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Epstein–Barr virus (EBV) is an oncogenic virus associated with various malignancies, including classical Hodgkin lymphoma (cHL). Despite its known association, the specific role of humoral immune response to EBV remains poorly characterized in cHL. To address this, we conducted a study using a custom protein microarray to measure the antibody responses in cHL patients and matched healthy controls recruited from an East‐Asian hospital‐based case–control study. We identified 16 IgG antibodies significantly elevated in EBV‐positive cHL compared with controls, defining an "East‐Asian antibody signature of EBV‐positive cHL." We evaluated responses against these 16 antibodies in a distinct European population, leveraging data from our previous European cHL case–control study from the UK, Denmark, and Sweden. A subset of antibodies (14/16, 87.5%) from the "East‐Asian antibody signature of EBV‐positive cHL" exhibited significant associations with cHL in the European population. Conversely, we assessed the "European antibody signature of EBV‐positive cHL" identified in our prior study which consisted of 18 EBV antibodies (2 IgA, 16 IgG), in the East‐Asian population. A subset of these antibodies (15/18, 83.3%) maintained significant associations with cHL in the East‐Asian population. This cross‐comparison of antibody signatures underscores the robust generalizability of EBV antibodies across populations. Five anti‐EBV IgG antibodies (LMP‐1, TK, BALF2, BDLF3, and BBLF1), found in both population‐specific antibody signatures, represent a "core signature of EBV‐positive cHL." Our findings suggest that the antibody responses targeting these core EBV proteins reflect a specific EBV gene expression pattern, serving as potential biomarkers for EBV‐positive cHL independent of population‐specific factors. [ABSTRACT FROM AUTHOR]

Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy that has been etiologically linked to Epstein-Barr virus (EBV) infection, with EBV gene transcripts identified in almost all cases. However, the humoral immune response to EBV in NKTCL patients has not been well characterized. We examined the antibody response to EBV in plasma samples from 51 NKTCL cases and 154 controls from Hong Kong and Taiwan who were part of the multi-center, hospital-based AsiaLymph case–control study. The EBV-directed serological response was characterized using a protein microarray that measured IgG and IgA antibodies against 202 protein sequences representing the entire EBV proteome. We analyzed 157 IgG antibodies and 127 IgA antibodies that fulfilled quality control requirements. Associations between EBV serology and NKTCL status were disproportionately observed for IgG rather than IgA antibodies. Nine anti-EBV IgG responses were significantly elevated in NKTCL cases compared with controls and had ORshighest vs. lowest tertile > 6.0 (Bonferroni-corrected P-values < 0.05). Among these nine elevated IgG responses in NKTCL patients, three IgG antibodies (all targeting EBNA3A) are novel and have not been observed for other EBV-associated tumors of B-cell or epithelial origin. IgG antibodies against EBNA1, which have consistently been elevated in other EBV-associated tumors, were not elevated in NKTCL cases. We characterize the antibody response against EBV for patients with NKTCL and identify IgG antibody responses against six distinct EBV proteins. Our findings suggest distinct serologic patterns of this NK/T-cell lymphoma compared with other EBV-associated tumors of B-cell or epithelial origin. [ABSTRACT FROM AUTHOR]

The humoral immune response to Epstein–Barr virus (EBV) in classical Hodgkin lymphoma (cHL) stratified by EBV tumor status is unclear. We examined IgG and IgA antibody responses against 202 protein sequences representing 86 EBV proteins using a microarray and sera from 139 EBV‐positive cHL cases, 70 EBV‐negative cHL cases and 141 population‐based controls frequency matched to EBV‐positive cHL cases on sex and age by area (UK, Denmark and Sweden). We leveraged existing data on the proportion of circulating B‐cells infected by EBV and levels of serum CCL17, a chemokine secreted by cHL tumor cells, from a subset of the cHL cases in the UK. Total IgG but not IgA response level was significantly different between EBV‐positive cHL cases and controls. The distinct serological response included significant elevations in 16 IgG antibodies and 2 IgA antibodies, with odds ratioshighest vs. lowest tertile > 3 observed for the following EBV proteins: LMP1 (oncogene), BcLF1 (VCAp160, two variants) and BBLF1 (two variants). Our cHL IgG signature correlated with the proportion of circulating EBV‐infected B‐cells, but not serum CCL17 levels. We observed no differences in the anti‐EBV antibody profile between EBV‐negative cHL cases and controls. BdRF1(VCAp40)‐IgG and BZLF1(Zta)‐IgG were identified as the serological markers best able to distinguish EBV‐positive from EBV‐negative cHL tumors. Our results support the hypothesis that differences in the EBV antibody profile are specific to patients with EBV‐positive cHL and are not universally observed as part of a systematically dysregulated immune response present in all cHL cases. What's new? Previous studies of Epstein–Barr virus in classical Hodgkin lymphoma (cHL) have been limited to only a few antibodies or protein complexes. In this study, the authors used a new protein microarray technology to measure both IgG and IgA antibody responses against far more EBV proteins. They found systemic differences in the EBV antibody profile in cHL cases, which are both specific to EBV‐positive tumors, and include immune aberrations that reflect exposure to multiple stages of the viral life cycle. Evidence of increased, systemic exposure to EBV lytic‐cycle activity supports a role for ongoing viral activity in tumor pathogenesis. [ABSTRACT FROM AUTHOR]

• This study is the largest serological survey of the anti-Epstein–Barr virus (EBV) peptide immunoglobulin G (IgG) antibody response. • Three EBV proteins with one segment associated with the IgG response were identified. • Five EBV proteins with amino acid changes associated with the IgG response were identified. • The inclusion of geographically distinct populations increases the relevance of this study. Epstein–Barr virus (EBV) infection contributes to cancers in a fraction of seropositive individuals, but much remains to be learned about variation in EBV-directed humoral immunity in cancer-free adults. A protein microarray was used to probe serum from 175 Taiwanese and 141 Northern European adults for immunoglobulin G (IgG) antibody responses to 115 different peptide sequences, representing protein segments or protein variants, from 45 EBV proteins. It was posited that this antibody-based approach could identify EBV peptide sequences representing immunodominant regions relevant for B-cell immunity. Analyses of 45 EBV proteins with multiple protein segments or variants printed on the array identified eight EBV peptide sequences that appear to play a role in immunogenicity. This included: (1) three proteins with segments/regions associated with IgG reactivity (BALF5, LMP1, LMP2A); and (2) five proteins with sequence variants/amino acid changes associated with IgG reactivity (BDLF4, EBNA3A, EBNA3B, EBNA-LP, LF1). This examination of IgG antibody responses against 115 EBV peptide sequences in 316 cancer-free adults represents an important step toward identifying specific EBV protein sequences that play a role in generating B-cell immunity in humans. [ABSTRACT FROM AUTHOR]