Coupling of an antibody response to effector cells through the Fc region of antibodies is a fundamental objective of effective vaccination. We have explored the role of the Fc receptor system in a murine model of Cryptococcus neoformans protection by infecting mice deleted for the
common
chain of FcRs. Passive administration of an IgG1 mAb protects FcR
+/
mice infected with C. neoformans, but fails to protect FcR
/
mice, indicating that the
chain acting
through Fc
RI and/or III is essential for IgG1-mediated protection. In contrast, passive administration of an IgG3 mAb with identical specificity resulted in enhanced pathogenicity in
chain-deficient and wild-type mice. In vitro studies with isolated macrophages demonstrate
that IgG1-, IgG2a-, and IgG2b-opsonized C. neoformans are not phagocytosed or arrested in
their growth in the absence of the FcR
chain. In contrast, opsonization of C. neoformans by
IgG3 does not require the presence of the
chain or of FcRII, and the internalization of IgG3-treated organisms does not arrest fungal growth.
 |
Introduction |
Cryptococcus neoformans is an encapsulated fungus that infects immunosuppressed individuals and is responsible
for the death of 6-8% of AIDS patients (1). Antibodies to
the glucuronoxylomannan (GXM)1 portion of the capsular
polysaccharide modulate the infection (2). We have previously demonstrated that anticryptococcal IgG3 mAbs are
not protective in mouse models of cryptococcal infection (3). However, when the nonprotective IgG3 mAbs were
switched in vitro to other downstream IgG isotypes, these
antibodies became protective (4, 5). Since the IgG3 antibodies and their switch variants have identical antigen
binding sites (5), this observation underscores the importance of Fc-mediated functions for antibody efficacy against
C. neoformans. In principle, the Fc domain of IgG immune
complexes can interact with a variety of soluble and cell-bound molecules that may be involved in mediating the
protective capacity of this antibody. Thus, complement
C1q binding can lead to the activation of C3, which leads
in turn to either association with CR1/2 or generation of a
membrane attack complex through C5 (6). Direct interaction of IgG1 complexes with cognate FcRs could mediate
either fungal killing, or the arrest of fungal growth through
NK or macrophage-mediated antibody-dependent cytotoxicity (ADCC) (7), macrophage phagocytosis, or neutrophil
activation (8). Finally, IgG1, through its interaction with
the FcRn transporter (for review see reference 9), could be
involved in clearance of opsonized cells.
In this study, we have begun the dissection of the mechanisms by which IgG subclasses mediate their biological
responses by comparing the capacity of the IgG3 and the
IgG1 isotypes to (a) modulate cryptococcal infection in FcR-deficient mice in vivo and (b) mediate macrophage phagocytosis and the arrest of fungal growth in vitro. Three different classes of murine Fc receptors for IgG (Fc
RI, Fc
RII
and Fc
RIII) have been identified on immune effector
cells (for review see references 10). Activation by cross-linking of Fc
RI and III on macrophages, NK cells, mast cells, neutrophils, and other myeloid cells by antigen-antibody complexes leads to activation of diverse biological responses including phagocytosis, ADCC (for review see references 10, 12, 13), and release of inflammatory mediators
(for review see reference 14). The
subunit of Fc receptors
is an essential component of type I and III receptors for IgG
antibodies and is required for both receptor assembly and
signal transduction (15, 16). FcR
chain deletion leads to
impaired macrophage phagocytosis of IgG-coated SRBCs
despite persistent binding, and leads to defects in NK cell-
mediated ADCC (17). In contrast, cross-linking of Fc
RII
does not elicit a biological response on effector immune cells. However, when coligated to an activation receptor,
such as Fc
RIII, B cell receptor, or TCR, Fc
RII inhibits
the activation signal generated in those cells by inhibiting
calcium influx to the cell through the recruitment of the
SH2 inositol polyphosphate phosphatase SHIP (18, 19).
Deletion of Fc
RII results in mice with hyperresponsive B
cells, mast cells, and macrophages (20).
Here, we report that the FcR
chain-deficient mice and
heterozygous littermate controls are equally susceptible to
cryptococcal infection and that
chain is essential for
IgG1-mediated passive protection against this pathogen. In
addition, IgG3 mediated the phagocytosis of C. neoformans
and SRBCs in the absence of Fc
RI, II, or III function,
suggesting that it either uses a different FcR for IgG3 or a
signal transduction pathway that is different from the other
Fc
Rs. In contrast to the ability of IgG1 and IgG2a mAbs
to inhibit fungal growth, IgG3-mediated phagocytosis is
not associated with the arrest of fungal replication. The
findings in this study provide a rationale for the different
protective efficacies of IgG3 and IgG1 mAbs in mice infected with C. neoformans.
 |
Materials and Methods |
C. neoformans.
Strain 24067 (serotype D) was obtained from
the American Type Culture Collection (Rockville, MD) and
maintained on Sabouraud dextrose agar (Difco, Detroit, MI) at
4°C. For murine infection, C. neoformans was grown at 37°C in
Sabouraud dextrose broth (Difco) for 24 h. Yeast cells were
washed three times with PBS and the inoculum was determined
by counting in a hemocytometer and by scoring the CFU plated
on Sabouraud dextrose agar plates.
Monoclonal Antibodies.
The 3E5 IgG3 was made in response
to immunization with the GXM fraction of the C. neoformans
capsular polysaccharide conjugated to tetanus toxoid (21). The
IgG1, IgG2a, and IgG2b switch variants of 3E5 IgG3 were generated by in vitro isotype switching (5). The variable region sequence of the IgG1 switch variant was sequenced and is identical
to 3E5 IgG3 and all of the switch variants bind GXM (5). Ascites
was obtained by injecting 107 hybridoma cells into the peritoneal
cavity of Pristane-primed (Sigma Chemical Co., St. Louis, MO)
BALB/c mice. Antibody concentration was determined by an
ELISA relative to isotype matched standards of known concentration. For in vitro studies, antibodies were purified by protein G
chromatography (Pierce Chemical Co., Rockford, IL), and were
sterilized by filtering through a 0.2-mm-pore-size membrane
(Sigma Chemical Co.). For some in vitro experiments, the purified antibodies were incubated at 56°C for 30 min to inactivate complement. Purified anti-SRBC mAbs (anti-SRBC IgG1,
IgG2a, IgG2b, and IgG3) for rosetting assays were supplied by Dr.
B. Diamond (Albert Einstein College of Medicine; reference 22).
Animal Experiments.
Female C57BL/6J mice were purchased
from The Jackson Laboratory (Bar Harbor, ME). FcR
chain
knockout (FcR
/
) mice and wild-type (FcR
+/+) or heterozygous (FcR
+/
) controls had been backcrossed to C57BL/
6J for eight generations. Mice kept under specific pathogen-free
conditions were used for protection experiments at 6 wk of age.
10 mice per group were given 1 mg of IgG1, IgG3, or PBS as a
control. mAbs were administered via intraperitoneal injection 24 h
before intravenous challenge with 5 × 106 C. neoformans, and
mouse deaths were recorded daily.
Organ CFUs and Serum GXM Levels.
Groups of five mice
were treated with 1 mg of IgG1, IgG3, or PBS 1 d before infection. CFUs were determined 14 d after infection by plating homogenized brain or lung tissue on Sabouraud dextrose agar (5).
CFUs are expressed as the mean ± SD.
Serum GXM levels were determined by capture ELISA. Before ELISA, serum obtained 14 d after infection was diluted 1:25
with PBS, incubated overnight at 37°C with 0.2 mg/ml of proteinase K, and then heated for 20 min at 100°C (5). Serum GXM
concentration was determined relative to GXM standards of
known concentration.
In Vitro Macrophage Phagocytosis.
Bronchoalveolar macrophage
cells were obtained from C57BL/6J, FcR
+/+, FcR
/
, or
FcR
-chain and Fc
RII double knockout (FcR
/
/RIIB
/
)
mice (Clynes, R., unpublished observations). For the phagocytosis assay, 105 cells were plated per well in 96-well tissue culture
plates (Falcon; Becton Dickinson, Mountain View, CA) and cultured overnight at 37°C in the presence of 500 U of IFN-
per
ml (Genzyme, Cambridge, MA). Phagocytosis was measured in
the presence or absence of purified mAbs.
Phagocytosis of C. neoformans by macrophages without IFN-
pretreatment was studied in the same manner. After the addition of C. neoformans (E/T ratio of 1:5), the cells were incubated at
37°C for 4 h, washed three times with sterile PBS to remove nonadherent yeast cells, fixed with cold absolute methanol, and stained with a 1:20 solution of Giemsa stain (Sigma Chemical
Co.). Phagocytic indices were determined with a microscope at a
magnification of ×600 (Nikon Diaphot; Nikon Inc., Melville,
NY). The phagocytic index is the number of macrophages with
two or more internalized yeast cells/total number of macrophages
in each field. For each experiment, eight fields were counted (23).
In Vitro Macrophage Antifungal Activity.
The antifungal efficacy of primary macrophage cells was determined by counting
the C. neoformans CFU after coculturing with macrophage cells
(E/T = 5:1) in the presence and absence of mAb as previously
described (24). In brief, the macrophage cells were mixed with C. neoformans in the presence of 5 µg of mAb per milliliter as described for the phagocytosis assay, and the mixture was incubated
for 2 or 24 h. The supernatants from each well were then removed and the cells were lysed with sterile water for 30 min at
37°C, then vigorously aspirated and ejected in order to completely disrupt them. The supernatant was added back to the lysate, diluted with PBS, and plated on Sabouraud dextrose agar plates. Results are expressed as mean ± SD.
Rosetting Assay.
SRBCs were purchased from Colorado Serum Company (Denver, CO). The preparation of Ig-coated
SRBC and Fc rosetting was done as previously described (25, 26).
In brief, 1-5 µg of mAb was incubated with 1 ml of SRBCs (2 × 107 cells) for 30 min at 37°C, washed, and then diluted 1:10. The Ig-coated SRBCs were added to the adherent cells in 96-well
plates (E/T = 1:20), incubated for 30 min at 37°C, and then
washed and assayed for rosettes. Attachment of three or more
SRBCs signified a rosette. For phagocytosis, the cells were incubated for 1 or 2 h at 37°C, then free SRBCs were lysed with distilled water and intracellular SRBCs were assayed using phase
contrast microscopy. SRBCs incubated in the absence of mAbs
were used as controls. Results are expressed as the mean ± SD.
Statistics.
Data were analyzed with statistical software for
Macintosh (Instat version 2.01; GraphPDA Software for Science,
San Diego, CA) using the unpaired Student t test. Results were
also analyzed by the unpaired Wilcoxon test, which gave similar
results (4, 27).
 |
Results |
Effects of mAbs on Survival of FcR
+/
Mice.
We have
previously demonstrated that 3E5 IgG3 mAb was not protective against lethal infection of immunocompetent
C57BL/6J mice with C. neoformans, whereas its IgG1
switch variant prolonged the life of the infected animals
(27). C57BL/6J and the FcR
+/+ and FcR
+/
litter
mates of FcR
/
homozygous mice were infected with a
lethal dose of C. neoformans to quantify their susceptibility
to infection. All four mouse strains had similar susceptibility
to cryptococcal infection (P = 0.8; Table 1). To determine
the effect of the IgG3 and IgG1 isotypes on FcR
+/
mice,
we treated groups of 10 mice with IgG3, IgG1, or PBS and then challenged them with C. neoformans. Consistent with
previous results (27), IgG3 mAb tended to reduce animal
survival when compared to PBS controls (Fig. 1), although
the difference in survival time was not statistically significant (P = 0.14; Table 1). FcR
+/
mice given IgG1 mAb
were significantly protected compared to PBS controls (P
<0.02; Table 1 and Fig. 1). Animal survival in 3E5 IgG3-
and IgG1-treated C57BL/6J and FcR
+/+ mice was comparable to that in FcR
+/
mice (data not shown). Thus, the
in vivo data confirm that the isotype of the mAb is an important determinant of protection against C. neoformans and
that the heterozygous FcR
+/
mice do not differ in their
susceptibility to infection or response to passive antibody
from wild-type mice.

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|
Fig. 1.
Survival of FcR +/ mice given either mAbs IgG1, IgG3, or
PBS. 1.0 mg of each antibody was given intraperitoneally 24 h before intravenous challenge with 5 × 106 C. neoformans. Average survival and
standard deviation for the IgG1, IgG3, and PBS groups were 270 ± 130, 101 ± 56, and 147 ± 74 d, respectively.
|
|
Effects of mAbs on Survival of FcR
/
Mice.
To determine whether Fc
Rs play a role in antibody-mediated immunity against cryptococcal infection, FcR
/
mice were
challenged with C. neoformans as described above. Interestingly, FcR
/
mice had similar susceptibility to cryptococcal infection compared to FcR
+/
mice indicating that
lack of the FcR
chain does not reduce natural resistance
to cryptococcal infection (P >0.9; Fig. 2, inset). Passive administration of IgG1 mAb failed to protect FcR
/
mice
against infection, and it even appeared to lessen animal survival at early intervals after infection compared to PBS controls, but there was not a statistically significant shortening
of animal survival overall (Fig. 2 and Table 1). However,
IgG3 mAb did significantly reduce animal survival (P
<0.004). These results indicate that the FcR
chain is crucial for IgG1-mediated protection against cryptococcal infection, and suggest that the accelerated infectious process
provoked by IgG3 is mediated through a different pathway.

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Fig. 2.
Survival of FcR /
mice infected with C. neoformans
after the administration of mAbs.
Average survival and standard
deviation of FcR / mice for
the IgG1-, IgG3-, and PBS-treated groups were 112 ± 95, 64.0 ± 70, and 158 ± 57 d, respectively. The 3E5 IgG1 mAb failed to protect FcR / mice
(P = 0.20), whereas the IgG3
mAb decreased survival (P
<0.004). (inset) FcR / mice
were similarly susceptible to
cryptococcal infection as FcR +/
mice (P <0.8).
|
|
Effects of mAbs on Organ CFUs and Serum GXM Levels of
FcR
/
Mice.
The animal survival data for FcR
/
mice were extended by quantifying organ C. neoformans
CFUs and serum GXM antigen levels. Table 2 shows that
14 d after infection lung and brain CFU number and serum
GXM antigen in IgG1-treated FcR
/
mice were similar
to PBS-treated controls. In contrast, mice treated with IgG3
had many more organisms in their lungs compared to controls or IgG1-treated mice (P <0.02), but no increase in brain CFUs was found. The level of circulating GXM antigen in IgG3-treated mice was also elevated, suggesting a
higher fungal burden (P <0.03, Table 2). These results are
consistent with the animal survival studies and indicate that
the FcR
chain is necessary for IgG1-mediated protection.
Effects of mAbs on Macrophage Phagocytosis In Vitro.
Phagocytosis by macrophages derived from wild-type, FcR
/
and FcR
/
/RIIB
/
mouse strains was studied to further define the roles of FcRs in this model. In the absence
of capsule-specific mAbs, there was little or no phagocytosis of C. neoformans by lung macrophages (Fig. 3 A). Addition of IgG1, IgG2b, or IgG2a mAbs to the normal macrophage assay significantly increased the phagocytic index, especially after IFN-
stimulation (P <0.0001), whereas
the IgG3 mAb induced less phagocytosis (9%; P <0.0001).
Addition of IFN-
significantly increased IgG3-mediated
phagocytosis (19%) indicating that IFN-
caused an increase in expression of the Fc
R responsible IgG3-mediated phagocytosis. When IgG1, IgG2a, or IgG2b mAbs were added to FcR
/
macrophages, little or no phagocytosis
was observed even after stimulation with IFN-
(Fig. 3 B),
and analysis of macrophages from either the bone marrow
or the peritoneal cavity gave similar results (data not
shown). Organisms treated with IgG3 were poorly phagocytosed by FcR
/
macrophages without IFN-
stimulation.
However, IFN-
pretreatment of FcR
/
macrophages dramatically increased IgG3-mediated phagocytosis (P <0.0001).
IgG3 mAb pretreated by heating at 56°C to inactivate complement still provoked similar phagocytosis by the
macrophages from FcR
/
or FcR
/
/RIIB
/
mice
(data not shown). To exclude the possibility that the phagocytosis was mediated through Fc
RIIB, we assayed macrophages from Fc
RIIB
/
(20) and FcR
/
/RIIB
/
mice
and similar results were obtained (data not shown).

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Fig. 3.
Effects of 3E5 mAbs on phagocytosis by bronchoalveolar macrophage cells
from FcR +/+ and FcR / mice. Phagocytic index was determined at an E/T ratio
of 1:1 after 4 h of incubation. Each bar represents the average of eight fields, and
brackets denote standard deviation.
|
|
To confirm the data obtained from the macrophage assay
with anticryptococcal mAbs, we also examined mAb-mediated rosetting of SRBCs. Fig. 4 A shows that there is little
rosetting in the absence of mAbs in FcR
+/+ mouse macrophage cells. The anti-SRBC IgG1, IgG2a, and IgG2b induced high levels of rosetting, which was consistent with earlier reports (26). As with C. neoformans, IgG3 induced
lower rosetting levels compared to other IgG isotypes (P
<0.001). When the same mAbs were added to macrophages from the FcR
/
mice, IgG1 and IgG2b mAbs induced lower frequencies of rosetting, and only 30% of the
cells rosetted with IgG2a (Fig. 4 B). Again, IgG3-treated
SRBCs had a relatively low frequency of rosetting (13-
17%) with both macrophages from the FcR
/
and the
FcR
/
/RIIB
/
double knockout mice (Fig. 4, B and
C). Very limited rosetting was observed in IgG1-, IgG2a-, or
IgG2b-treated FcR
/
/RIIB
/
macrophages (Fig. 4 C).
Prolonged incubation (2 h) with IgG1-, IgG2b- or IgG2a-treated SRBCs did not result in phagocytosis (data not
shown). Consistent with the results from the macrophage
phagocytosis assay using C. neoformans, IgG3-treated SRBCs
had a 10-12% phagocytic index with the FcR
/
/RIIB
/
macrophages (data not shown). Taken together, these observations suggest that an IgG3 Fc receptor expressed on
the cell surface of mouse primary macrophages differs from
the other Fc
Rs or IgG3-mediated phagocytosis is dependent upon a different pathway of activation than the other
FcRs.

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Fig. 4.
Rosetting of anti-SRBC IgGs by macrophages from FcR +/+
(A), FcR / (B), and FcR / /RIIB / (C) mice. Anti-SRBC mAbs
(5 µg/ml) were incubated with SRBCs (2 × 107 cells) for 30 min before
adding to the adherent macrophages (E/T = 1:20). Attachment of three
or more SRBCs signified a rosette. SRBCs incubated in the absence of
mAbs were used as controls. Results are expressed as the mean ± SD.
|
|
Effects of mAbs on Macrophage on the Growth of C. neoformans In Vitro.
We next determined whether binding this
Fc
R-IgG3 would lead to fungal killing after phagocytosis.
Antifungal activity was quantified by measuring the CFU
after incubating antibody, C. neoformans, and macrophages
pretreated with IFN-
. Table 3 (FcR
+/+) shows that
IgG1 mAb significantly reduced the CFUs when incubated with wild-type alveolar macrophages at both early (2 h)
and later (24 h) coculture periods. In contrast, IgG3 mAb
did not restrain the growth of the organism after 2 or 24 h
of coculture. Macrophages obtained from FcR
/
mice
(FcR
/
) had little or no effect on CFU number in the
presence of IgG1 mAb (P <0.6). The CFUs of the IgG3-treated organisms increased the same as the controls (P >0.6)
when they were cocultured with FcR
/
macrophages.
These results strongly suggest that the Fc
Rs for IgG1 mediate phagocytosis and the release of factors leading to the arrest of fungal growth. In contrast, IgG3 induced phagocytosis of the organism but failed to inhibit fungal replication.
 |
Discussion |
The interaction of antibody-antigen complexes with effector cells results in a variety of different immune responses that are initiated through the binding of the antibody Fc region to cell surface Fc receptors. As a result, both
the structural heterogeneity of FcRs on effector cells and
the different antibody isotypes may contribute to the diversity of the response of effector cells (28, 29). Passive 3E5
IgG1 administration significantly prolongs survival of normal FcR
+/+ and FcR
+/
mice challenged with a lethal
dose of C. neoformans, whereas IgG3 with the identical variable region does not protect and even shows a tendency to
reduce animal survival. The different protective efficacy
mediated by this pair of IgG1 and IgG3 mAbs confirms our
previous findings (5, 27) and strongly suggests that Fc-mediated effector functions play an important role in protection against C. neoformans.
The role of the Fc
Rs in natural resistance against cryptococcal infection or any microbial pathogen is unknown.
Our finding that FcR
chain-deficient mice, which are unable to phagocytose through Fc
RI and III, have similar susceptibility to C. neoformans to normal C57BL/6J or FcR
+/
mice, suggests that Fc
RI and III are not essential for natural resistance against cryptococcal infection. Most wild-type
mice infected with C. neoformans do not develop an antibody response and antibody-mediated clearance is not believed to play a significant role in natural resistance (30).
Even in those animals that do produce antibodies, there is a
mixture of protective and nonprotective antibodies, and
the latter may block the effects of the former (4). It is likely
that FcR
chain-deficient mice have a similar response,
and therefore the presence or absence of Fc
Rs has no significant consequence for natural resistance.
The observation that passively administered 3E5 IgG1
fails to protect FcR
/
mice against cryptococcal infection clearly demonstrates that the FcR
chain is essential
for IgG1-mediated protection. An analogous situation has
been observed in a passive protection model to metastatic melanoma. Administration of an IgG2b mAb to the melanosome protein gp75 is able to protect wild-type mice
from significant lung metastasis. This protective effect is
abolished in FcR
chain-deficient mice, demonstrating the
essential role of Fc
R-mediated ADCC in the mechanism
of antibody protection (30a). Deletion of FcR
chain leads
to defects of macrophage phagocytosis, ADCC, and other
cytotoxic activities (13, 17), offering a likely explanation
for the lack of protection by passive administration of
IgG1, IgG2a, or IgG2b mAbs. The loss of the
chain in
vivo has also been shown to result in a decreased ability to
clear RBCs opsonized with rabbit IgG anti-mouse RBCs,
induce thrombocytopenia with an IgG1 mAb, or mount an
Arthus reaction to IgG1, IgG2a, or IgG2b immune complexes (17, 31). IgG3 immune complexes, in contrast, retained the ability to induce the cutaneous inflammatory response of an Arthus reaction (31). Those results are consistent
with the data presented here in which macrophages derived
from FcR
chain-deficient mice are unable to phagocytose
IgG1-, IgG2b-, and IgG2a-treated particles, but retain the
ability to bind and phagocytose IgG3-treated particles in
vitro and enhance infection in FcR
/
mice in vivo. Our
studies show that interaction of the IgG1-C. neoformans
complex with Fc receptors on normal macrophages significantly inhibits replication of C. neoformans. However, the
in vitro fungal inhibitory activity of IgG1 mAb is abolished
completely when FcR
chain-deficient macrophages are
tested. Consistent with the in vivo study, IgG3 treatment
permitted the organisms to replicate when tested with both
normal and FcR
/
macrophages.
Our data extends the earlier finding by Diamond et al.
(26) and suggests that there is either a separate receptor for
IgG3 or a different pathway to activate phagocytosis on primary mouse macrophages and macrophage-like cell lines.
IFN-
stimulates expression of Fc
Rs (32), which was confirmed in our in vitro studies using normal mouse macrophages. More importantly, treatment with IFN-
and IgG1
mAb had a synergistic effect on promoting phagocytosis and inhibiting proliferation of C. neoformans within normal
macrophages, which is abolished in FcR
deficient macrophages. In contrast, exposure to IFN-
significantly promotes IgG3 FcR expression in both normal and FcR
/
macrophages. The interaction of this receptor with IgG3
mAb failed to inhibit C. neoformans replication. We previously demonstrated that IFN-
plays an important role in
stimulating both IgG1-mediated protection and IgG3-mediated enhancement of infection (27). It is possible that
IgG3-mediated phagocytosis actually provides an intracellular sanctuary for C. neoformans that allows the fungus to
escape killing by other effector cells and serum factors.
Fungi could then proliferate freely within macrophage cells
and be disseminated, finally killing the host.
Received for publication Received for publication 26 November 1997 and in revised form 16 December 1997..
This work was supported by a grant (R35 CA-39838) from the National Institutes of Health (NIH) and by
the Harry Eagle Chair
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