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A Relationship Between Varicella-Zoster Virus–Specific Delayed Hypersensitivity and Varicella-Zoster Virus–Induced Anterior Uveitis
Takeshi Kezuka, MD, PhD;
Jun-ichi Sakai, MD, PhD;
Hiroshi Minoda, MD, PhD;
Masaru Takeuchi, MD, PhD;
Hiroshi Keino, MD, PhD;
J. Wayne Streilein, MD;
Masahiko Usui, MD, PhD
Arch Ophthalmol. 2002;120:1183-1188.
ABSTRACT
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Background We recently reported that acute retinal necrosis in humans develops
in a setting where delayed hypersensitivity (DH) to the varicella-zoster virus
(VZV) antigen was absent, implying that virus-specific DH mitigates against
acute retinal necrosis.
Objective To determine whether a similar correlation exists for patients with
anterior uveitis caused by VZV.
Design Using VZV and purified protein derivative (PPD) antigens to evaluate
DH, we skin tested patients with acute, VZV-induced anterior uveitis (herpes
zoster ophthalmicus [ZO-AU]) (n = 12), those with uveitis caused by VZV in
the absence of dermatitis (zoster sine herpete [ZSH-AU]) (n = 3), and age-matched
patients whose ophthalmic herpes zoster was unassociated with uveitis as controls
(n = 7). Varicella-zoster virus–induced anterior uveitis was diagnosed
by polymerase chain reaction methods and serum antibody titration. Serum samples
were collected and analyzed for anti-VZV antibody titers. Anterior uveitis
activity was assessed clinically. Delayed hypersensitivity skin tests were
repeated in patients with zoster sine herpete 3 months after onset, when ocular
recovery had taken place.
Results All patients with VZV-induced skin disease alone (control group) displayed
intense DH when tested with VZV and PPD antigens. By contrast, only 4 (33%)
of 12 patients with ZO-AU had a positive DH to VZV, whereas 11 (91.6%) of
these patients displayed positive PPD skin reactions. The clinical intensity
of anterior uveitis correlated negatively with VZV DH responses (P<.05).
Serum anti-VZV and anti–herpes simplex virus antibody titers were comparable
in DH-positive VZV cases and in DH-negative patients with uveitis. Patients
with uveitis and ZSH-AU also displayed absent VZV-specific DH, although their
PPD responses were normal.
Main Outcome Measures Varicella-zoster virus–specific DH, PPD-specific DH, VZV-specific
antibody titration, and intraocular pressure in patients with ZO-AU.
Conclusions Absence (or loss) of DH reactivity to VZV antigens seems to be a concomitant
feature of VZV uveitis of high intensity, implying that virus-specific DH
may interfere with the emergence of VZV-induced anterior uveitis, as it does
for acute retinal necrosis.
Clinical Relevance In a clinical setting, absence of virus-specific DH to anterior uveitis
caused by VZV may not only reveal a possible pathogenic mechanism, but a negative
DH response may prove useful in diagnosing ZSH-AU in the acute stage.
INTRODUCTION
OUR LABORATORY and clinical group has been interested in probing the
possible relationships between reactivated varicella-zoster virus (VZV) infection,
delayed hypersensitivity (DH) to VZV antigens, and the presence of VZV-related
eye diseases. Previously, we showed in a group of patients with acute ocular
inflammation secondary to reactivated VZV infection,1
that a high proportion of patients with VZV-induced acute retinal necrosis
displayed a transient loss of virus-specific DH, while their serum samples
contained high titers of anti-VZV antibodies. Upon resolution of the intraocular
inflammation, virus-specific DH was once again detectable in most of these
individuals.
Varicella-zoster virus infections display a bimodal age distribution.
Children may contract the virus through inhaled viral particles, which results
in a generalized vesicular rash (chickenpox). The virus may then reside dormant
in sensory nerve ganglia for many years. A second peak in the distribution
of infection occurs in the elderly. This may represent a reactivation of the
virus in the setting of declining cellular immunity.2
The ophthalmic division is the most frequently affected branch of the trigeminal
nerve,3 and when VZV in this branch is reactivated,
it can affect various ocular tissues, causing blepharitis, conjunctivitis,
scleritis, keratitis, anterior uveitis, vitritis, and retinitis.
Recovering virus from aqueous humor aids in making the diagnosis of
isolated herpetic iridocyclitis,4 and almost
invariably, the uveitis is on the same side as the affected trigeminal branch.
Uveitis caused by VZV is an extremely common manifestation of recurrent disease.
In some cases, virus particles have been found in the anterior chamber and
may contribute to the uveitis.5 However, the
exact cause of the iridocyclitis is not known, and both viral toxic and immunopathogenic
mechanisms have been considered. In the current study, we report that the
clinical intensity of anterior uveitis caused by VZV correlated negatively
with VZV DH responses, and this correlation reached statistical significance.
Therefore, impaired VZV DH reactivity in patients with high-intensity VZV-induced
uveitis suggests that the emergence of VZV-induced uveitis during acute VZV
reactivation may be dependent on the attenuation of DH reactivity to VZV.
A similar inverse correlation exists between VZV-induced acute retinal necrosis
and virus-specific DH.
PATIENTS AND METHODS
PATIENTS
Twelve patients with acute anterior uveitis with VZV-induced facial
skin disease (herpes zoster ophthalmicus [ZO-AU] group; mean ± SD age:
49.6 ± 18.2 years) were selected from the patient population with uveitis
at the Department of Ophthalmology, Tokyo Medical University Hospital from
1999 to 2001. Three patients with acute anterior uveitis caused by VZV without
VZV-induced facial skin disease (zoster sine herpete [ZSH-AU] group) were
also selected. Seven age-matched patients with VZV-infection of the facial
skin who displayed no uveitis (ophthalmic herpes zoster without uveitis group)
were chosen as VZV-infected controls. In addition, 6 patients with Vogt-Koyanagi-Harada
disease or HLA-B27–positive acute anterior uveitis were selected as
noninfected controls.
SAMPLES
All cases of serum samples and some cases of aqueous humor in patients
with anterior uveitis with VZV-like facial skin disease were collected at
the first visit to the clinic. Similar samples were collected from patients
with anterior uveitis without facial skin disease as a means to determine
the presence of VZV infection. Informed consent was obtained from each patient
before skin test assays were performed.
POLYMERASE CHAIN REACTION
For the diagnosis of anterior uveitis caused by VZV, polymerase chain
reaction (PCR) methods were performed by the technique described by Saiki
et al,6 Usui et al,7
and Kezuka et al.1
ASSAY OF ANTI-VZV ANTIBODY TITERS IN SERUM SAMPLES
For help with the diagnosis of anterior uveitis caused by VZV, viral
antibody titers of serum samples were determined by the fluorescent antibody
technique.
SKIN TEST ASSAY OF DH
At their first visit to the clinic, and before systemic steroid therapy
and an antiviral agent regimen were instituted, 14 patients with ZO-AU and
ZSH-AU, as controls, 8 age-matched patients with VZV infection of the facial
skin who displayed no uveitis, and 5 patients with Vogt-Koyanagi-Harada disease
or HLA-B27–positive acute anterior uveitis, were skin tested with 0.1
mL of VZV antigen (Tanabe Co, Osaka, Japan)8
and purified protein derivative (PPD) (Takeda Co, Osaka) antigens. Delayed
hypersensitivity reactions were evaluated 24 and 48 hours after the first
visit to the clinic. Skin tests were performed using the technique described
by Kezuka et al.1 In detail, 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), an antigen derived from the tubercle
bacillus, as the positive control antigen for skin tests. Positive responses
were characterized by cutaneous erythema at the injection sites, measuring
greater than 5 mm in diameter at 24 hours and 48 hours for VZV antigen8; and 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 ANTERIOR UVEITIS CAUSED BY VZV
At the first visit to the clinic, all patients with anterior uveitis
caused by VZV were divided into a "2+" (ie, severe) group and a "1+" (ie,
mild) group. The severity of disease in these patients proved to be greatest
on the day of their initial clinic visit, which typically occurred a few days
(or less) after the onset of disease. The observers were 2 of us (T.K. and
J.S.), who each time evaluated anterior chamber cells and flare using the
modified grading system described by Hogan et al.9
In fact, Hogan and colleagues proposed the grading system of evaluation of
uveitis that used an approximately 1 x 1-mm slit beam. They graded anterior
chamber cells and flare on a scale of 0 to 4+. We modified their system as
follows: 1+ indicates "mild uveitis" (equivalent to their grades 1+ and 2+)
and 2+ indicates "severe uveitis" (equivalent to their grades 3+ and 4+).
In specific detail, using a 1 x 1-mm slit beam, we considered 1+ as
"mild uveitis," with 5 to 20 cells in the anterior chamber, moderate anterior
chamber flare (iris and lens images are clear), and no large keratic precipitates;
we considered 2+ as "severe uveitis," with 20 cells in the anterior chamber,
marked flare (iris and lens images are hazy) in the anterior chamber, and
large keratic precipitates on the corneal endothelium. No patients had received
topical treatment prior to their first visit to our clinic, and treatment
with topical corticosteroids was administered after the first medical examination.
No patients had a history of corticosteroid-induced elevation of intraocular
pressure (IOP). Within 2 weeks after the first visit, the IOP of patients
with VZV-induced acute anterior uveitis was measured. Intraocular pressure
values in excess of 21 mm Hg were considered diagnostic of secondary glaucoma.
Differences between groups to be compared were analyzed by Mann-Whitney U test; P<.05 was considered
to be significant.
RESULTS
CHARACTERISTICS OF PATIENTS WITH VZV-AU AND THEIR CONTROLS
Fourteen patients selected from a clinical population with uveitis were
selected for study (Table 1).
These patients were diagnosed with uveitis caused by VZV and included patients
from the ZSH group. Within this group, the uveitis of 8 patients was categorized
as severe, while that of 4 others was categorized as mild. Based on history,
these patients first visited the clinic within 2 to 37 days after the onset
of skin disease, except for those in the ZSH-AU group. Serum samples were
collected during the acute phase of the disease. The formal diagnosis of VZV-AU
was established by the titer of anti-VZV antibody, and in cases of patients
with ZSH, the diagnosis was established by PCR analysis using the aqueous
humor (data not presented).
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Table 1. Patients With VZV-Induced Uveitis*
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VZV-SPECIFIC DH IN PATIENTS WITH ZO-AU
To investigate the relationship between cell-mediated immune responses
to the VZV antigen and the presence of ZO-AU, we performed skin testing for
patients with VZV-AU and ophthalmic herpes zoster without uveitis with VZV
antigens. The results of this study are presented in Table 2. There was no significant difference between 24-hour and
48-hour erythema responses in any of the subjects. All 7 patients in the control
group displayed intense DH when tested with VZV antigen. By contrast, only
1 (12.5%) of 8 patients with severe ZO-AU displayed a positive VZV skin test.
Moreover, 3 (75.0%) of 4 patients with mild ZO-AU displayed a positive VZV
skin test. The clinical intensity of anterior uveitis correlated negatively
with VZV DH responses (P<.05), and the difference
between DH responses in patients with ZO-AU as compared with patients with
ophthalmic herpes zoster without uveitis is statistically significant (P<.001). Thus, patients with ZO-AU have a very high
probability of displaying no virus-specific DH at the time of diagnosis, unlike
in VZV-infected patients without uveitis, whose DH to VZV antigens is uniformly
intense.
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Table 2. Delayed Hypersensitivity Responses Elicited by the VZV Antigen
in Patients With ZO-AU*
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COMPARISON OF DH TO VZV AND PPD IN PATIENTS WITH
ZO-AU
The impaired DH to VZV antigens demonstrated above can be explained
in 2 ways. (1) Patients with ZO-AU suffer from a global loss of DH reactivity
to many (or all) antigens; and (2) patients with ZO-AU suffer from a selective
loss of DH reactivity to VZV viral antigens, but not to other antigens. To
discriminate between these possibilities, each patient was also skin tested
with PPD, an antigenic preparation derived from the tubercle bacillus that
is not cross-reactive with VZV antigens. As described previously, vaccination
with BCG is very common in Japan, and as a consequence, a high proportion
of normal individuals possesses DH directed at PPD (approximately 95% are
PPD positive). Thus, 95% of our patients, irrespective of diagnosis, should
be PPD positive. The results of PPD skin tests among our patients with ZO-AU
are presented in Table 1 and Table 3. All 7 patients with VZV-induced
skin disease alone (controls) displayed intense DH when tested with the PPD
antigen. Similarly, 11 (91.6%) of 12 patients with uveitis displayed positive
PPD skin test reactions. These results indicate that patients with ZO-AU possess
DH toward PPD at the same frequency as controls. Thus, the impaired DH to
VZV antigens observed in patients with both mild and severe ZO-AU seems to
be selective and limited to the antigens derived from VZV.
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Table 3. Delayed Hypersensitivity Responses Elicited by PPD in Patients
With ZO-AU*
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COMPARISON OF VIRUS-SPECIFIC CELLULAR AND HUMORAL IMMUNE RESPONSES
IN PATIENTS WITH ZO-AU
Acute retinal necrosis caused by VZV correlates positively with an elevation
of serum anti-VZV antibody titers. We have previously reported that the magnitude
of the anti-VZV antibody response in these patients is inversely proportional
to their ability to display VZV-specific DH.1
We wondered if patients with ZO-AU with impaired VZV-specific DH might resemble
patients with acute retinal necrosis in this manner. We analyzed the titers
of anti-VZV and anti–herpes simplex virus antibodies in serum samples
from patients with ZO-AU using a fluorescent antibody technique. Serum samples
collected from patients with VZV skin disease without uveitis served as controls.
As the data presented in Table 1
and Table 4 reveal, anti-VZV and
anti–herpes simplex virus serum antibody titers were comparable in DH-positive
and DH-negative patients with ZO-AU. This result indicates that ZO-AU is associated
with elevated serum anti-VZV antibody titers, and that the magnitude of the
antibody titer is not related to the ability of these patients to display
VZV-specific DH.
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Table 4. Comparison of VZV-Specific DH and Serum-Antibody Responses
in Patients With ZO-AU*
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COMPARISON OF IOP ELEVATION IN PATIENTS WITH ZO-AU
The results presented thus far can be interpreted to mean that the presence
of DH directed at VZV antigens protects against the development of severe
ZO-AU in patients infected with the virus. Elevated IOP is a characteristic
feature of acute ZO-AU. Using this as an indicator of the presence of AU,
we measured the IOP of patients with ZO-AU and compared their levels with
the presence or absence of virus-specific DH. The results are displayed in Table 5. The average IOP detected among
patients with ZO-AU who had negative DH responses was 27.4 ± 6.4 mm
Hg, whereas the average IOP detected among patients with ZO-AU who had positive
DH was 20.3 ± 5.7 mm Hg (P<.05). This comparison
suggests that the absence of a positive VZV DH skin test in a patient with
uveitis may herald the development of severe ZO-AU.
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Table 5. Comparison of IOP Elevation in Patients With ZO-AU*
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VZV-SPECIFIC DH IN PATIENTS WITH ZSH
To test the validity of this suggestion, we examined VZV DH responses
in patients with VZV without dermatitis (ZSH). In our experience, diagnosing
uveitis caused by VZV in the absence of an attendant dermatitis is difficult.
Along with VZV skin testing for patients with ZSH, we also skin tested patients
with Vogt-Koyanagi-Harada disease or HLA-B27–positive acute anterior
uveitis as controls. We skin tested 3 patients with ZSH, in whom VZV DNA was
detected in aqueous humor samples using the PCR (data not presented). As presented
in Table 6, these patients with
ZSH failed to display VZV-specific DH, whereas 5 (83%) of 6 patients with
Vogt-Koyanagi-Harada disease or HLA-B27–positive acute anterior uveitis
responded to VZV antigens. As anticipated, PPD responses of patients with
ZSH were normal (Table 1).
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Table 6. Delayed Hypersensitivity Responses Elicited by VZV Antigen
in Patients With ZSH-AU*
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We completed these studies on 2 of 3 patients who recovered from ZSH
by repeating VZV skin tests 3 months later. In both cases, VZV-specific DH
responses were detected at this time (data not shown). Thus, a VZV-skin test
applied during the acute stage of disease might be diagnostically useful because
at this stage the test is negative, whereas when recovery is complete, VZV-specific
DH reactivity returns to normal.
COMMENT
Approximately 40% of patients who develop ophthalmic herpes zoster (ie,
reactivation of infection of the ophthalmic branch of the trigeminal nerve
with VZV) develop anterior uveitis. Individuals with involvement of the external
nasal nerve that supplies the side of the nose are at particular risk (Hutchinson
symptom). In the present study, we observed that patients with ophthalmic
herpes zoster without uveitis displayed intense VZV-specific DH, whereas patients
with a similar infection complicated by the presence of anterior uveitis displayed
no VZV-specific DH. At the simplest level, these results suggest that an important
factor in determining whether a VZV infection of the ophthalmic branch of
the trigeminal nerve will proceed to uveitis is whether the patient retains
a high level of VZV DH reactivity. This curious result is strongly reminiscent
of our previously reported finding that patients who develop VZV acute retinal
necrosis are selectively and transiently deficient in virus-specific DH reactivity.1 Together, these findings implicate the absence of
virus-specific DH in the pathogenesis of intraocular disease caused by VZV.
The corollary of this implication is that preservation of virus-specific DH
at the time of a VZV infection is an important barrier to the development
of intraocular infection with the virus.
Not only is acute uveitis itself a serious clinical problem in patients
with ophthalmic herpes zoster, but patients with ZO-AU are at a significant
risk of developing iris atrophy (20%), secondary glaucoma (10%), and secondary
cataracts.10 Of the patients with ZO-AU who
we enrolled in this study, 80% displayed elevated IOP compatible with secondary
glaucoma. This was especially true of patients with deficient VZV-specific
DH. Similarly, iris atrophy in our patients tended to be observed in patients
with impaired VZV DH (Table 1).
Together, these findings suggest that patients with impaired VZV DH are at
a higher risk of developing the secondary complications of ZO-AU, and that
once again, VZV DH functions as a barrier to the emergence of these secondary
complications.
Varicella-zoster virus typically infects humans via the skin. A large
majority of the Japanese population displays positive DH responses to the
VZV antigen by age 12 years because of spontaneous contraction of chickenpox.
Those who have not had a chickenpox infection by this time are offered the
VZV vaccination, and the vast majority of these individuals receive the vaccination.
This accounts for the observation that DH responses to VZV among the Japanese
are pervasive. A minority of adult Japanese people develop recurrent VZV infection,
which appears clinically as a vesicular rash that localizes to a dermatomal
distribution. The ophthalmic division of the trigeminal nerve is the most
frequently affected facial dermatome except in rare cases of herpes zoster
sine eruptio (ZSH).11-13
Usually, the diagnosis of ZSH is based on a PCR assay of aqueous humor,14-17 but
justification of paracentesis of the anterior chamber to obtain aqueous humor
is sometimes tenuous. In an indirect way, our findings—that the VZV
DH responses of 2 patients with ZSH were negative during acute infection,
but were restored to positivity when the disease had been inactive—suggest
that the skin test might be diagnostically useful in this difficult clinical
circumstance. That is to say, a negative VZV DH skin test in a patient with
suspected ZSH would tend to confirm the accuracy of the diagnosis. By contrast,
a positive VZV DH skin test in this clinical setting would argue against a
VZV infection of the anterior uvea. Since DNA amplification with PCR technology
tends to be most successful at the early stages of intraocular infection,
and since the VZV skin test is more convenient than anterior chamber paracentesis,
we think it worthwhile to further study the predictability of negative or
positive VZV DH responses in this situation.
Quite some time ago, Tanaka et al18 reported
the results of their study of VZV-specific DH reactivity in 12 patients with
ophthalmic herpes zoster. On the one hand, only 1 of their 12 patients with
this condition had a positive skin test reaction within 2 weeks of the onset
of the eruption, suggesting that cellular immunity to VZV antigens was impaired
during the development of ophthalmic herpes zoster. On the other hand, they
reported that all patients with ophthalmic herpes zoster displayed positive
skin test results when tested 3 weeks after the appearance of the cutaneous
manifestations of the disease. Unfortunately, the authors of that report failed
to mention the severity of ZO-AU in their patients. Nonetheless, that report
strongly resembles our current findings on patients with ZSH, as well as our
previous report on patients with acute retinal necrosis. In both instances,
DH reactivity to VZV antigens was impaired at the time of the onset of intraocular
infection with VZV, yet the impairment proved to be transient. To explain
these results, we have previously proposed that idiopathic reactivation of
VZV in the anterior segment of an eye might promote transient suppression
of DH, thereby silencing virus-specific CD4+ T cells that are required
to prevent VZV infection of intraocular tissues.
Herpes zoster ophthalmicus and ZSH-AU are inflammatory ocular diseases
restricted to the anterior segment of the eye, whereas VZV-induced acute retinal
necrosis is a retinal infection. In the mouse system, BALB/c mice that receive
an anterior chamber injection of an antigen acquire an unusual systematic
immune response, termed "anterior chamber–associated immune deviation"
(ACAID).19-20 In this system,
impaired antigen-specific DH coexists with high serum titers of antigen-specific
antibodies. The results presented in this article serve to support our hypothesis
that anterior chamber–associated immune deviation may be the immunologic
mechanism that is triggered in the eyes of some patients undergoing idiopathic
reactivation of VZV in the trigeminal ganglion. For reasons yet to be revealed,
zosteriform spread of antigenic VZV particles to the anterior chamber leads
to suppression of virus-specific T cells that mediate DH, and by so doing,
rob the eye of the protection afforded by these CD4+ T cells. Acute
viral infection of sensitive intraocular tissues ranging from iris to retina
is the inevitable consequence. If we could understand how to abort anterior
chamber–associated immune deviation in this situation, intraocular complications
of ophthalmic herpes zoster might be eliminated from clinical ophthalmology.
AUTHOR INFORMATION
Submitted for publication October 2, 2001; final revision received April
24, 2002; accepted May 16, 2002.
Corresponding author: Takeshi Kezuka, MD, PhD, Department of Ophthalmology,
Hachioji Medical Center, Tokyo Medical University, 1163, Tate-machi, Hachioji-city,
Tokyo, 193-8639, Japan (e-mail: tkezuka{at}tokyo-med.ac.jp).
From the Department of Ophthalmology at Hachioji Medical Center (Dr
Kezuka), and the Department of Ophthalmology at Tokyo Medical University (Drs
Sakai, Minoda, Takeuchi, Keino, and Usui), Tokyo, Japan; and Schepens Eye
Research Institute, Department of Ophthalmology, Harvard Medical School, Boston,
Mass (Dr Streilein).
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