IgA1 mesangialeposition. These data suggest a functional co-peration between pIgA1 and TfR in the mech-nisms of IgA1 deposition and HMC prolifera-ion and activation. These mesangial changesre implicated commonly in the developmentf ongoing glomerular injury in IgAN and alsoay explain the recurrence of IgA1 deposits in

he mesangium after renal transplantation (Fig. 1).inally, there is some evidence for the expressionf other IgA receptors in the mesangium, buturrently they remain unidentified.42,43

ESANGIAL IgA COMPLEXESCTIVATE THE MYELOID FC�RIND MEDIATE DISEASE PROGRESSION

linical observations studying progression ofgAN associated with mononuclear cell infiltra-ion in the kidney suggest that leukocytes maylay a role in glomerular damage and interstitialissue injury.49,50 Experimental evidence for the

mplication of the classic myeloid IgA receptor, d

amely Fc�RI, in glomerular infiltrating leuko-ytes in IgAN come from studies by Kashemt al.51 These investigators detected Fc�RIessenger RNA in patient’s glomeruli and

heir damaged tissues.51 Additional observa-ions have indicated that in IgAN leukocytesave large amounts of IgA bound to trans-embrane Fc�RI16,52 and that the level of re-

eptor occupancy correlates with the presencef glomerulosclerosis.16

Recently, we provided evidence that multi-eric aggregation of Fc�RI induces an inflamma-

ory response with priming and cytokine/chemo-ine release that is an integral component of IgANathogenesis mediating disease progression.22

revious studies have indicated that the Fc�RIchain partly associates with the common FcR�

hain, which contains an immunoreceptor ty-osine-based activation motif (ITAM) in its cyto-lasmic domain. The Fc�RI-FcR� interaction has a

igure 1. Pathophysiologic circuits in the developmentf mesangial injury initiated by the interaction of IgA1-ICith a mesangial IgA receptor, the TfR. Interaction ofacromolecular IgA complexes with the TfR initiates an

nflammatory feedback loop by inducing enhanced TfRxpression and mesangial cell proliferation as well asytokine/chemokine production. The latter further in-rease the inflammatory response and development ofbrosis by influencing other cell types that promotengoing inflammation. Whether the mesangial cell pro-

iferation is a direct result of IgA-TfR interaction or occursecondary to cytokine production by activated mesan-ial cells still is unresolved (dotted arrows).

ual function because it can mediate either cell

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92 I.C. Moura et al

ctivation after multimeric aggregation of the re-eptor or inhibition after interaction with mono-eric ligand.13 Although in health the interaction

etween serum IgA and Fc�RI favors an anti-nflammatory outcome,12,13 in disease this bal-nce is tipped toward an inflammatory re-ponse. This may be relevant in IgAN, in whichne observes the presence of circulating IgA-IC,hich when bound to myeloid Fc�RI could

rigger inflammatory signaling.16,52

The importance of this Fc�RI-FcR� interac-ion in the promotion of inflammatory damageas revealed through analysis of the differences

n disease development in transgenic mice ex-ressing either wild-type FcR�-associated or

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igure 2. Proposed model for IgAN pathogenesis involveneration of pathologic macromolecular IgA complexhe circulation. This leads to the following: (1) cleavageeneration of soluble Fc�RI/IgA complexes, and (2) activf transmembrane FcR�-associated Fc�RI. Second, solubinding of IgA1 to TfR initiates the production of inflaerived inflammatory mediators act on primed monoc

nterstitium, thereby further amplifying the inflammat

isease.

utant FcR�-less Fc�RI. Although both trans-enic mice spontaneously develop mesangialgA deposits and hematuria (see earlier), onlynimals expressing wild-type Fc�RI that canssociate with FcR� develop proteinuria andacrophage accumulation in the glomeruli anderiglomerular space.22 Furthermore, only mac-ophages carrying wild-type Fc�RI, but nothose carrying FcR�-less Fc�RI, were able toigrate to the kidney on adoptive transfer,

learly suggesting the dependency of this che-otaxis on the association of the receptor with

cR�. Therefore, binding of pathologic IgA-ICnd signaling through FcR� results in primingf monocytes that together with mesangial

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gA receptors. The essential steps are as follows. First, theults in enhanced IgA binding to blood monocytes inRI molecules that are not associated with FcR� and thepriming) of circulating monocytes through cross-linkingRI/IgA molecules are deposited in the mesangium andory cytokines and chemokines. Third, mesangial cell–

o promote inflammatory cell infiltration into the renalocess and promoting progression to end-stage renal

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Glomerular response to IgA deposition 93

ell–produced chemokines promotes the mi-ration of leukocytes into the renal interstitiumnd periglomerular regions, thereby amplifyinglomerular lesions through Fc�RI/FcR�2 activa-ion. Lessons from transgenic studies have sug-ested that in situ cross-linking of mesangial TfRy IgA-IC in glomeruli is an initial necessaryvent, but not sufficient to promote diseaserogression. This is summarized in Fig. 2.Although wild-type Fc�RI transgenic mice

how increased macrophage infiltration they doot develop end-stage disease, suggesting thathis model resembles patients with a mild dis-ase course. This may be owing to the low-affin-ty binding of pIgA to Fc�RI and consequent re-uced cross-linking of Fc�RI by macromoleculargA or IgA complexes in the mouse. We have,owever, been able to show the importance ofontinuous Fc�RI cross-linking in the develop-ent of renal failure by using a murine model of

evere glomerulonephritis induced by the injec-ion of anti–glomerular basement membrane an-ibodies into wild-type Fc�RI transgenic mice. Inhis model renal injury was worsened markedly inice transgenic for Fc�RI associated with FcR�,

ut no worsening of the observed glomerulone-hritis was seen in Fc�RIR209L transgenic mice,ighlighting the pathogenic role of FcR� signal-

ng in disease progression. Consistent withhese observations, serum IgA-IC from patientsith IgAN induced cell activation and inflam-atory cytokine production, indicating that se-

um IgA can trigger inflammatory signalinghrough Fc�RI in IgAN and that this is rele-ant for disease. Such inflammatory signalingay be enhanced further if patients express

n increased proportion of signal-competentcR�-associated receptors.22 Together withhe results obtained in transgenic mice theseata also may help explain the well-describedeterogeneity in the natural history of IgANecause the potential for inflammatory signal-

ng was different between patients.22

Finally, other non-IgA receptor–mediated,ut IgA-dependent systems, also may contrib-te to progression of IgAN. It has been shownhat the complement system can be activatedy human IgA via both the alternative and the

ectin pathways, which are driven mainly by

BL.53 Activation of the lectin pathway in the

enal mesangium is supported by deposition ofBL and MBL-associated serine protease in as-

ociation with IgA in the mesangial area of pa-ients with IgAN.30 Recent data support a roleor the lectin pathway of complement in locallomerular complement activation in IgANnd suggest that complement activation alsoay influence progression of the disease.31

herefore, it is likely that deposited pIgA con-ributes to the development of renal damagey both local activation of complement (re-iewed by Oortwijn, pp. 58-65) and mesan-ial cell activation.

ONCLUDING REMARKS

ccumulated data in patients and animal modelseveal that the pathogenesis of IgAN involves mul-iple factors that combine to generate a heterog-nous picture of disease development. The essen-ial events can be divided into 3 steps: (1) theeneration of aberrant macromolecular IgA1 thatromotes shedding of soluble Fc�RI and primingf monocytes through signal-competent FcR�-as-ociated transmembrane Fc�RI, (2) mesangial ac-ivation mediated by interaction of macromolec-lar IgA1 with mesangial IgA receptors, and (3)isease progression through the combined actionf mesangial and leukocyte cell activation thatay involve several inflammatory pathways.

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circulating IgA in patients with IgA nephropathy

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