Chronic Graft-versus-Host Autoimmune Disease in Fc Receptor chain-deficient Mice Results in Lipoprotein Glomerulopathy
Yutaka Kanamaru*,
Atsuhito Nakao*,
Isao Shirato,
Ko Okumura*,
Hideoki Ogawa*,
Yasuhiko Tomino and
Chisei Ra*
*Atopy (Allergy) Research Center, Division of Nephrology, Department of Medicine, Juntendo University School of Medicine, Tokyo, Japan; and Department of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University School of Medicine, Tokyo, Japan.
Correspondence to Dr. Atsuhito Nakao, Atopy (Allergy) Research Center, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. Phone: 81-3-5802-1591; Fax: 81-3-3813-5512; E-mail: anakao{at}med.juntendo.ac.jp
ABSTRACT. Lipoprotein glomerulopathy (LPG) is a unique renaldisease characterized by intraglomerular lipoprotein thrombiassociated with severe proteinuria and frequent progressionto renal failure. The histologic hallmark of LPG is the presenceof laminated thrombi, consisting of lipid droplet, within thelumina of dilated glomerular capillaries. The findings of thrombiconsisting of lipoproteins raised the possibilities that LPGmight be related to a primary abnormality in lipid metabolism.However, the precise pathogenic basis of LPG remains unresolved.It was herein found that chronic graft-versus-host disease (GVHD)induced by the transfer of Ia-incompatible spleen cells fromB6.C-H2bm12 into coisogenic C57BL/6 mice with deficiency ofFc receptor chain (FcR) resulted in glomerulopathy that resembledLPG. The uptake of acetylated LDL was partially decreased inperitoneal macrophages isolated from FcR-deficient mice comparedwith wild-type mice, suggesting that partial impairment of modifiedLDL uptake might contribute to the development of LPG associatedwith chronic GVHD in FcR-deficient mice. LPG has been suggestedto be a disorder of primary abnormality in lipid metabolism;these findings would therefore provide novel insight into thedisease process.
Lipoprotein glomerulopathy (LPG) is a unique renal disease thatis characterized by intraglomerular lipoprotein thrombi associatedwith severe proteinuria and frequent progression to renal failure(1). Histologically, deposition of thrombus-like substancesin markedly dilated glomerular capillaries is observed, whichis positively stained for Sudan III or oil red O and containsapo B and apo E. Under electron microscopy, the lipid thrombiare finely, almost concentrically lamellated, with numeroussmall lipid vacuoles, suggesting that they have been seriallydeposited within the glomerulus.
The findings of thrombi consisting of lipoproteins raised thepossibilities that LPG might be related to a primary abnormalityin lipid metabolism (2). Many affected patients indeed havefeatures of type III hyperlipidemia, characterized by elevatedIDL and high apo E levels, and the glomerulopathy in Japanesepatients has been shown to be associated with apo E polymorphism,especially a novel apo E variant (apo E Sendai) (3). However,the single European LPG patient was homozygous for apo E-III,the most common phenotype in whites (4,5). The pathogenic basisof LPG therefore remains unresolved.
It has been shown that the transfer of allogenic T cells recognizinga difference at the MHC class II loci into non-irradiated, non-autoimmunemice leads to chronic graft-versus-host disease (GVHD), whichresembles the clinical feature of SLE, with similar autoantibodyspecificities, Ig deposition, and renal pathology (6). We hadbeen studying roles of Fc receptors (FcRs) in various diseaseprocesses; we therefore induced the chronic GVHD in Fc receptor chain (FcR)-deficient mice to determine whether FcRs contributedto the chronic autoimmune GVHD. FcRs (FcRI, FcRIII, and FcRI)are expressed on hematopoietic cell lineage and require a homodimerof the subunit (FcR) for surface expression and signal transductionin the mouse system (7), and FcR-deficient mice showed no expressionof FcRI, FcRIII, and FcRI (8).
Unexpectedly, we found that chronic GVHD induced by the transferof spleen cells with different MHC class II into FcR-deficientmice resulted in glomerulopathy that resembled LPG. Our findingsthus implicated FcR or FcRs in the development of LPG associatedwith chronic GVHD.
Mice
C57BL/6 (B6) and coisogeneic B6.C-H-2bm12 (bm12) were purchasedfrom Jackson Laboratories (Bar Harbor, ME), bred, and maintainedin SPF facility of Juntendo University. FcR-/- mice were generatedas described previously and have C57BL/6 background (8). Animalexperiments were approved by the Institutional Review Boardof Juntendo University.
Induction of Chronic GVHD
Chronic GVHD was induced as described previously (6). Briefly,recipient mice between 2 and 4 mo of age were injected with1 x 108 donor splenocytes, prepared by pressing donor spleensthrough a wire-mesh screen into phosophate-buffered saline (PBS).The resulting single cell suspensions were washed, counted,and injected intravenously. Five mice in each group were usedfor the study. Blood samples were obtained from experimentalmice at the induction of GVHD and at 2-wk to 4-wk intervalsthereafter, and the sera were stored at -20°C for lateranalysis.
Evaluation of Proteinuria/Hematuria and Lipid Profiles
Urine samples (10 µl) at each time point were evaluatedfor proteinuria and hematuria as described previously (9). Serumsamples at each time point were evaluated for the concentrationof urea nitrogen, creatinine, total cholesterol, LDL, HDL, andtriglyceride (TG) by standard methods.
Histology
Mice were killed at 5 mo after GVHD induction, and the kidneyswere removed, fixed in 4% paraformaldehyde, embedded into paraffin,sectioned, stained with periodic acid-Schiff (PAS) solutionand examined by light microscopy for histologic changes. Oil-redstaining was performed by standard procedure using the renalsamples without fixation.
Immunofluorescence Study
Kidney sections were stained with Rhodamin-labeled goat anti-mouseIgG (Cappel, Durham, NC) or rabbit anti-mouse apo E antibody(Cortex Biochem, San Leandro, CA) before incubation with FITC-labeledpolyclonal goat anti-rabbit IgG (Zymed, South San Francisco,CA) as described previously (9).
Electron Microscopy
For electron microscopy, small blocks of a specimen were fixedin 2.0% glutaraldehyde before postfixation in 1% osmim tetrooxideand embedded in Epon 812 according to the conventional methods.The samples were double stained with uranyl acetate and leadcitrate.
Preparation of Peritoneal Macrophages
Mouse peritoneal macrophages were obtained as described previously(10). Briefly, mice were injected intraperitoneally with thioglycollatebroth 4 d before harvest. Mice were sacrificed, and their peritonealcavities were rinsed with 5 ml of cold divalent cation-freephosphate-buffered saline (PD). Cells suspended in PD were washedtwice by centrifugation, and resuspended in RPMI1640 (Life Technologies,Gaithersburg, MD) containing 10% fetal calf serum (FCS) at aconcentration of 5 to 10 x 106 cells/ml. The cells were theneither plated on glass coverslips or kept in suspension in polypropylenetubes on ice. Recovery of thio-macrophages kept in suspensionwas confirmed by FACS caliber (Becton Dickinson, Mountain View,CA) with FITC-labeled Mac-3 antibody (PharMingen, San Diego,CA), and the purity was >98%. The macrophage suspensionswere used for acetylated LDL uptake assay within 4 h.
Acetylated LDL Uptake
Purified acetylated-LDL labeled with the fluorescence probe,Dil (Dil-Ac-LDL) was purchased from Biomedical TechnologiesInc. (Cambridge, MA). Thio-macrophages were incubated for 4h at 37°C in the presence of Dil-Ac-LDL (10 µg/ml)in RPMI 1640 -10% FCS. After the incubation, media containingDil-Ac-LDL were removed before the cells washed 4 times withPBS. Uptake of acetylated LDL by thio-macrophages was visualizedby FACS caliber, and mean fluorescence intensity was calculatedusing Cell Quest software (Becton Dickinson).
Statistical Analyses
Data are summarized as mean ± SD. The statistical analysesof the results were performed by the amount of variance usingFisher’s least significant difference test for multiplecomparisons. P < 0.05 was considered to be significant.
Unirradiated FcR-deficient mice (FcR-/-) that had genetic backgroundof C57BL/6 (B6) or wild-type B6 (FcR+/+) mice received intravenousinjections with a single dose of 1 x 108 age- and sex-matcheddonor splenocytes of coisogenic B6.C-H-2bm12 (bm12) mice toestablish chronic GVHD as described previously (6). Strain B6and bm12 differ only in three amino acids in the -chain of theI-A molecule. Anti-double stranded DNA antibody was detectedin the sera of all the experimental groups to the same extentafter 3 mo of GVHD induction (data not shown), confirming thatchronic GVHD had been equally established in FcR+/+ and FcR-/-mice.
Proteinuria was measured monthly in female recipients to assessrenal involvement during chronic GVHD. Urine protein concentrationspeaked at around 400 mg/dl in both FcR+/+ and FcR-/- mice, andthere was little difference between the two mouse strains inthe degree of proteinuria during chronic GVHD (Figure 1A). Therewas also little difference in the degree of hematuria betweenFcR+/+ and FcR-/- mice during chronic GVHD (Fig. 1B). Serumurea and creatinine levels were within normal limits in FcR+/+and FcR-/- mice during the course of chronic GVHD (data notshown). In addition, serum lipid profiles of FcR-/- mice werealso comparable to those of FcR+/+ mice 5 mo after inductionof GVHD (Table 1).
Figure 1. Comparable levels of proteinuria and hematuria between Fc receptor chain+/+ (FcR+/+) and FcR-/- mice during the course of chronic graft-versus-host disease (GVHD). Chronic GVHD was induced by intravenous injections with a single dose of 1 x 108 age- and sex-matched donor splenocytes of coisogenic B6.C-H-2bm12 (bm12) mice to FcR-deficient mice (FcR-/-) (genetic background of B6) or wild-type B6 (FcR+/+) mice. Levels of proteinuria (A) and hematuria (B) in FcR+/+ and FcR-/- mice were monitored after the induction of chronic GVHD. As a control, splenocytes obtained from B6 mice were intravenously injected into FcR-/- mice. Data are mean ± SD for five mice in each group. The results are one representative out of three independent experiments.
Glomerular samples taken from FcR+/+ and FcR-/- mice 5 mo afterinduction of chronic GVHD were examined histologically (Figure 2).Active glomerular disease was seen in FcR+/+ mice 5 mo afterinduction of GVHD as previously reported (6), including mesangialhypercellularity, thick capillary walls, and matrix expansion.Mononuclear infiltrates were also evident in the renal interstitium.In contrast, to our surprise, glomerular samples taken fromFcR-/- mice 5 mo after induction of chronic GVHD showed enlargedcapillary lumina with pale-stained and mesh-like substances.Importantly, about 90% of the total glomeruli in the kidneysection of FcR-/- mice had such laminated thrombus-like substanceswithin the lumina of dilated glomerular capillaries 5 mo afterinduction of GVHD. We could not find such lesions in renal samplesof FcR+/+ mice 5 mo after induction of GVHD. In addition, noglomerular abnormality was observed in FcR-/- mice receivingautologous (B6) splenocytes (i.e., without GVHD) 5 mo afterthe transfer of the cells (Figure 3A), suggesting that the developmentof thrombus-like substances in the kidney of FcR-/- mice waschronic GVHD-dependent.
Figure 2. Development of lipoprotein glomerulopathy (LPG) in FcR-deficient mice after induction of chronic GVHD. Chronic GVHD was induced in FcR+/+ or FcR-/- mice as described in Figure 1. Five months after the induction of GVHD, kidney sections were stained with periodic acid-Schiff (PAS). Representative renal photomicrographs of FcR+/+ (left) or FcR-/- mice (right) were shown. (Upper panels) The thrombus-like substances were seen in most of the glomeruli obtained from FcR-/- mice, but not in FcR+/+ mice. (Middle panels) Mononuclear infiltrates in the renal interstitium were equally observed between FcR+/+ and FcR-/- mice. (Bottom panels) Laminated thrombi within the lumina of dilated glomerular capillaries were clearly seen in FcR-/- mice, but not in FcR+/+ mice. Active nephritic, changes such as mesangial hypercellularity, thick capillary walls, and matrix expansion, were seen in FcR+/+ mice.
Figure 3. Glomerular findings in FcR-/- mice receiving splenocytes derived from B6 or B6. C-H-2bm12 mice. Photomicrographs of PAS stain in the glomeruli of FcR-/- mice receiving B6 splenocytes (A) and B6. C-H-2bm12 splenocytes (B) 5 mo after the cell transfer. (A) Normal appearance of the control mice without GVHD. (B) Representative non-LPG lesion seen in the glomeruli of FcR-/- mice. Similar nephritic changes to FcR+/+ (hypercellularity, thick capillary walls, and matrix expansion) occurred in FcR-/- mice.
Because of the presence of thrombus-like substances in mostof the glomeruli, it was difficult to see accurately whethersimilar nephritic lesions to FcR+/+ mice occurred in FcR-/-mice after induction of GVHD. However, we found that some glomeruli(about 10% of total glomeruli) that had not developed thrombus-likelesions in FcR-/- mice showed active glomerular pathology, includinghypercellularity, thick capillary walls, and matrix expansionas observed in FcR+/+ mice (Figure 3B). In addition, mononuclearinfiltrates in the renal interstitium were evident in FcR-/-mice as well as in FcR+/+ mice (Figure 2). Furthermore, thequantity of IgG deposition in the glomerular regions was comparablebetween FcR+/+ and FcR-/- mice (Figure 4). Taken together withlittle difference in the severity of proteinuria and hematuria(Figure 1), these results suggest that chronic GVHD had beenequally established in FcR+/+ and FcR-/- mice.
Figure 4. Comparable deposition of mouse IgG between the glomeruli of FcR+/+ and FcR-/- mice. Chronic GVHD was induced in FcR+/+ or FcR-/- mice as described inFigure 1. Five months after the induction of GVHD, kidney sections were stained with Rhodamin-labeled anti-mouse IgG to detect Ig deposition. Equal deposition of mouse IgG located predominantly within the capillary walls was observed between FcR+/+ and FcR-/- mice.
The histologic findings observed in FcR-/- mice 5 mo after inductionof GVHD closely resembled to those of human LPG; we thereforeperformed specific staining for lipoproteins and electron microscopyanalyses. The substances were clearly stained positive withoil-red O and with an antibody against apo E (Figure 5). Furthermore,electron microscopy examination revealed that the thrombus-likesubstances had various electron densities shaped lamella structureswith numerous small lipid vacuoles (Figure 6), suggesting thatthey had been serially deposited within the glomerulus. As describedin the Introduction, all of these findings are characteristicfeatures of human LPG (1). We thus concluded that chronic GVHDin FcR-/- mice resulted in the development of LPG.
Figure 5. Positive staining of the thrombus-like substances in the glomeruli of FcR-/- mice with oil-red O and anti-apo E antibody. The thrombus-like substances were stained with oil-red O (left) or anti-apo E antibody before incubation with the FITC-labeled secondary antibody (right) in the glomeruli of FcR-/- mice. Numerous red droplets were seen in the capillary lumina (left) (frozen section), and apo E was present mainly in the capillary lumina (right).
Figure 6. Electron micrographs showing lipoprotein thrombi. Electron photomicrographs of the concentrically lamellated lipid thrombi in the glomeruli of FcR-/- mice with numerous small lipid vacuoles. (Right panel) magnified picture of the square region in the left panel.
It was shown that FcRs on macrophages were involved in the recognitionand clearance of LDL (11–13). We thus hypothesized thatdeficiency of FcRs on macrophages in FcR-/- mice might affectuptake of modified (oxidized or acetylated) LDL at chronic inflamedkidney, resulting in lipoprotein deposition in LPG. We thencompared the uptake of acetylated LDL by thioglycollate-elicitedperitoneal macrophages between FcR+/+ and FcR-/- mice. The uptakeof acetylated LDL by activated peritoneal macrophages was partiallyreduced in FcR-/- mice compared with macrophages purified fromFcR+/+ mice (Figure 7). These findings indicate that clearanceof modified LDL by macrophages was partially reduced in FcR-/-mice, which might be associated with the in vivo lipoproteindeposition in LPG.
Figure 7. Partial reduction of uptake of acetylated LDL by peritoneal macrophages from FcR-/- mice. Mean fluorescence intensity of peritoneal macrophages that internalized Dil-Ac-LDL measured by FACScan (, absence of Dil-Ac-LDL; , presence of Dil-Ac-LDL). Data are mean ± SD for five mice in each group. Similar results were obtained by two other experiments. * P < 0.05, significantly different from the mean value of the corresponding control response
In this study, we demonstrate that chronic autoimmune GVHD inFcR-deficient mice resulted in the development of LPG. We andothers have previously shown that an induced-model of immunecomplex-mediated glomerulonephritis or a spontaneous model oflupus nephritis in FcR-/- mice resulted in reduction of thediseases (14,15). In either case, the development of LPG-likelesion in the kidney was not observed. Therefore, it seemedthat the development of LPG was specific to chronic GVHD modelin FcR-/- mice. Actually, two clinical reports noted the recurrenceof LPG in the transplanted kidney (4,16,17). Sustained inflammationinduced by chronic GVHD might thus be a predisposing factorfor LPG.
Macrophages possess several different receptor pathways involvedin the recognition and clearance of modified (oxidized) LDL,including scavenger receptors and FcRs (18). Regarding FcRs,the FcR subtypes, FcRI and FcRII, were reported to be involvedin LDL uptake (11–13). FcR-/- mice failed to express FcRIand FcRIII, but FcRII expression was retained (8); therefore,our findings that uptake of acetylated LDL by macrophages waspartially reduced in FcR-/- mice (Figure 7) could be attributedto the deficiency of FcRI.
Molecular mechanisms underlying the development of LPG in ourexperimental system requires further investigation. Our in vitrofindings that uptake of acetylated LDL by macrophages was partiallyreduced in FcR-/- mice raised one possibility that deficiencyof FcRs on macrophages might affect uptake of modified (oxidized)LDL at chronic inflamed kidney, resulting in the developmentof LPG. It was shown that interferonv (IFN-) inhibited expressionof scavenger receptors, whereas it enhanced expression of FcRs(19,20). We thus speculate that partial reduction of modified(oxidized) LDL uptake by macrophages could eventually resultin the lipoprotein deposition in the kidney during the longcourse of chronic GVHD. Cytokines such as IFN- induced by chronicGVHD might facilitate the process through favoring expressionof FcRs on macrophages. In contrast, in the absence of chronicinflammation, scavenger receptors might be sufficient for theclearance of modified (oxidized) LDL in FcR-/- mice. Mesangialcells may be also involved in the pathologic process, becauseexpression of FcRI in mesangial cells is induced by IFN- (21).However, the complexity of cellular interactions between donorand host cells in GVHD system would raise several other possibilitiesof the mechanisms underlying the development of LPG.
It appeared that primary abnormality in lipid metabolism, suchas the presence of particular apo E variants, did not contributeto the development of LPG in our system, because FcR+/+ micethat had same genetic background as FcR-/- mice, except forFcR chain, did not develop LPG-like lesions after inductionof chronic GVHD. LPG is considered to be a heterogenous disorder(2); it is therefore likely that our findings reflect the pathophysiologyof particular subsets of LPG, especially cases relevant to renaltransplantation (5). Genetic screening for FcR or FcRs in suchpatients will thus be interesting for future studies.
In summary, we found that chronic autoimmune GVHD in FcR-deficientmice resulted in the development of LPG. LPG has been suggestedto be a disorder of primary abnormality in lipid metabolism;therefore, our current findings provide novel insight into thedisease process.
Acknowledgments
We thank Hiroko Ushio, Keiko Maeda, Chiaharu Nishiyama, ToshiroTakai, Shigehiro Masaki, Yushiro Akizawa, Masanari Hasegawa,Takahiro Uchida, Tomoko Tokura, Masaaki Abe, Kohtaro Yokotefor helpful discussion and technical assistance and Emiko Kawasakiand Michiyo Matsumoto for secretarial assistance. This workwas supported in part by grants from the Ministry of Education,Science, Sports, and Culture, Japan.
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Received for publication August 7, 2001.
Accepted for publication February 23, 2002.
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[Abstract][Full Text][PDF]
chain-deficient Mice Results in Lipoprotein Glomerulopathy
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Abstract
Introduction
chain (FcR
RI) are expressed on hematopoietic cell lineage and require a homodimer of the 
-chain of the I-A molecule. Anti-double stranded DNA antibody was detected in the sera of all the experimental groups to the same extent after 3 mo of GVHD induction (data not shown), confirming that chronic GVHD had been equally established in FcR
, absence of Dil-Ac-LDL; 
, presence of Dil-Ac-LDL). Data are mean ± SD for five mice in each group. Similar results were obtained by two other experiments. * P < 0.05, significantly different from the mean value of the corresponding control response