Comparative Analysis of the Humoral Immune Response to the EBV Proteome across EBV-Related Malignancies

Abstract

Background: Epstein-Barr virus (EBV) is linked to multiple cancers, including classical Hodgkin lymphoma (cHL), endemic Burkitt lymphoma (eBL), nasopharyngeal carcinoma (NPC), and extranodal natural killer/T-cell lymphoma (NKTCL). Methods: Anti-EBV IgG and IgA antibody responses targeting 202 sequences from 86 EBV proteins were measured using the same EBV whole proteome array across four case-control studies investigating EBV-positive cHL, eBL, NPC and NKTCL (407 cases/620 controls). We grouped EBV-targeted antibodies into pathways by immunoglobulin type (IgA and IgG) and life cycle stage (latent, immediate early lytic, early lytic, late lytic, and glycoprotein) and evaluated their association with each cancer type. In an additional analysis, we focused on the subset of 46 individual antibodies representing the top candidates for each cancer and compared their associations across the four cancer types using multivariable linear regression models. Results: IgA antibody responses targeting all EBV life cycle stages were associated with NPC but limited to anti-early lytic stage for cHL. NPC and eBL were associated with IgG antibodies across the viral life cycle; cHL with antibodies in the early lytic, late lytic and glycoprotein stages; and NKTCL with antibodies in the latent, immediate early lytic and early lytic phases. EBNA3A, BBLF1, BDLF4, and BLRF2 IgG antibodies were associated with all cancer types. Conclusion: Our observed similarities and differences across four EBV-associated cancers may inform EBV-related oncogenesis. Impact: Understanding the comparative humoral immune response across EBV-related cancers may aid in identifying shared etiologic roles of EBV proteins and inform unique pathogenic processes for each cancer.

Epstein–Barr virus and multiple sclerosis: moving from questions of association to questions of mechanism

“…Serology against further EBV antigens – such as VCA‐specific antibodies – have been reported as elevated in MS, have been detected in CSF and also correlated with loss of brain volume in patients 30,31 . However, the exact role of inflated antibody responses against EBV antigens in MS development and progression remains somewhat unclear, and the extension of antibody studies to take of advantage of recently developed EBV proteome‐wide assays may be informative in that context 32 …”

“…30,31 However, the exact role of inflated antibody responses against EBV antigens in MS development and progression remains somewhat unclear, and the extension of antibody studies to take of advantage of recently developed EBV proteome-wide assays may be informative in that context. 32 In addition to increased EBV seroprevalence and perturbed antibody responses in MS, features of virus carriage have been shown to interact with multiple known environmental and genetic disease risk factors. Whilst HLA-DRB1*15: 01 has been linked to elevated anti-EBNA IgG titres, no associations have been shown for HLA alleles with history of IM, although one small study showed an effect for HLA-DRB1*01: 01.…”

“… 30 , 31 However, the exact role of inflated antibody responses against EBV antigens in MS development and progression remains somewhat unclear, and the extension of antibody studies to take of advantage of recently developed EBV proteome‐wide assays may be informative in that context. 32 …”

Identification of HLA-A*11:01 and A*02:01-Restricted EBV Peptides Using HLA Peptidomics

“…Furthermore, the elevated levels of antibodies targeting lytic antigens have been correlated with tumor progression in NPC patients. Recent research also showed that IgA and IgG antibodies targeting all EBV life cycle stages were associated with NPC [15], which may shed light on the unique pathogenic and therapeutic processes for NPC.…”

Epstein–Barr Virus BALF0/1 Subverts the Caveolin and ERAD Pathways to Target B-cell Receptor Complexes for Degradation

“…EBV has evolved multiple mechanisms to interfere with antigen presentation pathways, thereby suppressing cell-mediated immune responses (8)(9)(10)(11)(12)(13)(14)(15). However, elevated antibody titers against viral antigens are found in numerous EBV-associated disease states, including with infectious mononucleosis, endemic Burkitt lymphoma, nasopharyngeal carcinoma, classical Hodgkin Lymphoma, and multiple sclerosis (16)(17)(18). While Epstein-Barr virion evasion of complement activation has been described (PMID 2844953), viral strategies to protect virion from immunoglobulin, including that produced within the infected cell where viral particles mature, are less well-studied.…”