Healthy individuals mount vigorous humoral and cellular immune responses to primary EBV infection.10 Although antibodies to the viral membrane proteins neutralize virus infectivity, the cellular immune response is essential for controlling virus-infected cells during both lytic and latent phases.
Humoral Immune Responses
Heterophile Antibodies
Heterophile antibodies, originally described by Paul and Bunnell, are present in 90% to 95% of EBV infections at some point during the illness. However, in infants and children younger than the age of 4 years with primary EBV infection, heterophile antibody responses may not be detected. Heterophile antibodies are immunoglobulin M (IgM) antibodies, which agglutinate erythrocytes from different species including bovine, camel, horse, goat, and sheep. EBV-induced heterophile antibodies have no reactivity against guinea pig kidney cells in contrast to naturally occurring antibodies (Forssman antibodies) or antibodies present in patients with serum sickness and other conditions.
In addition to heterophile antibodies, cold agglutinins directed preferentially against the anti-I antigen on red cell membranes are frequently detected in the sera of patients with IM; however, hemolytic anemia is rare. Other antibodies (including anti-I, anti-N, Donath Landsteiner antibodies, platelet antibodies, and anti–smooth muscle antibodies) have been described in association with EBV infection
Epstein-Barr Virus–Specific Antibodies
EBV-specific antibody responses are detected with immunofluorescence assays developed in the first decades of EBV research. EBV antibodies are directed against (1) EBNA, (2) early antigen (EA), (3) the membrane antigen expressed on the surface of cells late in the lytic cycle, and (4) the viral capsid antigen (VCA) expressed within cells late in the lytic cycle. Each antigen is a composite of several dis tinct viral proteins, and attempts have been made to replace the afore mentioned assays with tests using specific viral proteins; however, no single test has attracted widespread use.
VCA-IgM and IgG antibodies are usually present at the onset of clinical symptoms because of the prolonged viral incubation period (Table 1). VCA-IgM antibodies are a good marker for an acute infection because they rapidly disappear within 4 to 8 weeks.
Table1. Frequently Determined Epstein-Barr Virus–Specific Antibodies
VCA-IgG antibodies persist for life and are commonly used to document prior EBV infection. IgG antibodies against EA are present at the onset of the clinical illness in approximately 70% of patients. EA antibodies are divided into methanol-sensitive (anti-D) and methanol-resistant (anti-R) antibodies, and the majority of EA antibodies detected are anti-D antibodies. The presence of anti-D antibodies is consistent with recent infection, because titers disappear after recovery. IgG antibodies to EBNA appear late in the course of almost all cases of EBV infection and persist throughout life; their presence early in a suspected case of primary EBV infection excludes the diagnosis. Aberrations in this pattern of serum reactivity are observed in many EBV-associated diseases and will be discussed under the specific dis ease sections. For example, the absence of EBNA antibodies despite previous EBV infection is one of the serologic markers suggestive for chronic active EBV (CAEBV) infection.
Cellular Immune Responses
In normal individuals, primary EBV infection often results in a massive expansion of activated, antigen-specific T cells. Using tetramer technology to enumerate antigen-specific T cells, it has been documented that the CD8+ T-cell response may be dominated by T cells specific for a limited number of epitopes, as seen with T-cell responses against other herpesviruses. T cells specific for epitopes derived from immediate early and several early EBV proteins of the lytic cycle are dominant during the acute phase of IM, and long-term persistence of EBV-specific, CD8+ T cells has been documented after primary EBV infection. As many as 5.5% of the circulating CD8+ T cells in a healthy virus carrier may be positive for a single EBV epitope, illustrating how persistent EBV infection can influence the composition of the host’s T-cell pool. Besides EBV-specific CD8+ T cells, EBV-specific CD4+ T cells play an important role in the control of EBV infections, and EBNA1-specific CD4+ T cells have been implicated in the control of newly infected B cells. As for CD8+ T-cell responses, there is a marked hierarchy of immunodominance, with the majority of CD4+ T cells being specific for EBNA1 and to less extent EBNA3C.
