Lupus nephritis: Lessons from experimental animal models

REVIEW ARTICLE Lupus nephritis: Lessons from experimental animal models C. J. PEUTZ-KOOTSTRA, E. DE HEER, Ph. J. HOEDEMAEKER, C. K. ABRASS, and J. A. BRUIJN UTRECHT and LEIDEN, THE NETHERLANDS, and SEATTLE, WASHINGTON

Lupus nephritis is a frequent and severe complication of SLE. In the last decades, animal models for SLE have been studied widely to investigate the immunopathology of this autoimmune disease because abnormalities can be studied and manipulated before clinical signs of the disease become apparent. In this review an overview is given of our current knowledge on the development of lupus nephritis, as derived from animal models, and a hypothetical pathway for the development of lupus nephritis is postulated. The relevance of the studies in experimental models in relationship with our knowledge of human SLE is discussed. (J Lab Clin Med 2001;137:244-60)

Abbreviations: GvHD = graft-versus-host disease; ICAM-1 = intercellular adhesion molecule 1; IgG = immunoglobulin G; IgM = immunoglobulin M; IL = interleukin; MHC = major histocompatibility complex; mRNA = messenger RNA; PDGF = platelet-derived growth factor; RANTES = regulated upon activation normal T cells expressed and secreted; SLE = systemic lupus erythematosus; TGF-β = transforming growth factor β; TNF-α = tumor necrosis factor α; TXA = thromboxane

S

ystemic lupus erythematosus is a chronic autoimmune disease affecting multiple organs that is characterized by periods of remittance and relapse. Genetic, immunologic, hormonal, infectious, and environmental factors are all involved in the development of the disease. Autoantibodies are almost invariably present in the circulation.1-3 In Northern Europe and North America approximately 1 of 750 people will have SLE, with 80% of the cases occurring

From the Departments of Pathology, Utrecht University Medical Center, Utrecht, and Leiden University Medical Center, Leiden; and the Department of Nephrology, Veteran Affairs Medical Center, Seattle. Submitted for publication May 25, 2000; revision submitted December 11, 2000; accepted December 15, 2000. Reprint requests: C. J. Peutz-Kootstra, MD, PhD, Department of Pathology, Utrecht University Medical Center, PO Box 85500, 3508 GA Utrecht, The Netherlands. Copyright © 2001 by Mosby, Inc. 0022-2143/2001 $35.00 + 0 5/1/113755 doi:10.1067/mlc.2001.113755 244

in women during their childbearing years.1 Patients with SLE show diverse manifestations of the disease. Dermatitis, polyarthritis, glomerulonephritis, and vasculitis, as well as pulmonary, cardiovascular, hematologic, and central nervous system involvement, may occur, either together or separately.4 Glomerulonephritis in the form of lupus nephritis becomes clinically apparent in 50% to 80% of patients with SLE, resulting in end-stage renal failure in 10% to 20% of patients.2,5,6 Inflammation of the glomerulus eventually results in protein leakage from the circulation into the urinary space (ie, the development of proteinuria). Lupus nephritis is characterized by the presence of immunoglobulins of almost all isotypes in the glomerulus in combination with the presence and activation of complement components. Electron-dense deposits (immune aggregates) are observed in the mesangium, as well as subendothelially and subepithelially along the glomerular capillary walls. Histologically, a spectrum of glomerular lesions occurs, ranging from no abnormalities or mild mesangial proliferation to full-blown proliferative and

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Table I. World Health Organization morphologic classification of lupus nephritis (modified) I.

Normal glomeruli A. No abnormalities (by all techniques) B. Normal, as determined by means of light microscopy, but deposits seen with electron microscopy or immunofluorescence microscopy

II.

Pure mesangial alterations (mesangiopathy) A. Mesangial widening, mild hypercellularity (+), or both B. Moderate hypercellularity

III.

Focal segmental glomerulononephritis (associated with mild or moderate mesangial alterations) A. Active necrotizing lesions B. Active and sclerosing lesions C. Sclerosing lesions

IV.

Diffuse glomerulonephritis (severe mesangial, endocapillary or mesangiocapillary proliferation, and/or extensive subendothelial deposits) A. Without segmental lesions B. With active necrotizing lesions C. With active and sclerosing lesions D. With sclerosing lesions

V.

Diffuse membranous glomerulonephritis A. Membranous glomerulopathy B. Associated with lesions of Category II (a or b)

VI.

Advancing sclerosing glomerulonephritis

crescentic glomerulonephritis. In its classification for renal involvement in SLE, the World Health Organization combines observations made with light microscopy, immunofluorescence, and electron microscopy (Table I).7 This classification has proven to be very useful in clinical practice because in renal biopsy specimens taken from then untreated patients, the World Health Organization classification correlates well with prognosis and response to further therapy.2,5,8,9 To investigate the mechanisms underlying the development of glomerulonephritis in patients with SLE, animal models are widely used. 10 In human SLE it is obvious that disease variables can be studied with noninvasive methods only in a retrospective way. In animal models it is possible to study and manipulate immunoregulatory abnormalities and glomerular alterations occurring before the clinical signs of glomerulonephritis become apparent. In this review an overview is given of the way in which renal disease develops in 3 different models of SLE, followed by a summary of the autoantibody reactivity toward various antigens in murine SLE and the mechanisms that may account for the observed B-cell hyperreactivity. How autoantibodies in the circulation contribute to immune complex formation in the glomerulus is subsequently discussed. After glomerular injury is inflicted by immunoglobulins, local alterations in the glomerulus result in further deterioration of renal function. A summary of such local glomerular alterations is given, emphasizing the role of the glomerular matrix in the disturbance of glomerular structure and function. The clinical impli-

cations of these new insights are discussed in the final section of the article. MODELS OF SLE

Table II11-22 lists the majority of murine models of SLE that are being studied at present, excluding those of drug-induced SLE and genetically engineered animals (transgenes and knockouts). In this review studies in NZB/W F1 mice and MRL/lpr mice and in mice with chronic GvHD are discussed because these 3 models have been most intensively studied and severe glomerulonephritis develops in these mice. Other animal models of SLE have been reviewed in depth elsewhere.3,10 Development of an SLE-like disease in MRL/lpr mice can be largely attributed to their lpr trait, resulting in marked lymphoproliferation with lymphadenopathy, splenomegaly, and hypergammaglobulinemia.10,11 Autoantibodies reactive with a number of different antigens have been detected (Table III).23-45 At the approximate age of 6 months, MRL/lpr mice have severe immune complex glomerulonephritis with mesangial and endothelial cell proliferation, occasional crescent formation, thickening of the glomerular capillary wall, and tubulointerstitial nephritis with vasculitis.10,23 In the glomeruli immunoglobulins (predominantly IgG2a and IgG324) and C3 are found. The mice die of endstage renal failure with azotemia and high levels of proteinuria approximately 3 months later.10 NZB/W F1 mice are obtained by crossing NZW mice with NZB mice. The F1 hybrid mice also have auto-

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Table II. Most commonly studied murine models of SLE

Spontaneous models Mice with lpr mutation MRL/MP-lpr/lpr mice (MRL/lpr) C3H-lpr/lpr mice Mice with New Zealand background NZBxNZW mice (NZB/W F1) NZBxSWR mice (SNF1) NZB mice (NZB) BXSB mice Palmerston North mice SWR x SJL F1 mice Induced models Chronic GvHD DBA/2 in C57BLI10*DBA/2 FI BALB/c in C57BL10*BALB/c F1 BALB.D2 in C57BL10*BALB.D2 F1 BALB/c in BALB/c*A/J F1 Host-versus-graft-disease BALB/c*A/J F1 in BALB/c 16/6 idiotype-bearing human anti-DNA mAb

Glomerulonephritis

Reference No.

Severe No

11 11

Severe Severe Mild Severe in males Moderate Mild

Severe Moderate Moderate Mild Moderate Moderate

12 13, 14 15 16 * 17

18 19 19 20 21 22

*Waller SE, Gray RH, Fulton M, Wigley RD, Schnitzer B. Palmerston North mice: a new animal model of systemic lupus erythematosus. J Lab Clin Med 1978;92:932-45.

antibodies reactive with a variety of antigens (Table III). Histologically, various alterations in the kidneys occur, including mesangial proliferation, thickening of the glomerular capillary wall, glomerulosclerosis, tubular atrophy, and interstitial inflammation.10,12,23 Immunoglobulins (predominantly IgG2a and IgG2b) and C3 are found in the glomeruli from 6 months of age onward.10,46 Mice die of end-stage renal failure with proteinuria and azotemia at the age of 6 to 12 months.10 Induction of chronic GvHD by means of injection of DBA/2 lymphocytes in (C57BL/10*DBA/2) F1 hybrids results in the development of a lupus-like disease characterized by the presence of autoantibodies in the circulation with a reactivity pattern reminiscent of SLE.18,26 Six to 8 weeks after disease induction, immunoglobulins of all IgG isotypes are detected in the glomeruli, with IgG1 as the most prominent.47 At the same time, mesangial proliferation, mesangial matrix expansion, and thickening of the glomerular basement membranes with spike formations occur. Glomerulosclerosis develops, and the mice die of end-stage renal failure with high proteinuria levels, ascites, and hyperlipidemia 3 months after disease induction.47,48 B-CELL ACTIVATION AND ANTIBODY PRODUCTION IN MURINE SLE

The presence in the circulation of autoantibodies with various specificities (Table III) suggests a major role

for polyclonal B-cell activation in the pathogenesis of SLE. Indeed, in various experimental models of immune complex glomerulonephritis, including models of lupus nephritis, polyclonal B-cell activation underlies the development of autoantibodies with subsequent glomerular disease.49 An antigen-independent polyclonal B-cell stimulation on the basis of repetetive structures in proteins, such as those present on the surface of pneumococcus or in lipopolysaccharides, leads to the presence of predominantly IgM-type autoantibodies in the circulation, which subside after several weeks.49,50 In contrast, in murine SLE autoantibodies associated with disease development, the so-called pathogenic autoantibodies are of another immunoglobulin isotype (IgG instead of IgM),51-53 have a higher affinity for certain antigens,54,55 and have somatic mutations in their immunoglobulin Vh gene regions.56-61 These findings indicate that factors associated with an antigen-dependent propagation of B-cell clones are required for the presence of pathogenic autoantibodies in the circulation. The concept that next to polyclonal B-cell stimulation additional triggers are necessary for the secretion of pathogenic autoantibodies by B cells in lupus nephritis has been studied and reviewed by others.62-64 Evidence for polyclonal B-cell activation was found in MRL/lpr mice,65 NZB/W F1 mice,65,66 and mice with chronic GvHD.51 Because of the lpr mutation, MRL/lpr mice lack expression of the Fas antigen, lead-

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Table III. Selection of observed reactivities of autoantibodies in murine SLE Mouse strain

MRL/lpr

NZB/W F1

GvHD

Nuclear antigens Double-stranded DNA Single-stranded DNA Histones Nucleosomes Sm P Transfer RNA

+23 +25 +27 +30 +32,33 –33 ND

+25 +23 +27 +31 –32,33 –33 +25

+26 +26 +28,29 +31 –32,33 –33 +34

Cytoskeletal proteins Myosin Actin Vimentin

+35 +35 +36

+35 +35 ND

ND ND ND

Cell surface proteins on Thymocytes Erythrocytes Renal cells

± 23,37 ± 23 +38

+23 +23 ND

+26 +26 +39

Circulating and cell-surface proteins Complement factors (Clq) Immunoglobulins

+40 +23

+40 +23

+ ND

Basement membrane proteins Proteoglycans Collagens Laminins Fibronectin

+41 +42 +43-45 ND

+41 ND ND ND

+41 +39 +39,45 +39

ND, Not determined.

ing to impaired apoptosis.67,68 This defective apoptosis subsequently leads to an increased number of activated B cells, which is not associated with an altered education of T cells in the thymus but probably results from a failure in peripheral tolerance.35,69-71 In NZB/W F1 mice a T cell–independent intrinsic B-cell defect most likely underlies the polyclonal B-cell activation.71,72 In addition, a lack of suppressor CD8+ T-cell activity may play a role in NZB/W F1 mice.73 In mice with chronic GvHD, a decreased number of functionally active CD8+ T cells in the donor inoculate, normally suppressing the alloreactive donor CD4+ T cells, is responsible for the polyclonal activation of host B cells.74,75 The additional triggers that direct B cells to secrete pathogenic autoantibodies may very well be provided by T cells. CD4+ T cells have the tools to induce B-cell proliferation and differentiation by secreting cytokines, such as IL-4, IL-6, and IL-10,76-79 and T cells play an important role in the development of murine SLE.80-84 The investigation of aberrant CD4+ T-cell activity has resulted in intriguing new insights into SLE.85-88 However, caution is required in regarding the CD4+ T cells as the sole initiators of B-cell differentiation in lupus because, for example, natural killer cells are involved

in the development of lupus as well,89-91 and these cells can stimulate autoantibody production by activated B cells.92 Evidence from several experimental models indicates that T-cell help with the expression of adhesion molecules involved in cognate T-B–cell interaction93,94 is essential for the generation of pathogenic autoantibodies. How B cells secreting these pathogenic autoantibodies are generated is a topic of current research. The development of these autoantibodies may, for example, be associated with diminished elimination or aberrant selection of self-reactive B cells in germinal centers,95,96 but it may also be associated with expression of novel disease-relevant autoantigens in the periphery. This so-called epitope spreading of the immune response has been described only for antinuclear autoantibodies in lupus nephritis.97,98 In a later section of this article, we will argue that alterations in the glomerular matrix might also drive B cells to secrete pathogenic autoantibodies. Cytokines may very well play a crucial role in initiating and maintaining lupus disease, and in both processes they can have protective, as well as diseaseaggravating, effects.99-101 To provide a simplified model for cytokine secretion by T cells, secretion pat-

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Fig 1. Schematic representation of a hypothetical pathway for the development of experimental lupus nephritis. GBM, Glomerular basement membrane.

terns can be divided into a TH1 type (IL-2 and interferon γ), which is primarily involved in delayed-type hypersensitivity responses, and a TH2 type (IL-4, IL-5, IL-6, and IL-10), which is primarily involved in antibody responses.102 Imposing this TH1/TH2 paradigm on lupus shows that disease development is not strictly driven by either TH1- or TH2-type cytokines in MRL/lpr103-106 and NZB/W F1 mice.104,107-111 Chronic GvHD, however, has unequivocally been shown to be a disease mediated by TH2-type cytokines.112,113 GLOMERULAR IMMUNE COMPLEX FORMATION IN LUPUS NEPHRITIS

Glomerular immune complex formation in lupus nephritis can be caused by immune complex trapping from the circulation, by binding of autoantibodies with antigens deposited in the glomerulus, by direct binding of autoantibodies to intrinsic glomerular antigens, or by a combination of these mechanisms.114-116 Antigen-independent trapping of immune complexes from the circulation in the glomerulus may depend, for instance, on the (positive) charge of the antibodies,117 on antigen-independent sticking to matrix components (eg, fibronectin), on reaction with immune-complex

binding proteins (eg, mesangial matrix protein 50/100),118 or on binding of immune complexes to Fc receptors present on glomerular mesangial cells.119 In addition, the site of the glomerulus where circulating immune complexes were trapped was found to be dependent on the ratio between antigens and antibodies, which is influenced by the affinity of the antibodies for the antigen.120 In murine serum sickness large complexes formed with antibodies having a high affinity for antigen are found predominantly subendothelially and in the mesangium.121 A more membranous type of nephropathy with immune complexes predominantly present subepithelially along the glomerular capillary wall develops when antibodies have a low affinity for the antigen.121 Although attempts were made to extrapolate these findings to the involvement of antinuclear autoantibodies in lupus nephritis, hypothesizing that complexes of DNA and anti-DNA were trapped in glomeruli from the circulation, evidence for the presence of DNA/anti-DNA complexes in the circulation of patients with SLE has never been found.122 However, complexes of DNA and histones (ie, nucleosomes) have been found in the circulation of patients with SLE,123 pointing toward a possible

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role for circulating complexes composed of these nucleosomes and their antinucleosomal antibodies in glomerular immune complex aggregation. A second mechanism for immune complex formation in lupus nephritis is binding of autoantibodies to antigens planted in the glomerulus. Evidence for this hypothesis emerged when the reactivity of antinuclear autoantibodies with cell-surface antigens was found to be mediated by nuclear components.41,124,125 Berden et al showed that antinuclear autoantibodies bind in the glomerulus by means of nucleosomes (ie, complexes of DNA and histones).126,127 The observation that nucleosomes bind to the glomerular capillary wall is presumably related to their strong (charge-based) affinity for components of the glomerular basement membrane,128 such as collagen type IV,129 and the negatively charged heparan sulfate proteoglycans.41 Nucleosomal particles have been detected in the circulation of patients with SLE123; in MRL/lpr mice it was found that these particles were released in the circulation as a consequence of aberrant apoptosis.127 A third mechanism accounting for immune complex formation is a direct, antigen-specific interaction of autoantibodies with glomerular antigens. Components of the glomerular basement membrane, in particular laminin, were found to be targets of autoantibodies in MRL/lpr mice43-45,130 and in mice with chronic GvHD (see below).45,131,132 Furthermore, monoclonal autoantibodies derived from MRL/lpr mice are known to interact with antigens isolated from glomerular mesangial and endothelial cells and to bind in the glomerulus, where they cause distinct histologic abnormalities.38,133 The observations that autoantibodies in patients with SLE react with nuclear and cytoplasmic antigens that are crucial for protein synthesis and cell replication134 led to the intriguing hypothesis that these autoantibodies may interfere directly with vital cell functions.135-137 MEDIATORS OF GLOMERULAR INFLAMMATION

The formation or deposition of immune complexes in the glomerulus can by itself lead to glomerular dysfunction.138,139 However, glomerular damage on immune complex formation is thought to be a consequence of activation of cellular and humoral mediator systems.115 The fact that immunoglobulins may be present along the glomerular capillary wall in the absence of functional glomerular damage illustrates the complexity of mechanisms leading to glomerular malfunction.140-142 In MRL/lpr mice it has been shown that the presence of B cells is essential for the development of lupus nephritis.143 It is believed that the site of immune complex formation determines the type of the glomerular lesion: a membranous glomerulopathy develops when subepithelial immune complexes are present with

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decreased activation and influx of leukocytes, whereas a more proliferative type of glomerulopathy is observed with mesangial and subendothelial immune complexes.144 In experimental lupus nephritis autoantibodies with different reactivity patterns can induce different histologic lesions after passive transfer into naive mice.38,133 Knowledge of factors involved in glomerular inflammation in lupus nephritis is largely deduced from studies in animal models of glomerular diseases other than lupus nephritis and from cell culture studies. Complement activation in glomeruli occurs through the classical pathway after immune complex binding and plays an important role in immune complex– mediated glomerular disease in several experimental models. 145 Complement components are synthesized by many different cell types, including renal cells,145 and their expression is enhanced by immune complex binding146 and by various cytokines.145,147 In addition to the role of complement in the clearance of immune complexes, complement factors are instrumental in the initiation of glomerular inflammation. For example, in vitro studies have shown that C5b-9 (or the membrane attack complex) stimulates glomerular mesangial and epithelial cells to synthesize inflammatory mediators, such as IL-1, TNF-α, prostaglandin E2, and TXA2.148,149 Furthermore, complement factors can directly induce cytoskeletal alterations 150 and secretion of extracellular matrix components 151,152 in glomerular epithelial cells. In experimental lupus nephritis increased synthesis of complement components has been found in the renal cortex in association with deteriorated renal function.153 Damage caused by factors present in the glomerulus, such as immune complexes and complement components, may result in the production of leukocyte-attracting factors. Platelet-activating factor,154 leukotrienes,155 PDGF,156 TXA2, IL-8,157 prostanoids,154 glomerular macrophage colony-stimulating factor, 158 colonystimulating factor, 159 monocyte chemoattractant protein 1,158,160,161 and RANTES162 are chemotactic factors that can be produced by glomerular cells, and some of these may even alter glomerular cell phenotype. In addition to the expression of chemoattractants, resident glomerular cells can express adhesion molecules, such as selectins and ICAM-1, thereby contributing to the influx of leukocytes in the glomerulus.163-167 Increased expression of glomerular macrophage colonystimulating factor, colony-stimulating factor, vascular cell adhesion molecule 1, ICAM-1, RANTES, and osteopontin has been found in glomeruli of MRL/lpr mice,159,168-171 and increased ICAM-1 expression was found in glomeruli of mice with chronic GvHD.172 Studies that prevented the influx of leukocytes or eliminated their presence altogether showed that these

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cells are involved in the development of glomerulonephritis.173-177 In MRL/lpr and NZB/W F1 mice glomerular F4/80-positive macrophages are detected as glomerular disease develops153,178; however, in mice with chronic GvHD, they remain absent.179 By using different strain combinations of mice for the induction of chronic GvHD, we found that the presence of CD11a-, CD45-, and MHC class II–positive cells in the glomeruli correlates with the development of glomerulosclerosis in lupus nephritis.179 The precise identity of these intriguing cells and their functional role in the development of glomerulosclerosis in chronic GvHD still remain to be established. The most important effector mechanism of leukocytes in tissues is the secretion of mediators that alter the phenotype of local cells, resulting in changes of tissue structure and function. The involvement of these mediators in modulating glomerular function has been reviewed extensively by others. In brief, leukocytes secrete oxidants, eicosanoids, catalytic enzymes, and many different cytokines that affect the glomerulus.180 Secreted cytokines (eg, IL-1 and TNF-α) induce and enhance the expression of chemotactic factors and adhesion molecules by glomerular cells,162,181,182 finally leading to local alterations, such as glomerular matrix accumulation or mesangial proliferation. For example, TGF-β,183-185 basic fibroblast-like growth factor,186 PDGF,187,188 and TXA2189,190 are involved in glomerular matrix accumulation. Mediators affecting the proliferation of glomerular cells are, among others, PDGF, 187,188 basic fibroblast-like growth factor, 191 IL-1, 181 and IL-6.192 Most of these mediators can be secreted both by glomerular cells and by infiltrating leukocytes, thus exemplifying the delicate balance between normal glomerular function and the development of glomerular disease. In MRL/lpr and NZB/W mice, increased mRNA expression, protein expression, or both of IL-1, TNFα, TXA2, TGF-β, and PDGF has been found in the renal cortex.193-197 In mice with chronic GvHD, no glomerular expression of TGF-β1 mRNA could be detected.198 Systemic modulation of the effect of certain mediators has shown that IL-1, TXA2,199 IL6,106,110 IL-4,113 IL-10,108 endothelin,200 and nitric oxide201,202 can enhance the development of renal disease in murine SLE, whereas development of the disease is slowed down by the administration of prostaglandin E analogues.203 It should be kept in mind, however, that these factors may have systemic, as well as local, glomerular effects, as shown for IL-1.204-206 Therefore the results obtained with systemically administered substances with respect to their local glomerular effects in lupus nephritis should be interpreted with caution.

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Several other contributors to the genesis of lupus nephritis need to be mentioned as well, although their roles will not be discussed in detail here. For instance, the interstitium is not an innocent bystander in the development of end-stage renal disease, as has been reviewed extensively by others.207-210 On the contrary, interstitial inflammation and tubular atrophy correlate well with deterioration of renal function in glomerulonephritis.211 In MRL/lpr mice and in NZB/W F1 mice interstitial nephritis and glomerular disease coincide10; however, in mice with chronic GvHD, interstitial leukocyte infiltrates are only found in mice with end-stage renal failure.142 Furthermore, the development of vasculitis, a severe complication of SLE, can contribute to renal failure in experimental lupus nephritis. MRL/lpr mice have systemic vasculitis with prominent involvement of the arteries in the kidneys.212,213 Interestingly, the development of glomerulonephritis and arteritis in these mice can be segregated genetically.213 Vasculitis can also occur in NZB/W F1 mice but is less severe and less common than in MRL/lpr mice.23,214,215 In mice with chronic GvHD, vasculitis is not a prominent histologic feature. In summary, the development of glomerular lesions in lupus nephritis is a multifactorial process in which glomerular immunoglobulins, complement, mediators secreted by leukocytes and by resident glomerular cells, and systemic factors are involved. ALTERATIONS IN THE GLOMERULAR MATRIX

The disturbed glomerular structure and function in lupus nephritis are associated with quantitative and qualitative alterations in the glomerular matrix, ultimately leading to the development of glomerulosclerosis and chronic renal failure. Extracellular matrix components can bind to each other, and they can affect various biologic functions, such as cell attachment, spreading, proliferation, and differentiation.216,217 The important role of extracellular matrix components in modulating tissue function is exemplified by their altered expression during glomerular development.218221 Physiologic turnover of the extracellular matrix is maintained by a balanced interplay between matrix synthesis and matrix degradation.222 The altered expression of matrix components during the development of glomerular disease and the underlying mechanisms have been studied and reviewed by us and others.223,224 Here alterations in the glomerular matrix, in relation to the development of lupus nephritis, will be considered. In experimental lupus nephritis expansion of the mesangial matrix and thickening of the glomerular capillary wall occur. In MRL/lpr mice the expression of heparan sulfate, the side chain of heparan sulfate proteoglycan, seems to be decreased in the glomerular cap-

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illary walls as the disease progresses.225 In NZB/W mice remodeling of the glomerular matrix is associated with increased expression of the α1 chains of collagen types I, III, and IV and of laminin and heparan sulfate proteoglycan.200 During development of glomerular disease in these mice, an additional increase of tissue inhibitor of matrix metalloproteases and of matrix metalloproteases occurs, thus regulating matrix degradation.200 In mice with chronic GvHD, expansion of the mesangial matrix and thickening of the glomerular basement membranes are associated with increased glomerular expression of collagen type IV, laminin, and heparan sulfate proteoglycan at the mRNA and protein levels.48,226 Furthermore, qualitative alterations occur in these matrix components in domains involved in cell-matrix and matrix-matrix interactions223,227,228 and thus may play a prominent role in the development of renal failure.217,224 The alterations in kidney laminin expression will be discussed in more detail below because laminin is an important component of the glomerular basement membrane, and autoantibodies against laminin play a nephritogenic role in MRL/lpr mice and in mice with chronic GvHD.45,227,229 The laminins are a family of at least 11 trimeric glycoproteins composed of an α, a β, and a γ chain and are involved in modulating cell behavior in developmental, normal, and disease states. Laminin fragments can influence cell adhesion, differentiation, migration, and proliferation. Furthermore, laminins play an important role in maintaining tissue integrity by binding to other basement membrane components, such as nidogen and collagen type IV.230,231 During the development of chronic GvHD, laminin 1 protein expression is increased in the mesangium and in the glomerular basement membrane, which is preceded by increased steady-state mRNA levels for the laminin β1 and γ1 chains.48,226 By using monoclonal antibodies generated against proteolytically digested fragments of laminin 1 involved in matrix-matrix and cell-matrix interactions, it was found that, in this model, certain laminin epitopes that are present in the normal glomerular basement membrane during embryogenesis only219 reappear in the glomerular basement membrane as the disease progresses.227 This is at least in part due to altered expression of laminin chains because the glomerular expression of the laminin α1 chain increases, whereas expression of the β1 chain decreases and β2 and γ2 chain expression remains unaltered.229 Mechanisms that may be involved in this altered composition of the glomerular basement membrane are altered local matrix protein synthesis or degradation, redistribution of matrix components within the glomerulus, and also conformational folding of matrix components and

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their binding proteins in the glomerular capillary wall. As exemplified below, binding of autoantibodies in the glomerular capillary wall may affect its composition as well and thus the development of immune complex glomerulonephritis. During development of glomerular disease in mice with chronic GvHD (and in MRL/lpr mice), autoantibodies reactive with renal tubular epithelial antigens and in particular with dipeptidyl peptidase IV (CD26), which is involved in cell-matrix interaction, appear in the circulation. Glomerular binding of anti-CD26 autoantibodies results in a patchy distribution of CD26 on the surface of glomerular visceral epithelial cells in mice with chronic GvHD. This altered CD26 distribution may be involved in the detachment of the epithelial cells from the glomerular basement membrane and the increased proteinuria in these mice.232 Likewise, antilaminin autoantibodies are detected in sera and glomerular eluates of MRL/lpr mice and mice with chronic GvHD,44,45,131 and antiglomerular basement membrane autoantibodies are a conditio sine qua non for the full-blown development of lupus nephritis in mice with chronic GvHD.19,131,233 Recently, we found that autoantibodies react with only laminin chains in glomerular matrix extracts of diseased mice and that, as the disease progresses, the laminin chain reactivity of autoantibodies alters in conjunction with altered glomerular laminin chain expression in mice with chronic GvHD. In particular, autoantibodies reactive with the laminin α1 chain and with the lamininbinding molecule filamin appear in the circulation, whereas this epitope is neoexpressed in glomeruli of diseased mice.229 It is tempting to speculate that the appearance of the laminin α1 chain and filamin in the glomerulus has elicited epitope spreading and a maturation of antilaminin α1/antifilamin autoantibody– producing B cells in this model. Indeed, in HgCl2induced glomerulonephritis in rats, a model also associated with a polyclonal activation of B cells, antigen-driven formation of autoantibodies reactive with the P1 fragment of laminin occurs.234 How these novel glomerular epitopes can be presented to T cells, B cells, or both remains speculative at present; however, glomerular cells express proteins that are capable of modulating the immune response in lupus nephritis. In MRL/lpr mice glomerular expression of vascular cell adhesion molecule 1,168 ICAM-1,169 and MHC class II molecules235 is increased as lupus nephritis develops. Several investigators have shown that tubular epithelial and mesangial cells are capable of expressing MHC class II antigens and of interacting with T cells.236-240 Altogether, these findings raise the intriguing possibility that exposure of novel glomerular antigens may lead to specific T-cell activation and the secretion of patho-

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genic, antigen-specific autoantibodies by B cells. The identification of epitopes inducing pathogenic autoantibodies may ultimately lead to more specific immunotherapy, as has recently been shown for nucleosomal epitopes in NZB mice.241 CLINICAL IMPLICATIONS AND FUTURE PERSPECTIVES

The mechanisms for the development of experimental lupus nephritis discussed above and summarized in Fig 1 can be largely extrapolated to human SLE. Briefly, in human subjects SLE is also characterized by increased activation of B cells. Lymphocyte abnormalities and alterations in the cytokine secretion profile are associated with this increased B-cell activity and the generation of pathogenic autoantibodies.63,100,242,243 Autoantibodies reactive with the antigens listed in Table III can be detected in the circulation of patients with SLE.244,245 In particular, autoantibodies reactive with the extracellular matrix components fibronectin,246 heparan sulfate proteoglycans,247 and laminin248 are detectable in sera of patients with SLE. Immunoglobulins bind in the glomerulus, presumably according to the same mechanisms unraveled in experimental models for SLE. Leukocytes infiltrate glomeruli249 concomitantly with the expression of glomerular adhesion molecules250 and MHC class II molecules251 on glomerular cells. An increased expression of all three TGF-β isoforms and their receptors has been found on glomerular cells of patients with lupus nephritis, which correlated with increased fibronectin ED-A expression and with disease activity.252,253 Furthermore, increased levels of connective tissue growth factor,254 IL-4,255 IL4 receptor,255 and nitric oxide synthases256 have been reported in biopsy specimens of patients with lupus nephritis. With the expansion of the glomerular matrix, an increased expression of laminin, fibronectin, and collagen type IV is observed in glomerular disease,257,258 whereas expression of heparan sulfate in the glomerular capillary walls was decreased in lupus nephritis.259 However, at present, there is no gold standard to predict a relapse of glomerular disease in patients with SLE, and therapeutic interventions resulting in the prevention of glomerular disease are lacking. Studies described in this review may help to develop strategies aimed at the prevention of renal disease development in SLE. First, it is conceivable that predictive parameters for the redevelopment of renal disease may be found either systemically or in the glomerulus itself. Regarding serologic parameters, until now, attention was focused largely on the role of antinuclear autoantibodies. The detection of autoantibodies reactive with renal antigens, and especially the shift of autoantibody reactivity toward a more antigen-driven response, may turn out

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to be a valuable predictive parameter as well. By means of immunohistochemistry and molecular biologic techniques, it becomes more and more feasible to gather other than histologic data from renal biopsy specimens when, by means of conventional histologic analysis, no abnormalities are detectable.260 In chronic GvHD we found that steady-state mRNA levels for matrix components are increased as early as 4 weeks after disease induction,236 and altered mRNA splicing was detectable 2 weeks after disease induction.228 Histologically, however, glomerular matrix expansion and hypercellularity are first detectable 6 to 8 weeks after disease induction.48 Interestingly, therapeutic intervention with antiadhesion molecule autoantibodies 2 weeks after disease induction122 or with cyclosporin up to 6 weeks after disease induction142 attenuated renal disease development, thus showing that the early assessment of glomerular abnormalities may result in the commencement of early therapies preventing the development of renal disease. Furthermore, the glomerular expression of adhesion molecules, leukocyte subsets, and cytokines may be predictive for the development of more severe or end-stage renal disease as well.179 These findings indicate that measuring glomerular steady-state mRNA levels, preferably by using quantitative techniques, and performing additional immunohistochemical analyses will provide novel predictive parameters for the development of renal disease to the pathologist and the clinician. The analysis of early glomerular biopsy specimens (ie, specimens from patients with SLE without clinical signs of renal involvement) may ultimately contribute to the preservation of renal function in these patients. At present, lupus nephritis is treated with aspecific, aggressive immunosuppressive agents only.261 Investigations with experimental models aimed at gaining insight into disease mechanisms may ultimately lead to the development of specific therapeutic strategies. Systemically, the development of pathogenic autoantibodies may be prevented by blocking T-B–cell interactions (eg, with antiadhesion molecule monoclonal antibodies).93,94,172 Also, cytokine secretion patterns can be successfully manipulated, leading to the prevention of glomerulonephritis in experimental SLE.111,113 Other potential therapeutic strategies aim at diminishing the presence of nucleosomes in the circulation or at inducing tolerance to epitopes involved in the generation of pathogenic autoantibodies. Of course, side effects of these strategies will have to be monitored carefully, such as the spleen enlargement observed in mice with GvHD treated with anti-CD11a/CD54 monoclonal antibodies.172 Therefore further studies investigating the mechanisms underlying B-cell activation and the development of pathogenic autoantibodies in experimental

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lupus nephritis will be necessary before promising systemic interventions at an early stage in the development of renal disease in SLE can be introduced in the clinic. A second experimental but challenging field for the development of novel therapeutic strategies is the manipulation of mediators involved in local glomerular damage. In experimental SLE development of renal disease is attenuated by blocking, for example, the effects of IL-1, TXA2,199 IL-6,106,110 endothelin,262 and nitric oxide.201,202 These therapeutic agents are administered systemically. Whether their therapeutic effects were caused by modulation of systemic or local glomerular mechanisms still remains to be investigated. Newly developed techniques aimed at delivering proteins locally in the glomerulus (eg, by means of gene transfer studies)170,263 will help to further unravel the role of local glomerular inflammatory mediators and may provide us with local therapeutic means.

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