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Evidence for Antigen-Specific Immune Deviation in Patients With Acute Retinal Necrosis
Takeshi Kezuka, MD, PhD;
Jun-ich Sakai, MD, PhD;
Norio Usui, MD, PhD;
J. Wayne Streilein, MD;
Masahiko Usui, MD, PhD
Arch Ophthalmol. 2001;119:1044-1049.
ABSTRACT
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Background Because experimental acute retinal necrosis (ARN) induced by herpes
simplex virus in mice develops only if mice fail to acquire virus-specific
delayed hypersensitivity (DH), although they produce antiviral antibodies
(ie, anterior chamber–associated immune deviation), we sought to determine
whether a similar inverse correlation exists for patients with varicella-zoster
virus (VZV)–induced ARN.
Design Patients with acute, VZV-induced ARN and age-matched control subjects
were skin tested with VZV and purified protein derivative antigens to evaluate
DH. Varicella-zoster virus–induced ARN was diagnosed using polymerase
chain reaction and intraocular antibody quotient. Serum samples were collected
and analyzed for anti-VZV and anti–herpes simplex virus antibody titers.
Acute retinal necrosis activity was assessed clinically, and DH skin tests
were repeated 3 months after onset when ocular recovery had taken place.
Results Whereas controls displayed intense DH when tested with VZV and purified
protein derivative antigens, a subset of patients with ARN displayed absent
VZV-specific DH (although their purified protein derivative responses were
normal). Patients with the most severe ARN had the lowest DH responses to
VZV antigens. Serum anti-VZV antibody titers were higher in patients with
ARN than in controls, and antiviral titer correlated inversely with the intensity
of anti-VZV DH responses. Varicella-zoster virus–specific DH responses
were restored in patients who recovered from ARN.
Conclusion Varicella-zoster virus–ARN develops in a setting where DH reactivity
to viral antigens is absent, implying that virus-specific DH might ameliorate
the severity of ARN.
Clinical Relevance Linking virus-specific DH to vulnerability to ARN in individuals infected
with VZV might reveal an underappreciated pathogenic mechanism.
INTRODUCTION
ACUTE RETINAL necrosis (ARN, Kirisawa-Urayama uveitis) is a destructive
retinal disease in which an acute and rapidly progressing retinal inflammation
leads to severe impairment of vision within days of onset.1-4
The clinical expression of this disease is usually limited to the eye, and
the clinical features within the affected eye include acute peripheral necrotizing
retinitis, retinal arteritis, vitritis, and panuveitis. As the inflammatory
disease progresses it can promote retinal detachment that causes further visual
deterioration.5 It is generally believed that
ARN arises in the setting of an ocular infection with a member of the family
of herpes viridae, such as varicella-zoster virus (VZV) or herpes simplex
virus (HSV),6-8
but the precise pathogenesis of the retinal necrosis is still in doubt.
A similar intraocular inflammatory process that leads to ARN has been
produced in laboratory animals.9-20
In this animal model system, the pathogenesis of ARN is linked to a deviant
systemic immune response to the virus. To determine whether a similar circumstance
might occur in humans with ARN, we studied the immune responses of a group
of patients with acute disease in which reactivated VZV was found in the affected
eye. Our results indicate that a high proportion of patients with ARN associated
with VZV displayed a transient loss of virus-specific delayed hypersensitivity
(DH), but their serum samples contained high titers of anti-VZV antibodies.
On resolution of the intraocular inflammation, virus-specific DH recurred
in most of these individuals.
PATIENTS AND METHODS
PATIENTS
Twenty-three patients with ARN (mean ± SD age, 50.4 ±
8.8 years) were selected from the uveitis clinic population of the Department
of Ophthalmology, Tokyo Medical University Hospital, Tokyo, Japan, from 1989
to 1999. Thirteen healthy persons, 12 patients with noninfectious uveitis
(without sarcoidosis), and 7 patients with VZV infection of the skin who displayed
no uveitis were also selected as control subjects.
SAMPLES
Aqueous humor and serum samples from patients with ARN were collected
at the first visit to our office. Vitreous samples from patients with ARN
were collected at the time of vitrectomy. Informed consent was obtained from
each patient before skin test assay and collection of blood.
POLYMERASE CHAIN REACTION
For the diagnosis of ARN, polymerase chain reaction (PCR) methods were
performed using the technique described by Saiki et al21
and Usui et al.22 In brief, a 25-µL aliquot
of each sample was mixed with 25 µL of detergent buffer (potassium chloride,
50 mmol/L; Tris hydrochloride, 10 mmol/L [pH 8.3]; magnesium chloride, 1.5
mmol/L; gelatin, 0.1 mg/mL; 0.45% NP40; 0.45% Tween 20; and proteinase K,
0.06 mg/mL). Each sample was incubated at 60°C for 60 minutes and then
reincubated at 95°C for 10 minutes to inactive proteinase K. Fifty microliters
of PCR mixture was added to the samples after the incubations (final concentration:
potassium chloride, 50 mmol/L; Tris hydrochloride, 10 mmol/L [pH 8.3]; magnesium
chloride, 1.5 mmol/L; gelatin, 0.1 mg/mL; 0.2 µmol/L of the primer;
200 µmol/L of deoxynucleotriphosphates; and 2.5 U of Taq polymerase).
Target sequence of the primer used in the PCR mixture was DNA segment from
VZV (EcoRI D fragment, primer: 5'-TTCAGCCAACGTGCCAATAAA-3'
and 5'-GACGCGCTTAACGGAAGTAAC-3'). Amplification was performed
as follows: 1 minute at 94°C for denaturation, 2 minutes at 55°C for
annealing, and 2 minutes at 72°C for extension. Thirty-five cycles were
performed, and the 72°C step was extended to 6 minutes in the final cycle.
The PCR products were visualized with UV light as a single band by staining
with ethidium bromide after agarose gel electrophoresis (2.5% NuSieve/Seakem
agarose gel).
ASSAY OF ANTI-VZV ANTIBODY TITERS IN SERA AND INTRAOCULAR FLUIDS
For help with the diagnosis of ARN, viral antibody titers of intraocular
fluid (IOF) (aqueous humor and vitreous fluid) and serum samples were determined
by the fluorescent antibody technique. Paired IOF and serum samples were tested
at the same time. The antibody quotient was calculated from the total IgG
levels in IOF and serum samples as follows: antibody quotient = (VZV-specific
IgG titers in IOF/total IgG levels in IOF)/(VZV-IgG titers in sera/total IgG
levels in sera). A coefficient of 6 or greater is considered diagnostic.
SKIN TEST ASSAY OF DH
At their first visit to the clinic, and before systemic corticosteroid
therapy was instituted, 23 patients with acute, VZV-induced ARN and, as controls,
13 age-matched healthy subjects and 7 age-matched patients with VZV infection
of the skin who displayed no uveitis were skin tested with 0.1 mL of VZV (Tanabe
Co, Osaka, Japan)23-25
and purified protein derivative (PPD) (Takeda Co, Osaka) antigens to evaluate
DH for 24 and 48 hours at the first visit to our office. We used varicella
virus of Kawaguchi strain for the preparation of skin antigen. The test antigen
preparation includes VZV glycoproteins (gp 3 and gp 5) (80-100 µg/mL).
We used PPD tuberculin, 0.5 µg/mL, as the positive control antigen for
skin tests. Positive responses were characterized by cutaneous erythema at
the injection sites that measured (1) greater than 5 mm in diameter at 24
and 48 hours for VZV antigen23-25
and (2) greater than 10 mm in diameter at 48 hours for PPD antigen. In some
patients, the VZV skin test was repeated 3 months after the initial onset
of intraocular disease.
CLINICAL EVALUATION OF ARN
At the first visit to the clinic, patients with ARN were divided into
severe and mild groups. In the severe group, the affected eyes displayed advanced
damage to the vascular arcade of the retina. In the mild group, the affected
eye displayed damage that was only observable in the peripheral retina (Table 1).
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Table 1. Criteria for Severity of VZV-ARN*
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STATISTICAL EVALUATIONS
Differences between groups to be compared were analyzed using the Mann-Whitney
test; P<.05 was considered statistically significant.
RESULTS
DESCRIPTION OF PATIENTS WITH ARN ASSOCIATED WITH INTRAOCULAR VZV
Twenty-three patients, selected from a uveitis clinical population,
participated in this study. These patients were diagnosed as having ARN, with
11 categorized as severe and 12 as mild. Based on history, these patients
came to the clinic within 7 to 14 days of the onset of ocular disease. Serum,
aqueous humor, and vitreous fluid (removed at the time of vitrectomy) samples
were collected during the acute phase of the disease. The formal diagnosis
of ARN associated with VZV was established by PCR analysis of the ocular samples.
Results from 4 typical patients with a clinical diagnosis of ARN are displayed
in Figure 1. Varicella-zoster virus
sequences were detected in all 4 aqueous humor samples, and similar sequences
were detected in 3 of 4 vitreous samples. Aqueous humor and vitreous samples
from other patients with ARN in which VZV sequences were not detected were
excluded from the present study. Varicella-zoster virus sequences were never
detected in aqueous humor or vitreous samples from patients with other types
of posterior uveitis (data not shown).
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Figure 1. Detection of varicella-zoster
virus gene sequences by polymerase chain reaction. The typical amplified products
of polymerase chain reaction from aqueous humor and vitreous humor are separated
in a 2.5% agarose gel and visualized by ethidium bromide staining. Lanes 1
to 4 are products from varicella-zoster virus genomes. N indicates negative
control; P, positive control; and bp, base pair.
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In addition to virologic studies, ocular fluids and serum samples were
assayed for content of total IgG and titers of anti-VZV antibodies. An antibody
quotient was calculated as the quotient of VZV-specific IgG/total IgG in ocular
fluids divided by VZV-specific IgG/total IgG in serum. The mean ± SD
antibody quotient for patients with ARN who have VZV sequences in ocular fluids
was 56.2 ± 28.8 mg/dL. A coefficient greater than 6 is believed to
reflect intraocular antibody formation and is considered diagnostic for local
virus infection. Subsequently, all studies were performed in patients with
VZV-ARN, defined as having VZV sequences and a significant anti-VZV IgG quotient
in ocular fluids.
VZV-SPECIFIC DH IN PATIENTS WITH ARN
For the possible relationship between cell-mediated immune response
to VZV and VZV-ARN, we skin tested patients with VZV-ARN and controls with
VZV antigen. Varicella-zoster virus antigen was injected intradermally into
the skin of the forearm. The erythema response at the injection site was measured
at 24 and 48 hours. The results of this study are presented in Table 2. There was no significant difference between 24- and 48-hour
erythema responses in any of the subjects. As anticipated, all control subjects
displayed a positive VZV skin test response. By contrast, less than 50% of
patients with VZV-ARN displayed a positive VZV skin test response. This difference
is highly significant (P<.001). Two (9%) of 23
patients with ARN had bilateral disease, and both displayed negative VZV skin
test and positive PPD skin test responses (data not shown). Thus, at least
with respect to VZV-specific DH, patients with VZV-ARN can be classified into
2 groups: one contains patients with a positive VZV skin test response and
the other contains those with a negative VZV skin test response.
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Table 2. DH Responses Elicited by VZV Antigen in Patients With VZV-ARN*
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TUBERCULIN-SPECIFIC DH IN PATIENTS WITH ARN
The absence of VZV-specific DH in the second group of patients with
VZV-ARN can be explained in 2 ways. First, some patients with VZV-ARN might
lack the ability to display DH to any antigen. Second, some patients with
VZV-ARN might have a selective deficit in DH directed at VZV antigens but
not to other antigens. To distinguish between these 2 possibilities, each
patient was also skin tested with PPD, an antigen derived from the tubercle
bacillus. In Japan, vaccination with bacille Calmette-Guérin is common,
and as a consequence a high proportion of healthy individuals possess DH directed
at PPD. The results of this study of PPD reactivity for patients with VZV-ARN
are presented in Table 3. Seventy-eight
percent of patients with VZV-ARN displayed positive PPD skin test responses.
This proportion of PPD-positive subjects is similar to, albeit slightly lower
than, that observed in the healthy population (approximately 95% are PPD positive).
Among patients with VZV-ARN who had a positive skin test response to VZV antigens,
8 of 9 displayed reactivity to PPD. Similarly, among patients with VZV-ARN
who had no response to VZV antigens, 10 of 14 displayed reactivity to PPD.
The proportion of PPD-positive to PPD-negative patients in DH+ (positive DH
to VZV antigens) is statistically indistinguishable from the proportion of
PPD-positive to PPD-negative patients in DH– (negative DH to VZV antigens)
(P = .045). Taken together, these results indicate
that a group of patients with VZV-ARN has a selective deficit of the capacity
to mount DH to VZV antigens, not a global, nonspecific inability to display
DH reactivity.
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Table 3. DH Responses Elicited by PPD in 23 Patients With VZV-ARN*
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COMPARISON OF VIRUS-SPECIFIC DH AND ANTIBODY RESPONSES OF PATIENTS
WITH VZV-ARN
Serum samples collected from patients with VZV-ARN were analyzed semiquantitatively
using a fluorescent antibody technique for the titer of anti-VZV antibodies.
Serum samples collected from patients with noninfectious uveitis (excluding
sarcoid) were similarly analyzed. The VZV-specific DH and antibody titer results
of each patient are presented in Table 4. Anti-VZV serum antibody titers of patients with VZV-ARN in DH–
(DH-negative group) were significantly higher than those in patients with
VZV-ARN in DH+ (DH-positive group) (P = .03). Moreover,
anti-VZV antibody titers in serum samples from both groups of patients with
VZV-ARN were higher than those in noninfectious uveitis controls (P = .007). We also measured the anti-HSV serum antibody titer of patients
with VZV-ARN. The results were comparable for patients who were between DH–
and DH+ (data not shown). These results indicate, first, that VZV-ARN is associated
with an elevation of serum anti-VZV antibody titers and, second, that the
magnitude of the antibody response is inversely proportional to the ability
of the patient with VZV-ARN to display VZV-specific DH.
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Table 4. Comparison of VZV-Specific Cell-Mediated and Serum Antibody
Responses in Patients With VZV-ARN*
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COMPARISON OF VIRUS-SPECIFIC DH AND CLINICAL SEVERITY OF VZV-ARN
In the mouse model of ARN, DH to virus-specific antigens is inversely
proportional to the severity of ARN. As displayed in Table 5, we compared the clinical severity of VZV-ARN with the presence
or absence of virus-specific DH. Most patients with DH reactivity to VZV antigens
displayed mild VZV-ARN. By contrast, most patients who lacked VZV-specific
DH displayed severe ARN (P = .053). These results
provide circumstantial evidence to support the contention that the presence
of DH directed at VZV antigens protects against the development of severe
ARN.
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Table 5. Comparison of Severity of VZV-ARN and VZV-Specific DH in 23
Patients With VZV-ARN*
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DETECTION OF VZV-SPECIFIC DH IN PATIENTS WITH VZV-ARN DURING RECOVERY
In our clinical experience, ARN generally runs its course within 3 months
of onset of the disease. Eleven patients with VZV-ARN and a negative VZV-specific
DH response at 1 week were skin tested again with VZV antigens 3 months after
disease onset. Clinical examination of the affected eyes at this time revealed
little evidence of ongoing inflammation. Two patients with VZV-ARN whose DH
reactivity was positive during acute disease were also tested at 3 months.
The recovery phase results are presented in Figure 2 in comparison with DH results obtained at 1 week (during
acute disease). With one exception, all of the subjects displayed positive
skin test responses to VZV antigens (P<.001).
These results suggest that the absence of virus-specific DH during acute ocular
inflammation in a group of patients with VZV-ARN is transient.
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Figure 2. Detection of varicella-zoster
virus (VZV)–specific delayed hypersensitivity in patients with VZV–acute
retinal necrosis (ARN) after resolution. Patients with VZV-ARN, first skin
tested with VZV antigens during the first week of their disease, were skin
tested again after 3 months. The proportion of patients with positive skin
test responses at 3 months is higher than the proportion with positive test
responses at 1 week (P<.001).
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COMMENT
Although the precise pathogenesis of ARN is incompletely understood,
there is convincing evidence that active replication by a herpes virus in
the affected eye (especially in the retina) is an essential element. Because
ARN typically occurs in individuals usually considered to be immune competent,4 it is fair to question the role of the immune system
in protecting against this disease. Rochat et al26
performed DH skin tests to 7 common antigens (Candida,
diphtheria, PPD, Proteus, Streptococcus, tetanus
toxoid, and Trichophyton) in 9 patients with the
clinical diagnosis of ARN. They reported that 4 of 9 patients were "anergic,"
ie, lacked positive skin test responses to any of the test antigens. In addition,
flow cytometric analysis of peripheral blood leukocytes revealed an excessively
high number of B lymphocytes. These results led the authors to suggest that
a non–antigen-specific imbalance of the systemic immune system (impaired
cellular immunity with intact humoral immunity) might be involved in ARN pathogenesis.
Our study addressed these same points, but our results led us to a somewhat
different conclusion. Although we skin tested our subjects with only one nonviral
antigen (PPD) as a test of their global immune competence, the high incidence
of positive DH to PPD in our patients with VZV-ARN indicated that as a group
they were not anergic and that their systemic immune response seemed to be
intact. Instead, our findings point to a virus antigen-specific aberration
in the immune response of at least some patients with VZV-ARN.
We skin tested our patients with ARN shortly after the clinical diagnosis
was made and before corticosteroid therapy was initiated. It is pertinent
that most of the Japanese population acquires positive DH responses to VZV
antigens by age 12 years. The timing of skin tests with respect to the clinical
stage of ARN and the presence or absence of corticosteroid treatment were
not described in the study by Rochat et al.26
Almost all of our patients with ARN who initially had a negative VZV skin
test response reacquired this reactivity after 3 months. This indicates that
the ability of such patients to display DH is volatile and that a negative
response at one time might change to positive through time. Therefore, one
explanation for the difference between our findings and those of Rochat et
al might reside in the timing of skin tests and treatment with corticosteroids.
Nonetheless, we found no evidence of significant impairment of DH directed
at a nonviral antigen (PPD) at the time of disease onset or thereafter. Based
on our results, we conclude that the loss of DH in patients with VZV-ARN is
restricted to VZV antigens.
The virus-specific immune features of some of our patients with VZV-ARN
closely resemble those of BALB/c mice that develop ARN after injection of
HSV-1 into the anterior chamber of the fellow eye.14-15,17, 27-28
The systemic deficit in DH was limited to VZV antigens (not PPD). In mice
with ARN, only DH to HSV antigens is impaired. Absence of VZV-specific DH
correlated with a very high serum titer of anti-VZV antibodies. In mice with
HSV-induced ARN, high titers of anti-HSV antibodies are found in the serum.
But VZV-ARN in humans and HSV-ARN in mice are not identical. For example,
patients with VZV-ARN who lack DH during acute disease reacquire virus-specific
DH as the disease resolves. By contrast, mice with HSV-ARN continue to lack
virus-specific DH for at least 7 weeks after the disease subsides.10-17
More important, mice that acquire virus-specific DH after anterior chamber
injection of HSV-1 never develop ARN in the contralateral eye,16
whereas a significant proportion of our patients with acute VZV-ARN displayed
strong VZV-specific DH. The similarities and differences between human and
mouse ARN probably mean that the mouse disease is an imperfect model system
for the human disease. In addition, the differences in DH reactivity and anti-VZV
antibody titers observed in our patients with VZV-ARN might reflect heterogeneity
in the pathogenesis of human ARN.
The mouse model system of ARN most closely resembles the patients with
VZV-ARN we assigned to DH–: absence of DH, high titers of serum anti-VZV
antibodies. From what has been learned about the immune contribution to ARN
in mice, we can speculate on the role of the immune system in the pathogenesis
of this form of VZV-ARN in humans. Absence of the virus-specific CD4+ T cells that mediate DH robs the individual of the ability to prevent
immunologically the spread of virus within the nervous system from the site
of entry. Moreover, this unique pathway of viral migration has been linked
to the type of antiviral immune response generated in recipient mice. BALB/c
mice that receive an anterior chamber injection of HSV-1 (KOS strain) acquire
an unusual systemic immune response, termed anterior chamber–associated
immune deviation (ACAID).14-19
In this response, there is, on the one hand, a selective impairment of virus
antigen-specific DH, whereas, on the other hand, there is a high serum titer
of anti-HSV antibodies. Circumstantial evidence suggests that the lack of
virus-specific DH in these mice is permissive to the spread of virus from
the injected to the uninjected eye.15 In the
case in which HSV-1 is injected into the anterior chamber of one eye of a
mouse, viral progeny traverse the central nervous system and reach the contralateral
optic pathways.20 Within 7 days of anterior
chamber injection, large numbers of viral progeny descend via the optic nerve
into the contralateral eye and trigger acute necrosis of the retina. The affected
retina becomes heavily infiltrated with polymorphonuclear neutrophils and
mononuclear cells. Because this pattern only occurs in immunologically competent
mice, the pathogenesis is believed to involve virus-specific immune effector
mechanisms. Mice with ARN acquire virus-specific antibodies and CD8+ cytotoxic T cells, and either or both of these effectors could cause
the destruction of the virus-infected retina. If this proposed pathogenic
mechanism is operative in VZV-ARN, a way to prevent or halt the disease from
further progression might be to confer virus-specific DH reactivity on the
affected patient. Experiments to test this possibility have not yet been tried
in the mouse model system.
Because the incidence of positive skin tests to VZV antigens is so high
in the healthy population of Japan, the change observed in VZV DH reactivity
in one group of patients with VZV-ARN warrants comment. Of subjects who initially
had ARN and no VZV-specific DH, almost all displayed VZV DH when tested 3
months later, as their ocular disease resolved. This interesting result must
be considered in the context of studies of ACAID in mice. Kosiewicz et al29 reported that DH to an antigen could be suppressed
in sensitized mice if the same antigen is injected into the anterior chamber
of the eye. That is, ACAID can be imposed on an already established state
of specific immunity. Evidence indicates that most Japanese people possess
DH directed at VZV, including individuals destined to develop VZV-ARN. Reasoning
from the mouse experiments, we propose that idiopathic reactivation of VZV
in the anterior segment of one eye of such individuals might promote suppression
of DH, thereby eliminating the virus-specific CD4+ T cells that
are required to prevent neural spread of the virus from the site of reactivation.
Acute retinal necrosis in the contralateral eye might be the inevitable consequence.
As active virus is cleared from both eyes through time, the antigenic stimulus
to ACAID is removed, and VZV-specific DH can reemerge, as observed in our
patients.
Anterior chamber–associated immune deviation has been widely studied
in mice, rats, guinea pigs, and rabbits, implying that it is not a phenomenon
restricted to laboratory rodents.30-33
Eichhorn et al34 reported in 1993 that ACAID
was induced in adult cynomolgus monkeys by intraocular injection of ovalbumin.
This finding demonstrates the principle that ACAID can occur in primates.
We believe that the results reported herein provide the first evidence compatible
with the existence of an ACAID mechanism in humans. Our evidence, like that
of Eichhorn et al, is circumstantial. Experimental proof of the existence
of ACAID is possible to obtain in laboratory animals but not in humans because
the definitive experiments involve the transfer of regulatory T cells from
one individual to another.
AUTHOR INFORMATION
Accepted for publication February 1, 2001.
We thank Toshihiro Ichikawa, MD, PhD, and Gakushi Matsuura, MD, PhD,
(Tokyo Medical University) for valuable advice and Hiroshi Minoda, MD, PhD,
(Tokyo Medical University) for expert assistance with PCR.
Corresponding author and reprints: Takeshi Kezuka, MD, PhD, Department
of Ophthalmology, Tokyo Medical University, 6-7-1, Nishishinjuku, Shinjuku-ku,
Tokyo 160-0023, Japan (e-mail: tkezuka{at}tokyo-med.ac.jp).
From the Department of Ophthalmology, Tokyo Medical University, Tokyo,
Japan (Drs Kezuka, Sakai, N. Usui, and M. Usui); and Schepens Eye Research
Institute and the Department of Ophthalmology, Harvard Medical School, Boston,
Mass (Dr Streilein).
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