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MediCity Research Laboratory, Turku University, and National Public Health Institute, Turku, Finland
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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4
7/41-integrin-VCAM-1,
L-selectin-peripheral lymph node addressins, and CD44). Of these, only
ICAM-1 significantly supported binding of immunoblasts. In contrast,
P-selectin glycoprotein ligand-1-P-selectin interaction accounted for
practically all synovial adherence of mucosal macrophages. In addition,
blocking of vascular adhesion protein-1 significantly inhibited binding
of all these leukocyte subsets to joint vessels. We conclude that
different leukocyte populations derived from inflamed gut bind avidly
to synovial vessels using distinct repertoire of adhesion molecules,
suggesting that their recirculation may contribute to the development
of reactive arthritis in inflammatory bowel
diseases. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Normally naive lymphocytes continuously recirculate between different lymphoid tissues of the body (8, 9, 10). When a lymphocyte finds its cognate Ag in Peyer’s patches, which represent the organized lymphoid tissue of the gut, the cell starts to divide and differentiate. The progeny of activated immunoblasts is ultimately transferred back to the circulation via the efferent lymphatics. In contrast to the random migration pattern of naive cells, these effector cells now have the remarkable capacity to selectively re-enter the intestinal tissues, especially lamina propria, to exert their immune functions (11, 12).
Lymphocytes as well as other types of leukocytes use multiple adhesion
and activation molecules to exit from the circulation
(8, 9, 10). Normally L-, E-, and P-selectins and their
carbohydrate-containing mucin-like counterparts (like P-selectin
glycoprotein ligand-1 (PSGL-1) for P- and E-selectin, and
peripheral lymph node addressins (PNAd) for L-selectin) mediate the
initial phases of extravasation (13). However, CD44 and
vascular adhesion protein-1 (VAP-1) also contribute to the rolling of
blood-borne cells (14, 15). Chemokines are thought to be
the key players in converting loosely rolling cells into stably bound
cells (16). This takes place by activation of leukocyte
CD18 integrins and 47
and 41
(17), which then bind to their endothelial
counter-receptors belonging to the Ig superfamily (ICAM-1, ICAM-2, and
VCAM-1). Finally, the leukocyte leaves the blood by transmigrating
between the endothelial cells into the tissue stroma by poorly
characterized mechanisms (18).
Binding of lamina propria lymphocytes from normal gut to different vascular beds and the adhesion molecules involved have been described (6, 19). However, gut leukocytes in IBD include an inflammation-associated population, and binding of IBD-originating mucosal leukocytes to mucosal and lymph node vessels is different from that of normal mucosal leukocytes (20, 21). Therefore, we studied here whether mononuclear leukocytes isolated from gut specimens of patients with IBD would bind to vessels in joints and which adhesion molecules mediate the interactions between IBD gut leukocytes and synovial vasculature. Our results indicate that different subsets of mucosal immune cells use profoundly distinct adhesion molecules to attach to vessels in synovial membrane. These leukocyte-endothelial interactions may regulate homing of activated, gut-originating immunoblasts and macrophages into distant joints and hence help to explain the onset of reactive arthritis following IBD.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Isolation of lamina propria leukocytes was performed according to the method described by MacDermott et al. (19, 22). In brief, surgical specimens of the affected gut from 17 IBD patients (10 Crohn’s disease and 7 ulcerative colitis) were obtained over 5 years and were analyzed freshly each time. Lamina propria was dissected free, epithelial cells were detached by EDTA treatments, and leukocytes were released from the remaining lamina propria pieces by overnight digestion with type I collagenase. Mononuclear cells were collected by Ficoll centrifugation.
Synovial samples from chronically inflamed synovectomy specimens were collected from eight patients. Normal synovial tissue was removed from a cadaver donating bone transplants. All tissue collection procedures were approved by local ethical committees.
Monoclonal Abs
The mAbs against leukocyte homing receptors and endothelial
adhesion Ags used in this study are listed in Table I
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Isolated mononuclear cells were stained with the primary mAbs and appropriate FITC-conjugated second stage reagents for flow cytometry as previously described (19). At least 10,000 cells were analyzed using a FACScan instrument and CellQuest software (Becton Dickinson, San Jose, CA).
In vitro frozen section assay
The nonstatic Stamper-Woodruff assay that has been successfully used for studying the functions of different classes of cell adhesion molecules was used for the binding experiments (6, 19). To that end, 8-µm frozen sections were cut from synovial specimens onto microscopic slides with predrawn wax-pen circles and incubated with saturating concentrations of mAbs against endothelial adhesion molecules for 30 min at 7°C. Lamina propria leukocytes in suspension were pretreated with an irrelevant negative control mAbs, added to sections (2 x 106 cells in 50 µl of RPMI 1640 medium supplemented with 10% FCS) under constant rotation (60 rpm), and allowed to bind for another 30 min. Thereafter, the nonadherent cells were tilted off, and the adherent cells were fixed to the sections with glutaraldehyde. In other experiments aliquots of the lamina propria cells were preincubated with anti-homing receptor mAbs before adding the cells on top of synovial sections. Thereafter, the assay was continued as described above.
The numbers of small lymphocytes, large immunoblasts, and macrophages bound to synovial vessels were counted under darkfield microscopy. The characteristic size and light-scattering patterns allow clear distinction among these three leukocyte subtypes in this assay (6, 19). Large immunoblasts were defined as clear cells with a diameter at least 1.3 times (and two-dimensional surface area >1.75 times) larger than that of small lymphocytes. Macrophages were large cells with ruffled membrane, which appeared white in the darkfield microscopy. At least 100 vessels were counted from each sample in each individual experiment. Altogether the total numbers of vessel-adherent small lymphocytes, immunoblasts, and macrophages counted in the negative controls were 1079, 670, and 1415 cells, respectively, from 1125 vessels. The effect of mAbs was expressed as the percentage of bound cells in the presence of the given mAb compared with the number of bound cells in the presence of appropriate noninhibiting control mAb. The numbers of independent assays are shown in the figures. The proportions of small lymphocytes, immunoblasts, and macrophages in the input population were also counted microscopically to assess the relative adhesiveness of the three leukocyte subclasses.
Transfectant binding assay
Adhesion of lamina propria cells to endothelial cells (Ax) transfected with an expression plasmid encoding VAP-1 or with a vector only was analyzed using a modification of a previously described protocol (23). In brief, Ax cells are a spontaneously immortalized cell line originating from endothelial cells of rat high endothelial vessels. The parental cells have lost their capacity to bind lymphocytes in vitro, but VAP-1 transfection reconstitutes the adhesion cascade (23, 24). The VAP-1 or mock (=control) transfectants were plated on microscopic slides within wax-pen circles. When the cells were confluent, 2 x 106 leukocytes were added to the circle and allowed to bind under constant rotation (60 rpm) at 7°C for 30 min. The nonbound cells were gently washed off by two dippings in cold RPMI 1640, and the adherent leukocytes were fixed to endothelial monolayers in 1% glutaraldehyde. The slides were evaluated under normal light microscope, and the number of adherent leukocytes in predefined area of 6.25 mm2 was counted using an ocular grid. The relative adhesion ratio of 1.0 was arbitrarily assigned to describe the number of PBL bound to the Ax VAP-1 transfectants. The relative adhesion ratios of other leukocyte populations were compared with that by taking into account the percentage of each leukocyte subclass in the input population.
Statistical methods
The mean ± SEM of the binding experiments are shown. The inhibitory effect of mAbs was compared with negative control treatments using paired, two-tailed Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Because homing of mucosal leukocytes to joints might be important
in the pathogenesis of reactive arthritis following gastrointestinal
inflammation or infection, we analyzed whether leukocytes isolated from
lamina propria of gut specimens obtained from IBD patients can adhere
to synovial vessels. Using an in vitro adhesion assay, it was evident
that three easily identifiable leukocyte subclasses from IBD gut (small
lymphocytes, large immunoblasts, and macrophages) all specifically
interacted with chronically inflamed synovial vessels (Fig. 1A). In contrast, a completely
normal synovial membrane is very thin and contains few vessels;
consequently, very few leukocytes bound to these vessels, precluding
any meaningful further experimentation (data not shown). In the
inflamed membrane the relative adhesiveness of the three gut-derived
leukocyte types was evaluated as follows. The numbers of different cell
types bound per one vessel were counted. The percentage of each cell
type in the input population was also microscopically counted. Then,
value 1.0 was assigned to the number of small lymphocytes bound per one
vessel, and the relative adhesion ratios (assuming that there would be
as many (absolute cell number) immunoblasts and macrophages in the
starting population as there were small lymphocytes) for the two other
cell populations were calculated. These results showed that
immunoblasts bound 2.5 ± 0.7 times better (n =
13) and macrophages 14.8 ± 4.3 times better (n =
4) to synovial HEV than did small lamina propria lymphocytes. Taken
together, all subpopulations of gut leukocytes bound well to activated
joint vessels, and especially the synovia-binding capacity of activated
gut immunoblasts and macrophages was remarkable.
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To study which lymphocyte-homing receptors mediate the interaction
between small lymphocytes and synovial vessels, we took advantage of
function-blocking mAbs and the nonstatic in vitro frozen section assay.
Inhibition of lymphocyte L-selectin, 4
integrins, and CD44 resulted in a statistically significant inhibition
(Fig. 2). Because better inhibition was
obtained by blocking 4 integrins than by
blocking 7 integrins, both
41 and
47 heterodimers
probably contribute to synovial binding, especially because
41 binds better to
VCAM-1 than does 47
(25, 26) (although possible differences in the affinities
of mAbs should be taken into account as well). Marginal inhibition was
also observed with function-blocking mAbs against PSGL-1 and CD18. On
the endothelial side, preincubation of synovial sections with mAbs
against ICAM-1, VCAM-1, PNAd, and VAP-1 yielded significant inhibition
of binding of small lymphocytes from IBD guts to joint vessels. In
contrast, blocking of E- or P-selectin or ICAM-2 did not significantly
alter this interaction. Thus, small lamina propria lymphocytes isolated
from IBD gut use VAP-1, CD44, and interactions between CD18 integrins
and ICAM-1, 4 integrins and VCAM-1, and
L-selectin and PNAd to bind to synovial vessels.
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Large lymphocytes activated in the IBD gut used a completely
different molecular repertoire to adhere to synovial vessels (Fig. 3). On lymphocyte side blocking of
PSGL-1, L-selectin, CD44, 4 integrins,
7 integrins, and CD18 were all inefficient in
significantly perturbing the interaction. Analyses of the contribution
of endothelial adhesion molecules revealed that only VAP-1 (by 46%)
and ICAM-1 (by 23%) markedly inhibited this interaction, whereas the
other vascular molecules played no significant role. In fact,
pretreatment of synovial sections with anti-ICAM-2 mAb actually
increased the number of synovia-adherent immunoblasts. Hence, activated
mucosal immunoblasts from IBD gut mainly use VAP-1 in synovial
adherence, but other, molecularly undefined mechanisms apparently
contribute significantly to this interaction.
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Because mucosal macrophages also avidly adhered to synovial
vessels and might play an important role in carrying gut-derived Ags to
joints, the molecular nature of their synovial adherence was
determined. This interaction was clearly selectin dependent, because
blocking of PSGL-1 on macrophages or its counter-receptor P-selectin on
synovial vessels practically abolished binding of this leukocyte subset
(Figs. 1
B and 4). Also
E-selectin and VAP-1 on the endothelial site contributed significantly
to this interaction (Fig. 4). Thus, blocking of the PSGL-1-P-selectin
interaction almost totally prevents synovial adherence of mucosal
macrophages originated from IBD bowel, whereas it has no significant
effect on the same adhesive event in the case of lamina propria
lymphocytes.
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Because the synthesis of PSGL-1 on mucosal leukocytes has not been
analyzed previously, we subjected the leukocytes isolated from lamina
propria of IBD patients to immunofluorescence and FACS analyses. These
studies revealed that significant numbers of the cells from all subsets
of mucosal leukocytes stained with an anti-PSGL-1 mAb, although the
PSGL-1 expression was weaker than in blood lymphocytes or monocytes
(Fig. 5). The expression was brightest in
macrophages and immunoblasts, but 
30% of small lymphocytes also
displayed PSGL-1 positivity. Because it was the macrophages, that
showed by far the strongest PSGL-1 dependence in their synovial
binding, these data suggest that, like on PBL (27, 28),
the expression of PSGL-1 on different leukocyte subpopulations in the
lamina propria does not directly correlate to its functional
activity.
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Because VAP-1 was the only endothelial adhesion molecule involved
in binding of all mucosal leukocyte subsets to synovial vessels, we
further examined these interactions using a transfectant model. Ax
endothelial cells stably transfected with VAP-1 are >95% VAP-1
positive, whereas VAP-1 is completely absent from the mock
transfectants (data not shown) (23). These assays showed
that small lymphocytes, immunoblasts, and macrophages all adhered to
nonstimulated Ax cells transfected with VAP-1 (Fig. 6 and Table II). Only negligible binding was
detectable to mock transfectants. When the binding to mock
transfectants was subtracted from the binding to VAP-1 transfectants,
and the frequency of these three mucosal leukocyte subsets in the input
population was determined, we could estimate the relative avidity of
binding (Table II). These data from four independent experiments
revealed that all gut-derived leukocyte types bound better to Ax VAP-1
transfectants than did lymphocytes isolated from peripheral blood.
Moreover, among gut cells immunoblasts bound best to VAP-1
transfectants (relative adhesion ratio, 4.2), followed by small
lymphocytes and macrophages (relative adhesion ratios, 3.4 and 2.9,
respectively). These results are in line with the data from frozen
section assays, because the contributions of VAP-1 to the binding of
these leukocyte subsets to synovial vasculature were also almost equal.
In contrast, P-selectin, which accounts for the superior adhesion of
mucosal macrophages to synovial venules, is lacking from these
transfectants (24). Thus, VAP-1 can indeed support binding
of all mononuclear leukocyte classes isolated from IBD gut.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This study is the first one in which synovial binding of leukocytes
isolated from the gut of patients suffering from IBD (hereafter
referred to as IBD lymphocytes/immunoblasts/macrophages) to synovial
vasculature is analyzed. Previously we have analyzed the binding of
leukocytes isolated from normal, noninflamed gut (hereafter called
normal gut lymphocytes/immunoblasts/macrophages) to vessels in gut,
peripheral lymph nodes, and synovium. We have also analyzed binding of
IBD cells to mucosal and lymph node venules. From those large materials
we know that our synovial samples always contain E-selectin-,
P-selectin-, VAP-1-, VCAM-1-, ICAM-1-, and ICAM-2-positive vessels and
completely lack MAdCAM-1. Because PNAd is absent from 20% of synovial
samples, care was taken to confirm its presence in the samples used for
adhesion assays. Earlier flow cytometric analyses by us and others have
revealed that IBD leukocytes have the LFA-1int,
CD44high,
7int,
4 integrinlow to int,
L-selectinlow phenotype (21, 29).
Here we further showed that the cells are modestly positive for
PSGL-1.
Comparison of the present results with those from studies with normal
gut cells reveals significant alterations in the behavior of IBD
leukocytes (Table III). Direct comparison
of these data can be performed, because the protocols for cell
isolation and adhesion assays have remained exactly the same, and they
were all performed in the same laboratory and analyzed by the same
persons. In fact, due to the long collection period needed for human
gut resectants, the assays with IBD and normal cells have been
performed at an overlapping time period, and hence even many of the
same synovial samples have been used for both cell types. Our published
results show that normal gut lymphocytes can also bind to synovial
vessels (6, 19). Of lymphocyte-homing receptors, only
4 integrin and CD44 blocked this interaction
by 25–30%, and on endothelial cells only VAP-1 supported the binding.
Interestingly, 7 integrin or VCAM-1 had no
effect on binding of normal gut lymphocytes to synovial vessels. Thus,
small IBD lymphocytes displayed a much more promiscuous usage of
adhesion molecules in their synovial adherence. In regard to
4 integrins the observed difference indicates
that normal gut lymphocytes may only use
41 for synovial
adhesion, while both
41 and
47 may contribute to
the synovial adherence of small IBD cells. The finding that multiple
adhesion molecules contribute to binding of small IBD cells is in
agreement with the concept that the selectivity of gut homing is lost
in a severely inflamed gut (21, 30, 31). Under normal
conditions small lymphocytes in lamina propria are thought to be mainly
memory cells that gain entrance into this nonorganized lymphoid organ
primarily by binding of
47 integrin to
mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Under
chronic inflammation, many other inflammation-inducible endothelial
adhesion molecules appear in lamina propria (21, 32),
which help to recruit cells belonging to nonmucosal pools into the
intestine as well. Our present findings indicate that isolated IBD
small lymphocytes are still equipped with the capacity to bind to these
other endothelial determinants. In addition, the residence of IBD
leukocytes in an inflammatory microenvironment may increase the
functional activity of other homing receptors as well
(33). Comparison of the present results to earlier data
also shows that small IBD lymphocytes from gut bind to synovial vessels
4 times and IBD blasts 10 times better than small lymphocytes from
peripheral blood of IBD patients, showing selectivity of synovial
adherence of gut-originating lymphocytes.
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). These data suggest that resident and
additional IBD gut-infiltrating immunoblasts mainly use the same
endothelial determinants for recognizing synovial vasculature. IBD macrophages bound very well to joint vessels. Although these leukocytes are thought to be mostly sessile cells, there is evidence that tissue macrophages can leave the stroma by reverse transmigration and are indeed found in efferent lymph (34, 35). Therefore, these cells can be envisioned to play an important role in carrying mucosal Ags into distant tissues such as synovium. In joints gut-originated memory cells and immunoblasts, which have already become activated in the intestine against the same Ag, may then very rapidly trigger a reactive inflammation at this nonintestinal location. We are aware that our hypothesis faces two approximations. Firstly, due to the unavailability of surgical synovial samples from joints that are healthy or at the early stages of arthritis progression, the use of chronically inflamed samples was mandatory for us. Secondly, we have measured leukocyte-endothelial cell interactions in vitro using an assay that well reflects but does not necessarily fully reproduce the in vivo migration pathways. Nevertheless, it is the best method available to study leukocyte adhesion to physiologically relevant endothelial cells expressing natural adhesion molecules in humans. Bearing these limitations in mind, we believe that our findings are indicative of a possible connection between mucosal and synovial homing during the pathogenesis and/or aggravation of reactive arthritis in IBD.
Gut-derived macrophages were exquisitely sensitive in their synovial recognition to blockade of the P-selectin-PSGL-1 pathway. Interestingly, Ag-fed macrophages are able to elicit brisk induction of endothelial P-selectin when they are incubated on endothelial cells (36). Thus, these Ag-processing cells might be able to trigger the onset of inflammatory changes on synovial vasculature, which would then lead to increased immigration of this leukocyte class. Moreover, the contribution of VAP-1 to synovial targeting of macrophages derived from IBD bowel deserves special mention. VAP-1 is not involved in blood monocyte adhesion to inflamed vessels in lymph nodes, nor does it support synovial adherence of macrophages isolated from noninflamed gut (6, 15). Hence, in the inflamed gut some nonphysiological stimuli involved in the synthesis of the as yet uncharacterized leukocyte ligand of VAP-1 apparently takes place, possibly on those macrophage subtypes that appear to be unique for IBD intestine (37).
We show here that lamina propria leukocytes from IBD and normal gut use
distinct adhesion mechanisms to recognize synovial vessels.
Collectively, our analyses of IBD leukocyte binding to mucosal and
synovial vasculature suggest that selective interference of either
adhesive interaction would be possible. The basal leukocyte trafficking
to gut takes place mainly via MAdCAM-1, which, in contrast, is
completely absent from synovial vessels (38). Thus,
interference with MAdCAM-1 or its
47 integrin receptor
is effective in ameliorating IBD-like inflammations in the gut
(39, 40), but probably contributes very little or not at
all to leukocyte trafficking to inflamed joints. Blockade of VAP-1, in
contrast, would severely affect leukocyte binding to joints, whereas it
only minimally influences lymphocyte trafficking into normal gut
(41). Moreover, when selective blockade of gut-originating
macrophages to joint would be desirable, interference with the
PSGL-1-P-selectin pathway would be most feasible. Future trials with
antiadhesive therapy will eventually show whether the modulation of
cell trafficking will be useful as an adjunctive therapy to combat the
disabling joint complications of Crohn’s disease and ulcerative
colitis.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Marko Salmi, MediCity Research Laboratory, University of Turku, Tykistökatu 6A, FIN-20520 Turku, Finland.
3 Abbreviations used in this paper: IBD, inflammatory bowel diseases; PSGL-1, P-selectin glycoprotein ligand-1; PNAd, peripheral lymph node addressins; VAP-1, vascular adhesion protein-1; MAdCAM-1, mucosal addressin cell adhesion molecule-1.
Received for publication October 2, 2000. Accepted for publication January 18, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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E7 and its ligands E-cadherin in the synovium of patients with rheumatoid arthritis. Scand. J. Immunol. 44:293.[Medline]
47 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 74:185.[Medline]
4 integrin binding interfaces on VCAM-1 and MAdCAM-1: integrin binding footprints identify accessory binding sites that play a role in integrin specificity. J. Biol. Chem. 272:19429.47, a gut homing integrin, by circulating and mucosal T cells in colonic mucosal inflammation. Gut 40:241.4 integrin monoclonal antibody. J. Clin. Invest. 92:372.
7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) reduce inflammation in the colon of scid mice reconstituted with CD45RBhigh CD4+ T cells. J. Immunol. 158:2099.[Abstract]
47-mediated adhesion to vascular cell adhesion molecule-1, mucosal addressin-1, fibronectin, and lymphocyte aggregation. J. Immunol. 153:3847.[Abstract]
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