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*
Department of Microbiology and Immunology, Allegheny University of the Health Sciences, Philadelphia, PA 19129; and
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10021
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain knockout mice. Inflammatory
macrophages from these knockout mice were unable to mediate
phagocytosis or Ab-dependent cell-mediated cytotoxicity (ADCC) through
FcRI, FcRII, or FcRIII. Passive transfer of either P.
y. yoelii hyperimmune sera or anti-GST-PYC2 sera directed
to the major merozoite surface protein (MSP-1) of this parasite enabled
both BALB/cByJ mice and FcR -chain-deficient mice to resist lethal
P. y. yoelii 17XL (Py17XL) challenge. mAb302, a
protective IgG3 Ab, also passively protected both strains of mice. Most
of these samples contain Ab isotypes that would not be able to protect
mice if their protective effects required Ab-dependent cell-mediated
cytotoxicity. These results establish that, in this infection,
protection is directly mediated by Abs and does not require the
participation of Fc receptors. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Humoral immunity plays an important role in host defense against the erythrocytic stages of human, simian, and rodent malarias (2, 3, 4). IgG isotypes have been implicated as important components of this acquired immunity, since passive transfer of human, monkey, or rodent IgGs can provide significant protection to naive recipients from malarial infection (2, 5, 6, 7, 8, 9). In addition, studies with immunodeficient mice have shown that resolution of infection with the rodent parasite Plasmodium yoelii yoelii requires humoral immunity (4). Transfer of hyperimmune serum (10) or of various mAbs, such as mAb302 (8, 9), can impart passive immunity to mice against a normally lethal challenge with P. y. yoelii. Moreover, mice immunized with a fusion protein (GST-PYC2) encoding the carboxyl region of P. y. yoelii merozoite surface protein-1 (MSP-1)3 also survive parasite challenge (11, 12, 13). Previous studies from our laboratory (13, 14), which have been confirmed by others (15), established that this protection is primarily mediated by Abs.
The mechanisms whereby Abs can transfer protective immunity to malaria are not well understood. Some evidence indicates that the main protective role of Ab is to interfere with the merozoite invasion of RBC (16, 17, 18). Abs have also been found to interfere with intraerythrocytic development of the parasite in in vitro studies (19). In contrast, studies using human immune sera demonstrated that passive protective activity of human immune globulins could not be correlated with inhibition of either penetration or intraerythrocytic development of Plasmodium falciparum parasites. Instead, protective activity was reported to correlate with an in vitro Ab-dependent cellular inhibitory (ADCI) assay involving mononuclear cells. These results suggest that protective IgG isotypes do not function independently but rather through interaction with FcRs found on mononuclear cells (20).
FcRs are surface glycoproteins known to be widely distributed on cells
of the immune system, and, by binding IgG and IgE, to couple humoral
and cellular responses (21). FcRI, found on monocytes/macrophages
and neutrophils, is the high affinity IgG receptor. By binding
monomeric IgG, FcRI mediates Ab-dependent cell-mediated cytotoxicity
(ADCC) and phagocytosis after Ab cross-linking. FcRII and FcRIII
are low affinity IgG receptors, also found on many cells of the immune
system, and are responsible for triggering ADCC, phagocytosis, and the
release of inflammatory mediators when cross-linked by immune
complexes. In mice, FcRI binds IgG2a Abs preferentially, while
FcRII and FcRIII have higher affinities for the IgG1 and IgG2b
isotypes. Mouse IgG3 was reported recently to bind with low affinity to
FcRI on macrophages (22) but may bind to a fourth, independent
IgG3-specific receptor (23, 24).
A subunit of FcRIII and Fc
RI, the -chain, is required for
efficient cell surface expression of these receptors as well as signal
transduction by these FcRs (21, 25). A mouse strain genetically
deficient in the subunit lacks FcRIII and FcRI expression on
NK cells, macrophages, and mast cells (26). Macrophages from these mice
may have diminished expression of FcRI, and IgG2a binding does not
occur through this receptor, indicating a functional requirement for
the subunit. Though not required for ligand binding or surface
expression in transfected fibroblasts, the -chain has been found to
be associated with FcRI in a human cell line, where it may function
as a signal-transducing subunit (27). No evidence to date indicates
that the -chain associates with FcRII, yet in FcR
-chain-deficient mice the contribution of this receptor to
macrophage phagocytic function also is lost (26). Thus, inflammatory
macrophages from these knockout mice were unable to mediate
phagocytosis or ADCC through FcRI, FcRII, or FcRIII (26). To
illuminate the effector mechanisms by which Abs mediate protection
against malaria, we utilized these FcR -deficient mice to determine
whether Abs inhibit parasitemias in mice directly or require FcRs on
host mononuclear cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Six- to eight-week-old male BALB/cByJ mice were purchased from
The Jackson Laboratory (Bar Harbor, ME), and FcR -chain-deficient
mice (BALB/c background, both +/- and -/-) were raised at Taconic
Farms (Germantown, NY) after 12 successive backcrosses to generate
congenic lines. The lethal P. y. yoelii 17XL strain (Py17XL)
was maintained as described previously (11, 13). Challenge infections
were initiated by i.v. injection of 1 x 104
erythrocytes parasitized with the lethal variant, Py17XL. The
course of infection was monitored by microscopic examination of stained
blood films.
Recombinant construct and fusion protein
The recombinant construct and resultant fusion protein were described previously (11). Briefly, the carboxyl-terminal region of the P. y. yoelii 17XL MSP-1 gene was PCR amplified and joined in frame to the 3' end of the Schistosoma japonicum glutathione S-transferase gene (GST) within the pGEX/2T vector. The resultant fusion protein, designated GST-PyC2, was expressed in Escherichia coli and isolated by affinity chromatography. The PyC2 portion of the fusion protein was isolated from GST-PyC2 while bound to glutathione-agarose (Sigma, St. Louis, MO) with thrombin (ICN Biochemicals, Costa Mesa, CA).
Abs and immune sera
To generate polyclonal sera to PyC2 Ag, BALB/cByJ mice were immunized with GST-PyC2 recombinant fusion protein as described previously (11). Briefly, 5-mo-old BALB/c mice were immunized with 75 µg of GST-PyC2 (providing 25 µg of PyC2) administered s.c. in 200 µl (two sites, 100 µl each site) of Ribi adjuvant system (RAS, Ribi Immunochemical Research Laboratories, Hamilton, MT) suspended in PBS. All mice were boosted s.c. with an equivalent dose at 3 wk and i.p. at 6 wk and 9 wk after the first inoculation. Eleven wk after the first inoculation, these immunized animals were exsanguinated, and serum was isolated. Anti-GST-PyC2 serum was also generated by using alum (Imject Alum; Pierce, Rockford, IL) as an adjuvant and administered in three s.c. injections by the schedule described above (using 60 µg of protein per dose, providing 20 µg of PyC2). Py hyperimmune serum (PyHIS) was prepared in BALB/cByJ mice by repeated infection as described previously (28). mAb 302 was used directly from ascites fluid, at a concentration of 1 mg/ml as determined by radial immunodiffusion in agarose. All sera and ascites preparations were stored at -20°C.
ELISA
ELISAs were performed as described (13, 14). Briefly, wells of Maxi-sorb immunoplates (Nunc, Naperville, IL) were coated with PyC2 at 1 µg/ml in carbonate buffer (pH 9.6). Wells were blocked with 0.2% Tween 20 (Sigma) in 25 mM Tris-HCl (pH 8.0)-150 mM NaCl (Tris-buffered saline). Dilutions were made as indicated in 0.1% Tween 20-Tris buffered saline and added to wells in duplicate. For isotype analysis, bound Abs were detected with affinity-purified, biotinylated rabbit anti-mouse (IgG1, IgG2a, IgG2b, IgG3, or IgM) Abs (Zymed Laboratories, South San Francisco, CA), avidin-alkaline phosphatase (Zymed), and p-nitrophenyl phosphate (Sigma 104; Sigma). Isotype-specific reagents were shown to possess minimal cross-reactivity, and their relative concentrations were adjusted to provide equivalent levels of reactivity against mAbs of different isotypes before analysis of sera and ascites fluid. Isotype distribution assays were terminated by addition of 5 M NaOH (50 µl per well) and read at 405 nm using a Bio-Tek (Winooski, VT) instruments EL308 EIA plate reader.
Challenge infection and transfer of immunity with serum and IgG
One day before parasite challenge (day -1), groups of naive
BALB/cByJ (+/+) and FcR -chain knockout (-/-) mice were given 0.5
ml of PyHIS normal mouse serum, mAb 302 ascites fluid, or polyclonal
anti-GST-PyC2 serum by i.p. injection. An equal dose was
administered to all groups on days 0 and +1 relative to challenge
infection. In some experiments, mAb 302 ascites fluid was diluted by
1:6 or 1:64 in PBS, as indicated. Infection control animals were
untreated.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain-deficient
(-/-) mice on a BALB/c genetic background were given 0.5 ml of either
polyclonal anti-GST-PyC2 serum, mAb 302 ascites fluid, or
polyclonal PyHIS by i.p. injection on days -1, 0, and +1 relative to
challenge with Py17XL. As shown in Figure 1
, animals receiving only the parasite
challenge rapidly succumbed to infection, with all animals but one
having greater than 50% parasitemia by day 8 in both wild-type mice
and FcR -chain-deficient mice. One infection control BALB/cByJ mouse
had a delayed onset of parasitemia (the animal became patent on day 6)
but eventually was removed from the study by day 13 due to high
parasitemia. In contrast, mice given PyHIS did not develop patent
parasitemias. Both immunocompetent and knockout mice were completely
protected and showed no parasitemias up to day 18, when the experiment
was terminated (Fig. 1). Those mice given anti-GST-PyC2 serum
clearly demonstrated a delay in the onset of a patent parasitemia and a
protracted period of parasite inhibition, at levels normally seen when
using this sera (13). We have previously shown that mice immunized with
GST alone in RAS at equivalent amounts to that used in GST-PyC2
immunizations were not protected from lethal malarial challenge (11),
and passive transfer of anti-GST sera also did not elicit any
degree of protection (13). Therefore, the protection seen can be
attributed only to the anti-PyC2 specificities. When
anti-GST-PyC2 sera was given to infected animals, both wild-type
and knockout mice developed patent parasitemias by day 6, and there was
no significant difference in the levels of parasitemia at any given
time point between these two strains of mice, except on day 10.
Surviving mice had no detectable parasitemias by day 18 in both groups.
Thus, the effectiveness of the polyclonal anti-GST-PyC2 serum in
mediating protection was equivalent in both BALB/cByJ (+/+) mice and
FcR -chain-deficient (-/-) mice. Finally, mAb 302 (an IgG3
isotype) ascites fluid was also able to inhibit patent parasitemia in
both mouse strains, with no parasites detected in blood films for 18
days after inoculation (Fig. 1). This last result was anticipated,
since IgG3 isotypes may still bind to specific Fc receptors even in the
knockout mice (23, 24). To determine the effects of serum transfer in
-chain heterozygous mice, these mice were also infected with Py17XL
and given anti-GST-PyC2 sera, PyHIS, and mAb 302. FcR
-chain-heterozygous (+/-) mice exhibited the same parasitemia
curves after serum transfer as the (-/-) knockout mice (data not
shown).
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). All
samples were diluted 1:500. Normal mouse serum had no reactivity to
PyC2 Ag (data not shown). mAb 302 is of the IgG3 isotype and so had no
reactivity in ELISA when secondary Abs other than anti-IgG3 were
used. In anti-GST-PyC2 serum, there is a predominance of IgG1,
IgG2a, and IgG2b isotypes, with lesser amounts of IgG3 and IgM (14).
These results contrast with the isotype distribution of PyC2-specific
Abs in P. y. yoelii 17XL hyperimmune serum, which is
predominantly IgG1, IgG2a, and IgG3, with lesser amounts of IgG2b and
IgM, an observation in agreement with earlier assessments of isotype
distribution in these sera (13, 14). In hyperimmune serum, antimalarial
Abs of the IgG2a isotype have previously been found to modulate
parasitemias in mice infected with P. y. yoelii, and
other isotypes do not cause an altered course of infection (10).
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-chain-deficient mice,
though unable to engage in phagocytosis or ADCC through IgG1, IgG2a, or
IgG2b Abs, still may possess a separate IgG3 receptor on
macrophage/monocyte cell lineages (23, 24). We therefore addressed the
possibility that the small amounts of IgG3 Abs present in all of the
polyclonal sera used in this study (Fig. 2
) were responsible for the
passive protection found in knockout mice. Attempts to remove IgG3
isotypes from PyHIS by using anti-IgG3 affinity columns were not
successful, and so we sought other approaches to demonstrate that IgG3
isotypes alone are probably not mediating all of the protection we see
in the various sera used in these studies. If the small fraction of
PyC2-specific IgG3 found in polyclonal anti-GST-PyC2 serum is
indeed responsible for mediating the partial protective effects of this
serum, then mAb 302 should also be able to protect mice partially at
equivalent levels, since mAb 302 is by far the most effective Ab yet
identified in clearing P. y. yoelii 17XL infections in mice.
By diluting mAb 302 ascites fluid in a series of fourfold dilutions
(starting at 1:500 dilution) and comparing OD values of these dilutions
in a PyC2-specific ELISA against polyclonal serum diluted 1:500, it was
determined that mAb 302 had an IgG3 PyC2-specific reactivity 64 times
higher than undiluted polyclonal serum (data not shown). mAb 302 was
then tested for its ability to protect mice passively against lethal
challenge with P. y. yoelii 17XL when diluted 1:6 or 1:64 in
PBS (Fig. 3). Groups of naive BALB/cByJ
mice were given 0.5 ml of either undiluted or diluted mAb 302 ascites
fluids by i.p. injection on days -1, 0, and +1 relative to parasite
challenge with Py17XL. As shown in Figure 3, animals receiving parasite
challenge only or ascites fluid diluted 1:64 succumbed to infection,
with all animals having greater than 50% parasitemia by day 8. In
contrast, those mice given mAb 302 ascites fluid diluted 1:6 clearly
demonstrated a delay in the onset of a patent parasitemia and a
protracted period of parasite inhibition, and undiluted mAb 302 ascites
fluid was able to inhibit patent parasitemia completely, with no
parasites detected in blood films for 20 days after inoculation (Fig. 3). These results demonstrate that, when the highly protective IgG3 mAb
302 is diluted to levels at which it reacts equivalently to PyC2 as
does the IgG3 fraction of polyclonal anti-GST-PyC2 serum, it is no
longer protective. Therefore, the polyclonal IgG3 anti-PyC2 Abs
present in anti-GST-PyC2 sera are unlikely to be solely responsible
for passive protection.
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-chain-deficient mice (-/-) were given 0.5 ml of this
alum-generated polyclonal anti-GST-PyC2 serum or normal mouse serum
by i.p. injection on days -1, 0, and +1 relative to parasite challenge
with Py17XL. As shown in Figure 4,
animals receiving normal mouse sera rapidly succumbed to infection,
with all animals having greater than 50% parasitemia by day 6 in both
BALB/cByJ mice and FcR -chain-deficient mice. In contrast, those
mice given anti-GST-PyC2 serum generated with alum clearly
demonstrated a delay in the onset of a patent parasitemia and a
protracted period of parasite inhibition. Though the levels of
protection seen when using alum-generated sera are quite variable in
each individual mouse (Fig. 4), they are quite significant, since all
mice given alum-generated sera have a delay in parasitemia levels by at
least 1 whole day when compared with infection control animals. When
anti-GST-PyC2 sera was given to infected animals, both wild-type
and knockout mice developed patent parasitemias by day 4, and there was
no significant difference in the levels of parasitemia at any given
time point between these two strains of mice from days 4 to 8. Thus,
the effectiveness of the alum-generated polyclonal anti-GST-PyC2
serum in mediating protection was similar in both BALB/cByJ (+/+) mice
and FcR -chain-deficient (-/-) mice, supporting the interpretation
that IgG3 isotypes are not solely responsible for generating the
protection seen in these studies.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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subunit found in several FcRs
on monocytes/macrophages and other cells of the immune system. These
FcR -chain knockout mice are profoundly immunocompromised and cannot
mediate phagocytosis or ADCC through FcRI, FcRII, or FcRIII
(26). We found no differences in the inhibition of parasitemia by
various protective polyclonal and mAbs in wild-type and FcR -chain
knockout mice, indicating that FcR-mediated phagocytosis and ADCC are
not essential mechanisms in parasite clearance in this model system.
The sera used in these studies showed great variability in isotype
compositions, and though some sera protected against lethal challenge
better than others, equivalent protection was seen in all mice given
similar sera, whether they were immunocompetent mice or knockout mice. We sought to exclude the possible protective role of IgG3 in polyclonal sera in two types of experiments. The first used alum as an adjuvant, a procedure that resulted in the production of predominantly IgG1 Abs. The second approach was to compare the amount of IgG3 Abs in the polyclonal sera with the protective activity of a similar amount of a monoclonal IgG3 (mAb 302). It is possible that polyclonal IgG3s may be of higher affinity or of superior specificity to the mAb 302 and that the small amounts of these isotypes present in polyclonal sera are responsible for all of the protection seen in passive transfers using these sera. However, many efforts have been made by ourselves and others to produce mAbs against this region of the MSP-1 molecule, and most of the Abs generated have no protective activity (data not shown). Thus, superior Abs have not been found by cell fusions. We believe that this comparison is a valid experimental system since, in view of the above, it is highly unlikely that the polyclonal Abs to PyC2 (many of which have no biologic activity at all) are superior to mAb 302 in passive protection.
There may be differences in the mechanisms of Ab-mediated parasite clearance in humans as compared with murine model systems. IgG isolated from the sera of adults immune to P. falciparum has been reported to act cooperatively with monocytes in in vitro parasite growth inhibition assays (20), suggesting that Abs may interact with Fc receptors on phagocytic cells to control parasitemia in vivo. In addition, in malaria-exposed individuals, IgG1 and IgG3, the two cytophilic isotypes in humans, predominate in protected subjects (29). Humans living in malaria endemic areas also have Abs that recognize multiple plasmodial Ags, and these Abs are often of the cytophilic isotypes in individuals with significantly reduced risk of malaria attacks or lower parasitemias and disease sequelae (30, 31, 32, 33, 34, 35, 36). However, these findings are not absolute, since levels of IgG1 have also been found to be higher in nonprotected subjects (37). In addition, other isotypes, such as IgM, have also been implicated in protection against P. falciparum in human subjects (38). In mice, protection against P. y. yoelii does not appear to be isotype specific. Both cytophilic and noncytophilic Abs are able to control parasitemia in this infection (8, 9, 10, 39), so that the isotype of protective Abs is not an important factor in humoral effector function.
In this study, anti-GST-PyC2 sera generated with RAS adjuvant (with
a majority of IgG1, IgG2a, and IgG2b isotypes), alum-generated
anti-GST-PyC2 sera (predominantly IgG1), mAb 302 ascites fluid
(IgG3 isotype), and PyHIS (whose protective capacity is primarily
mediated by IgG2a) (10) all were able to mediate protection against
P. y. yoelii 17XL infections in mice. These protective
effects were not limited to immunocompetent BALB/c mice but also
functioned at equal efficiencies in FcR -chain-deficient animals.
Most of these samples contain Ab isotypes that would not be able to
protect mice if their protective effects required ADCC, since the
knockout mice are unable to perform ADCC with IgG1, IgG2a, and IgG2b
Abs (26). Our data thus indicate that, in this infection, Abs are able
to control parasitemia independently and do not require binding to Fc
receptors. At present, it is not known how these Abs inhibit parasites,
but they may act by blocking merozoite invasion (17) or may inhibit
processing of MSP-1, which may be required for erythrocyte entry (40).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Carole A. Long, Allegheny University of the Health Sciences, Department of Microbiology and Immunology, 2900 Queen Lane, Philadelphia, PA 19129. E-mail address:
3 Abbreviations used in this paper: MSP-1, merozoite surface protein-1; Py17XL, Plasmodium yoelii yoelii 17XL; PyHIS, Plasmodium yoelii yoelii 17XL hyperimmune serum; pRBC, parasitized RBC; GST, glutathione S-transferase of Schistosoma japonicum; RAS, Ribi adjuvant system; ADCC, Ab-dependent cell-mediated cytotoxicity.
Received for publication April 6, 1998. Accepted for publication April 21, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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receptor and the mast cell receptor for IgE share an identical subunit. Nature 341:752.[Medline]
chain deletion results in pleiotrophic effector cell defects. Cell 76:519.[Medline]
RI) with the subunit of the IgE receptor. Proc. Natl. Acad. Sci. USA 90:6023.This article has been cited by other articles:
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), mAb 302 ascites fluid (
), or PyHIS
(
) 1 day before parasite challenge with Py17XL. This dose of serum
was repeated on the 2 subsequent days. Infection control animals were
untreated (
). B, Naive FcR 
), mAb
302 ascites fluid (
), or PyHIS serum (
) 1 day before parasite
challenge with Py17XL. This dose of serum was repeated on the 2
subsequent days. Infection control animals were untreated (•).
n = 4 for PyHIS and mAb 302 groups, and
n = 5 for infection control and polyclonal serum
groups. r = removed, due to high parasitemia. Data shown are the
means ± SE of the percent parasitemia on each day.
