CLINICAL RESEARCH

Manuel Weber, MD, DMD,*

Differences in Inflammation Jutta Ries, PhD,*
Maike Bu€ttner-Herold, MD,†
and Bone Resorption between Carol-Immanuel Geppert, MD,‡
Marco Kesting, MD, DMD,* and
Apical Granulomas, Radicular Falk Wehrhan, MD, DMD*

Cysts, and Dentigerous Cysts

ABSTRACT
SIGNIFICANCE
Introduction: Dental cysts can be of inflammatory (radicular cysts) or noninflammatory
(dentigerous cysts) origin. Apical periodontitis is a necrosis of the pulp and infection of the root Apical granulomas, radicular
canal causing the development of apical granulomas or radicular cysts. The immunology of cysts, and dentigerous cysts
granuloma and cyst formation is important because modern root filling materials are show immunologic differences.
immunologically active and can contribute to the resolution of apical granulomas. In contrast, High infiltration of HLA-DR–
radicular cysts often require apicectomy. A better understanding of the pathophysiology of and CD83-positive
inflammation and bone resorption in apical periodontitis could be the basis for developing new proinflammatory cells is
root filling materials with superior immunomodulatory properties. Methods: Forty-one apical associated with radicular cyst
granulomas, 23 radicular cysts, and 23 dentigerous cysts were analyzed in this study. A tissue formation. Additionally, bone
microarray of the 87 consecutive specimens was created, and human leukocyte antigen–DR resorption markers MCSF and
isotype (HLA-DR)-, CD83-, receptor activator of nuclear factor kappa B ligand–, macrophage Gal3 are significantly increased
colony-stimulating factor (MCSF)-, galectin-3 (Gal3)-, CD4-, and CD8-positive cells were in radicular cysts compared
detected by immunohistochemistry. Tissue microarrays were digitized, and the expression of with apical granulomas. The
markers was quantitatively assessed. Results: HLA-DR, CD83, MCSF, and Gal3 expression development of apical
was significantly (P , .05) higher in radicular cysts compared with apical granulomas. HLA- periodontists toward
DR, CD83, MCSF, receptor activator of nuclear factor kappa B ligand, and Gal3 expression in granulomas or radicular cysts
dentigerous cysts was significantly (P , .05) lower than in both periapical lesions (apical could be immunologically
granulomas and radicular cysts). CD4 and CD8 infiltration was not statistically different be- controlled. Therefore, the use
tween apical granulomas and radicular cysts. Dentigerous cysts showed a significantly (P , of root filling materials with anti-
.05) lower T-cell infiltration than apical periodontitis. The CD4/CD8 ratio was not significantly inflammatory properties might
different between the analyzed groups. Conclusions: The development of radicular cysts in be beneficial.
apical periodontitis is associated with an increased expression of myeloid inflammatory
markers and bone resorption parameters. Antigen-presenting cells and myeloid cells might be
From the Departments of *Oral and
more relevant for the pathogenesis of apical periodontitis than T cells. Increased inflammation
Maxillofacial Surgery and
might promote the formation of radicular cysts and more pronounced bone †
Nephropathology and ‡Institute of
resorption. (J Endod 2019;-:1–9.) Pathology, Friedrich-Alexander University
Erlangen-Nu €rnberg, Erlangen, Germany

KEY WORDS Address requests for reprints to Dr Manuel

Weber, Department of Oral and
Apical granuloma; apical periodontitis; bone resorption; follicular cyst; periapical lesion; Maxillofacial Surgery, Friedrich-Alexander
University Erlangen-Nu €rnberg,
radicular cysts
€ckstraße 11, 91054 Erlangen,
Glu
Germany.
Infection and necrosis of the dental pulp causes apical periodontitis, which manifests as apical E-mail address: manuel.weber@
uk-erlangen.de
granulomas or radicular cysts. Both periapical lesions have an inflammatory origin but show a different 0099-2399/$ - see front matter
clinical course1. In contrast to radicular cysts, dentigerous cysts have no inflammatory cause2 and are
Copyright © 2019 American Association
classified as developmental odontogenic cysts3. In most cases, apical periodontitis is initially treated by of Endodontists.
orthograde endodontic treatment4. If an apical lesion develops into a cyst, endodontic therapy alone is https://doi.org/10.1016/
sometimes not sufficient, and apicectomy or even extraction of the affected teeth is required4. j.joen.2019.06.014

JOE  Volume -, Number -, - 2019 Inflammation and Bone Resorption in Granulomas and Cysts 1
 Although it is known that apical
periodontitis is caused by inflammatory
reactions5, the exact pathogenesis of the
different periapical lesions is not yet understood.
In a previous study, we analyzed macrophages
in apical periodontitis. Tissue macrophages can
occur in an M1 or M2 polarized state. M1
macrophages are proinflammatory and can
contribute to tissue destruction. In contrast, M2
polarized macrophages act anti-inflammatory
and mediate tissue regeneration and wound
healing6–9. We could demonstrate that radicular
cysts show a significant shift toward
proinflammatory, M1 polarized macrophages
compared with apical granulomas10.
Dentigerous cysts had a significantly lower
macrophage infiltration and M1 polarization
compared with both periapical pathologies
(apical granulomas and radicular cysts)10.
These data indicate that radicular cyst formation
is associated with M1 polarization of
macrophages, and the development of
granulomas or cysts might be immunologically
determined10. Because apical periodontitis is
characterized by inflammation and bone
resorption11, additional inflammatory cells and
signaling pathways associated with these
processes were studied to better understand
apical periodontitis.
Human leukocyte antigen–DR isotype
(HLA-DR) is an antigen presentation receptor
expressed on antigen-presenting cells like
dendritic cells (DCs) and macrophages12. HLA-
DR–based antigen presentation is essential for
the activation of CD4- and CD8-positive T cells
and thus for the initiation of specific adaptive
immune responses12. Proinflammatory M1
macrophages are characterized by a high HLA-
DR expression, whereas anti-inflammatory M2
macrophages are HLA-DRlow13,14.
Consequently, HLA-DR can be regarded as a
relevant proinflammatory marker.
Besides M1 polarized macrophages,
mature myeloid DCs are highly potent
antigen-presenting cells with proinflammatory
properties15. These DCs show a high
expression of CD83 and HLA-DR16.
Inflammation is a relevant driver of
bone resorption11,17, which is relevant for the
formation and growth of cystic jaw bone
lesions18. Bone resorption is mediated by
osteoclasts19. Receptor activator of nuclear
factor kappa B ligand (RANKL) and
macrophage colony-stimulating factor
(MCSF) signaling are the most relevant
pathways for osteoclast differentiation and
activation19,20.
Antigen presentation in combination
with specific coactivating signals leads to
adaptive T-cell responses21. In chronic
infectious diseases like human
immunodeficiency virus infection,
2 Weber et al.
T-cell–mediated inflammation can contribute
to bone loss22. In osteoporosis, T cells
contribute to bone loss via RANKL signaling23.
Galectin-3 (Gal3) is expressed in
macrophages and contributes to the regulation
of innate and adaptive immune responses.
Gal3 is also present in differentiating
osteoblasts and osteoclasts and might
contribute to the osteoblast-osteoclast cross
talk24. Anti-inflammatory as well as
proinflammatory effects of Gal3 were
described24,25. In rheumatoid arthritis,
increased Gal3 levels were detected in inflamed
joints24,26. Rats with induced arthritis showed
increased Gal3 expression in macrophages in
areas with severe bone destruction24.
The root filling material most suitable for
endodontic treatment is a subject of constant
debate27–29. The use of mineral trioxide
aggregate (MTA) as root-end filling material
during endodontic treatment or apicectomy has
shown good clinical results30–32. This might be
explained by the immune modulatory properties
of MTA because it was shown that MTA
induces a shift toward anti-inflammatory M2
polarization of macrophages in vivo33. Thus, M2
polarizing agents, like MTA, might antagonize
M1 polarization associated with radicular
cysts10 and therefore contribute to the
prevention of cyst formation in apical
periodontitis.
Because MTA also has negative
properties including dislocation, discoloration,
or difficulties of removal in endodontic
retreatment31, a better understanding of the
pathophysiologic processes in apical
periodontitis could pave the way for the
development of superior new apical sealing
materials in endodontic treatment.
The current study was intended to clarify
if the expression of parameters of inflammation
(HLA-DR, CD83, CD4, and CD8) and bone
resorption (RANKL, MCSF, and Gal3) differ
between noncystic periapical lesions (apical
granulomas) and cystic periapical lesions
(radicular cysts). Additionally, inflammatory
odontogenic cysts (radicular cysts) were
compared with developmental odontogenic
cysts (dentigerous cysts).
MATERIALS AND METHODS
Patients and Tissue Harvesting
A previously described10 cohort of 87
consecutive specimens of apical granulomas,
radicular cysts, and dentigerous cysts was
analyzed in this study. The study protocol was
approved by the local ethical committee of the
University of Erlangen-Nuremberg, Erlangen,
Germany (reference number 351_15 Bc).
Specimens were obtained during dental
surgery procedures in consecutive patients
with no clinical signs of acute infection. Surgery
was performed under local anesthesia or
general anesthesia. Complete enucleation/
curettage was performed in all cases. There
was no case with large jaw cysts requiring
continuity resection included. No surgical
procedure specific to this study was
performed because tissue samples from
routine histologic diagnostics were analyzed.
Each specimen included was confirmed
to show representative regions of apical
granulomas, radicular cysts, and dentigerous
cysts. In addition to clinical information, the
following histologic criteria were used to
differentiate between the pathologies: apical
granulomas represent an advanced form of
apical periodontitis in which the growth of
granulomatous tissue attempts to confine
irritating agents escaping from root canal.
Granulomatous tissue is composed of acute
and chronic inflammation (lymphocytes
variably intermixed with neutrophils, plasma
cells, histiocytes, mast cells, and eosinophils)
in a fibrotic stroma surrounded by a fibrous
capsule. In some cases, epithelial rests of
Malassez (epithelial layer) can be identified.
Dentigerous and radicular cysts have
few common histologic features. They are both
layered by nonstratified, nonkeratinizing
squamous epithelium with scattered mucinous
cells. In some cases, radicular cysts can have
hyalinized calcification called “Rushton bodies,”
even if the certain diagnosis is made on the
relation of the cyst with the tooth, because
periapical cysts are always related to a nonvital
element, whereas follicular cysts are associated
with an impacted tooth. Patients with a history
of malign or autoimmune diseases as well as
irradiated patients were excluded.
The study cohort consisted of 41 apical
granulomas, 23 radicular cysts, and 23
dentigerous cysts. Apical granulomas were
obtained from 41 patients (28 males and 13
females) with a mean age of 57 years, radicular
cysts were derived from 21 patients (13 males
and 8 females) with a mean age of 52 years,
and dentigerous cysts were obtained from 15
patients (10 male and 5 female) with a mean
age of 22 years.
Tissue Microarray Construction and
Immunohistochemical Staining
A tissue microarray (TMA) for apical
granulomas, radicular cysts, and dentigerous
cysts was assorted as previously described10.
For radicular cysts and dentigerous cysts,
stroma tissue in direct proximity to the cyst
lumen was selected for TMA construction.
Each tissue core had a diameter of 1.5 mm.
Immunohistochemical staining and quality
control were performed as previously
described10,34.
JOE  Volume -, Number -, - 2019
FIGURE 1 – Virtual microscopy of a TMA slide (1!, 7!, and 35! magnification). The figure shows an overview of a TMA slide stained for CD8-positive cells (1! magnification)
and a scheme of the TMA indicating the number of each tissue sample. Samples 5 and 27 are exemplarily selected and magnified (7! and 35! magnification).
The following primary antibodies were
used: anti–HLA-DR (M0746, monoclonal
mouse, 1:250; Dako Agilent, Santa Clara, CA),
anti-CD83 (sc-19677, monoclonal mouse,
1:100; Santa Cruz, Dallas, TX), anti-MCSF
(ab-183316, monoclonal rabbit, 1:100;
Abcam, Cambridge, UK), anti-RANKL
(ab9957, polyclonal rabbit, 1:100, Abcam)
anti-Ga13 (sc-20157, clone H-160, polyclonal
rabbit, Santa Cruz), anti-CD4 (ORG-8756,
clone 1F6, monoclonal mouse, 1:10;
Novocastra, Newcastle, UK), and anti-CD8
(IS62330-2, clone c8/144B, monoclonal
mouse, 1:100, Dako Agilent).
Quantitative Immunohistochemical
Analysis
TMAs were completely scanned and digitized
using the method of “whole slide imaging”
(Fig. 1). The scanning procedure was
performed in cooperation with the Institute of
Pathology of the University of Erlangen-
Nu€rnberg using a Pannoramic 250 Flash III
Scanner (3D Histech, Budapest, Hungary) in
the 40! magnification mode. Scanning and
virtual microscopy were performed as
previously described10.
For each TMA sample, 2 visual fields
showing the highest expression rates of each
marker were selected (hot spot analysis)
(Fig. 2A–E). The area analyzed per tissue
sample and marker was 1.4 mm2.
Micrographs of the selected areas were
imported into Biomas software (MSAB,
Erlangen, Germany) for cell counting.
Quantitative analysis was performed to
determine the number of infiltrating HLA-DR-,
CD83-, RANKL-, M-CSF-, Gal3-, CD4-, and
JOE  Volume -, Number -, - 2019
CD8-positive cells in all specimens.
Assessment of the cell density per mm2 was
performed as previously described10,34,35.
Statistical Analysis
To analyze the immunohistochemical staining
and spatial distribution patterns, the cell count
per mm2 was determined. The results are
expressed as median and standard deviation.
Box plot diagrams represent the median,
interquartile range, minimum, and maximum.
Two-sided, adjusted P values .05
were considered significant. The analyses
were performed using the Mann-Whitney U
test with SPSS 22 for Mac OS (IBM Corp,
Armonk, NY).
RESULTS
Inflammation and Bone Resorption
Marker Expression in Apical
Granulomas, Radicular Cysts, and
Dentigerous Cysts
The HLA-DR cell count in radicular cysts was
significantly higher than in apical granulomas
(median 5 1959 cells/mm2 and 334 cells/
mm2, respectively; P 5 .017) and also
significantly higher than in dentigerous cysts
(median 5 43 cells/mm2, P , .001; Table 1,
Fig. 3A). Compared with dentigerous cysts,
apical granulomas showed a significantly
higher (P , .001) HLA-DR expression (Table 1,
Fig. 3A).
Radicular cysts revealed a significantly
increased CD83 expression compared with
apical granulomas (median 5 43 cells/mm2
and 5 cells/mm2, respectively; P 5 .003)
and dentigerous cysts (median 0 cells/mm2,
Inflammation and Bone Resorption in Granulomas and Cysts
P , .001; Table 1, Fig. 3B). Moreover,
CD83 expression in apical granulomas was
significantly higher (P 5 .006) than in
dentigerous cysts (Table 1,
Fig. 3B).
RANKL expression in radicular cysts
was significantly higher than in dentigerous
cysts (median 5 4841 cells/mm2 and 1464
cells/mm2, respectively; P , .001). The
difference in RANKL expression between
apical granulomas and radicular cysts was
statistically nonsignificant (Table 1, Fig. 3C).
Compared with dentigerous cysts, apical
granulomas (median 5 4487 cells/mm2)
displayed a significantly higher
(P , .001) RANKL expression (Table 1,
Fig. 3C).
MCSF expression in radicular cysts was
significantly higher than in apical granulomas
(median 5 94 cells/mm2 and 10 cells/mm2,
respectively; P , .001) and also significantly
higher than in dentigerous cysts (median 5 4
cells/mm2, P , .001; Table 1, Fig. 3D). Apical
granulomas had a significantly higher (P 5
.032) MCSF expression than dentigerous cysts
(Table 1, Fig. 3D).
Radicular cysts displayed a
significantly higher density of Gal3-positive
cells (median 5 3551 cells/mm2) compared
with apical granulomas (median 5 1141
cells/mm2, P , .001) and dentigerous cysts
(median 5 291 cells/mm2, P , .001;
Table 1, Fig. 3E). Gal3 expression in apical
granulomas was significantly higher (P ,
.001) compared with dentigerous cysts
(Table 1, Fig. 3E). In summary, all analyzed
inflammation and bone resorption markers
showed the highest expression in radicular
3
 A

FIGURE 2 – Typical expression patterns of the analyzed inflammatory, bone resorption, and T-cell markers. Micrographs show the typical expression pattern of all markers (HLA-DR,
CD83, RANKL, MCSF, Gal3, CD4, and CD8) in (left column ) apical granulomas, (middle column ) radicular cysts, and (right column ) dentigerous cysts. All micrographs are given in
high-power magnification (35! magnification). (A ) HLA-DR and (B ) CD83 show a cytoplasmatic staining with accentuation of the plasma membrane. (C ) RANKL and (D ) MCSF
stainings display a cytoplasmatic expression pattern. (E ) Gal3 has a cytoplasmic and nuclear expression. (F ) CD4 and (G ) CD8 reveal a membranous expression pattern.

cysts compared with apical granulomas and
radicular cysts.
T-cell Infiltration and Expression
Ratios in Apical Granulomas,
Radicular Cysts, and Dentigerous
Cysts
Dentigerous cysts showed a significantly
lower infiltration by CD4-positive T cells
than radicular cysts (median 5 31 cells/
mm2 and 597 cells/mm2, respectively;
P , .001) and apical granulomas (median 5
568 cells/mm2, P , .001; Table 2, Fig. 4A).
The difference in the CD4 cell count
between apical granulomas and radicular
cysts was statistically nonsignificant
(Table 2, Fig. 4A).
Both apical granulomas and radicular
cysts showed a significantly higher infiltration of
CD8-positive T cells compared with
dentigerous cysts (median 5 298 cells/mm2,
388 cells/mm2, and 63 cells/mm2, respectively;
P , .001 for both; Table 2, Fig. 4B). No
significant difference in CD8 expression was
detected between apical granulomas and
radicular cysts (Table 2, Fig. 4B).
The CD4/CD8 ratio revealed no
significant differences between apical
granulomas, radicular cysts, and dentigerous
cysts (Table 2, Fig. 4C). There was no difference

4 Weber et al. JOE  Volume -, Number -, - 2019

TABLE 1 - Inflammation and Bone Resorption Marker Expression (Cells/mm2) in Apical Granulomas, Radicular Cysts, and Dentigerous Cysts

HLA-DR CD83 RANKL MCSF Gal3

Cell count (cells/mm2)
Marker Median SD Median SD Median SD Median SD Median SD
Group n
Apical granuloma 41 334 4773 5 134 4487 2012 10 336 1141 2552
Radicular cyst 23 1959 2557 42 201 4841 1687 94 520 3551 3723
Dentigerous cyst 23 43 109 0 17 1464 1382 4 25 291 663
P values
Apical granuloma vs radicular cyst .017 .003 .419 ,.001 ,.001
Apical granuloma vs dentigerous cyst ,.001 .006 ,.001 .032 ,.001
Radicular cyst vs dentigerous cyst ,.001 ,.001 ,.001 ,.001 ,.001

SD, standard deviation.

Values represent median, SD, and P value (Mann-Whitney U test, SPSS 22).

A B

C D

FIGURE 3 – Inflammation and bone resorption marker expression (cells/mm2) in apical granulomas, radicular cysts, and dentigerous cysts. Box plots show the median cell counts
(positive cells/mm2) of inflammation and bone resorption markers ([A] HLA-DR, [B] CD83, [C] RANKL, [D] MCSF, and [E] Gal3) in apical granulomas, radicular cysts, and dentigerous
cysts. All P values generated by the Mann-Whitney U test are indicated. Expression of the analyzed inflammation and bone resorption markers is significantly increased in radicular
cysts compared with apical granulomas and dentigerous cysts, except for (C ) RANKL expression, which shows no significant difference between radicular cysts and apical granulomas.

JOE  Volume -, Number -, - 2019 Inflammation and Bone Resorption in Granulomas and Cysts 5
TABLE 2 - T-cell Infiltration (Cells/mm2) and CD4/CD8 Expression Ratio in Apical Granulomas, Radicular Cysts, and Dentigerous Cysts

Cell count (cells/mm2) and expression ratios CD4 CD8 CD4/CD8

Ratio Median SD Median SD Median SD
Group n
Apical granuloma 33 568 882 298 367 1.48 5.30
Radicular cyst 20 597 486 388 356 1.47 0.88
Dentigerous cyst 13 31 208 34 63 1.34 4.92
P values
Apical granuloma vs radicular cyst .849 .359 .408
Apical granuloma vs dentigerous cyst ,.001 ,.001 .262
Radicular cyst vs dentigerous cyst ,.001 ,.001 .570

SD, standard deviation.

Values represent median, SD, and P value (Mann-Whitney U test, SPSS 22).

in the expression of all analyzed markers
between mandibular and maxillary cysts.
DISCUSSION
Proinflammatory Antigen-
presenting Cells in Apical
Periodontitis and Dentigerous Cysts
Inflammation of periapical tissue can cause the
development of apical granulomas or radicular
cysts. We were able to detect significantly
increased densities of HLA-DR– and CD83-
expressing cells in radicular cysts compared
with apical granulomas. CD83 is a marker for
mature dendritic cells capable of efficient
antigen presentation and T-cell activation15,16.
HLA-DR is expressed by mature myeloid
dendritic cells and M1 polarized,
proinflammatory macrophages but also by
other cell types capable of antigen
presentation15,16. Therefore, the increased
expression of HLA-DR and CD83 in radicular
cysts indicates that these lesions have a
significantly stronger proinflammatory state of
immunoreactivity compared with apical
granulomas.
Previously, we analyzed macrophage
infiltration and polarization in apical
granulomas and radicular cysts10.
Proinflammatory M1 macrophages contribute
to inflammation, antigen clearance, and tissue
destruction, whereas anti-inflammatory M2
macrophages mediate peripheral immune
tolerance, tissue regeneration, and wound
healing6–9. Macrophage polarization showed a
significant swift toward proinflammatory M1
polarization in radicular cysts compared with
apical granulomas10. However, total
macrophage density was not significantly
different between apical granulomas and
radicular cysts10.
These results are interesting in the
context of the increased HLA-DR and CD83
cell density detected in radicular cysts in the
current study. The increased M1 polarization of
macrophages in radicular cysts is
accompanied by an augmented infiltration of
mature CD83-positive dendritic cells and an
increased HLA-DR expression and maybe by
myeloid cells like proinflammatory
macrophages and dendritic cells.
Consequently, the development of apical
periodontitis into a radicular cyst appears to be
associated with a proinflammatory state.

A B

FIGURE 4 – The T-cell count (cells/mm2) and CD4/CD8 expression ratio in apical granulomas, radicular cysts, and dentigerous cysts. Box plots show the median T-cell counts (positive
cells/mm2) of (A ) CD4- and (B ) CD8-positive cells in apical granulomas, radicular cysts, and dentigerous cysts. (C ) The CD4/CD8 ratio. All P values generated by the Mann-Whitney U
test are indicated.

6 Weber et al. JOE  Volume -, Number -, - 2019

 In contrast, dentigerous cysts showed a
significantly lower HLA-DR and CD83
infiltration compared with radicular cysts. This
indicates that inflammation is not the driving
force in the progression of jaw bone cysts with
developmental origin.
With regard to apical periodontitis, the
results of the current study show that
increased inflammation is associated with cyst
formation. The results underline the
importance of counteracting bacterial infection
of the periapical region by sufficient
endodontic treatment and thus eliminating the
trigger of inflammation36. In addition, there is
evidence that root filling materials also
influence an immunologic response in
periapical tissues33 and may therefore be
prognostically relevant. Consequently, the
used root filling materials and sealers should
be investigated for their immunomodulatory
properties. In this regard, materials with anti-
inflammatory properties33 might be beneficial
in the prevention of radicular cyst
formation.
T-cell Infiltration in Apical
Periodontitis and Dentigerous
Cysts
In contrast to macrophages and dendritic cells,
there was no significant difference in the
infiltration of CD4- and CD8-positive T cells
between apical granulomas and radicular
cysts. Additionally, the CD4/CD8 ratio did not
reveal a significant difference between both
analyzed periapical lesions.
A previous immunohistochemical
analysis of apical granulomas and radicular
cysts accordingly revealed no significant
difference regarding the infiltration of CD8-
positive T cells37. However, another report
describes a significantly increased infiltration of
CD8-positive T cells in radicular cysts
compared with apical granulomas5. A recent
study analyzed programmed cell death 1
(PD1), an immune regulatory receptor
expressed predominantly by activated T
cells38. PD1 expression was significantly
increased in apical granulomas compared with
radicular cysts38. The increased expression of
the immune-suppressive receptor PD139 in
apical granulomas is in line with the results of
the current study, which showed a significantly
lower expression of the proinflammatory
markers HLA-DR and CD83 in apical
granulomas compared with radicular cysts.
Additionally, a significantly increased
JOE  Volume -, Number -, - 2019
expression of FoxP3-positive regulatory T cells
in apical granulomas compared with radicular
cysts was described40. These data support
the hypothesis that the formation of cystic
periapical lesions might be determined by the
immune system and associated with increased
inflammation.
Results of the current study indicate that
CD4 and CD8 T-cell infiltration in dentigerous
cysts is significantly lower than in apical
periodontitis. However, the CD4/CD8 ratio
revealed no significant difference between all
analyzed lesions. These data suggest that a
shift in the CD4/CD8 ratio is not involved in the
pathogenesis of cystic jawbone lesions.
Bone Resorption Parameters in
Apical Periodontitis and
Dentigerous Cysts
Osteoclasts are the primary bone-resorbing
cells essential for physiologic bone
homeostasis41. Analogous to macrophages,
osteoclasts derive from mononuclear
precursor cells of the myeloid lineage. The
main cytokines that promote differentiation and
activation of osteoclasts are MCSF and
RANKL41. Under physiologic conditions,
osteoblasts are the main source of MCSF and
RANKL, maintaining the balance between
bone formation and bone resorption.
However, inflammatory cells can also produce
MCSF and RANKL and thus induce bone
resorption41. For any kind of expanding
pathology in bone, it is essential to activate
osteoclasts. For this reason, bisphosphonates
or RANKL inhibitors, which block osteoclasts,
are used for the treatment of bone
metastases42,43.
The current study revealed significantly
increased MCSF expression in radicular cysts
compared with apical granulomas. Elevated
MCSF expression might be an indicator of
increased activation of osteoclasts and
consecutive bone resorption in radicular cysts.
In contrast to MCSF, RANKL was not
significantly up-regulated in radicular cysts in
comparison with apical granulomas. MCSF
and RANKL were significantly lower in
dentigerous cysts compared with both
periapical lesions. This finding is consistent
with the lower expression of inflammatory cells
in dentigerous cysts and could indicate that
inflammation-driven apical periodontitis has a
higher bone resorptive potential than
developmental cysts, which are associated
with a low inflammatory state. Results of the
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Inflammation and Bone Resorption in Granulomas and Cysts
current study are contrary to previous analyses
comparing RANKL expression in radicular and
dentigerous cysts, which could detect no
significant difference in the expression of the
cytokine18,44. However, in contrast to the
current report, no quantitative assessment
was used.
Gal3 is a phylogenetically highly
conserved lectin involved in a variety of
immunologic and cell biologic processes. In
the context of malignant diseases, Gal3
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Gal3 is involved in tissue remodeling and bone
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expression was significantly up-regulated in
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granulomas. In dentigerous cysts, Gal3 was
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expression in apical periodontitis is
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CONCLUSION
The development of radicular cysts might be
an immunologically controlled process. The
increased infiltration of proinflammatory cells in
radicular cysts is accompanied by an
increased expression of bone resorption–
associated cytokines. Antigen-presenting cells
seem to be more relevant for the
pathophysiology of apical periodontitis than
T cells. In contrast to apical periodontitis, the
progression of dentigerous cysts seems to be
less dependent on immunologic factors.
ACKNOWLEDGMENTS
The authors thank Rudolf Jung for
manufacturing the tissue microarrays and
Susanne Schoenherr and Elke Diebel for
technical assistance. We would also like to
thank the dental students Sabrin Abu-Hossin,
Franziska Gerhardt, and Lisa Go €ring for
processing the tissue specimens and
operating the immunohistochemistry
autostainer apparatus; Tilo Schlittenbauer for
collecting the tissue samples; and Luitpold
Distel for his assistance in the cell counting
procedure.
The authors deny any conflicts of
interest related to this study.
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