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*
Renal Immunopathology Center, San Carlo Borromeo Hospital, Milan,
Italy.
§
Division of Nephrology, San Carlo Borromeo Hospital, Milan,
Italy.
Department of Pathology, San Raffaele Hospital, Milan, Italy.
Department of Nephrology, San Anna Hospital, Como, Italy.
Correspondence to Dr. Maria Pia Rastaldi, Renal Immunopathology Center, Division of Nephrology, San Carlo Borromeo Hospital, Via Pio II, 3, 20153 Milan, Italy. Phone: 39240222343; Fax: 39240222222; E-mail: mp.rastaldi{at}oscb.sined.net
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, interleukin-1) were
prominent in ANCA + RV, whereas in cryoGN, 30% of glomerular macrophages
seemed activated and cytokine expression was limited to a few glomerular cells
(P = 0.01). Moreover, only in ANCA + RV proliferative markers were
shown on glomerular macrophages and apoptotic macrophages were found. From the
data, it seems that ANCA + RV and cryoGN differ profoundly in macrophage
properties, namely adhesion, proliferation, and apoptotic clearance. Moreover,
acute activation and cytokine production seem to be present in a greater
number of macrophages in ANCA + RV, giving this disease a stronger severity
that could be taken into account for therapeutic strategies. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It is widely known, since it was demonstrated by Atkins et al. in 1972 (3), that a high number of macrophages accumulate in necrotizing crescentic lesions, where they are considered to have a key role in amplifying glomerular inflammation and participating in crescent formation (4), although their precise properties are not yet completely understood, especially in human disease. Macrophages are indeed very heterogeneous, and specific actions are directly influenced by the particular microenvironment in which they are present (5,6).
Most glomerular macrophages are believed to be derived from blood monocytes, and their entrance is permitted by the glomerular endothelial expression of adhesion molecules, especially Ig-like molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), that establish a firm adhesion to the endothelium (7,8).
In glomeruli, monocytes become macrophages and when properly activated are
able to produce an arsenal of chemical mediators with many different
properties. Acutely activated macrophages can be recognized by overexpression
of HLA class II antigens, de novo expression of 27E10 antigen, and
production of proinflammatory products, such as tumor necrosis factor-
(TNF-) and interleukin-1 (IL-1)
(9,10,11).
Instead, mature macrophages do not possess the 27E10 epitope on their surface
(11). Once a macrophage
completes its action, its exit is thought to depend mostly on lymphatic
drainage, although apoptosis could be another possible mechanism of clearance
(12).
To provide evidence of macrophage properties in ANCA-positive renal vasculitis (ANCA + RV) at time of renal biopsy, we conducted an immunohistochemical and in situ hybridization study, seeking various markers for the main steps of macrophage infiltration: adhesion to endothelium, acute activation, production of proinflammatory cytokines, proliferation, and apoptosis. Results were compared with those obtained in cryoglobulinemic glomerulonephritis (cryoGN), which occurs almost exclusively in type II mixed cryoglobulinemia (13). The disease has a typical morphologic picture of membranoproliferative exudative glomerulonephritis, with massive glomerular macrophage infiltration in most cases and macrophages mainly interposed in the double contours of the capillary wall (14). Moreover, presence of renal arteritis can be detected in renal biopsies of these patients, although, at least in our wide experience, no glomerular necrotizing extracapillary lesions have been found (13).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Tissue samples for light microscopy, in situ hybridization, and in situ terminal DNA transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining were fixed in 4% buffered paraformaldehyde and embedded in paraffin. Routine stainings were performed according to standard techniques.
For immunofluorescence and immunoperoxidase staining, the unfixed renal tissue was embedded in optimal cutting temperature (OCT) compound (Miles Scientific, Naperville, IL), snap-frozen in a mixture of isopentane and dry ice, and stored at -80°C. Subsequently, 5-µm sections were placed on slides and stored at -20°C until immunostained.
Immunoperoxidase Labeling
We used an avidin-biotin technique, as described previously
(15), whereby a biotinylated
secondary antibody reacts with several peroxidase-conjugated streptavidin
molecules. Briefly, after incubation with 0.5% avidin (Sigma Chimica,
Gallarate, Milan, Italy) and 0.01% biotin (Sigma) to suppress endogenous
avidin-binding activity, tissue sections were fixed in a
methanol-H2O2 solution (to block endogenous peroxidase).
After washing, sections were sequentially incubated with the primary antibody
(see Table 2), with the
secondary biotinylated antibody (Dako, Glostrup, Denmark) and with the
peroxidase-labeled streptavidin (Dako). Peroxidase activity was detected with
3,5-diaminobenzidine (DAB; Dako), and then sections were counterstained with
Harry's hematoxylin (BDH, Poole, England), dehydrated, and mounted in Entellan
(Merck, Darmstadt, Germany). Specificity of labeling was demonstrated by the
lack of staining after substituting phosphate-buffered saline (PBS) and proper
control immunoglobulins (Zymed, HistoLine, Milan, Italy) for the primary
antibody.
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Double Staining
According to the double-staining procedure published by Lan et al.
(16), sections were treated as
for the single stain from the beginning of the procedure to the DAB
development, except for the use of Tris-buffered saline (TBS) instead of PBS.
After washing, sections were then microwaved twice at 750 W for 5 min in
citrate buffer. They were sequentially cooled, pretreated with levamisole,
preincubated with normal serum, and incubated with the second primary
antibody. After washing in TBS, sections were then labeled with a biotinylated
secondary antibody (Dako) and alkaline phosphatase-conjugated streptavidin
(Dako). Alkaline phosphatase activity was finally detected with Fast Red
(Sigma). After sections were washed in distilled water and counterstained with
Mayer's hematoxylin (Sigma), they were then mounted with an aqueous mounting
medium (Ultamount, Dako). Specificity of labeling was demonstrated by the lack
of staining after substituting TBS and irrelevant immunoglobulins for the
first and/or second primary antibody.
In Situ Hybridization
Following the method published by Yamawaki et al.
(17), we deparaffinized and
rehydrated the tissues, then permeabilized them with saponin-TBS. Postfixation
was carried out with 4% buffered paraformaldehyde. Sections were then
acetylated with a solution of acetic-anhydride/triethanolamine. After washing,
a prehybridization solution, containing SSC 10X, Denhardt's solution 10X,
formamide 50%, Dextran sulfate 10%, and salmon sperm DNA 200 µg/ml (all
from Sigma), was applied for 1 h. Oligonucleotide digoxigenin-labeled probes
(oligonucleotide cocktails specific for VCAM-1, IL-1, and TNF-; all
from R&D Systems, Abingdon, UK) were appropriately diluted in the
prehybridization solution and applied overnight in a water-saturated
atmosphere. After hybridization, stringency washes were done with SSC 4X, SSC
2X - 50% formamide at 45°C, and again with SSC 1X at room temperature for
30 min. Specimens were pretreated with levamisole, washed in buffer, and
covered with antidigoxigenin antibody alkaline-phosphatase-conjugate
(Boehringer Mannheim, Mannheim, Germany) for 3 h. The enzymatic reaction was
developed with Fast Red. After sections were washed in distilled water, they
were mounted with an aqueous mounting medium (Ultamount).
Positive controls were done using digoxigenin-labeled oligonucleotides for housekeeping genes (ß-actin and G6PDH) and oligo-dT (all from R&D Systems). Negative controls were made using irrelevant oligonucleotides, i.e., digoxigenin-labeled oligonucleotide for rat insulin, (R&D Systems) and substituting the prehybridization solution for the probe solution.
Combined TUNEL and Immunohistochemistry
A standard TUNEL method
(18) was applied with some
modification. Briefly, tissues were deparaffinized and rehydrated. After
suppression of endogenous avidin-binding activity, sections were treated with
Proteinase K (Sigma), then endogenous peroxidase was blocked by 3%
H2O2. After washing, sections were covered with the
appropriate labeling buffer (Clontech, M-Medical, Firenze, Italy). On each
section, a solution of TdT enzyme and biotinylated dNTP mix with the addition
of Mn++, prepared following manufacturer's instructions (Clontech),
was then applied. After treatment with stop buffer (Clontech),
peroxidase-labeled streptavidin (Dako) was applied. Peroxidase activity was
detected with DAB. After washing, sections were again microwaved in citrate
buffer. They were sequentially cooled, pretreated with levamisole,
preincubated with normal serum, and incubated with the primary antibody.
Sections were then incubated with a biotinylated secondary antibody (Dako) and
alkaline phosphatase-conjugated-streptavidin (Dako). Alkaline phosphatase
activity was detected with Fast Red. Specificity of TUNEL reaction was tested
by positive (pretreatment of separate slides with DNase; Sigma) and negative
controls (substitution of an irrelevant protein for TdT enzyme).
Quantitative Evaluation
All immunostained sections were evaluated by an electronic image analysis
system (ETC3000, Graftek, Villanterio, Pavia, Italy). Images were digitized
using a videocamera (Kappa CF15/2, Gleichen, Germany) connected to a Leitz
Diaplan microscope (Leica, Milan, Italy) and to a Pentium 120 computer
(Maxwel, Rozzano, Italy) equipped with a frame grabber (Neotech Ltd, Eastleigh
Hampshire, UK). An automated macro composed by a color threshold procedure,
filtering and Danielsson algorithm, was applied on all digitized images. Cell
count was performed considering the number of positive cells per glomerulus or
per granulomatous lesion (200x). Glomerular analysis was performed after
drawing a precise line along the Bowman's capsule. The electronic system was
then programmed for region-of-interest analysis. A mean of 9 ± 2.3
(minimum, 6; maximum, 15) glomeruli/biopsy were analyzed. In periglomerular
granulomas, it was impossible to discriminate between intraglomerular and
periglomerular infiltration, but a limit to the periglomerular area was done
assuming as standard area of evaluation the digitized image of the granuloma
taken at the microscopic enlargement of 200 x and corresponding to 76800
µm (2). Results were
automatically exported and elaborated in an electronic file (Microsoft Excel
4.0) using the mean and the SD of the mean.
Statistical Analysis
Statistical significances (P < 0.05) were analyzed using the
2 test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Normal Kidney
Rare monocyte-macrophages were present at the glomerular level (0.9
± 0.4 CD68-positive cells/glomerulus). ICAM-1 was positive on
glomerular endothelium. VCAM-1, completely negative in the glomerular tuft,
was positive only on Bowman's capsule. In situ hybridization for
VCAM-1 was completely negative in the glomerular tuft.
A complete negativity or a mild mesangioparietal staining was observed in
normal glomeruli for HLA class II antigens. 27E10 antigen was completely
negative. Whole glomerular negativity was also observed, by
immunohistochemistry as well as by in situ hybridization, for
TNF- and IL-1.
No glomerular cells were positive for proliferation markers proliferating cell nuclear antigen (PCNA) and Mib-1. No cells were stained by TUNEL reaction.
ANCA-Positive Renal Vasculitis
Glomerular monocyte-macrophages were 44.8 ± 28.2 per glomerulus,
almost exclusively accumulated in areas of necrotizing extracapillary lesions.
Their presence was massive in periglomerular granulomatous reactions (163
± 82.4 cells/granuloma) (Figure 1, a
and b).
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ICAM-1 glomerular positivity was intense and diffuse to the whole tuft in all glomeruli. VCAM-1 specifically stained the areas of necrotizing extracapillary damage, labeling 66.4 ± 15.2 cells/glomerulus (Figure 1d). 126.4 ± 58 VCAM-1-positive cells were found in periglomerular granulomatous reactions. VCAM-1 mRNA was detected in the same glomerular areas, where it stained 54.9 ± 10.1 cells/glomerulus (Figure 1e). In granulomatous lesions, 106.2 ± 58.6 cells were positive.
A strong expression of HLA class II antigens was localized in areas of necrotizing extracapillary lesion (59.6 ± 10.8 cells/glomerulus) and in granulomatous reactions, where 158.4 ± 60.1 cells were labeled. 27E10 antigen was intensely positive in areas of necrotizing extracapillary damage (62.8 ± 12.2 cells/glom), and its expression was massive in periglomerular granulomas (198.2 ± 20.8 cells/granuloma) (Figure 1, g and h).
TNF- and IL-1 staining were similar in both intensity and
distribution: glomerular staining was detected in areas of necrotizing
extracapillary damage (46.7 ± 10.8 TNF-positive cells/glomerulus; 39.5
± 6.2 IL-1-positive cells/glomerulus) and in granulomatous reactions
(142.6 ± 68.9 TNF-positive cells/granuloma; 138.1 ± 62.8
IL-1-positive cells/granuloma). In situ hybridization paralleled
immunohistochemistry (40.6 ± 9.4 TNF-positive cells/glomerulus; 31.2
± 19.8 IL-1-positive cells/glomerulus; 110.3 ± 54.2 TNF-positive
cells/granuloma; 122.2 ± 63.7 IL-1-positive cells/granuloma)
(Figure 1, j and k).
PCNA was positive on 14 ± 2 cells/glomerulus (Figure 1m) and 38.3 ± 12.2 cells/granuloma. Of them, 5 ± 0.4 cells/glomerulus and 13.2 ± 0.6 cells/granuloma were double stained for PCNA and CD68 antigen (Figure 1n). Mib-1 staining was present on 6.7 ± 2.3 cells/glomerulus and 18.8 ± 7.9 cells/granuloma. By double staining, 2.04 ± 0.3 cells/glomerulus and 4.7 ± 2.1 cells/granuloma also were found to be CD68 positive.
With the use of the TUNEL reaction coupled with immunohistochemistry, it was possible to recognize some CD68-positive cells that were also positive for TUNEL reaction (1.6 ± 0.7 cells/glomerulus; 3.2 ± 0.4 cells/granuloma).
The variability of all markers among different specimens is given in Table 3 (values in parentheses). Considering singularly every specimen, glomeruli without necrotizing extracapillary lesions appeared almost normal also at the immunohistochemical and in situ hybridization evaluation. No statistical significance was reached comparing cases divided by ANCA pattern or by diagnosis.
Cryoglobulinemic Nephritis
Glomerular macrophages were present in very high numbers (64.8 ±
12.3 cells/glomerulus), homogeneously occupying the entire glomerular tuft
(Figure 1c). No granulomatous
lesions but rare periglomerular macrophages were found (2.6 ± 0.4).
ICAM-1 positivity was strong and diffuse in all glomeruli. Conversely, VCAM-1 was completely negative or showed only a scattered cellular positivity (0.03 ± 0.004 cells/glomerulus) (Figure 1f). VCAM-1 mRNA was not detected.
Expression of HLA class II antigen was found on scattered glomerular cells
(10 ± 2.1 cells/glomerulus). 27E10 antigen was present on 19.8 ±
2.4 cells/glomerulus (Figure
1i). Scattered positivity was also found for TNF- (8.2
± 1.3 cells/glomerulus) and IL-1 (7.4 ± 0.9
cells/glomerulus), both the protein and the mRNA
(Figure 1l).
PCNA was positive on 0.7 ± 0.1 cells/glomerulus, and Mib-1 was detected very rarely on cells (0.09 ± 0.04). Double staining did not show monocyte-macrophages positive for both proliferation markers (Figure 1o). No macrophages were double-stained by CD68 marker and TUNEL reaction.
The variability of all markers among different specimens is given in Table 3 (values in parentheses). Almost no variability was found among different glomeruli in the same specimen.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Among Ig-like adhesion molecules, ICAM-1 is expressed by glomerular endothelium in normal kidneys and has been found to be upregulated in most glomerulonephritis (7,19,20). Also in our cases, independent of the disease, ICAM-1 upregulation was present in all glomeruli examined.
Conversely, we detected VCAM-1 glomerular positivity only in renal vasculitis and only in damaged glomeruli, where the molecule clearly stained the areas of necrotizing extracapillary lesions, leaving the remaining tuft negative. This is especially relevant because it is a de novo production, confirmed by VCAM-1 mRNA positivity in the same areas. A similar expression of VCAM-1 has been observed by our group (1,21) in other forms of glomerular capillaritis, i.e., necrotizing IgA nephritis, Henoch-Schönlein syndrome, and glomerulonephritis associated with endocarditis, and never found in other glomerular diseases, suggesting that necrosis of glomerular capillaries and VCAM-1 production are strictly related events and that in these lesions VCAM-1 is fundamental in monocyte adhesion.
Moreover, in renal vasculitis, VCAM-1 seems to be expressed also by macrophages, not only in the glomerular tuft but also in periglomerular granulomatous lesions. Detection of VCAM-1 mRNA in these cells cannot exclude that soluble VCAM-1 links to its integrin receptor very late activation-4 on macrophage surface, as proposed by Ogawa et al. (22), but certainly confirms our previous results (23) and results obtained by other investigators (24,25). A possible explanation is related to macrophage activation and consequent production of adhesion molecules by themselves. To our knowledge, there are no culture studies demonstrating production of VCAM-1 by macrophages, but, for instance, ICAM-1 production by eosinophils after cytokine stimulation has been demonstrated by Czech et al. (26). Moreover, isolation from human synovium of macrophages expressing VCAM-1 has been performed by Koch et al. (27) in patients with rheumatoid arthritis. Although their significance is not completely clarified, expression of Ig-like adhesion molecules by leukocytes can be important in cell-cell and cell-matrix interaction, contributing to overall tissue inflammation.
Acute activation of macrophages seems to occur in both renal vasculitis and cryoGN, whereas normal kidney resident macrophages did not show activation markers. Cell culture studies show that acute macrophage activation is followed by increase in expression of HLA class II molecules on the cell surface (28). Although we have found a strong expression of HLA class II antigens in areas of macrophage accumulation, statistically different not only from normal kidneys but also from cryoGN, demonstration of a cellular increase is difficult in the tissue. Instead, a better marker for acute activation can be the so-called 27E10 antigen (29). 27E10 is a dimer of two calcium-binding proteins, MRP8 and MRP14, monomeric and intracytoplasmic in normal conditions. Formation of the dimer and expression on the cell surface occur only after acute activation. The molecule disappears from the cell surface when the macrophage proceeds in its further steps of maturation and has been found completely absent from tissues with chronic inflammation (30). Our data show that in glomerular lesions in renal vasculitis, almost all macrophages are simultaneously acutely activated, whereas in cryoglobulinemic nephritis, only approximately one third of glomerular macrophages are 27E10-positive cells and in normal kidneys the molecule is completely absent. Moreover, a massive 27E10 expression characterizes periglomerular granulomas, differentiating these peculiar and acute lesions from other kinds of tissue granulomas, in which the molecule has been found completely negative (30).
Recent experimental models have demonstrated that TNF- and IL-1
production strictly depends on macrophage infiltration
(31,32).
Moreover, in cell separation experiments, it has been demonstrated that
macrophages that express 27E10 epitope produce the greatest quantities of
TNF- and IL-1 (30). Our
data seem to confirm these results; in fact, TNF- and IL-1 expression,
in terms of protein as well as mRNA, exactly paralleled 27E10 staining. A
stronger expression of both cytokines has been detected in renal vasculitis in
comparison with cryoGN, despite a similar number of macrophages, suggesting
that acute activation directly influences the quantity of proinflammatory
products in the tissue, making the disease more severe. TNF- and IL-1
possess and share a large spectrum of proinflammatory activities, and new
promising treatments can be based on their inhibition
(33). Recent research has
shown, in fact, that inhibition of IL-1, through IL-1 receptor antagonist
administration, is able not only to prevent the development of anti-glomerular
basement membrane nephritis in rats
(34) but also to induce, by
late administration, regression of the disease
(35), and similar effects have
been obtained by blocking TNF- by administration of a soluble form of
its receptor
(34,36).
In renal vasculitis but not in cryoGN or normal kidneys, we found glomerular and periglomerular macrophages positive for proliferation markers. Similar results have recently been obtained in experimental models, where proliferating macrophages have been found, for instance, in anti-glomerular basement membrane nephritis but not in normal resident macrophages or in a model of hypercholesterolemic glomerulonephritis (36). In agreement with those authors, we suggest that local macrophage proliferation can be an important mechanism of damage amplification, but further follow-up studies are required to understand better whether in human diseases the presence or absence of macrophage proliferation is also associated with a different prognosis.
Given the intense accumulation of macrophages, as a result not only of recruitment but also of proliferation, our results that the presence of macrophage apoptosis was found only in renal vasculitis are not surprising. Apoptosis could in fact be relevant for macrophage clearance from the kidney, counterbalancing their overaccumulation, and could be an important regulatory mechanism of progression of renal damage, as also suggested by Lan et al. (37).
Taken together, our data seem to clarify some properties of macrophage infiltration in renal vasculitis, especially in comparison with cryoGN. In fact, despite their comparable number in glomerular areas of accumulation, macrophages show qualitative differences in terms of glomerular localization, VCAM-1-mediated adhesion, proliferation, and apoptosis. Moreover, acute activation and production of proinflammatory products seem to be present at the same time in a greater number of macrophages in renal vasculitis, giving to this disease a stronger severity that could be taken into account for therapeutic strategies.
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Acknowledgments |
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