(Investigative Ophthalmology and Visual Science. 2001;42:3233-3238.)
© 2001
by The Association for Research in Vision and Ophthalmology, Inc.
Human S-Antigen Determinant Recognition in Uveitis
Marc D. de Smet1,2,
George Bitar2,
Sumeet Mainigi2 and
Robert B. Nussenblatt3
1 From the Department of Ophthalmology, University of Amsterdam, The Netherlands; and the
2 Clinical Immunology Section and
3 Laboratory of Immunology, National Eye Institute, Bethesda, Maryland.
 |
Abstract
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PURPOSE. Soluble antigen (S-Ag) is a member of the arrestin family of protein
with which it shares a high level of homology. It is an immunologically
privileged retinal antigen that can elicit experimental autoimmune
uveitis (EAU) and is thought to be a target for ocular inflammatory
diseases. This study was conducted to identify in humans, the
immunogenic determinants of human S-Ag and to establish whether a
specific response profile occurs in particular ocular inflammatory
conditions.
METHODS. Peripheral blood lymphocyte responses were measured against a panel of
40 overlapping synthetic peptides of human S-Ag in patients with
chronic uveitis and compared with control subjects. Patients with
Behçet disease, sarcoidosis, Vogt-Koyanagi-Harada, and
sympathetic ophthalmia were tested.
RESULTS. A limited number of immunodominant determinants were identified for
Behçet disease and sarcoidosis. These were all located at sites
of limited homology with other known arrestins. In addition, several
individual patients had prominent proliferative responses to multiple
determinants well above that of control subjects. This determinant
spread was observed in all disease entities except sympathetic
ophthalmia, which did not show any immunoreactivity to S-Ag.
Significant response shifts were also noted over time in two patients.
CONCLUSIONS. The results indicate that there are specific immunodominant
determinants to human S-Ag in patients with certain forms of uveitis.
However, in individual patients, response is not limited to these
determinants. In the chronic stage of disease, response is spread over
many determinants.
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Introduction
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Soluble retinal antigen (S-Ag) also known as rod arrestin,
or 48K protein, is a major component of rod outer
segments1
the normal physiological role of which is to
quench the visual transduction cascade induced by light activation of
rhodopsin.2
3
Although closely related to ß-arrestins,
which are ubiquitously distributed throughout the
body,4
5
6
rod photoreceptor arrestins are confined to the
retina in an immune-privileged site.7
In addition to its
normal physiologic function, S-Ag is one of several ocular antigens
capable of inducing experimental autoimmune uveitis (EAU) in
susceptible hosts.8
EAU is mediated by activated,
antigen-specific CD4+ T cells,9
and
can be induced by immunization with several S-Ag–derived
peptides.10
11
12
Pathologically, the process resembles a
number of human conditions thought to be of autoimmune
origin.8
S-Ag is thought to be immunopathogenic in humans,
either causing or prolonging certain forms of uveitis. In accordance
with this notion, a large number of patients with uveitis were found to
respond to bovine S-Ag in lymphocyte proliferation
assays.13
14
15
In addition, lymphocyte responses have been
noted to a few peptide determinants derived from both the bovine and
human S-Ag sequences.13
16
17
The immune response against a whole protein is usually targeted toward
a small number of peptide determinants. To initiate the immune response
requires binding to major histocompatibility complex (MHC) molecules on
the surface of antigen-presenting cells (APCs) and presentation to
receptive T cells.18
19
Because of the polymorphism of MHC
molecules, the majority of immunogenic peptide determinants bind
strongly to only a single or a limited set of MHC
molecules.20
However, some peptide determinants bind to
several heterogeneous MHC molecules and may even cross
species.21
22
In the case of myelin basic protein, for
example, certain peptides, encephalitogenic in experimental animals,
have been found to be recognized by lymphocytes from patients with
multiple sclerosis.23
24
In this study, we decided to use
a panel of overlapping synthetic peptides of human S-Ag to test their
immunoreactivity in patients with various forms of uveitis as well as
in control subjects. It is then possible to define a spectrum of immune
reactivity for each disease entity and to identify the limited set of
determinants with particularly high immunoproliferative responses.
Response to a few of these determinants was also observed over time.
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Materials and Methods
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Antigen Synthesis and Preparation
Forty overlapping oligomeric peptide determinants of human S-Ag,
spanning the entire length of the human S-Ag sequence,25
were synthesized by Applied Biosystems (Foster City, CA). Each peptide
determinant measured 20 amino acids in length, except for the last one,
which measured 15 amino acids. Each peptide determinant overlapped the
previous sequence by 10 amino acids. The exact sequence and the
nomenclature used throughout this article are shown in Figure 1
. Peptides were synthesized by solid-phase chemistry using
t-butyloxycarbonyl derivatives of the amino acids on an
automated peptide synthesizer and were purified by HPLC to at least
95% purity. The amino acid composition of each peptide was verified
using amino acid analysis and automated gas-phase sequencing. In
proliferation assays, a final concentration in each well of 20 and 100
µg/ml was used.
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Figure 1. Sequence of human S-Ag and its overlapping peptide determinants. The
nomenclature is indicated under each determinant.
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Patient Selection
Patients participating in this study were selected from the pool
of patients under observation in the uveitis clinic of the National Eye
Institute, Bethesda, Maryland. Control subjects were taken from
among the NEI medical and paramedical staff, and were age matched as
closely as possible with the study population. Before participating in
the study, all patients gave informed consent for a protocol approved
by the Medical Review Board of the National Eye Institute and in
compliance with the tenets of the Declaration of Helsinki. In
all patients with active uveitis involving the posterior segment, the
disease was controlled with cyclosporine (1.0–5.0 mg/kg · d) and
prednisone (2.5–30 mg/d). Any patient with a reactivation of uveitis
in the 3 months before this study was considered to have clinically
active disease. A decrease in visual acuity by two lines or more on an
Early Treatment Diabetic Retinopathy Study (ETDRS) reading card was
associated with evidence of vitreal or retinochoroidal inflammation
characterized an active uveitis. Patients had one of the following
disorders: Behçet disease, ocular sarcoidosis,
Vogt-Koyanagi-Harada (VKH) syndrome, or sympathetic ophthalmia. The
diagnosis for each condition was established as described
elsewhere.13
Patients with Behçet disease met the
diagnostic criteria from the International Behçet’s Disease
Study Group.26
Those with ocular sarcoidosis had typical
retinochoroidal granulomatous uveitis. Patients with VKH met the
criteria of the American Uveitis Society27
or had typical
fundus and fluorescein findings. Patients with sympathetic ophthalmia
had a clinical picture compatible with the diagnosis and a history of
multiple surgeries or ocular trauma in one eye. Characteristics of the
patients are given in Table 1
.
Lymphocyte Proliferation Assays
Mononuclear lymphocytes were separated on isolymph gradient
(Gallard-Schlesinger, Carle Place, NY) from heparinized blood shortly
after the sample was obtained. Cells were resuspended in RPMI 1640 with
HEPES (Gibco, Grand Island, NY), supplemented with glutamine (2 mM),
penicillin (100 U/ml), streptomycin (100 µg/ml), and 10% commercial
heat-inactivated human AB serum (Biocell Laboratories, Carson, CA).
These cells were immediately placed in culture at a density of 2 x 105 cells/well in the presence of antigen, in
flat-bottomed, 96-well plates (Costar, Cambridge, MA). All assays were
plated in triplicate. Antigen concentrations were either 20 or 100
µg/ml. Peptides were tested simultaneously. For control of immune
reactivity, purified protein derivative (PPD; Parke-Davis, Morris
Plains, NJ) and purified phytohemagglutinin (PHA; Murex Diagnostics,
Dartford, UK) were also tested. For the last 12 hours before harvesting
at day 5, each well was pulsed with
[3H]thymidine (2 Ci/mmol, 0.5 µCi per 10
µl/well; New England Nuclear, Boston, MA). Results are expressed as a
stimulation index (SI = mean counts per minute in
stimulated cultures/mean counts per minute in unstimulated control
cultures).
Data Analysis
SIs for each peptide determinant were analyzed in two ways.
First, the results obtained from control subjects were compared with
those from patients per disease entity for each peptide determinant.
Comparisons were made using a nonparametric test for analysis of
variance (Kruskal-Wallis) with a postanalysis correction for comparison
of data pairs (Dunn test). Statistical analysis was performed by
computer (Prism software, ver. 2.0; GraphPad Inc., San Diego, CA). The
second analysis method involved the determination of the frequency with
which the SI in patients was above the tolerance limit of control
samples. This tolerance limit for a given peptide determinant was set
as the mean SI of control subjects + 2 SD.
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Results
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Patient Characteristics and Assessment of Lymphocyte Response
Twenty-nine patients and 15 volunteers were tested for their
lymphocyte proliferative responses to a panel of overlapping human S-Ag
peptide determinants at 20 µg/ml and 100 µg/ml. Because the optimal
culture conditions for lymphocyte proliferation with these peptide
determinants was not known, both concentrations were used. All patients
had shown evidence of retinal inflammatory disease for at least 8
months (8–120 months) before being tested. All patients had a chronic
remitting course of disease at the time, with the exception of the
patients with sympathetic ophthalmia, in whom the disease was quiescent
for more than 1 year before testing. A number of patients had a history
of an acute inflammatory episode in the 6 months before testing (Table 1)
. Control of lymphocyte responsiveness was determined in each group
by testing with PPD and PHA, as indicated in the Methods section. The
average SIs were as follows: control subjects: PHA 44, PPD 75;
Behçet disease: PHA 78, PPD 24; sarcoidosis: PHA 66, PPD 11; VKH:
PHA 42, PPD 27; sympathetic ophthalmia: PHA 47, PPD 7. There was no
significant difference between groups in the response to PHA. There was
also no significant difference between the various patient groups with
regard to the response to PPD. Their responses were lower than in the
control group, in which the difference was largely due to a few high
responders.
Determinant Mapping Using Analysis of Variance
Proliferative responses to individual peptides were highly
variable. In general the response to antigen was strongest with the
higher antigen concentration (Figs. 3
4)
. To test for internal consistency, one volunteer was repeatedly tested
at different time points over a period of 1 year. Each proliferative
response remained well within the mean + 2 SD of control subjects,
except at one of the nine time points, when deviant responses were
noted to several peptides. Analysis of variance used to compare SIs
from each patient group to control subjects revealed a statistically
significant difference in only a limited number of peptides (Table 2)
. These were found in two disease entities: Behçet disease and
sarcoidosis.
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Figure 3. Average SIs for each determinant at a peptide concentration of 100
µg/ml per well. Error bars, SD. Data are shown for disease categories
showing a significant deviation from control subjects. The profile for
sympathetic ophthalmia is similar to that in control subjects, except
for determinant 3 (mean SI, 4.0 ± 3.5).
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Figure 4. Proportion of responders above the tolerance limit per determinant. The
tolerance limit was set as the mean + 2 SD of the response in control
subjects. In sympathetic ophthalmia, one responder was found for
determinants 2, 3, 6, 11, 21, 25, 27, and 38.
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Determinant Mapping Using a Tolerance Limit Threshold
Although an analysis of variance showed that there were no
statistically significant differences for most peptide determinants
between control subjects and patients, several patients had SIs
considerably higher than that of control subjects for particular
determinants. Because these could correspond to a subset of patients
with an active immune response, a different approach was used to
identify these determinants. Response in these cases can be better
characterized as having overcome a minimal threshold (or tolerance
limit) of response, defined as the mean of control subjects + 2 SD.
This analysis showed in all disease entities a heterogeneous response
to S-Ag. In the case of sympathetic ophthalmia, the following
determinants gave significant responses: 2, 6, 11, 21, 22, 25, 27, and
38. In each case, only one patient, but not always the same one,
produced an SI above threshold. For the remaining disease entities, the
number of significant responders varied considerably among disease
entities and among determinants (Fig. 4)
. Determinant 21 and 22 in sarcoidosis and determinant 35 in VKH were
prominent in a majority of patients. Overall, patients with sarcoidosis
were most likely to show a heightened response. Response heterogeneity
was observed in all disease entities but was limited in sympathetic
ophthalmia (Table 3)
.
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Table 3. Maximum Number of Immunoproliferative Determinants Recognized by
Individual Patients per Disease Category
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Two patients with Behçet disease were tested on two separate
occasions. In one case, the responses were measured 3 months later and
in the other after 6 months. A shift in antigenic response was noted
for certain determinants (Table 4)
. A similar shift was not observed in a normal volunteer.
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Discussion
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Patients with uveitis showed a high degree of heterogeneity in
their lymphoproliferative response to determinants of human S-Ag. Such
heterogeneity is not surprising, given that patients carried a variety
of diagnoses and were at different stages of disease activity and
duration. However, two patterns of response were observed, one of which
appeared to be disease specific and the other specific to individual
patients. The first relates to a generalized increase in lymphocyte
proliferation accompanying selected determinants in patients with
Behçet disease or sarcoidosis, whereas the second relates to the
observation that a number of patients had heightened immune responses
to specific determinants, significantly above the mean of control
subjects. This heightened response in the presence of whole S-Ag, had
previously been shown to be a sign of disease activity within weeks of
the assay.28
The immunogenic determinants associated with Behçet disease and
sarcoidosis (Table 2)
are adjacent to highly immunogenic or pathogenic
determinants in the experimental model EAU. Determinants 19, 20, and 36
induce uveitis in the Lewis rat.29
Determinant 18 is
immunoproliferative in the cynomolgus monkey.30
Because
the determinants we studied are 20 amino acids long, the minimal
immunologic trigger for each determinant is nested somewhere within the
peptide sequence. Use of smaller synthetic peptides should make it
possible to identify the minimal immunogenic sequence and in particular
reveal whether the same sequence is immunogenic in all species. The
identification of appropriate targets may be facilitated by selecting
sequences that do not have homology with known nonretinal arrestins and
that are not expressed in the thymus.31
32
33
The second pattern of response was observed in a limited number of
patients for most disease entities studied, except sympathetic
ophthalmia. A heightened response was present to a variable but
significant number of determinants. Each response pattern was patient
specific and involved more determinants in patients with long-standing
chronic disease (Table 3)
. Recent observations in experimental
autoimmune encephalitis have shown that with disease recurrence, there
is a decrease in autoreactivity to the primary determinant and the
emergence of other, previously cryptic determinants, the appearance of
which is linked with disease progression.34
35
This
process follows a rather predictable course in which the spread to new
determinants characterizes particular phases of the disease and is
amenable to peptide-based therapy.36
A similar plasticity
of self-recognition has been observed in patients with multiple
sclerosis.37
Over a 12- to 18-month follow-up of patients
with multiple sclerosis, antigen spread was noted but also an abrupt
shift in responses to an extensive array of self-determinants. We infer
that a similar process is present in patients with uveitis.
Certain patients showed an immune response, which over time either
significantly increased or decreased baseline level (Table 4) . However,
variations were present among disease entities, because the response in
sympathetic ophthalmia was limited to a few determinants. The
relatively limited determinant spread in this latter disease may
indicate that S-Ag does not play a role in the disease process, because
the overall response profile was very similar to that of control
subjects. Pathologic changes in this disease are located within the
choroid, and experimentally, a similar disease pattern is induced by
using choroidal antigens.38
Determinant spreading is
likely to be an integral part of the immune response over time to
antigens that contribute to the disease process. Inherent in
determinant spreading is a shift in response over time. We observed in
two patients, but not in a volunteer, such a shift in antigenic
responses over time (Table 4)
. This shift in autoreactivity is unlikely
to be an artifact, because repeat testing of a volunteer over a
12-month period showed only limited variations in SIs that remained
within 2 SD of the mean of all control subjects. These shifts in
responses correspond well to the observations made in multiple
sclerosis and experimental autoimmune encephalomyelitis (EAE)
and suggest that antigen spreading also occurs in patients with
uveitis.36
37
This deserves to be studied in more detail
with a number of patients observed after surgery.
In summary, the present study demonstrates the existence of a number of
disease-specific antigenic determinants in two disease entities: namely
Behçet disease and sarcoidosis. These were associated with unique
sequences within the human S-Ag sequence and were related to pathogenic
sites in the experimental model. It also demonstrates the existence of
a number of determinants associated with immune responses in individual
patients. These responses were present in patients with a retinal
disease pattern. The observations give credence to the notion that
retinal autoantigens play a role in certain forms of uveitis. Further
study of determinant responses in patients with uveitis may help to
identify the exact site of the immune activation and may provide the
rationale for an attempt at peptide-based therapy.
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Figure 2. Average SIs for each peptide determinant at a concentration of 20
µg/ml per well. Error bars, SD. Data are shown for the disease
categories that showed a significant deviation from the mean of control
subjects. The profile of patients with sympathetic ophthalmia was
similar to that of control subjects, except for determinant 3 (mean SI,
1.9 ± 1.4) and determinant 6 (mean SI, 2.1 ± 1.6).
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Footnotes
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Supported by a grant from the Edmond and Marianne Blaauwfonds of the
University of Amsterdam.
Submitted for publication January 30, 2001; revised July 17, 2001;
accepted July 30, 2001.
Commercial relationships policy: N.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be marked
"advertisement" in accordance with 18 U.S.C. 
1734
solely to indicate this fact.
Corresponding author: Marc D. de Smet, Rm G2–217, Department of
Ophthalmology, Academic Medical Center, Meibergdreef 9, Amsterdam
1105AZ, The Netherlands. m.d.desmet{at}amc.uva.nl
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O. M. Z. Howard, H. F. Dong, S. B. Su, R. R. Caspi, X. Chen, P. Plotz, and J. J. Oppenheim
Autoantigens signal through chemokine receptors: uveitis antigens induce CXCR3- and CXCR5-expressing lymphocytes and immature dendritic cells to migrate
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C. A. Deeg, S. Reese, H. Gerhards, G. Wildner, and B. Kaspers
The Uveitogenic Potential of Retinal S-Antigen in Horses
Invest. Ophthalmol. Vis. Sci.,
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[Abstract]
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A D Dick
A bird in the hand . . .
Br J Ophthalmol,
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Top
Abstract
Introduction
