Expression of KIR and C-type lectin receptors in Behçet's disease
G. Saruhan-Direskeneli1,
F. A. Uyar1,
A. Çefle2,
S. Ç. Onder2,
E. Ek
io
lu-Demiralp3,
S. Kamal
,
M. Inanç2,
L. Ocal2 and
A. Gül2
1Department of Physiology and 2Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University and 3Department of Immunology, Marmara University Medical Faculty, Istanbul, Turkey.
Correspondence to: G. Saruhan-Direskeneli, Department of Physiology, Istanbul Faculty of Medicine, 34093 Çapa, Istanbul, Turkey. E-mail: gsaruhan{at}istanbul.edu.tr
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Abstract
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Objective. Behçet's disease (BD) is a multisystemic disorder with a possible underlying pathology of immune-mediated vasculitis. Genetic susceptibility associated with HLA-B*51 and B*2702 has been implicated in its pathogenesis. Considering the recently defined regulatory mechanisms of NK cells through HLA class I binding receptors, we hypothesized that interactions of NK and T cells through the NK receptors may be important in the pathogenesis of BD.
Methods. The impact of different expression patterns of HLA-recognizing receptors on NK or T cells was analysed in 51 patients with BD and 32 healthy controls. We used flow cytometry to investigate the expression of KIR3DL1 from the polymorphic killer immunoglobulin-like receptor (KIR) family, which binds a shared HLA-Bw4 motif on HLA-B51 and *2702 alleles, and CD94 from the conserved C-type lectin receptor family, which binds HLA-E. Thirty-three of the BD patients and 19 of the controls carried the same HLA-Bw4 motif.
Results. CD3+ T cells were increased in patients with BD compared with controls (81 vs 75%, P = 0.001), whereas the NK cells did not show any difference between the two groups. Increased expression of CD94 in BD was observed on CD16+CD56+ cells (66 vs 57, P = 0.04) and on CD3+ (7.7 vs 4.0, P < 0.001) and CD3+CD56+ (44 vs 35, P = 0.02) T cells. KIR3DL1 expression on the NK and T cells was not statistically different between the two groups. No effect of HLA-Bw4 motif was observed on the expression of CD94 and KIR3DL1 in both the patients and the controls.
Conclusion. The absence of a correlation between KIR3DL1 expression and HLA-Bw4 motif confirms previous work reporting that the expression of these molecules is regulated separately. Increased expression of CD94 may suggest that NK receptors play a pathogenic or regulatory role in BD.
KEY WORDS: Behçet's disease, NK cell, KIR3DL1, CD94, HLA-B51, HLA-Bw4.
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Introduction
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Behçet's disease (BD) is an inflammatory disorder characterized by recurrent attacks of oral and genital aphthous ulcerations, uveitis and skin lesions [1]. It is now recognized as a systemic disease also affecting the joints, all types and sizes of blood vessels, the lungs and the central nervous and gastrointestinal systems, with vasculitis as the main underlying pathology.
The aetiopathogenesis of BD is unknown. However, immunological abnormalities triggered by some microbial agents or other environmental factors in genetically susceptible individuals are claimed to play an important role. Both innate and adaptive immune systems are activated in BD, and there is a proinflammatory and Th1 type of cytokine profile [2, 3].
Natural killer (NK) cells are lymphocytes of innate immunity that both exert cytotoxic activity and produce cytokines. However, an increased number of NK cells, with lower activity, has been reported in the peripheral blood of patients with active BD [4, 5]. An elevated number of NK cells with a high anti-candidial index in the inactive stage of BD, compared with healthy controls, has also been shown [6, 7]. More recently, increased expression of CD16 or CD56 antigens on peripheral blood CD4+ cells of BD patients without an increase in NK cells has been demonstrated [8]. The proportion of T lymphocytes expressing both T-cell and NK-cell markers, CD56+ T cells (a subgroup of natural killer T cells), has also been found to be higher in BD patients compared with patients with other causes of uveitis [9]. Hence, the data on the involvement of NK cells in the pathogenesis of BD are still controversial.
Recent developments in NK cell research have revealed broad functional diversity of these cells. The clonal diversity of NK cells is due to the combinatorial expression of different cell surface molecules, including several receptors for polymorphic epitopes of MHC class I. The class I specificity of individual NK cells is determined by an array of receptors present at the cell surface [10]. The first group of NK receptors, the killer immunoglobulin-like receptors (KIR), bind to conserved epitopes shared by different allelic groups of HLA class I molecules, and engagement of these receptors has been shown to be associated with selective inhibition or activation of NK- or T-cell-mediated cytotoxicity [10]. A member of this group of receptors, KIR3DL1 (p70), found on NK cells, binds residues 7783 of HLA-B alleles, which have been designated Bw4 by serology and are shared by the BD-associated HLA-B alleles B*5101 and B*2702 [11]. On the other hand, CD94/NKG2 heterodimers, members of the other complementing group of NK receptors, namely C-type lectin like receptors, bind the non-classical class Ib HLA-E molecules, loaded with the nanomeric peptides of the leader sequences of the other HLA class I molecules. These heterodimeric receptors are inhibitory if CD94 binds with NKG2-A (p43) and activatory when CD94 binds with NKG2-C (p39). The actions of NK cells are mediated by the integration of inhibitory and activating signals sent by these receptors upon ligand binding [12].
The expression of the CD94 receptor on NK as well as T cells varies depending on the inducing environment, whereas the expression of the KIR family, KIR3DL1 in particular, is genetically determined [12, 13]. In this study, we aimed to investigate the expression of two types of NK-cell receptors, HLA-Bw4 binding polymorphic KIR (KIR3DL1) and the conserved CD94 on the peripheral blood cells of patients with BD and healthy controls, and to evaluate their possible effects on HLA-B51-related pathogenic mechanisms in BD.
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Materials and methods
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Patients and controls
The patient group consisted of 51 patients with BD (29 male, 22 female) followed at the BD Outpatient Clinic of the Division of Rheumatology, Istanbul University. All patients met the International Study Group criteria for the classification of BD [14]. Their mean age was 41.5 ± 9.7 (range 2267) yr, the mean age at onset was 28.7 ± 8.0 (range 1343) yr and the mean disease duration was 12.9 ± 8.1 (range 441) yr. All of the patients were on treatment (colchicines, n = 49; corticosteroids, n = 25; azathioprine, n = 13; cyclophosphamide, n = 3; cyclosporin, n = 2) and did not describe a particular BD-related manifestation at the time of blood collection. These patients were typed for full HLA-B alleles by molecular methods (Table 1) [15]. Thirty-seven of 51 BD patients were HLA-Bw4-positive. Cells from a group of 32 ethnically and HLA-B-typed, non-related healthy volunteers were tested as controls. Nineteen of the control group had Bw4-containing alleles. The local ethics committee (Ethics Committee of Istanbul Faculty of Medicine) approved the study and all study subjects provided written informed consent according to the Declaration of Helsinki prior to blood collection.
Monoclonal antibodies
Fluorescence-conjugated monoclonal antibodies (mAb) and their target antigens used in the study were as follows: CD45/FITC (fluorescein isothiocyanate)-CD14/R-PE (R-phycoerythrin) (to distinguish the non-monocyte/macrophage leucocytes) (Ancell, Bayport, MN, USA); CD3-Cy-Chrome (anti-TCR/
-chain, T-cell marker), CD16-Cy-Chrome (anti-Fc
RIII, NK marker), CD56-R-PE (anti-NCAM, NK marker), CD94-FITC (70 kDa dimer = Kp43, NK receptor), KIR3DL1-FITC (anti-NKB1, 70 kDa, KIR) and the corresponding three fluorescence isotype controls (Pharmingen, San Diego, CA, USA).
Flow cytometry
The reactivity of mAb with blood cells was assessed by direct staining of EDTA (ethylenediamine tetraacetate) blood samples with three different fluorescence labels. For every antibody combination, 0.5 µg of antibody per 106 cells was incubated on ice for 20 min (10 µl/100 µl blood) and lysis buffer was added (0.15 M NH4Cl, 0.01 M KHCO3, 100 µM EDTA). After 10 min, the samples were centrifuged twice at 1200 r.p.m. for 10 min to wash away the antibodies. All samples were then tested in a flow cytometer and the results were analysed using CellQuest software (FACSort; Becton Dickinson, Mountain View, CA, USA). Results are expressed as percentages of the respective positive cells in the mononuclear cell gate.
Statistical analysis
The parameters compared between patients and controls were subjected to the non-parametric MannWhitney U-test.
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Results
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Cell populations
We analysed fresh peripheral blood leucocytes for CD3, CD16 and CD56 expression in the patients and healthy controls. As shown in the Table 2, the mean value of CD3+ cells was increased in the peripheral blood of BD patients (P = 0.002). The total numbers of NK cells (CD56+/CD16+) and CD56+ T cells did not reveal any difference between BD patients and controls.
Expression of the non-polymorphic NK receptor CD94 was increased in the BD group compared with the healthy controls (14.1 vs 9.8%, P = 0.001) (Table 2). The increased expression of CD94 was found on CD16+CD56+ NK cells (65.6 vs 56.7%, P = 0.03), CD56CD3+ (7.7 vs 4.0%, P < 0.001) and CD56+CD3+ (43.7 vs 34.6%, P = 0.02) T cells simultaneously (Fig. 1).

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FIG. 1. The distribution of KIR3DL1 and CD94 receptors on NK (CD56+ CD16+) and T cells (CD3+ CD56+/-) of BD patients and controls. Significant differences are marked with an asterisk and are indicated in Table 2.
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The expression of KIR3DL1 receptor did not differ between the patients and controls (3.4 ± 3.9 and 2.9 ± 2.9% respectively). The individual expression ratios of KIR3DL1 varied extensively among the groups (between 0.0 and 20.4%). This variation was detected on NK cells (CD56/CD16/KIR3DL1+) of both BD patients (16.2 ± 16.2%) and controls (17.5 ± 13.8%) within the ranges of 076.2 and 048.5% respectively. KIR3DL1 expression on CD56+CD3+ T cells was also heterogeneous: mean values were 9.0 ± 10.5 and 7.6 ± 9.0% respectively (Fig. 1). Moreover, the expression of KIR3DL1 on CD56+CD16+ cells correlated with the expression on CD56+CD3+ cells both in BD patients (P = 0.01, r = 0.36) and in the control group (P = 0.005, r = 0.49). According to the recent study by Gardiner et al. [13], the binding level of KIR3DL1-specific antibody also revealed different reaction patterns: 55% of BD and 44% of control cells showed low binding of DX9, whereas 6 and 9% respectively showed a high level of binding. Among all tested samples, 12% of the BD cells and 13% of control cells did not bind DX9 at all. However, the distribution with respect to these patterns was also not different between the two groups.
Receptor expression related to HLA-B distribution
We did a subgroup analysis to investigate whether the BD-associated increase in Bw4-bearing alleles in BD patients influenced the heterogeneous expression of KIR3DL1 and CD94. The expression of KIR3DL1 was compared between the patients and controls, who were classified into subgroups according to the presence or absence of Bw4 antigen, which is found on both the B51 and the B*2702 molecule. Alleles containing the Bw4 sequence [16] were present in 19 out of 32 controls (59.3%) and in 37 out of 51 patients (72.5%) studied for receptor expression; of these Bw4+ alleles, 68% (13/19) and 70% (26/37) were alleles with isoleucine at position 80, respectively (Table 1). A slight increase in CD3+CD56+ cells in Bw4+ controls was prominent compared with Bw4 alleles (7.8 vs 4%). The HLA-B alleles with the Bw4 sequence did not have any significant influence on the expression of KIR3DL1 or the high or low binding of anti-KIR3DL1 antibody in the patients and controls (Table 3). There was no effect of the HLA-B alleles or their Bw4 motifs on the increased expression of CD94 on CD56+CD16+ and CD3+CD56+ cells (Table 3).
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TABLE 3. The distribution of subsets in BD and control groups according to the presence or absence of the HLA-Bw4Ile80 motif
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Discussion
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The recently described interaction of NK cell receptors with HLA class I molecules on target cells has opened a new perspective on the function of HLA expression and its regulatory influences. In this study, the expression of a member of each NK receptor subgroup, namely KIR3DL1 and CD94, which are expressed mainly on NK cells but also on T cells, was evaluated in patients with BD in order to look for putative functional implications of HLA-B51 association with BD [1722].
In the peripheral blood, the NK cell population, which we defined as both CD16+ and CD56+, did not differ between BD patients and controls in the present study, which is similar to the findings of some previous reports [8]. The discrepancies between these results and other work [6, 7] could be related to clinical status (different types and activities of BD manifestations) and the number of patients, or to different treatment modalities. The definition of NK cells by the presence of CD56 and absence of CD3 in other studies and the limitations of immunofluorescence methods, due to the number of monoclonals used in the same assay, may also have contributed to these different results.
T cells and NK cells appear to have evolved complementary functions in the immune response, T cells responding to antigen in the context of MHC and NK cells responding to cells that have lost MHC class I expression, according to the missing self hypothesis [23]. A possible regulatory role of NK receptors in the pathogenesis of BD has been supported by the enhanced CD94 expression. Increased expression of CD94 over a relatively wide range was detected on CD56+CD16+ NK cells and on CD3+ T cells in BD. CD94 is reported to be present on most NK cells, with variable fluorescent staining intensity corresponding to functionally distinct subsets [24]. The expression pattern of CD94 on NK cells has revealed that inhibitory and activating pathways are differently coupled to this receptor depending on the associated molecules, which belong to the NKG2 family and require CD94 for surface expression [25]. The molecules associated with CD94 have been not determined in the present study and the functional relevance of the increase in CD94 expression on NK cells and other T cells, including 
T cells, in BD needs to be explored. The expression of molecules associated with CD94 in relation to disease activity, type of organ involvement and treatment will be evaluated further in BD patients.
The CD94 on T cells may be expressed primarily by CD8+ cells of the memory phenotype, as shown by Mingari et al. [26, 27] by in vitro stimulation with cytokines, superantigens or alloantigens. They reported that the expression of inhibitory NK receptors, such as CD94/NKG2A, can be a regulatory mechanism in the fine tuning of the T-cell receptor-mediated responses of cytotoxic T cells which have acquired NK-like activity, and this may be important in the pathogenesis of BD. The increased serum levels of interleukin (IL)-12 in active and inactive states of BD is consistent with the proposed effect of these cytokines on CD94 expression [28, 29]. The possibility of in vivo cytokine-induced (IL-12, IL-15 or transforming growth factor ß) expression of CD94 and associated NKG2 molecules [30] on T cells and their functional role in BD also needs to be investigated further.
Recent investigations support a direct pathogenic role for HLA-B51 in the pathogenesis of BD, and there may be various possible ways in which HLA-B51 can interact with T and NK cells. We have recently identified a weak association of HLA-B*2702 with BD [15]. Since HLA-B*2702 and B51 share the same KIR binding sequence, we have hypothesized that HLA-B51 may exert its pathogenic action by binding these receptors on NK and cytotoxic T cells. In the present study, we tested the effects of different distributions of HLA-B alleles in BD on the expression of HLA-recognizing receptors on NK or T cells. Our results did not reveal an effect of increased frequency of the HLA-B51 allele in BD on KIR3DL1 expression. The frequency of KIR3DL1+ cells reacting with DX9 antibody showed a wide range (020.4%), and the mean frequency did not differ between patients and controls. NKB1 (DX9) expression on CD56+CD3 cells in healthy individuals has been reported as being between 0.1 and 61% (mean, 14%) [31]. More recently, different cell surface phenotypes detected with DX9 antibody have been shown to be due to the expression of different alleles of the KIR3DL1 gene [13]. Although functional differences among these alleles have not yet been elucidated, the variable expression of KIR3DL1 (or reactivity with DX9 antibody) in our samples and the reported abnormal expression in Japanese BD patients [32] may be related to KIR gene polymorphisms. This should be investigated at the allelic level.
The absence of an association between KIR3DL1 expression and the HLA-Bw4 motif confirms previous work showing that the these molecules are subject to separate regulation [16], but does not exclude the possible interaction and involvement of these molecules in the pathogenesis of BD. Evidently, epistatic interaction between the activating KIR allele KIR3DS1 and HLA-B Bw4-80Ile has been demonstrated in progression to AIDS [34]. It has also been shown that the activating and inhibitory KIR receptors and their ligands may interact in a coordinated fashion and that, in the presence of respective HLA ligands, corresponding inhibitory and activating KIRs may neutralize their counteracting effects [35]. In the present work, only the expression level of the inhibitory receptor subtype of the KIR3 family was studied in relation to HLA-B alleles, whereas the activating receptors of the KIR3 and KIR2 families have been found to be associated with AIDS, and with psoriatic arthritis and rheumatoid arthritis, depending on the accompanying HLA-B or HLA-C alleles, respectively [3436]. The study of activating receptors of KIR3 family members binding HLA-Bw4 alleles is under way.
In conclusion, increased expression of CD94 may suggest that NK cell receptors play a pathogenic or regulatory role in BD. The importance of CD94 expression in BD needs to be explored in functional studies.
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Acknowledgments
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This study was supported by the Istanbul University Research Fund (Project No. 1076). The work of AG was also supported by the Turkish Academy of Sciences, in the framework of the Young Scientist Award Program (EA-TUBA-GEBIP/2001-1-1).
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Submitted 27 June 2003;
Accepted 30 September 2003