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1 State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Sun Yat-Sen University, Guangzhou, PR China
2 State Key Laboratory of Oncology in Southern China; Department Nasopharyngeal Carcinoma, Cancer Center, Sun Yat-Sen University, Guangzhou, PR China
3 Da'an Gene Diagnostic Center, Sun Yat-Sen University, Guangzhou, PR China
Correspondence
Yi-Xin Zeng
zengyix{at}mail.sysu.edu.cn
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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A supplementary table showing the xMAP fluorescence intensity values is available with the online version of this paper.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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; Epstein et al., 1965; Khanna et al., 1995). EBV infects more than 90 % of the population worldwide and usually establishes a lifelong persistence in the host (Cohen, 2000). Most populations get primary infection in childhood and are asymptomatic, but Westerners whose primary infection is delayed until adolescence may develop infectious mononucleosis (Amon & Farrell, 2005). More strikingly, the virus is associated with a spectrum of cancers presenting endemic features, such as Burkitt's lymphoma in Africa and nasopharyngeal carcinoma (NPC) in Southern China and South-East Asia (Pattle & Farrell, 2006; Raab-Traub et al., 1987).
EBV is closely correlated with NPC, which could be reflected by consistent expression of EBV gene products in NPC tumour cells and general elevation of serum antibody levels against EBV antigens in NPC patients (Busson et al., 2004; Gastpar et al., 1981; Henle & Henle, 1976; Old et al., 1966; Raab-Traub, 2002). In comparison with healthy EBV carriers, NPC patients typically show strong IgG and especially IgA reactivities to lytic antigens (Fachiroh et al., 2004; Henle & Henle, 1976), so an EBV serological assay could facilitate diagnosis and prognosis of NPC. IgA antibody titres against the EBV viral capsid antigen (VCA) and the diffused early antigens (EA-D) are regularly tested in many clinical centres (Deng et al., 1995; Hadar et al., 1986; Henle & Henle, 1976; Ho et al., 1998). However, the EBV serological spectrum differs among individuals and so other antigens have been further verified as useful indicators of NPC in recent years. These markers include nuclear antigen EBNA1 (Foong et al., 1990), transactivators Zta and Rta (Dardari et al., 2001; Feng et al., 2001; Yip et al., 1994), replication factors DNA polymerase and alkaline DNase (Littler et al., 1991), nucleotide metabolism factors ribonucleoside reductase and thymidine kinase (Fones-Tan et al., 1994; Littler et al., 1991), and several tegument and capsid antigens (Fachiroh et al., 2004, 2006), which were derived from natural EBV proteins, recombinant products or synthetic peptides.
EBV envelope glycoproteins are of particular interest in studies because they bind to the EBV receptor on the cells and initiate infection. EBV enters B cells by interaction of the major glycoprotein gp350/220 (BLLF1) with CD 21 and then penetrates by the complex of viral glycoproteins gp25 (Pickard et al. , 2004), gp42/38 and gp85 (gH) (Tao et al., 2006). Furthermore, EBV glycoproteins play important roles in humoral immune responses and sera against these proteins often neutralize virus. So far, 12 EBV glycoproteins have been characterized (Johannsen et al., 2004). However, few of them have been shown as valuable markers for NPC diagnosis. gp350/220 is the major target of the EBV-neutralizing antibody and several studies detected IgA-gp350/220 in NPC patients with higher titres than healthy controls, but these tests were based upon a relatively small number of samples (Khanna et al., 1999; Littler et al., 1991; Xu et al., 1998).
To investigate the values of EBV envelope proteins for NPC diagnosis, we utilized Luminex multi-analyte profiling (xMAP) technology to examine antibodies against several EBV antigens in NPC patients and healthy controls. xMAP technology is based on flow-cytometric analysis of microbeads that act as solid supports for individual assay reactions. Each bead has a unique spectral address and represents a detection reaction. To date, more than 100 distinct reactions could be carried out simultaneously on the various beads in very small sample volumes. The individual beads are identified and their assays are read with a Luminex-100 or -200 instrument (Earley et al., 2002; Elshal & McCoy, 2006; Kettman et al., 1998). After screening antibodies to several glycoproteins, we found antibodies against gp78, a membrane protein with unknown function, were statistically higher in NPC populations than in healthy controls. In this study, we further detected the IgA and/or IgG levels to gp78, VCA, EA-D and EBNA1 in NPC patients and controls and analysed the combination of these EBV serological markers for NPC diagnosis.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). Four herpes simplex virus (HSV)-positive sera of children were also detected. Written informed consent was obtained from all study participants.
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). Sequences with high possibility of hydrophilicity, surface-orientation and flexibility were chosen. About 20 residues of each peptide were selected and synthesized by adding six carbon and one biotin at the N terminus (Hanyu), and then further purified by HPLC to achieve >90 % purity. The peptide sequences used in this study were gp78 (TSTSHRPHRRPVSKRPTHK), gp350/220 (HHAEMQNPVYLIPETVPYIK) and BLRF1 (EAQDQFYSYTCNADTFS).
xMAP analysis.
Coupling of proteins to beads.
Coupling of EBVVCA-gp125, EA-D and EBNA1 (Biodesign) to the carboxylated beads (Luminex) was performed according to a protocol reported previously (Skogstrand et al., 2005). Briefly, 2.5x106 beads were washed with activation buffer (10 mM NaH2PO4, pH 6.3), resuspended in 80 µl activation buffer and sonicated for 10 s. N-hydroxysulfosuccinimide (10 µl; Pierce) solution and 10 µl 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (Pierce) solution, both diluted in activation buffer to 50 mg ml–1, were added to the bead suspension. After mixing, the beads were incubated with rotation for 20 min at room temperature in the dark. The activated beads were subsequently washed twice with coupling buffer (10 mM NaH2PO4, 150 mM NaCl, pH 7.4) and then incubated with 500 µl azide-free protein solution (diluted to 250 µg ml–1 in coupling buffer) for 2 h. The beads were washed three times with washing buffer (1xPBS, 0.05 % Tween-20) and resuspended in 100 µl blocking/storage buffer (1xPBS, 1 % BSA). Finally, the beads were counted with a haemocytometer, adjusted to a concentration of 1.25x106 beads ml–1 with storage buffer and stored protected from light at 4 °C.
Peptide conjugation.
Coupling of biotinylated peptides to LumAvidin microspheres (Luminex) was performed according to the manufacturer's instructions. Briefly, equal volumes of beads and peptide (10 µg ml–1 in storage buffer) were mixed and incubated overnight at 4 °C. After washing twice (with PBS and 0.05 % Tween-20) and resuspension in storage buffer (PBS, 1 % BSA, 0.05 % NaN3), the beads were counted with a haemocytometer, adjusted to a concentration of 1.25x106 beads ml–1 with storage buffer and stored protected from light at 4 °C.
Serum sample test.
The conjugated beads were diluted with storage buffer to 1000 beads in 50 µl per reaction well and then added to the 96-well filtration system (Millipore). Sera diluted 1 : 21 in storage buffer (20 µl per well) were added and incubated with the beads for 30 min and protected from light at room temperature. After washing three times, 150 µl R-phycoerythrin (R-PE)-conjugated goat anti-human IgA or IgG (1 : 200 in PBS; Jackson ImmunoResearch) was added to each reaction well and incubated for 30 min. The detection analysis was performed with a Luminex multi-analytic system 100 (Bio-Rad). All tests were carried out in duplicate.
Statistical analysis.
All statistic analysis was performed with SPSS 13.0 for Windows and the GraphPad Prism 4.0 program. The unpaired t test was used to compare the mean values from NPC and healthy groups, one-way analysis of variance (ANOVA) was used to compare mean fluorescence intensity (FI) of IgA-gp78 or IgG-gp78 among populations with different ages and cancer stages and receiver operating characteristic (ROC) curve analysis was done to determine the cut-off values. Linear correlations between the FI values of antibodies against gp78 and VCA, EA-D or EBNA1 were analysed with Pearson's method.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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; Urquiza et al., 2005). Our results also revealed that IgA to one of the gp350 peptides was statistically higher in NPC patients than in healthy controls (P=0.005). However, IgG values to gp350 and antibodies to BLRF1 had no significantly distinct distribution in NPC and healthy populations. Interestingly, IgA- and IgG-gp78 reactivities in NPC patients were both higher than controls.
After examining a total of 95 NPC patients and 91 healthy controls, we found the mean xMAP FI values of IgA-gp78 for NPC patients and controls were 1790 and 377, respectively, with high discriminatory value (P<0.0001). Similarly, the difference in IgG FI values was also statistically significant, displaying mean FI values of 12 261 and 4404 for NPC patients and healthy controls, respectively, being significantly higher in NPC patients than in controls (P<0.0001) (Fig. 1a and b).
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). When the FI value 500 was chosen as the cut-off of IgA-gp78, the sensitivity and specificity were 79 % (95 % CI, 69–87 %) and 71 % (95 % CI, 60–79 %), respectively. As for IgG-gp78, if FI values higher than 6000 were defined as positive results, the sensitivity and specificity were 74 % (95 % CI, 63–82 %) and 73 % (95 % CI, 63–81 %), respectively. The positive predictive values (PPV) and negative predictive values (NPV) both exceeded 70 % for IgA-gp78 and IgG-gp78 assays (Table 2)
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The distribution of IgA-gp78 and IgG-gp78 levels according to individual cancer stage is shown in Fig. 2, and the relationship between them was assessed by one-way ANOVA. Our results showed no significant relationship for cancer stages with IgA-gp78 (P=0.587) or IgG-gp78 (P=0.440) levels.
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). The data suggested the immunological responses to different EBV antigens varied significantly within an individual, which also resulted in the diversity of EBV antibody profiles among NPC patients. Thus, it is conceivable to improve the diagnostic capacity of NPC by combination of different EBV biomarkers.
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Antibody reactivities against gp78 peptide in HSV-positive sera
Eight members of the family Herpesvirus infect humans. All the herpesviruses have a general similarity in capsid structure and so the genes involved in the lytic cycle are quite similar. However, the proteins involved in cell type-specific infection, such as latent antigens and some surface proteins, are quite unique to each virus (Farrel, 2005). Several envelope proteins of EBV have homologues in HSV, such as pairs of EBV gp110 HSV-1 gB, EBV gp85 and HSV-1 gH (Gong et al., 1987; Heineman et al., 1988).
To investigate whether the antibodies to the gp78 peptide cross-react with HSV, we examined four HSV-positive sera of children. Our results showed the serum of HSV-NO.4 had high IgG-gp78 and IgA-VCA values, with FI reaching 12 106 and 2909, respectively. However, the other three sera had low levels of antibody to the six EBV markers, including IgA- and IgG-gp78 values (Supplementary Table S1). Since we did not find gp78 homologues in the HSV genome, it is possible that individual HSV-NO.4 might be simultaneously infected by HSV and EBV.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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; Foong et al., 1990; Xu et al., 1998). However, high titres of EBV IgG are usually not specific for NPC and can be observed in other EBV-infected individuals as well (Gulley, 2001). The major membrane glycoprotein-350/220 in particular could trigger equal antibody responses in both NPC patients and healthy controls, and its IgG antibody was verified to counteract EBV particles (North et al., 1982). In this study, a synthetic peptide of gp78 was used to detect the serum IgA and IgG levels by xMAP analysis. Herein, gp78 is more specific, since both IgA and IgG reactivities to gp78 were higher in the NPC population than in the healthy one.
The sensitivity and specificity of IgA-gp78 and IgG-gp78 for NPC diagnosis both exceeded 70 %, comparable to IgA-VCA and -EA (Henle & Henle, 1976; Leung et al., 2004). Our results suggest that serum IgA and IgG recognize at least one common gp78 epitope, but that the IgA and IgG responses within an individual could differ significantly, as described previously (Fachiroh et al., 2004), implying distinct mechanisms to activate IgA- and IgG-producing B cells. The function of gp78 remains unknown to date. Although the majority of EBV seropositive individuals produce antibodies against it (Mackett et al., 1990), gp78 levels in NPC patients were much higher, suggesting gp78 might be important for EBV replication in epithelial rather than lymphoblastoid cells. Furthermore, EBV gp78 is an envelope protein and the strong immune response induced by gp78 in NPC patients might be involved in counteracting EBV invasion, therefore gp78 might be a vaccine candidate.
To date, an immunoenzymic assay has been employed extensively in South China to detect IgA to EBV VCA and EA-D using EBV-infected cell lines as a target. However, it is only semiquantitative and poorly standardized and a certain amount of expertise is required. In this study, we used xMAP technology to detect EBV serology, which was automatic and the data could be quantified (Chen et al., 1999; Fulton et al., 1997). Simultaneous examination of antibodies to gp78, VCA, EA-D and EBNA1 revealed a positive correlation between them, but with relatively poor r values. It is plausible because these antigens are expressed in EBV lytic replication and their antibody responses have a similar tendency, but distinct individual characteristics. In fact, combination of these six markers could greatly improve the values for NPC diagnosis and mass screening with proper standards. To detect multiple markers simultaneously is the remarkable advantage of xMAP assay compared with ordinary ELISA. Up to now, several diagnostic kits based on xMAP technology have been developed (Biagini et al., 2005; Dunbar et al., 2003; Klutts et al., 2004 ; Lukacs et al., 2005). Because of the distinct EBV serology spectrum in individual NPC patients, the multiplexed bead assay has powerful potential to allow serological diagnosis of NPC in the future.
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ACKNOWLEDGEMENTS |
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Received 25 December 2007;
accepted 6 February 2008.
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