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,
Departments of
*
Neurology and
Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, OR 97201;
Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97201; and
§
R. S. Dow Neurological Sciences Institute, Legacy Good Samaritan Hospital and Medical Center, Portland, OR 97209.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsTCR V{alpha} and V{beta}...An EAE-specific V{alpha}2 CDR3...DiscussionReferences |
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2 in the iris/ciliary body
and, although one would expect an influx of nonspecific inflammatory T
cells, these biases were still evident at the peak of AU. An analysis
of the TCR Vß8.2 and V2 sequences derived from the iris/ciliary
body demonstrated the presence of the same complementarity determining
region 3 motifs found in MBP-specific T cells that are pathogenic for
EAE and found in T cells derived from the central nervous system of
rats with EAE. Finally, T cells isolated from the iris/ciliary
body of rats with AU were found to proliferate in a specific fashion to
MBP Ags. Thus, it appears that MBP-specific T cells are pathogenic for
AU as well as EAE in the Lewis rat. In addition, the long-term presence
of this highly restricted MBP response in the iris/ciliary body
indicates that distinct immunoregulatory mechanisms exist in the
environment of the eye. This provides an interesting model with which
to address questions pertaining to the nature of T cells infiltrating
the eye and their regulation during EAE and other systemic
diseases. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsTCR V{alpha} and V{beta}...An EAE-specific V{alpha}2 CDR3...DiscussionReferences |
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50% of uveitis cases are known to be associated
with underlying systemic diseases such as diabetes, sarcoidosis,
rheumatoid arthritis, Vogt-Koyanagi-Harada disease, Behçet’s
disease, multiple sclerosis
(MS)4, and others (1, 2, 3). In
uveitis, inflammatory cells attack the uvea, which consists of the
iris, ciliary body, and choroid; these cells appear to be initiated by
an autoimmune process. Neighboring tissues such as the retina
and vitreous are also often affected. The most common form of uveitis
is anterior uveitis (AU), which is characterized by an accumulation of
inflammatory cells in the iris and trabecular meshwork, with cells
sometimes found within the ciliary body (4, 5). AU has been found to
precede, to be concurrent with, or to occur following various systemic
diseases (1, 6, 7, 8, 9). An experimental model for AU has been developed in the Lewis rat. Lewis rats that are immunized with myelin basic protein (MBP) develop experimental autoimmune encephalomyelitis (EAE), an inflammatory disease of the central nervous system (CNS) that is characterized by ascending limb paralysis and perivascular lesions in the brain and spinal cord. Recent studies (4, 5, 10) have demonstrated that AU often develops in Lewis rats with EAE, thus providing a model system with which to study the association between AU and a systemic disease. The target autoantigens in EAE and possibly AU consist of the myelinated neurons found within the CNS and the iris, respectively. EAE is often referred to as a model for the human paralytic disease MS. Although AU is not the most common form of eye inflammation associated with MS, the incidence of uveitis in MS is higher than in the general population, varying from 2.7 to 27% depending upon the MS population and the criteria of diagnosis (11). Recently, AU has specifically been identified in a number of MS cases (8, 9, 12).
Encephalitogenic T cells that infiltrate the CNS have been
characterized as CD4+, MHC class II-restricted cells that
secrete lymphokines of the Th1 subset (13, 14). T cell lines and clones
that recognize the immunodominant MBP epitope at residues 72–89 have
been isolated from rats with EAE, and many demonstrate biased
expression of the TCR Vß8.2 and V2 genes (15, 16). In a
recent report, phenotyping inflammatory infiltrates isolated from the
iris/ciliary body of MBP-immunized rats with AU demonstrated TCR
Vß8.2 expression on 30% of total CD4+ T cells (4). In
addition, similar to what has been reported in the spinal cord of rats
with EAE, the activation marker OX-40 was expressed on 17% of total
CD4+ T cells that were isolated from the iris/ciliary body
of rats with AU (4).
EAE-associated AU can be induced by immunization with guinea pig MBP as well as with the MBP peptides 71–90 or 87–99 (4, 5). Immunization with adjuvant alone has failed to induce AU, indicating that this disease is triggered by specific Ag (4, 5). In addition, AU can also be induced by passive immunization with MBP-specific T cells (4, 5). The kinetics of AU appears to differ from that of EAE. The onset of AU as determined by histologic assessment coincided with the onset of EAE at day 11 after MBP immunization (4). However, while clinical symptoms of EAE and inflammation in the spinal cord peaked at days 13 to 14, inflammation in the anterior segment of the eye peaked later at day 18 (EAE recovery). In a separate report, AU was found to appear after recovery from MBP-induced paralysis (5).
In recent studies, we have analyzed the TCR V region genes encoding the
AgR on T cells that infiltrate the spinal cord of MBP-immunized rats at
the onset of EAE (17, 18, 19). Consistent with other studies (20, 21), the
Vß8.2 gene was highly expressed in the spinal cord at EAE onset, as
were EAE-associated Vß8.2 complementarity determining region 3 (CDR3)
motifs. The biased expression of three V genes at EAE onset was also
recently demonstrated. In agreement with other studies (15, 16), V2
expression was overused, but an increased expression of V1 and
V23 in spinal cord T cells relative to T cells that had been derived
from the lymph nodes (LNs) of the same animals was also noted (19).
Finally, the presence of a V CDR3 motif associated with the spinal
cord-infiltrating T cell population was detected (19). It has been
proposed that the CDR3 loops of the TCR V and Vß chains interact
with peptide Ag presented by MHC molecules (22, 23, 24, 25). Thus, the presence
of conserved CDR3 motifs are likely to be highly significant to T cell
recognition and the specificity of the T cells responsible for
autoimmune pathogenesis.
Our present study addresses, at the molecular and functional level, the
question of whether T cells infiltrating the iris in AU are the same as
those that infiltrate the CNS to cause EAE. We demonstrate here that
the T cells isolated from the iris/ciliary body of rats with AU present
TCR V and Vß gene profiles that are very similar to those of T
cells isolated from the spinal cord of rats with EAE. Moreover, the TCR
V and Vß CDR3 regions of iris/ciliary body-derived T cells bear
motifs that are identical with those described for MBP-specific T cell
clones and with those found in TCR sequences derived from the CNS of
rats with EAE. Finally, the T cell lines generated from the
iris/ciliary body-derived T cells of rats with AU were found to
proliferate in a specific response to MBP Ags. The significance of
these findings and their importance to immunoregulatory mechanisms are
discussed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsTCR V{alpha} and V{beta}...An EAE-specific V{alpha}2 CDR3...DiscussionReferences |
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Female Lewis rats (6–8 wk of age) were used in groups of three to four animals per experimental timepoint and were obtained from Harlan Sprague-Dawley (Indianapolis, IN). The animals were housed and cared for in the Animal Resource Facility at the Portland Veterans Affairs Medical Center according to institutional and federal guidelines.
Induction of EAE and AU
Active EAE was induced by a s.c. injection in the footpad with 25 µg guinea pig MBP in CFA containing 150 µg Mycobacterium tuberculosis strain H37Ra (Difco Laboratories, Detroit, MI). Animals were monitored daily for clinical signs of EAE and AU. Rats developing EAE were scored using the following scale: 0 = no clinical signs; 1 = limp tail; 2 = hind limb weakness; 3 = paraplegia; and 4 = paraplegia with forelimb weakness, moribund condition. Rats developing AU were evaluated clinically by an independent observer using biomicroscopy. Clinical observations were graded on a scale of 0 to 3 based on the following criteria: 0 = no inflammation; 0.5 = mild dilation of iris vessels and/or flare in the anterior chamber; 1 = cells in the anterior chamber; 2 = infiltrates present in <50% of the surface of the iris, fibrin in the anterior chamber; and 3 = infiltrates present in >50% of the surface of the iris.
Isolation of T lymphocytes
T cells were recovered from the iris/ciliary body under sterile conditions by removal of the eye and microdissection to obtain the anterior segment, as described previously (4). The iris/ciliary body was placed into RPMI 1640 plus 10% FBS containing 200 U/ml collagenase and incubated at 37°C for 2 h. A single-cell suspension was obtained by passage through a nylon filter followed by two washings with RPMI 1640 medium. LN T cells were isolated as described previously (26).
Tissue isolation
For the isolation of whole tissue, the iris/ciliary body was recovered as described above, and the spinal cord was removed by insufflation as described previously (27). Tissue samples were quick-frozen and stored at -80°C before RNA isolation.
Lymphocyte proliferation assay
T cells that had been freshly obtained from the inflamed eyes
were pooled and resuspended in RPMI 1640 medium containing 10% FBS and
plated at a density of 5 x 105/ml. Irradiated rat
thymocytes at a density of 5 x 106 cells/ml and 100
µg/ml of MBP were added. After stimulation for 3 days, cells were
centrifuged and resuspended in RPMI 1640/10% FBS containing human
rIL-2 (Boeringer Mannheim, Indianapolis, IN) for 7 days. For the
proliferation assay, T cells were plated in RPMI 1640/10% FBS at a
density of 1 x 105 cells/well in the presence of
1 x 106 irradiated thymocytes/well. Con A, 10 µg of
MBP or MBP peptides, or RPMI 1640 medium as a control were also added
to each well. Wells were done in duplicate. Cultures were incubated for
72 h at 37°C and 5% CO2 and then pulsed with 1 mCi
of tritiated thymidine for an additional 16 h. Cells were
harvested onto glass fiber filters, and thymidine uptake was assessed
by liquid scintillation counting. Stimulation indices (SIs) of 
2 were
considered positive, whereas SIs of <2 were negative. Since duplicate
wells were used, statistical tests were not applied to the results.
RT-PCR analysis of TCR V gene expression
The profiles for Vß and V gene expression were generated by
semiquantitative RT-PCR as described previously (19). RNA was treated
with DNase I (Stratagene, La Jolla, CA) before cDNA synthesis. cDNA was
synthesized with 5 µg of iris/ciliary body tissue RNA or 1 µg of LN
RNA using oligo(dT) and Superscript reverse transcriptase (Life
Technologies, Gaithersburg, MD) in a total volume of 50 µl. Vß
profiles were generated using Vß-specific primers in separate
reactions together with the Cß region primer, RCßI (28). V
profiles were generated using V-specific primers together with the
C region primer, RC4 (19). Both C region primers were end-labeled
with [
-32P]ATP for the amplification reactions, which
consisted of 29 cycles of 94.5°C for 20 s, 55°C for 90 s,
and 72°C for 90 s, followed by a 5-min extension at 72°C. The
PCR products were separated on a polyacrylamide gel, dried, and then
exposed to x-ray film overnight. PCR bands were excised from the gel
and counted by liquid scintillation.
Sequence analysis
For the sequencing of the Vß8.2 chain, cDNA was first amplified with a 5' Vß8-specific primer, Vß8sacII, and a 3' C region primer, RCß-E (29), for 35 cycles. PCR products were diluted to 1/100 or to 1/1000, and 2 µl was used in a second amplification with an internal primer that was specific for Vß8.2 and the Cß region primer RCß-I for 32 cycles. A total of 0.5 µl of the reamplified product was ligated into the pCRII vector and used to transform OneShot competent cells (Invitrogen, San Diego, CA). Carbenicillin-resistant colonies were screened directly by boiling in 30 µl of water for 5 min and using 10 µl of the supernatant in an amplification reaction with RVß8.2 and RCß-I. PCR products of the expected sizes were detected by separation in a 2% agarose gel. Plasmid DNA was isolated using an alkaline lysis/polyethylene glycol precipitation procedure. Cloned TCRVß8.2 genes were sequenced on an ABI automated sequencer (Applied Biosystems, Foster City, CA) that was operated at the Portland Veterans Affairs Medical Center Core Sequencing Facility, using RCß-I as the sequencing primer.
The sequencing of the V2 chain was performed in a similar manner
using the rat V2 region primer RV2Eco
(5'-GACGAATTCCATGGCTCAGCAGGTCAAACAAA-3'), and the C region
primer C2-E (19). Transformed bacterial colonies were screened by
PCR using internal primers RV2 and RC4 (19) and were sequenced
using RC4. The TCR residue numbering system of Kabat et al. (30) was
used.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsTCR V{alpha} and V{beta}...An EAE-specific V{alpha}2 CDR3...DiscussionReferences |
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Lewis rats immunized with MBP/CFA developed classical monophasic EAE. The onset of both EAE and AU was observed on days 10 to 11 postimmunization. AU was mild and restricted to the anterior segment, with maximum severity observed on days 17 to 18. EAE peaked on days 13 to 14, and rats were in recovery from EAE by day 18.
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TCR V and Vß gene expression of iris/ciliary body- and spinal
cord-infiltrating T cells
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TopAbstractIntroductionMaterials and MethodsResultsTCR V{alpha} and V{beta}...An EAE-specific V{alpha}2 CDR3...DiscussionReferences |
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A). This level of Vß8.2
expression was at least comparable with what we have observed
previously in T cells isolated from the spinal cord at EAE onset (day
12 after immunization with guinea pig MBP) (17, 31).
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A), Vß8.2 expression in the iris/ciliary
body was still significantly elevated at day 18, which was the peak of
AU (28%, Fig. 1B) (31). Vß8.2 expression in the spinal
cord at day 18 was more elevated than at day 14, which is consistent
with what we have seen previously in late recovery from EAE (31).
V expression of T cells infiltrating the iris/ciliary body and
spinal cord were also examined at the two different timepoints. Both
the day 15 (Fig. 2A) and the
day 18 (Fig. 2B) iris/ciliary body did not present a
clear-cut bias for the expression of a single V gene, but there
appeared to be elevated levels of V1, V2, V10, and V11
expression. Since the expression of V1, V10, and V11 was also
elevated in the periphery, i.e., in the LN (V1, V10, and V11)
(19) and in splenic T cells (V1 and V10, Fig. 2B), an
overexpression of these Vs may not be specifically related to the
induction of AU. V2 overexpression, on the other hand, appeared to
be specific to the iris/ciliary body and spinal cord during disease
(Fig. 2, A and B (19)). Thus, for the subsequent
sequencing analysis of the V CDR3 regions described below, we
focused on the V2 genes that are expressed in the T cells
infiltrating the iris/ciliary body in rats with AU.
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The T cells infiltrating the iris/ciliary body in rats with AU
appeared to possess a phenotype that was similar to that of the
MBP-specific, pathogenic T cells that cause EAE. T cells from the
iris/ciliary body were found to be surface positive for CD4 and Vß8.2
(4), and we found that these cells also had increased specific
expression of V2. Next, we examined the CDR3 regions of these
T cells at the sequence level to look for similarities to MBP-specific
T cells. Figure 3, A and
B, presents the Vß8.2-associated CDR3 sequences obtained
from the iris/ciliary body on days 14 (peak of EAE) and 18 (peak of AU)
after MBP immunization, respectively. With the exception of two
sequences from the day 18 group, all of the Vß8.2 sequences from the
iris/ciliary body (11 sequences from day 14 and 9 sequences from day
18) contained one of two previously described Vß CDR3 motifs
(Asp96Ser97 or
X96Ser97) associated with EAE (29, 32).
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). As a control, we
obtained the Vß8.2 sequences of LN T cells from the same rats at days
14 and 18. As seen in Figure 4,
A and B, only 7 sequences were found to contain
either the Asp96Ser97 or the
X96Ser97 motif out of a total of 24 sequences
obtained for both days. Jß gene usage was also much less restricted
in the LN sequences.
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An EAE-specific V2 CDR3 motif is associated with iris/ciliary
body-infiltrating T cells
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TopAbstractIntroductionMaterials and MethodsResultsTCR V{alpha} and V{beta}...An EAE-specific V{alpha}2 CDR3...DiscussionReferences |
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2 expression appeared to be specifically elevated in the
iris/ciliary body-infiltrating T cells, we examined the
V2-associated CDR3 sequences obtained on days 14 and 18 (Fig. 5, A and B,
respectively). As we found with the Vß8.2 sequences above, most of
the V2 sequences from the iris/ciliary body contained a CDR3 motif
(the N3+ motif) that we previously described to
be associated with V sequences from spinal cord T cells at EAE onset
(19). We have also found that the N3+ motif is
present in MBP-specific, encephalitogenic T cell clones (19). In
contrast, the N3+ motif was not found in any of
the 20 control V2 sequences obtained from LN T cells at days 14 and
18 (Fig. 6, A and
B, respectively). In our previous study of V2 expression
in EAE, two different V2 genes, C14V2 and 510V2, were found to
be equally expressed in the spinal cord-infiltrating T cell population
(19). Similar results were found for the V2 sequences from the LN T
cell population of rats with AU (Fig. 6, A and
B). Interestingly, this was not the case for V2 sequences
from the iris/ciliary body (Fig. 5, A and B),
where we observed a notable preference for C14V2 gene expression
over that of the 510V2 gene. However, in a separate experiment,
V2+ sequences from T cells infiltrating the iris/ciliary
body of rats with AU demonstrated the presence of 510V2 sequences
bearing the N3+ CDR3 motif (data not shown).
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A total of 1 x 107 T cells were isolated and
pooled from the iris/ciliary body tissue of 30 rats at the peak of AU,
and 5 x 106 T cells were placed into culture. After
an initial 3-day stimulation with MBP Ag and APCs followed by a resting
period, T cells were tested for the ability to proliferate to MBP and
MBP peptides. As demonstrated in Figure 7, T cells isolated from the iris/ciliary
body responded specifically to whole MBP and to the dominant
encephalitogenic MBP peptide 72–89. However, no response was observed
to MBP peptides 55–69 (SI = 1.43x) and 87–99 (SI < 0.45x).
As expected, strong proliferative responses were observed in the
presence of Con A (SI = 60.1x, data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsTCR V{alpha} and V{beta}...An EAE-specific V{alpha}2 CDR3...DiscussionReferences |
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- and ß-chain CDR3 motifs, but they also
proliferated in a specific fashion to MBP Ags. The myelination of
sensory fibers in the iris that originate from the trigeminal nerve has
been documented in an electron microscopic study by Huhtala (33). Thus,
in the current work, we present data supporting a target-directed
(i.e., MBP-specific) mechanism in this experimental model of uveitis.
It is not clear whether the myelinated nerves of the iris are
more closely representative of peripheral nerves or whether they share
more similarity with myelination in the CNS. MBP is expressed as
different protein isoforms in both the CNS and peripheral nerves (34, 35). However, the different isoforms are present in varying amounts in
the CNS vs the periphery. For example, the 18.5-kDa form of MBP
constitutes 2 to 16% of myelin protein in peripheral nerves, but is
the major MBP form in the CNS (36). TCR V gene usage in experimental
autoimmune neuritis (EAN) induced by peripheral myelin Ags was
investigated in a recent study by Weilbach et al. (37). The induction
of EAN with peripheral myelin does not typically coincide with the
development of EAE and vice versa. Interestingly, the expression of
both Vß8.2 and V2 was detected in sciatic nerve tissue after EAN
induction with whole peripheral nerve myelin but was not detected after
induction with the myelin protein P2 (which constitutes 45–65% of
total peripheral myelin protein) or P2 peptides. Of the three Vß8.2
sequences obtained after disease induction with peripheral nerve
myelin, two contained EAE-associated CDR3 motifs (37). The constitution
of the various myelin proteins in the nerves of the iris is not known
and could conceivably contain higher levels of certain CNS proteins
than is found in peripheral nerves. Thus, differences in the
presentation of one MBP isoform over others may account for the
site-specific differences in MBP-induced disease. In addition, the
varying levels of the targeted autoantigen (i.e., MBP) expressed in the
CNS, iris, or peripheral nerves could also play a role in disease
severity.
As in the EAE model, it is likely that the TCR V and Vß CDR3
motifs detected in the AU sequences contribute to Ag recognition.
Another model of uveitis, experimental autoimmune uveoretinitis, which
affects the uveal tract, retina, and pineal gland, is inducible by
immunization with several retinal Ags, including interphotoreceptor
retinoid-binding protein and S-Ag (38, 39). Interestingly,
biased Vß8+ gene expression has also been correlated with
autoimmune pathology in this model (40, 41). However, the CDR3
sequences associated with the Vß8.2 response to S-Ag did not contain
EAE/AU-associated CDR3 motifs (42). Thus, although Vß8.2 may be used
in several autoimmune responses, the conserved CDR3 sequences that are
specific to the T cells inducing AU and EAE suggest that these are
Ag-directed responses.
Given the similarities described in the T cells infiltrating the iris/ciliary body and the CNS as well as similarities in pathology, it appears that AU and EAE share a common effector mechanism. In EAE, there is a breakdown of the blood-brain barrier and a cellular infiltrate accompanied by perivascular lesions in the white matter. AU is also characterized by cellular infiltration and perivascular lesions, with a disruption of the blood-iris barrier. As we have shown here and in previous work (31), T cells isolated from the inflammatory tissue in both cases respond specifically to MBP, particularly to the dominant encephalitogenic epitope MBP72–89. In addition, both EAE and AU are inducible by the secondary encephalitogenic epitope MBP87–99 (4, 28). T cell clones recognizing MBP87–99 were previously isolated from rats with EAE and were found to predominantly express the TCR Vß6 gene (28). An extension of the results presented here would predict that iris/ciliary body-infiltrating T cells isolated after AU induction with MBP87–99 would demonstrate a bias for TCR Vß6 expression.
In addition to the close similarities observed between AU and EAE, there are also interesting differences. For example, although the onset of both AU and EAE occurred simultaneously, AU peaked after recovery from EAE. It is possible that traffic across the blood-iris barrier may differ from traffic across the blood-brain barrier. However, work by Verhagen et al. (5) demonstrated that a disruption of both barriers by the systemic administration of LPS resulted in an earlier onset of both diseases but did not cause AU to peak earlier with respect to EAE. Whether there are significant differences in the Ag-presenting environment of the iris vs that of the CNS is also unknown. The presence of MHC class II+ dendritic cells as a distinct network in the tissues bordering the anterior chamber of the eye has been established (43, 44) and may play a role in the highly selective presentation of Ag at this site. In addition, dendritic cells isolated from rat iris tissue were able to stimulate unprimed T lymphocytes in vitro, and this stimulatory capability was markedly enhanced after culture for 48 h with granulocyte-macrophage CSF (45).
In a previous study, we observed a marked reduction in biased Vß8.2 gene expression by the peak of EAE and attributed this reduction to the influx of nonspecific inflammatory cells (31). In AU, we found that Vß8.2 expression remained high, even at the peak of AU. An examination of the sequence data suggests that EAE-associated CDR3 motifs may be present at a higher frequency in T cells from the iris/ciliary body than from the CNS (17, 19). These observations are consistent with certain aspects of immune regulation that are associated with the eye. The phenomenon of anterior chamber-induced immune deviation is a specialized response in which a selective suppression of delayed hypersensitivity occurs, but in which humoral and cytotoxic T cell responsiveness to intraocular Ag presentation remain intact (46, 47). Thus, extremely damaging inflammatory reactions are avoided at this highly sensitive tissue site, which may account for the extended Vß8.2 bias and the sequence restrictions observed later in AU. The mechanisms involved in anterior chamber-induced immune deviation are not fully understood but may involve the action of antiinflammatory cytokines and soluble mediators specific to the microenvironment of the anterior chamber (48). In this environment, it is also possible that T cells specifically activated in the iris do not undergo Fas-Fas ligand-induced apoptosis at the same rate as those activated in the CNS (49).
Since EAE is a model for MS, it seems highly relevant that AU has been associated with a number of MS cases. Several more recent reports have described symptoms of AU in patients with preexisting MS or in individuals who later developed MS (8, 9, 12). The Lewis rat model of EAE and associated AU provides an opportunity to investigate the occurrence of inflammatory eye disorders that accompany systemic diseases in general. Our observations of restricted TCR usage and Ag specificity in AU suggest that, at least in this model of uveitis, pathogenic T cells may be specifically targeted for treatment.
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Footnotes |
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2 A.C.B. and H.O. were both first authors of this paper.
3 Address correspondence and reprint requests to Dr. Abigail C. Buenafe, EAE Research L219, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd., Portland, OR 97201.
4 Abbreviations used in this paper: MS, multiple sclerosis; MBP, myelin basic protein; CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; CDR3, complementarity determining region 3; LN, lymph node; SI, stimulation index; EAN, experimental autoimmune neuritis.
Received for publication February 6, 1998. Accepted for publication April 17, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsTCR V{alpha} and V{beta}...An EAE-specific V{alpha}2 CDR3...DiscussionReferences |
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and Vß chain genes even though the major histocompatibility complex and encephalitogenic determinants being recognized are different. J. Exp. Med. 169:27. CDR3-specific motif associated with Lewis rat autoimmune encephalomyelitis and basic protein-specific T cell clones. J. Immunol. 158:5472.[Abstract]
ß receptor. EMBO J. 7:3745.[Medline]
ß TCR structure at 2.5 Å and its orientation in the TCR-MHC complex. Science 274:209.This article has been cited by other articles:
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  G. Adamus, G. G. Burrows, A. A. Vandenbark, and H. Offner Treatment of Autoimmune Anterior Uveitis with Recombinant TCR Ligands. Invest. Ophthalmol. Vis. Sci., June 1, 2006; 47(6): 2555 - 2561. [Abstract] [Full Text] [PDF]
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 F. Mor, F. Quintana, A. Mimran, and I. R. Cohen Autoimmune Encephalomyelitis and Uveitis Induced by T Cell Immunity to Self {beta}-Synuclein J. Immunol., January 1, 2003; 170(1): 628 - 634. [Abstract] [Full Text] [PDF]
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X. Zhang, S. Jiang, M. Manczak, B. Sugden, and G. Adamus Phenotypes of T Cells Infiltrating the Eyes in Autoimmune Anterior Uveitis Associated with EAE Invest. Ophthalmol. Vis. Sci., May 1, 2002; 43(5): 1499 - 1508. [Abstract] [Full Text] [PDF]
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A. F. de Vos, A. D. Dick, J. Klooster, L. Broersma, P. G. McMenamin, and A. Kijlstra Analysis of the Cellular Infiltrate in the Iris during Experimental Autoimmune Encephalomyelitis Invest. Ophthalmol. Vis. Sci., September 1, 2000; 41(10): 3001 - 3010. [Abstract] [Full Text]
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