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, MCP-1, and RANTES in Experimental Autoimmune Uveitis
From the Department of Ophthalmology, University of Aberdeen Medical School, United Kingdom.
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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, monocyte chemoattractant protein (MCP)-1, and
regulated on activation of normal T-cell–expressed and secreted
(RANTES) during disease progression in experimental autoimmune uveitis
(EAU) and their relationship with the presence of the T helper cell
(Th)1–type cytokine IFN
.
METHODS. EAU was induced by immunization of Lewis rats with retinal extract.
Consecutive cryostat sections were prepared from eyes at different
stages of EAU, graded for severity of uveitis and stained by using
antibodies to MCP-1, MIP-1, and RANTES and to cell surface markers.
Supernatants from superficial cervical lymph node cells were examined
by ELISA for IFN, IL-4, and IL-10.
RESULTS. MIP-1 and IFN were present most frequently and most extensively
at peak disease but also were detectable in the choroid 8 days after
immunization, before clinical disease onset. MCP-1 and RANTES were
present at peak disease, but much less frequently. RANTES was
occasionally found in the choroid before clinical disease. By days 19
to 21 after immunization, although infiltrating cells were present,
there were only residual low levels of chemokine staining. MCP-1 and
RANTES were detected on CD3-positive cells and on some ED1-positive
cells, whereas MIP-1 was also associated with vessels and areas of
exudate. Lymph node cells cultured from animals with peak disease had
increased levels of IFN and IL-10, but for IFN this occurred only
after stimulation in vitro with retinal extract.
CONCLUSIONS. Although MCP-1 and RANTES were associated predominantly with cells
infiltrating the retina, MIP-1 was also associated with resident
cells. All three are likely to exacerbate EAU—MIP-1, to the
greatest degree.
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Chemokines, which act as chemoattractants and activators of specific
leukocytes at the site of inflammation may be involved in this influx
of inflammatory cells.4
Chemokines have been shown to be
likely to be involved in leukocyte recruitment in the eye in a study of
patients in which IL-8, IP-10, monocyte chemoattractant protein
(MCP)-1, regulated on activation of normal T-cell–expressed and
secreted (RANTES), and macrophage inflammatory protein (MIP)-1ß were
significantly increased in the aqueous humor during the active stages
of anterior uveitis.5
The chemokine family can be divided
into two major classes, CC and CXC, on the basis of differences in the
positions of cysteines within a conserved four-cysteine
motif.6
The CC chemokines, such as MIP-1, MIP-1ß,
RANTES, and MCP-1, -2, and -3 have powerful chemoattractant and
activator properties for monocytes and T cells,4
6
whereas
the CXC chemokines, such as IL-8 and those that, like IL-8, contain the
ELR motif, are particularly important in the attraction of
neutrophils.6
Because evidence suggests that the
predominant cells in EAU are macrophages and T lymphocytes, not
neutrophils,1
we examined the location of the CC
chemokines MIP-1, MCP-1, and RANTES during disease progression in
EAU.
Helper T (Th) lymphocytes may be categorized in terms of the cytokines
they produce, with Th1 cells producing IFN and IL-2 and Th2 cells
producing IL-4, IL-5, IL-6, and IL-13.7
Although IL-10 in
humans is produced by both Th1 and Th2 subsets, in rodents it is
classified as a Th2-type cytokine.8
It is thought that
Th1-type T cells contribute to the pathogenesis of organ-specific
autoimmune diseases.9
In patients with clinically active
and inactive uveitis, there is evidence of a Th1-type
response.10
11
Th1-type T cells in experimental
autoimmune encephalomyelitis (EAE), which models the human
demyelinating disease multiple sclerosis,12
and in
insulin-dependent diabetes mellitus13
have been shown to
have the ability to transfer disease. EAU has also been shown to be
mediated by Th1 cells,14
with susceptibility to EAU
related to ability to generate a Th1-type response.15
16
17
Chemokine production has been shown in some instances to be linked to
Th1 response. For example, in one EAE model, production of both
MIP-1 and RANTES could be correlated with Th1 responses and MCP-1
with Th2 responses.18
Th cell subtypes have also been
shown to carry receptors for different sets of chemokines, Th1 cells
with receptors for MIP-1, and RANTES.19
We therefore
examined the production of IFN alongside that of the chemokines to
determine how chemokine location during disease development in EAU is
related to a Th1 response. Location of the chemokines rather than site
of synthesis is likely to be important, because it is possible that
chemokines are presented and act at sites away from those at which they
have been produced—for example, production by inflammatory cells or
cells within the tissue and then immobilization and presentation on the
luminal surface of endothelial cells by proteoglycans.20
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Immunohistochemistry
After the animals’ death under terminal anesthesia using
CO2, eyes were embedded in optimal temperature
cutting compound (OCT, Tissue-Tek; BDH, Poole, UK), snap frozen in
isopentane-liquid N2 and stored at -30°C.
Consecutive 8-µm cryostat sections were prepared on poly
L-lysine-coated slides (BDH) and air dried overnight. For
detection of chemokines, the tissue sections were fixed in formaldehyde
(2%) for 20 minutes at 4°C and washed three times in buffer
containing saponin (Tris-buffered saline [TBS ]-0.1% white saponin
[BDH]23
). This buffer was used for the remainder of the
procedure, unless stated otherwise. Sections were incubated with 10%
swine serum in buffer containing avidin B blocking solution according
to the manufacturer’s protocol (Vector, Burlingame, CA) for 15 minutes
before overnight incubation with primary antibody (1:100) in buffer
containing biotin blocking solution (Vector). Primary antibodies to rat
MCP-1, MIP-1, and RANTES were polyclonal rabbit antibodies obtained
from PeproTech EC, Ltd. (London, UK). Control antibody was rabbit IgG
(PeproTech EC). IL-4 antibody was a goat anti-rat antibody (R&D Systems
Europe, Ltd., Abingdon, UK) and control goat IgG (R&D Systems Europe,
Ltd.), and sections were preincubated with 10% rabbit serum. Sections
were washed three times in buffer for 5 minutes with rocking before
incubation for 30 minutes with 1:100 biotinylated swine anti-rabbit
antibody (Dako, Ltd., Cambridge, UK), which had been preabsorbed with
10% heat-inactivated normal rat serum for 30 minutes (1:100
biotinylated rabbit anti-goat antibody for IL-4). After they were
washed, sections were incubated with streptavidin, biotinylated
alkaline phosphatase complex (Dako) for 30 minutes, according to kit
protocol before addition of fast red substrate solution.
For detection of cell surface marker proteins, sections were first
fixed in acetone for 10 minutes, air dried, and incubated in TBS for 30
minutes with the following primary monoclonal antibodies: OX6 (1:50),
ED1 (1:100), ED2 (1:100), R73 (1:50) and W3/25 (1:50), all from Serotec
(Oxford, UK). OX6 detects major histocompatibility complex (MHC) class
II molecules: ED1 and ED2, infiltrating blood-borne macrophages, and
resident tissue macrophages, respectively: R73 (T-cell ß receptor)
and W3/25 (CD4). Isotype control IgG (Dako) was used at the same
concentrations. Sections were washed three times in TBS before
incubation for 30 minutes with biotinylated rabbit anti-mouse antibody
(1:100, Dako), which had been preabsorbed with 10% normal rat serum
for 30 minutes. Signal was amplified and detected as for chemokine
detection. For IFN detection, sections were fixed in acetone as
described earlier and incubated with primary monoclonal antibody to
IFN (1:100, Serotec). The procedure was continued as described, but
the buffer used contained saponin.
All incubations were at room temperature and all chemicals were obtained from Sigma (Poole, UK), unless stated otherwise.
Sections stained for cell surface markers were used to grade the disease and obtain a semiquantitative assessment of severity of uveitis according to both structural–morphologic and infiltrative changes, by using a slightly modified customized version of the grading system established in this laboratory.24 Sections stained for chemokines were also assessed semiquantitatively in terms of the percentage area of the retina stained compared with an IgG control antibody. This was performed by observers masked to the stage of disease and antibodies used.
Dual-Immunofluorescence Microscopy
Sections obtained from animals 11 days after immunization and
demonstrating peak EAU were prepared, fixed, and blocked according to
the procedure for chemokines and incubated with the first set of
antibodies, CD3, ED1, IFN, MCP-1, and control IgG all 1:100 for 45
minutes. Buffer throughout the procedure contained saponin (TBS-0.1%
white saponin). Sections were then washed three times for 5 minutes
with rocking. Appropriate biotinylated secondary antibody was
preabsorbed with 10% normal rat serum for 30 minutes before incubation
with the sections for 45 minutes and washing as before. Sections were
then incubated with 1:50 streptavidin Texas red (Amersham Life Science,
Ltd., Buckinghamshire, UK) for 45 minutes in the dark. Sections were
washed, and this and all subsequent procedures were performed with
light excluded. The second set of antibodies, anti-rat RANTES, MCP-1,
and MIP-1 at 2 mg/ml, were labeled using a protein-labeling kit
(Alexa 488; Molecular Probes, Eugene, OR) according to the
manufacturer’s instructions. They were diluted to 1:25 and
preincubated with 10% normal rabbit serum for 30 minutes before
addition to the sections and overnight incubation. Slides were washed
three times for 30 minutes each wash with rocking. All incubations were
at room temperature unless stated otherwise. Immunofluorescent staining
was visualized using a laser scanning confocal imaging system (model
1024; Bio-Rad Laboratories, Ltd., Hemel Hempstead, UK). Retinal cells
that were labeled fluorescently were counted in each high-power field.
Culture of Lymph Node Cells
Superficial cervical lymph nodes were disrupted by passing them
through a 250-µm stainless steel sieve. After two washes in RPMI,
cells were resuspended at 5 x 105/ml in
RPMI with 4 mM L-glutamine, 100 IU/ml penicillin, 100
µg/ml streptomycin, and 10% fetal bovine serum (FBS) and cultured
for 72 hours, with or without retinal extract at 0.8 mg/ml.
Supernatants were harvested by centrifugation at 300g for 10
minutes and stored at -80°C until ELISA.
Enzyme-Linked Immunosorbent Assay
Immunoreactive cytokine was quantified by sandwich ELISA for rat
IFN, IL-4, and IL-10 (Biosource International, Camarillo, CA),
according to the manufacturer’s instructions. Supernatants were added
in duplicate, and the cytokine being tested was revealed with a
monoclonal antibody conjugated to horseradish peroxidase. The minimum
amount of cytokine detectable using these assays was less than 13 pg/ml
for IFN, less than 2 pg/ml for IL-4, and less than 5 pg/ml for
IL-10.
Statistical Analysis
Experiments were repeated a minimum of three times, with four
animals in each experimental group. Data are presented as the mean ± SEM. The statistical significance of the results was assessed using
Student’s unpaired two-tailed t-test (GraphPad Software,
Inc., San Diego, CA).
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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, MCP-1, RANTES,
and IFN (Fig. 1B)
, IFN, and, very rarely, RANTES (Fig. 1D)
could be detected in the
choroid. IFN staining could be detected infrequently (Fig. 1A)
in
the retina.
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and IFN were
detected strongly at this stage, associated predominantly with
infiltrating cells and with granuloma formation and vasculitis (Table 1
, Figs. 1F
1G ). MCP-1 and RANTES were also detected at this stage of
EAU, although less frequently than MIP-1 and IFN (Table 1
), and
associated with more discrete patches of infiltrating cells (Figs. 1H
1I) . IL-4 was not seen (Fig. 1J)
. MIP-1 and MCP-1 were sometimes
detected associated with choroidal and retinal vessels, as well as
infiltrating cells; however, dual-immunofluorescence staining indicated
that in most cases they did not localize to the same cells (Fig. 2A) . At this stage staining for IFN, MIP-1, MCP-1, and RANTES was also
apparent in the ciliary body and iris.
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, MCP-1,
and IFN were detected, but to a much lesser extent than at peak
disease (Table 1)
. RANTES, however, was not detected.
To identify more clearly which cells were producing the majority of the
chemokines in EAU, dual-immunofluorescence microscopy was performed on
sections showing peak EAU. More ED1-positive cells were detected in the
infiltrate (>75%) than CD3-positive cells; however, whereas most of
the CD3-positive cells produced chemokines, only a small percentage of
the ED1-positive cells did (Table 2A)
. MCP-1 and RANTES were detected on CD3-positive cells mainly and on some
ED1-positive cells (Table 2B)
. Unlike MCP-1 and RANTES expression,
which was predominantly associated with infiltrating inflammatory
cells, substantial MIP-1 expression was also seen associated with
the exudate in the subretinal space (Fig. 2B)
and with vessels (Figs. 2C
2D)
.
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and IL-10 above background were not detected in
cultures of lymph node cells from control animals or immunized animals
showing no signs of EAU either by clinical or histologic grading (day
5). However, cells cultured from animals with peak disease (day 12), as
determined clinically and histologically, had increased levels of both
IFN and IL-10 (Fig. 3)
. In the case of IFN, this increase was only apparent after
stimulation of the cultures with retinal extract, indicating that
increased IFN production was a result of antigen-specific T cells
present in the cultures and that a Th1-type response was occurring.
This increase in IFN production was significant (P < 0.05) when compared with cultures, whether unstimulated with retinal
extract or from undiseased animals or animals at day 21. IL-10 was
significantly (P < 0.05) increased in diseased animals
compared with undiseased or those at day 21, whether or not the
cultures were stimulated with retinal extract, indicating that IL-10
production was not a function of antigen-specific T cells. By day 21,
both IFN and IL-10 had decreased to levels comparable with those of
undiseased animals. IL-4 was not detected in any of the samples (data
not shown).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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, MCP-1, and RANTES as the autoimmune inflammatory
disease EAU developed. Of the three chemokines investigated, MIP-1
appeared to be most closely associated with the development of EAU. It
was present most frequently and most extensively, particularly at peak
disease, but also was detectable in the choroid 8 days after
immunization, before clinical disease onset.
The location of chemokines during EAU was examined, rather than their
site of production. The use of saponin,23
however, locates
chemokines within a cell as well as on the cell surface.
Dual-immunofluorescence staining indicated that MIP-1, unlike MCP-1
and RANTES, was not only associated with infiltrating cells but
also with endothelial cells and other non-CD3-positive and
non-ED1-positive cells, which may include microglia. In EAE, astrocytes
produce MIP-1.25
26
MIP-1, in addition to its
detection, specifically associated with cells, was also shown to be
associated with acellular exudates in the subretinal space. These
acellular exudates are a result of lysis and fragmentation of the
photoreceptors and vessel leakage during peak disease, and areas of
fibrin deposition may be present.1
The ability of MIP-1
to bind to proteoglycans27
may account for its association
with these exudates.
In EAE, mRNA expression for a variety of chemokines including MIP-1,
MIP-1ß, RANTES, and MCP-1 has been detected before the onset of
clinical disease and throughout acute clinical disease.28
As with our findings in EAU, MIP-1 expression appeared to be of
particular significance in the pathogenesis of some EAE models. In EAE
induced by transfer of proteolipid protein (PLP)-specific T cells into
SJL/J mice, antibodies to MIP-1, but not to MCP-1 or RANTES, could
inhibit the development of acute and relapsing EAE, as well as the
infiltration of mononuclear cells into the central nervous system
(CNS).18
25
However, using DNA vaccines in a model in
which Lewis rats were immunized with myelin basic protein (MBP), it was
shown that vaccines for MIP-1 or MCP-1 prevented EAE, whereas RANTES
vaccine had no effect.29
Further evidence for a role for MCP-1 in autoimmune inflammatory
disease has been provided by the MBP model in which EAE and anterior
uveitis develops in Lewis rats. In this model MCP-1 was detected
preclinically in the iris-ciliary body and lumbar spinal cord,
increasing as disease developed and coinciding with expression of IL-2
and IFN.30
It was suggested that MCP-1 contributed to
the initial recruitment of inflammatory cells into both the eye and
CNS. However, in our study MIP-1 rather than MCP-1 appeared more
likely to be important in early recruitment, because it was detected
before MCP-1, at day 8 after immunization. This difference may be
linked to the less acute nature of posterior uveitis.
Both MIP-1 and MCP-1 were detected in association with choroidal and
retinal vessels, both with endothelial and perivascular cells. However,
dual-immunofluorescence microscopy indicated that they did not localize
to the same cells. Similar findings have been described at the
blood–brain barrier, where separate binding domains for MIP-1 and
MCP-1 have been identified on the parenchymal surface of brain
microvessels.31
IFN detection in the tissue sections paralleled disease development
and also MIP-1 production. As with MIP-1, IFN was also
detectable in the choroid at day 8 after immunization, extensive at
peak disease, and much reduced by days 19 to 21 after immunization.
This supports earlier studies on IFN mRNA expression in
EAU.32
33
IFN is produced by T cells, but
dual-immunofluorescence staining clearly showed that MIP-1 was
produced by other cells in addition to T cells. IFN production by T
cells may be stimulating MIP-1 production by macrophages. In
contrast, in rheumatoid arthritis T cells from synovial fluid express
MIP-1ß and RANTES in the absence of IL-2 and IFN-, and the
investigators speculate that these chemokines downregulate the
expression of specific T-cell–secreted cytokines, such as IL-2 and
IFN-, which can alter the Th1-to-Th2 balance.34
There
is no evidence to suggest that this happens in EAU.
The involvement of IFN in EAU indicated by immunohistochemistry was
corroborated by the production of IFN by cells cultured from the
draining lymph nodes, which was increased at peak disease but only by
antigen-specific cells. IL-4 was not detected, but IL-10 production was
increased at peak disease; however, unlike the increase in IFN, this
increase occurred both with and without antigen stimulation. IL-10 can
indicate a Th2 response, but IL-10 is also produced by macrophages and
is therefore not as definitive a marker of Th subtype as is IFN. It
is likely in this situation, given the substantial macrophage presence,
that IL-10 is more indicative of macrophage activation.
By day 21 after immunization, both IFN and IL-10 production by
draining lymph node cells had returned to background levels, although
infiltrating cells were still present in the retina, providing no
evidence that an increased Th2 response is important for disease
resolution and indicating, on the contrary, that a decrease in Th1
response is more significant in this respect. The absence of a Th2
cytokine increase in spontaneous remission of EAE35
and
studies on the basis for genetic susceptibility to EAU also indicate
that an inhibited Th1 response may be more important than an elevated
Th2 response.15
16
The importance of IFN in rat EAU has
previously been shown in transgenic animals in which constitutive
ocular expression of IFN led to early onset and increased severity
of EAU.36
In conclusion, the presence of the chemokines MIP-1, MCP-1, and
RANTES in the choroid and retina during the course of EAU is likely to
aid the cellular infiltration of both antigen-specific T cells and
effector macrophages. These chemokines may not be involved in the
actual initiation of cellular infiltration, as they were not detected
before infiltrating cells. MIP-1, in particular, was found
concomitant with the Th1 cytokine IFN, but this may be coincidental
rather than causal, in that both are products of activated infiltrating
cells. As there is no evidence for MIP-1 before IFN, MIP-1 may
not alter the Th1-to-Th2 balance by attracting Th1 cells over Th2. T
cells may produce MIP-1 and also stimulate macrophages to produce
MIP1 through IFN. Production of MIP-1 may then result in a
cascade effect by promoting the entry of more monocytes and T
lymphocytes into the retina.
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Footnotes |
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Submitted for publication July 5, 2000; revised January 3, 2001; accepted January 18, 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: Isabel J. Crane, Department of Ophthalmology, University of Aberdeen Medical School, Foresterhill, Aberdeen AB25 2ZD, UK. i.j.crane{at}abdn.ac.uk
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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4 integrin by CD4 T cells is required for their entry into brain parenchyma J Exp Med 177,57-68 in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis J Immunol 155,5003-5010[Abstract]
-dependent mechanism J Immunol 159,5132-5142[Abstract]
) production in vivo in experimental autoimmune uveoretinitis Immunology 75,463-467[Medline][Order article via Infotrieve]
increases the severity and accelerates the onset of experimental autoimmune uveitis in transgenic rats J Immunol 162,510-517This article has been cited by other articles:
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