anti-EBNA Titers Research Articles

Clinical significance of anti-Epstein-Barr virus antibodies in systemic chronic active Epstein-Barr virus disease.

Systemic chronic active Epstein-Barr virus disease (sCAEBV) is a rare and fatal neoplasm, involving clonally proliferating Epstein-Barr virus (EBV)-infected T cells or natural killer cells. Patients with sCAEBV have abnormal titers of anti-EBV antibodies in their peripheral blood, but their significance is unknown. We retrospectively investigated titers and their relationship with the clinical features of sCAEBV using the data collected by the Japanese nationwide survey. Eighty-four patients with sCAEBV were analyzed. The anti-EBV nuclear antigen (EBNA) antibody, targeting EBNA-expressing EBV-positive cells, was found in 87.5% of children (<15 years old), 73.7% of adolescents and young adults (15-39 years old), and 100% of adults (≥40 years old). Anti-EBNA antibody titers were significantly lower and anti-VCA-IgG antibody titers significantly higher in patients with sCAEBV than those in healthy controls (p < 0.0001). Patients with high anti-VCA-IgG and anti-early antigen-IgG antibody (antibodies against the viral particles) levels had significantly better 3-year overall survival rates than those with low titers, suggesting that patients with sCAEBV have a reduced immune response to EBV-infected cells.

Combined effects of smoking, anti-EBNA antibodies, and HLA-DRB1*1501 on multiple sclerosis risk

To examine the interplay between smoking, serum antibody titers to the Epstein-Barr virus nuclear antigens (anti-EBNA), and HLA-DR15 on multiple sclerosis (MS) risk. Individual and pooled analyses were conducted among 442 cases and 865 controls from 3 MS case-control studies-a nested case-control study in the Nurses' Health Study/Nurses' Health Study II, the Tasmanian MS Study, and a Swedish MS Study. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% CIs for the association between smoking, anti-EBNA titers, HLA-DR15, and MS risk. Study estimates were pooled using inverse variance weights to determine a combined effect and p value. Among MS cases, anti-EBNA titers were significantly higher in ever smokers compared to never smokers. The increased risk of MS associated with high anti-EBNA Ab titers was stronger among ever smokers (OR = 3.9, 95% CI = 2.7-5.7) compared to never smokers (OR = 1.8, 95% CI = 1.4-2.3; p for interaction = 0.001). The increased risk of MS associated with a history of smoking was no longer evident after adjustment for anti-EBNA Ab titers. No modification or confounding by HLA-DR15 was observed. The increased risk of MS associated with ever smoking was only observed among those who had high anti-EBNA titers (OR = 1.7, 95% CI = 1.1-2.6). Smoking appears to enhance the association between high anti-EBNA titer and increased multiple sclerosis (MS) risk. The association between HLA-DR15 and MS risk is independent of smoking. Further work is necessary to elucidate possible biologic mechanisms to explain this finding.

耳下腺リンパ上皮癌例

Lymphoepithelial carcinoma of the salivary gland is rare and manifests ethnic and geographic preferences. We report one such case in the parotid gland of a 55-year-old man with a painless mass in the left parotid region without facial nerve paralysis. The pathological lymph-node diagnosis of lymphoepithelial carcinoma necessitated total parotidectomy, left neck dissection, and facial nerve grafting followed by postoperative radiotherapy. In situ hybridization showed negative EBER, but serological results showed high VCA-IgA and anti-EBNA titers. The man remains free of locoregional recurrence and distant metastasis in the 3 years since surgery.

Significance of confirming Epstein-Barr virus nuclear antibody as tumor marker

Study of the association between Epstein-Barr virus (EBV) and the tumors of the nasopharynx renders an opportunity to introduce causal treatment Already have been proven the anti-EBV (anti-Epstein-Barr nucleus antigene) antibodies in the blood serum of the patients infected with EBV, while over 91% of the patients with nasopharyngeal malignant tumors also have a detectable anti-EBV marker. The aim of this research was to determine if there were anti-EBV antibodies in the serum of the patients with the already verified nasopharyngeal malignant tumors, and, if there were, to determine the quantitative ratio to the values in the serum of the healthy controls. The study involved 74 individuals in the period from 1994-2001 divided into four groups: group A counting 11 patients with undifferentiated carcinome of nasopharyngeal type (UCNT); group B counting 25 patients with UCNT X-ray treated at least three years before the onset of the study; group C including 28 healthy subjecets (blood donors), and the group D with 10 patients with planocellular nasopharyngeal carcinoma. Serologic diagnostics of the patients serum was performed using the techniques of Reedman and Klein for the detection of anti-EBV antibodies in the serum. The presence of the statistically significantly higher values of the mean geometric titer (MGT) of the anti-EBNA antibodies was determined in 36 patients with histologically verified UCNT as compared with the control groups including 10 patients with planocellular carcinomas of the nasopharynx and 28 blood donors. Presented were anti-EBNA titers with 95% confidence interval for any participants according to the Hoo clinical classification of nasopharyngeal tumors, as well as according to the fact if they had been radiotreated within the previous three years. The results of this study confirm the conclusions of the recent literature on the possible etiopathogenesis of nasopharyngeal tumors and the use of viral anti-EBNA antibodies as viral markers in the diagnostics of UCNT diseases.

Carboxyl-terminal domain of the Epstein-Barr virus nuclear antigen is highly immunogenic in man.

The carboxyl-terminal one-third of the Epstein-Barr virus nuclear antigen (EBNA-1) encoded by the BamHI restriction fragment K was synthesized in Escherichia coli by use of a high-expression plasmid. The resultant 28-kDa EBNA fusion polypeptide, comprising 5-10% of the total soluble bacterial protein, was purified to apparent homogeneity by phosphocellulose and hydroxylapatite column chromatography. Both rabbit monospecific antibodies and mouse monoclonal antibodies against 28-kDa EBNA gave nuclear immunofluorescence staining on Epstein-Barr virus (EBV)-infected lymphoblastoid cell lines and recognized the appropriate intact EBNA polypeptide bands on immunoblots. An ELISA with the purified 28-kDa EBNA as antigen was used to quantitate anti-EBNA antibody in human serum samples. The ELISA method was approximately 100-fold more sensitive than the classical anticomplement immunofluorescence assay. Anti-EBNA antibody was detected in sera from 100% of normal individuals who were seropositive for the viral capsid antigen, and low anti-EBNA titers were detected in serum from most patients with acute infectious mononucleosis. The assay gave the expected pattern of titers in sera from patients with rheumatoid arthritis, Burkitt lymphoma, or nasopharyngeal carcinoma, thus confirming the validity of this purified reagent for assessing EBNA antibody status. Approximately 10% of normal individuals and rheumatoid arthritis patients had anti-EBNA titers as high as those seen in nasopharyngeal carcinoma patients. In these high-titer individuals, greater than 1% of the total IgG are antibodies that recognize 28-kDa EBNA, which indicates that the carboxyl-terminal domain of EBNA is highly immunogenic.

Epstein-Barr nuclear antigen and viral capsid antigen antibody titers in multiple sclerosis.

To characterize the antibody response to the Epstein-Barr virus (EBV) in MS, we studied serum anti-EBV nuclear antigen (anti-EBNA) and anti-EBV capsid antigen (anti-EBVCA) titers. Both titers were assayed in 93 age- and sex-matched pairs of MS patients and controls. Anti-EBVCA titers were measured by indirect immunofluorescence and anti-EBNA titers by anticomplement immunofluorescence. The seropositivity rate of both anti-EBVCA and anti-EBNA in MS patients was 100%, compared with 84% in controls (p less than 0.0001). Both anti-EBVCA and anti-EBNA titers were significantly higher in MS patients than in controls (p less than 0.0001). The data suggest that EBV has a significant seroepidemiologic association with MS, but they do not define what role EBV antibodies play in the pathogenesis of the disease.

Elevated antibody titers to Epstein-Barr virus and low natural killer cell activity in patients with Chediak-Higashi syndrome

Four Venezuelan patients with the autosomal recessive Chediak-Higashi syndrome (CHS) were studied. The results confirm the severe reduction in natural killer (NK) cell activity, as previously described and showed also a decline in the activity of cells involved in antibody-dependent cellular cytotoxicity (ADCC). No defect was found in the production of immunoglobulins and of specific antibodies to measles, varicella, herpes simplex, and cytomegalo viruses. Two of the patients had extremely high antibody titers to the Epstein-Barr virus (EBV) specific viral capsid antigen (VCA), to the restricted (R) component of the EBV-induced early antigen complex, and to the EBV-associated nuclear antigen (EBNA). These two patients had enlarged livers, spleens, and lymph nodes indicative of the lymphoproliferative phase. The other two patients were initially negative for all EBV-associated antibodies but seroconverted subsequently and, in the course of a year, also developed high antibody titers to VCA and R. In one of these patients the primary infection was accompanied by moderate signs of infectious mononucleosis (IM) followed after more than 6 months by persistent hepatosplenomegaly. The other patient also developed signs of a lymphoproliferative syndrome with hepatosplenomegaly and jaundice and died 8 months later. Such high anti-R titers are seen frequently in Burkitt's lymphoma, but rarely in other conditions. It is likely that the high antibody titers reflect an increased production of VCA and R due to defective NK and ADCC cell activities so that productively infected B lymphocytes are no longer eliminated before they have synthesized maximal amounts of antigens. The high anti-EBNA titers suggest normal T lymphocyte function. The possibility that the accelerated, lymphoma-like phase of the CHS involves EBV-transformed cells is discussed.

Antibodies to Epstein-Barr virus associated antigens in Pima Indians with and without rheumatoid arthritis.

We investigated anti-rheumatoid arthritis-associated nuclear antigens (RANA) and other anti-Epstein-Barr virus (EBV) antibodies in a uniquely controlled study in female Pima Indians of Arizona, an RA prone population. Four groups of age and sex-matched individuals were formulated: (1) individuals positive for rheumatoid factor (RF) who had clinical evidence of rheumatoid arthritis (RA); (2) individuals seropositive for RF, but without arthritis; (3) individuals seronegative for RF, but with various kinds of arthritis; (4) those seronegative without arthritis. The mean anti-RANA in the seropositive RA group was significantly above those of the other groups but the anti-VCA and anti-EBNA titers did not differ. The anti-RANA was shown to be independent of RF. Comparing the Pima Indians to Caucasians in La Jolla, we found the mean anti-RANA titers of the Pimas to be significantly higher than those of the Caucasians. This study thus establishes clearly that elevated anti-RANA titers are characteristics of this American Indian group, just as they are of Caucasian groups. The elevated anti-RANA titers in RA patients may represent a unique hyperresponsiveness to this antigen, since there is no consistency in the reported levels of antibodies to other EBV-related antigens.

Immune deficiency in the X-linked lymphoproliferative syndrome. I. Epstein-Barr virus-specific defects.

Eleven males with XLP were evaluated for EBV-specific antibodies during periods of 2 to 7 yr. Variable responses to EBV-specific antigens were found. All 11 patients had subnormal anti-EBNA titers, which probably reflected a T cell deficiency. The patients showed four different patterns in their anti-VCA response: 1) two boys who had experienced malignant lymphoma mounted no antibodies at all; 2) two patients showed intermittent anti-VCA titers; 3) four males had persistently elevated anti-VCA titers; and 4) three patients showed normal anti-VCA titers. ADCC against EBV-infected cells was abnormally low in six patients and was elevated in two patients given gamma-globulin. ADCC titers did not correlate with anti-VCA titers. However, most patients with XLP failed to effect regression of autologous EBV-infected lymphoblastoid cell lines, indicating a deficiency in long-lived T cell-mediated immunity to EBV.

Discordant Epstein-Barr virus nuclear antigen (EBNA) antibody patterns in nasopharyngeal carcinoma.

Epstein-Barr virus nuclear antigen (EBNA) preparations from three sources were tested with sera from normal individuals and patients with Hodgkin's disease, breast carcinoma, Burkitt's lymphoma, and American and Chinese nasopharyngeal carcinoma. Individual sera with discordant antibody patterns were noted in all groups. Sera from both NPC groups gave significantly higher anti-EBNA titers on cell lines converted with P3HR-1 or B95-8 virus compared with anti-EBNA titers on Raji cells. Anti-EBNA titers of Chinese NPC sera showed no correlation among the three EBNA sources, while all other groups had highly correlated titers. Cross-absorption experiments present evidence for more than one antigenic determinant on EBNA. These results suggest an additional parameter for distinguishing Chinese NPC from other EBV-related disorders.

Antibodies to Epstein-Barr virus-specific antigens in patients with hairy-cell leukemia.

Antibody titers to Epstein-Barr virus (EBV)-specific antigens of 19 patients with hairy-cell leukemia (HCL) were markedly elevated. All patients showed high titers of IgG anti-viral capsid antigen (VCA) reactivity equal to or greater than 320 (reciprocal titer). The anti-VCA reciprocal geometric mean titer (GTM) was 1106 in contrast to a GMT of 80 for healthy controls (p less than 0.001). No IgM anti-VCA antibody was detected, but three patients had IgA anti-VCA antibodies. Fourteen patients had elevated anti-early antigen (EA) titers (GMT = 177) which were indicative of active infections with EBV. Seven of the 14 patients demonstrated the diffuse component antibody of the early antigen (EA) complex at a GMT of 98. Anti-Epstein-Barr virus nuclear antigen (EBNA) was detected in sera of 16 patients (GMT = 64, controls GMT = 79). It is noteworthy that three patients with anti-VCA titers lacked anti-EBNA titers. These anti-body responses suggest that immunodeficiency secondary to HCL allowed reactivation of the virus.

Correlation between anti-RANA and anti-EBNA titers in normal subjects with and without HLA-DRw4.

We have determined the relationship of antibody titers to the rheumatoid arthritis nuclear antigen (RANA) and of antibody titers to the Epstein-Barr nuclear antigen (EBNA) to each other and to the DRw4 B cell alloantigen in the sera of 34 normal white adults. By a sensitive indirect immunofluorescence (IF) assay, 76% had RANA antibody, compared to 23% by a micro-immunodiffusion assay. The correlation coefficient for the tube dilution titers of anti-RANA and anti-EBNA was 0.61 (P < 10(-4)). The 14 DRw4-positive subjects and the 20 DRw4-negative subjects did not differ with respect to anti-RANA titers (P = 0.51) or anti-EBNA titers (P = 0.89). We conclude that: 1) most normal adults have RANA antibody by IF; 2) anti-RANA and anti-EBNA titers are closely related; 3) the titers of these antibodies cannot be related to the presence of the DRw4 determinant in normal persons.

The relation between epstein-barr virus antibodies and clinical symptomatology and immunodeficiency in patients with Hodgkin's disease

Anti-Epstein-Barr virus (EBV) titers were measured in the sera of 37 patients with Hodgkin's disease and in 40 normal controls. The patients were grouped according to histologic type, clinical symptomatology (relapse or remission), and their immune state (immunodeficient or non-immunodeficient). Anti-Epstein-Barr nuclear antigens (EBNA) and antiviral capside antigens (VCA) titers were higher in patients with Hodgkin's disease than in the controls. Anti-EBNA titers were significantly higher in patients with lymphocyte predominance, and anti-VCA titers were significantly higher in patients with mixed cellularity. Patients in clinical relapse had higher anti-EBV antibody titers than patients in remission or those in the control group. Immunodeficent pateints had significantly higher anti-VCA titers than either the non-immuno-deficient or the control cases. We believe high anti-EBV titers are related to immunodeficiencies. The relationship between Hodgkin's disease and EBV is discussed.

Serum glycoproteins and immunoglobulins in nasopharyngeal carcinoma: Correlations with Epstein-Barr virus associated antibodies and clinical tumor stage

The consistent association of elevated antibody titers to the Epstein-Barr virus associated antigens in patients with nasopharyngeal carcinoma has led to correlations of antibody titers with tumor presence and extent. Recently, serum levels of specific glycoproteins and immunoglobulins have been correlated with tumor presence and extent in patients with head and neck squamous carcinomas, and elevation of the immunoglobulin IgA has been described in patients with nasopharyngeal carcinoma. These correlations prompted a study of 69 untreated patients with nasopharyngeal carcinoma and 53 healthy normal subjects in Taiwan to determine the relations among specific proteins (haptoglobin, α 1-acid glycoprotein, α 1-antitrypsin, α 2-HS-glycoprotein, prealbumin, and albumin), immunoglobulin levels (IgA, IgG, IgM), anti-EBV associated antibody titers, and clinical tumor stage. Elevated antibody titers to EBV-associated antigens (EBV-associated nuclear antigen, viral capsid antigen, and early antigen) were related to tumor presence but not significantly related to clinical tumor stage. Compared with the levels in normal subjects, serum levels of acute-phase proteins (haptoglobin, α 1-acid glycoprotein, α 1-antitrypsin) were significantly increased (p < 0.001) in patients with nasopharyngeal carcinoma, and levels of α 2HS-glycoprotein were significantly decreased (p < 0.001). Uniquely, serum levels of acute-phase proteins, particularly haptoglobin, were directly related to clinical tumor stage (p < 0.05 − 0.001). Furthermore, serum haptoglobin levels correlated directly with anti-EBNA antibody titers (p < 0.03) and serum levels of IgA (p < 0.01). Serum levels of α 2HS-glycoprotein correlated inversely with titers of IgA antibodies to early antigen (p < 0.03). The findings demonstrate that measurement of specific serum glycoprotein and immunoglobulin levels may be useful adjuncts to anti-EBV antibody titers in the serodiagnosis and monitoring of response to treatment of nasopharyngeal carcinoma and aid in the derivation of improved staging systems for these tumors.

Epstein Barr Virus (EBV) Associated Antibody (Ab) Patterns in Ataxia-Telangiectasia (A-T)

Serum anti-EBV ab titers determined by immunofluorescent techniques in 27 patients (pts) (ages 3.5-20 yr) with A-T showed elevated anti-viral capsid antigen (ag) (VCA⩾1:320) and anti-early ag (EA⩾1:10) titers in 55% and 48.2% of the pts. Anti-EBV associated nuclear ag (EBNA) titers were low (<1:10). in 44.2%. Comparison with 22 healthy family members, 23 healthy controls, 10 pts with primary immunodeficiency, 10 pts with Behçet's disease showed the geometric mean titers to be 6 fold higher for anti-VCA and 5 fold lower for anti-EBNA than in the healthy controls. Nineteen A-T pts with low anti-EBNA titers had suggestive evidence of greater T cell deficiency than 8 pts with normal anti-EBNA titers,detected by absolute lymphocyte count, skin tests and E rosettes. It is hypothesized that EBNA for maintained ab stimulation is derived from EBV transformed cells by cell mediated anti-cellular reactions.Therefore highly immunosuppressed pts should develop and maintain very low anti-EBNA titers. Low anti-EBNA Ab patterns were also observed in 5 pts with primary immunodeficiency and in 3 pts with Behçet's Disease.