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Histologic analysis of renal leukocyte infiltration in antineutrophil cytoplasmic antibodyassociated vasculitisImportance of monocyte and neutrophil infiltration in tissue damage.

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ARTHRITIS & RHEUMATISM
Vol. 50, No. 11, November 2004, pp 3651–3657
DOI 10.1002/art.20607
© 2004, American College of Rheumatology
Histologic Analysis of Renal Leukocyte Infiltration in
Antineutrophil Cytoplasmic Antibody–Associated Vasculitis
Importance of Monocyte and Neutrophil Infiltration in Tissue Damage
Sven Weidner,1 Marina Carl,1 Regine Riess,2 and Harald D. Rupprecht1
ular infiltration of CD68-positive macrophages with
serum creatinine concentration at the time of biopsy
(P ⴝ 0.001 and P ⴝ 0.006, respectively).
Conclusion. These data underscore a major role
of monocytes in addition to neutrophils in the tissue
damage of AAV.
Objective. The histopathologic lesions in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) have been studied extensively, but the exact
composition of the cellular infiltrate is unclear. We
undertook this study to analyze renal leukocyte infiltration and the cellular distribution within glomeruli and
interstitium in 65 renal biopsy samples obtained from
patients newly diagnosed as having AAV.
Methods. Renal cellular tissue infiltration was
assessed with an immunoperoxidase method. Furthermore, the infiltrating cell types were correlated with
clinical and histopathologic data.
Results. The predominant interstitial infiltrating
cells were T lymphocytes, while monocytes and, to a
lesser extent, granulocytes constituted the dominant
infiltrating cell types in glomeruli. Interestingly, lymphocyte infiltration was predominantly periglomerular,
especially around glomeruli with sclerosis or heavy
crescent formation, while interstitial monocyte and neutrophil infiltration was diffusely distributed over the
interstitial tissue. A significant correlation was found
for the glomerular infiltration of CD68-positive macrophages with the presence of glomerular necrosis as well
as with the number of glomeruli with crescents (P <
0.0001 and P ⴝ 0.005, respectively). No correlation was
found for interstitial fibrosis with the infiltration of any
leukocyte subset. Furthermore, a significant correlation
was found for the interstitial as well as for the glomer-
The antineutrophil cytoplasmic antibody
(ANCA)–associated vasculitides, Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA), and renal
limited vasculitis (RLV) are chronic autoimmune diseases with the development of fibrinoid necrosis and
tissue inflammation of histologic heterogeneity in several organ systems. The lesions seem to occur predominantly in vessel-rich tissues involved in filtration processes or are located at mucous membranes (1).
Consequently, one of the hallmarks of these diseases is
renal involvement, which is also linked to a higher
mortality (2,3).
Renal involvement in ANCA-associated vasculitis (AAV) is characterized by focal and segmental
necrotizing glomerulonephritis coupled with extracapillary proliferation and crescent formation of extremely
variable intensity. The most characteristic feature distinguishing this glomerular disease from other types of
glomerulonephritis is the scarcity or absence of immune
complex deposition (termed “pauci-immune”). This inevitably focuses our attention on the infiltrating cells as
initiators of tissue destruction. The analysis of crescentic
glomerulonephritis of various causes has demonstrated a
significant increase of glomerular granulocytes and
monocytes, while the interstitial infiltrates have been
found to be primarily composed of T lymphocytes and
monocytes (4–6).
The leukocyte subpopulations in the inflamma-
1
Sven Weidner, MD, Marina Carl, PhD, Harald D. Rupprecht, MD: Ludwig-Maximilians-University, Munich, Germany;
2
Regine Riess, MD: Klinikum Nürnberg, Nuremberg, Germany.
Address correspondence and reprint requests to Sven
Weidner, MD, Medizinische Poliklinik, Klinikum der Universität
München–Innenstadt, Pettenkoferstrasse 8a, D-80336 Munich, Germany. E-mail: sweidner@med.uni-muenchen.de.
Submitted for publication May 7, 2004; accepted in revised
form August 2, 2004.
3651
3652
WEIDNER ET AL
tory cell infiltrates within glomeruli and interstitium in
renal biopsy samples from patients with AAV have not
been completely analyzed. Although some data pointed
to a cell-mediated type of immunity with lymphocytes as
the supposed initiators of the inflammatory process (7),
there is increasing evidence for a dominant role of
monocytes in the tissue damage of AAV. In smaller
biopsy studies, the cell infiltrates of vasculitic tissue
lesions were primarily composed of monocytes (8,9).
Further characterization of these cells in the proliferative lesions and crescents of necrotizing glomerulonephritis demonstrated the accumulation of activated
monocytes (10).
In this study, we analyzed the pattern of renal
leukocyte infiltration and the distribution of leukocyte
subpopulations in the interstitial and glomerular compartment. Furthermore, we performed a correlation of
the infiltrating cell types with clinical and histopathologic data.
PATIENTS AND METHODS
Patient selection. Sixty-five renal biopsy samples from
65 patients newly diagnosed as having small-vessel vasculitis
according to the Chapel Hill Consensus Conference (CHCC)
criteria (11) were selected for this study. All patients had
clinical features of renal involvement and histologically focal
necrotizing glomerulonephritis with few or no immunoglobulin
deposits (pauci-immune). Only patients diagnosed as having
WG, MPA, or RLV were included. Biopsy samples from
patients with immune complex vasculitides such as HenochSchönlein purpura or cryoglobulinemic vasculitis were not
analyzed. Furthermore, biopsy samples from patients with
secondary vasculitis due to autoimmune diseases or from
patients with Goodpasture’s syndrome or anti–glomerular
basement membrane nephritis were excluded from this analysis. Biopsy samples were obtained before or within 24 hours of
the initiation of immunosuppressive treatment.
All patients received induction treatment with orally
administered cyclophosphamide and corticosteroids. In 32
patients, treatment with corticosteroids was preceded by intravenous (IV) pulse methylprednisolone for 3 consecutive days.
Plasmapheresis was additionally used in 3 patients. These 3
patients were included in the MEPEX (randomized trial of
adjunctive therapy for severe glomerulonephritis in ANCAassociated systemic vasculitis: plasma exchange versus intravenous methylprednisolone) trial of the European Vasculitis
Study Group, comparing plasmapheresis with IV pulse methylprednisolone for treatment of severe renal failure in systemic
vasculitis.
Patient classification. Patients were retrospectively
reclassified according to the CHCC criteria (11) as having WG,
MPA, or RLV. Patients were classified as having WG if they
had systemic vasculitis and the presence of granulomatous
inflammation in a biopsy specimen or the presence of clinical
signs strongly suggestive of granulomatous disease. These
Table 1.
Primary antibodies used for immunohistochemistry
Antibody
Specificity
Dilution
Anti-CD3
Anti-CD4
Anti-CD8
Anti-CD15
Anti-CD68
Anti-CD79
T lymphocytes
T helper cells
T cytotoxic/suppressor cells
Granulocytes
Macrophages
B lymphocytes
1:150
1:20
1:50
1:50
1:150
1:50
comprised involvement of the upper respiratory tract with
nasal inflammation (purulent/bloody nasal discharge), sinusitis, or otitis media or lower respiratory tract manifestation
with pulmonary nodules or fixed infiltrates. Patients were
classified as having MPA if they had systemic vasculitis and the
absence of granuloma formation in a biopsy specimen and the
absence of clinical signs strongly suggestive of granulomatous
disease. Patients were classified as having RLV if they had
biopsy-proven pauci-immune necrotizing glomerulonephritis
without symptoms of systemic vasculitis.
According to the CHCC, noninvasive evaluations
could be used to identify abnormalities that adequately predicted the presence of granulomatous inflammation without
having to perform a histologic examination. As required by the
CHCC nomenclature (11), ANCA antigen specificity was not
used as a definition criterion.
Periglomerular inflammation or heavy crescentic destruction of the glomerulus often appears as granuloma-like
lesions on renal biopsy. This phenomenon was not used to
classify patients as having WG, since it appears as a nonspecific
feature of any crescentic glomerulonephritis.
ANCA analysis. All patients had been tested for the
presence of ANCA by indirect immunofluorescence (IIF) as
well as for the presence of proteinase 3–ANCA (PR3-ANCA)
and myeloperoxidase-ANCA (MPO-ANCA) by enzymelinked immunosorbent assay (ELISA). The IIF tests and
ELISA systems used for ANCA detection were manufactured
by Euroimmun (Lübeck, Germany).
Renal biopsy tissue preparation. Renal tissue was fixed
in 4% paraformaldehyde immediately after biopsy and embedded in paraffin according to standard techniques. Sections
were stained with hematoxylin and eosin and mounted with
glycerol gelatin (Merck, Darmstadt, Germany).
Immunohistochemistry. To assess renal cellular tissue
infiltration, a 3-step immunoperoxidase method was used.
Staining for CD3, CD4, and CD8 demonstrated T lymphocytes
as well as T cell subsets. CD79 staining was performed for B
lymphocytes. CD15 was used as a marker for granulocytes and
CD68 for the demonstration of macrophages.
Sections were deparaffinized, rehydrated, and fixed in
methanol–H2O2 (Merck) to suppress endogenous peroxidase
activity. For CD3 staining, sections were pretreated with 0.1%
Pronase (Dako, Hamburg, Germany) for 10 minutes. Sections
stained for CD4, CD8, and CD79 required microwave pretreatment in citrate buffer for 4 minutes at 600W, followed by
10 minutes at 250W. Staining for CD15 and CD68 was
performed without pretreatment.
After washing in phosphate buffered saline (Biochrom,
Berlin, Germany), sections were incubated with the primary
monoclonal anti-human antibodies (see Table 1) for 1 hour.
CELLULAR INFILTRATION IN ANCA-ASSOCIATED VASCULITIS
Anti-CD3, anti-CD8, anti-CD15, anti-CD68, and anti-CD79
were from Dako. Anti-CD4 was from Novocastra (Newcastleupon-Tyne, UK). For CD3 staining, peroxidase-labeled goat
anti-rabbit IgG (Dianova, Hamburg, Germany) and horseradish peroxidase–labeled rabbit anti-goat IgG (Dako) were used
as second and third antibodies, respectively, at a dilution of
1:100. All other stainings were performed with rabbit antimouse IgG (Dako) and goat anti-rabbit IgG (Dianova) as
subsequent antibodies at a dilution of 1:100. Staining was
visualized with aminoethylcarbazole (Dako). Sections were
counterstained with Mayer’s hematoxylin (Sigma, Deisenhofen, Germany) and mounted with glycerol gelatin.
Tissue analysis and evaluation of leukocyte infiltration. Tissue analysis was evaluated with a blinded protocol.
Routine histopathologic assessment was performed by an
experienced nephropathologist in accordance with a previously
standardized scoring protocol (12). Each glomerulus was evaluated separately for the presence of fibrinoid necrosis, extracapillary proliferation, sclerosis (local, segmental, or global),
and rupture of Bowman’s capsule. The number of glomeruli
with any of these lesions was calculated as a percentage of the
total number of glomeruli in the individual biopsy sample. For
the correlation of cellular infiltration with histologic lesions,
these percentages were recoded on a 5-point scale as follows:
0 for 0%; 1 for ⱕ25%; 2 for ⱕ50%; 3 for ⱕ75%; and 4 for
ⱕ100%. The interstitial lesions were scored on a 4-point scale
(⫺ ⫽ absent; ⫹ ⫽ mild; ⫹⫹ ⫽ moderate; and ⫹⫹⫹ ⫽
strong).
The interstitial infiltrating cells were counted in 8 fields
at 400⫻ magnification, referring to an area of 0.16 mm2/field.
The results were expressed as the number of positive cells per
square millimeter. Glomerular infiltration was assessed as the
mean number of infiltrating cells per glomerular cross-section
(gcs).
Statistical analysis. Statistical analysis was performed
with SPSS 11.0 for Windows (SPSS, Chicago, IL). The mean ⫾
SD was reported for normally distributed data. The chi-square
test was used for comparison of categorical data. Bivariate
Spearman’s correlation was applied to determine an association of leukocyte infiltration with histopathologic lesions and
of leukocyte infiltration with renal function. Since several
parameters were used for these calculations, the level of
significance was set to P ⬍ 0.008 according to the Bonferroni
adjustment. For all other analyses, P values less than 0.05 were
considered significant. All tests were 2-tailed.
3653
Table 2. Frequency of ANCA subspecificities in association with
diseases, as determined by ELISA*
PR3-ANCA
MPO-ANCA
ANCA negative
Total
(n ⫽ 65)
WG
(n ⫽ 17)
MPA
(n ⫽ 27)
RLV
(n ⫽ 21)
31 (48)
28 (43)
6 (9)
14 (82)
3 (18)
0 (0)
9 (33)
17 (63)
1 (4)
8 (38)
8 (38)
5 (24)
* Values are the number (%) of patients. ANCA ⫽ antineutrophil
cytoplasmic antibody; ELISA ⫽ enzyme-linked immunosorbent assay;
WG ⫽ Wegener’s granulomatosis; MPA ⫽ microscopic polyangiitis;
RLV ⫽ renal limited vasculitis; PR3 ⫽ proteinase 3; MPO ⫽
myeloperoxidase.
Renal function and histopathologic lesions. The
mean ⫾ SD serum creatinine concentration at the time
of biopsy was 423 ⫾ 270 ␮moles/liter. Proteinuria was
present in all patients, with a mean ⫾ SD level of
1,700 ⫾ 1,916 mg protein/24 hours. Crescentic glomerulonephritis was present in 60 biopsy samples (92%),
with fibrinoid necrosis in 54 biopsy samples (83%).
Interstitial infiltration. There was a mean ⫾ SD
of 1,085.6 ⫾ 1,152.2 leukocytes/mm2 infiltrating the
interstitium. The values for interstitial leukocytes are
listed in Table 3. Interstitial infiltration was most prominent for CD3-positive lymphocytes, with a mean ⫾ SD
level of 328.3 ⫾ 376/mm2. The numbers of CD4-positive
lymphocytes and CD8-positive cells were approximately
the same (117.9 ⫾ 158.4/mm2 and 164 ⫾ 191.7/mm2,
respectively). Only 6 biopsy samples were negative for
CD3-positive cells, and 3 biopsy samples were completely negative for T cells. B lymphocytes were also
observed. There was a considerable number of CD68positive macrophages (241.3 ⫾ 401.9/mm2).
Lymphocyte infiltration was predominantly periglomerular, especially around glomeruli with sclerosis or
heavy crescent formation, while interstitial monocyte
and neutrophil infiltration was diffusely distributed over
the interstitial tissue (Figures 1A–F). Vascular infiltration was rare. There was no difference in interstitial
RESULTS
Patient classification and ANCA subspecificities.
Seventeen patients (26%) were classified as having WG
and 27 patients (42%) were classified as having MPA.
RLV was present in 21 patients (32%). By ELISA,
PR3-ANCA or MPO-ANCA were found in 59 patients
(91%). PR3-ANCA were detected in 31 patients (48%)
and MPO-ANCA were found in 28 patients (43%). Six
patients were ANCA negative. Table 2 shows the frequency of ANCA subspecificities in association with
diseases.
Table 3. Interstitial and glomerular leukocyte infiltration*
Marker
Interstitium,
cells/mm2
Glomerulus,
cells/gcs
CD3
CD4
CD8
CD15
CD68
CD79
Total leukocyte count
328.3 ⫾ 376
117.9 ⫾ 158.4
164 ⫾ 191.7
48.4 ⫾ 80.5
241.3 ⫾ 401.9
185.5 ⫾ 258.9
1,085.6 ⫾ 1,152.2
1.3 ⫾ 2.6
0.3 ⫾ 1.2
0.6 ⫾ 1.6
3.2 ⫾ 7.4
4.7 ⫾ 11.1
0.1 ⫾ 0.3
10.2 ⫾ 17.6
* Values are the mean ⫾ SD. gcs ⫽ glomerular cross-section.
3654
WEIDNER ET AL
Figure 1. Renal leukocyte infiltration in antineutrophil cytoplasmic antibody–associated vasculitis. Infiltration was assessed using a 3-step
immunoperoxidase method (see Patients and Methods). A, Periglomerular accumulation of CD3-positive T cells with residues of heavy crescent
formation. B, Prominent infiltration of CD4-positive T lymphocytes around a glomerulus with evident sclerosis. C, Diffuse interstitial infiltration of
CD8-positive T lymphocytes. D, A pattern similar to that in C with periglomerular accumulation near a sclerosed glomerulus is seen for
CD79-positive B lymphocytes. E, Intense interstitial infiltration of CD15-positive neutrophils with diffuse distribution over the interstitial tissue. F,
Diffuse distribution of infiltrated CD68-positive macrophages in the interstitial tissue, similar to the pattern in E. G, Glomerular infiltration of
CD15-positive neutrophils. H, Prominent glomerular infiltration of CD68-positive cells with presence of macrophages within crescents. (Original
magnification ⫻ 200 in A–C, E, and G; ⫻ 400 in D, F, and H.)
infiltration according to ANCA or diagnostic subgroups,
either for leukocyte subsets or for the total number of
infiltrating cells.
Glomerular infiltration. In all biopsy samples, a
mean ⫾ SD of 15.35 ⫾ 9 glomeruli (range 4–45) were
analyzed. The mean ⫾ SD total infiltrating leukocyte
CELLULAR INFILTRATION IN ANCA-ASSOCIATED VASCULITIS
count was 10.2 ⫾ 17.6/gcs. CD68-positive macrophages
were the dominant glomerular infiltrating cell type
(4.7 ⫾ 11.1/gcs), followed by granulocytes (3.2 ⫾ 7.4/gcs)
(Table 3, Figures 1G and H). Twenty-seven biopsy
samples were completely negative for glomerular macrophages. Glomerular lymphocyte infiltration, represented
by CD3-positive cells, was rare. When present, mean
lymphocyte infiltration was slightly higher for CD8positive lymphocytes than for CD4-positive cells (0.6/gcs
versus 0.3/gcs) (Table 3). A significant correlation was
found for simultaneous glomerular infiltration of CD15positive granulocytes with CD68-positive macrophages
(r ⫽ 0.52, P ⬍ 0.0001) and for CD4-positive lymphocytes
with CD8-positive lymphocytes (r ⫽ 0.611, P ⫽ 0.001).
There was no significant difference in glomerular infiltration according to ANCA or diagnostic subgroups,
either for leukocyte subsets or for the total number of
infiltrating cells.
Comparison of cellular infiltration with histopathologic lesions. All patients had pauci-immune glomerulonephritis. We analyzed 998 glomeruli in the 65
biopsy samples for the presence of histopathologic lesions. Twenty-eight percent of glomeruli were normal,
and 15.8% had sclerosis. Crescents were found in 41.3%
of glomeruli, and fibrinoid necrosis was present in
31.3%. A significant correlation was found for the
glomerular infiltration of CD68-positive macrophages
with the presence of glomerular fibrinoid necrosis as
well as with the number of glomeruli with crescents (r ⫽
0.856, P ⬍ 0.0001 and r ⫽ 0.773, P ⫽ 0.005, respectively).
No correlation was found for interstitial fibrosis with the
infiltration of any leukocyte subsets.
Renal function and cellular infiltration. The total
number of infiltrating glomerular leukocytes per individual biopsy sample showed a significant correlation with
initial serum creatinine concentration (r ⫽ 0.624, P ⫽
0.012), but not with serum creatinine concentration after
1 year. A significant correlation was found for the
interstitial as well as the glomerular infiltration of CD68positive macrophages with serum creatinine concentration at the time of biopsy (r ⫽ 0.646, P ⫽ 0.001 and r ⫽
0.754, P ⫽ 0.006, respectively), but not with serum
creatinine concentration after 1 year. No significant
correlation was found for the interstitial or glomerular
infiltration of other leukocyte subsets, either with initial
serum creatinine concentration or with serum creatinine
concentration after 1 year.
DISCUSSION
The pathogenetic concept of AAV involves the
ANCA-induced activation of neutrophils and monocytes
3655
with the release of oxygen radicals and granule components, resulting in endothelial necrosis. Further cellular
activation leads to cytokine and chemokine release with
the subsequent vascular and perivascular infiltration of
inflammatory cells. However, the precise composition
and distribution of the inflammatory infiltrate have not
been analyzed in detail.
In this study, the predominant interstitial infiltrating cells were T lymphocytes, while monocytes and,
to a lesser extent, granulocytes constituted the dominant
infiltrating cell types in glomeruli. Interestingly, interstitial lymphocytes were predominantly periglomerular,
especially around glomeruli with sclerosis or heavy crescent formation, while monocyte and neutrophil infiltration was diffusely distributed over the interstitial tissue.
The serum creatinine concentration at the time of biopsy
correlated significantly with the interstitial as well as the
glomerular infiltration of CD68-positive macrophages.
The presence of monocytes as the predominant
glomerular infiltrating cell type in renal tissue in AAV
has also been reported by other investigators (8,10).
Ferrario and Rastaldi were able to identify macrophages
mainly in areas of necrotizing crescentic lesions and
granulomatous infiltrates. The further analysis of these
cells revealed their acute activation status and the
expression of proinflammatory cytokines such as tumor
necrosis factor ␣ (TNF␣) and interleukin-1 (IL-1) at the
protein and messenger RNA levels (9).
The major role of neutrophils in the induction of
injury in AAV remains unchallenged. However, our data
provide important information on the possible initiation
and amplification of tissue injury by ANCA-stimulated
monocytes acting in concert with neutrophils. This is
demonstrated by the significant correlation of glomerular necrosis as well as the number of crescentic glomeruli
with glomerular monocyte infiltration.
It is evident that monocytes play an important
pathogenetic role in a wide range of chronic inflammatory processes including vasculitis (1) and glomerulonephritis. In vitro, monocytes are activated by ANCA,
resulting in the release of oxygen radicals and chemokine secretion (13–15). Oxygen-dependent mechanisms
have been implicated in the tissue damage of various
diseases. Several experimental models for inflammatory
hepatic and pulmonary diseases have demonstrated that
tissue injury occurs in part via macrophage-derived
reactive oxygen intermediates (16). This is consistent
with studies of experimental models of both immune and
nonimmune glomerulonephritis, in which macrophages
and their secretory products have been implicated in
glomerular tissue injury (17,18). Macrophages accumulating in animal models of proliferative glomerulone-
3656
phritis in rabbits and rats produced significant amounts
of reactive oxygen species (19,20).
Furthermore, macrophage activation also results
in the secretion of a wide range of molecules, including
proinflammatory cytokines as well as collagenases and
proteases responsible for tissue degradation. The local
release of TNF␣ and IL-1 has the capacity to induce or
further amplify tissue damage. In accordance with the
data obtained by Ferrario and Rastaldi, Noronha et al
demonstrated the in situ production of TNF␣ and IL-1␤
by mononuclear cells in renal biopsy samples in AAV.
The number of TNF␣- and IL-1␤–positive cells was
markedly increased in biopsy samples with active lesions.
Positive cells were also present in crescents surrounding
tuft necrosis and in the walls of arteries and arterioles
with acute vasculitic lesions (21). Given the correlation
of glomerular macrophages with glomerular necrosis as
well as the correlation of interstitial and glomerular
infiltration of macrophages with serum creatinine concentration at the time of biopsy, our data underscore the
importance of monocyte infiltration for tissue damage in
AAV.
Investigators in some studies have suggested
pauci-immune glomerulonephritis to be a disease of
delayed-type hypersensitivity due to the prominent presence of T cells (7,8). Delayed-type hypersensitivity, a
manifestation of cell-mediated immunity, is the immunologic profile of granuloma formation that is induced
by the deposition of a relatively indigestible antigenic
material within tissue. Mediated by a variety of cytokines, the initiating event is a complex interaction between antigen-presenting mononuclear phagocytes and
predominantly T helper cells, resulting in T lymphocyte
proliferation and activation. Oxygen radicals and nitric
oxide seem to play important roles in the initiation and
amplification of these processes. Although the release of
oxygen radicals by neutrophils and monocytes is considered to be the primary event in the necrotizing inflammation of AAV, to date it is not clear how these
mechanisms ultimately lead to granuloma formation.
However, secondary activation of monocytes after the initiation of the inflammatory process cannot be
excluded. This may occur by direct cellular contact
between stimulated T cells and monocytes. Contactmediated signaling of monocytes by stimulated T lymphocytes is a potent proinflammatory mechanism that
triggers massive up-regulation of the proinflammatory
cytokines IL-1 and TNF␣ (22,23). Thus, activated monocytes contribute to the secretion of proinflammatory
cytokines, further trapping inflammatory cells at these
sites. Macrophages start to proliferate locally and par-
WEIDNER ET AL
ticipate in granuloma formation (24,25). It remains a
matter of speculation whether the infiltrative pattern
observed in the present study with periglomerular lymphocytes and intraglomerular monocytes represents the
attempt to obtain direct cellular contact.
Our data support the notion of an important role
of monocytes in the tissue damage of AAV. These data
may provide a basis for the development of monocytetargeted interventions or for the potential of TNF␣directed treatment modalities. Further analysis with
cytokine and chemokine staining of renal biopsy samples
will be required to determine the immunologic mechanisms of cell infiltration and pattern of distribution.
ACKNOWLEDGMENT
The authors are very grateful to Birgit Hausknecht for
excellent technical assistance.
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vasculitisimportance, renar, damage, tissue, antibodyassociated, cytoplasmic, neutrophils, antineutrophil, monocyte, leukocytes, infiltrating, analysis, histological
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