PubMed · 2903367
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P G Isaacson, J Spencer, D H Wright. 1988-11-12. Classifying primary gut lymphomas.. https://doi.org/10.1016/s0140-6736(88)90574-0
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We infected umbilical cord blood lymphocytes (CBL) with EBV in vitro. Analysis of the cell population in 3- and 6-day-old cultures showed a relative increase of B cells and outgrowth of B cells after prolonged culture period. The immunomodulator PSK was added to parallel cultures. In these cultures, B cell growth was inhibited and the activation of T and NK cells was potentiated. This was detected by assessment of SH2D1A (also named SAP or DSHP) expression (a molecule which participates in signal transduction and is mutated in X-linked lymphoproliferative disease, XLP). Upon further cultivation, irradiated autologous EBV infected B cells and IL-2 were added to the cultures. After 17 days, the B lymphocytes were removed from the PSK containing cultures. The remaining populations, containing mainly T and NK cells, exerted cytotoxic function which could act on EBV infected autologous B cells, allogeneic LCL and on K562. Since cellular immunity to EBV is not transmitted to the newborn, EBV specific memory is not involved in the activation of effector cells. Our finding of an in vitro response of T and NK cells to EBV infected B lymphocytes in the absence of EBV specific immunological memory is of particular interest, because it may also operate in vivo and participate in the scenario of primary infection. Its potentiation by immunomodulators may have practical significance.
Epstein Barr virus (EBV) is a gamma herpesvirus that is associated with several specific lymphoid malignancies, some of which occur more frequently in immunocompromised individuals. EBV infection is almost ubiquitous in healthy adults, so establishing a causal role in lymphomagenesis has been difficult. Support for EBV being an oncogenic virus is derived from its ability to infect and transform normal human B-cells in vitro, resulting in their "immortalization" and leading to continuously growing lymphoblastoid cell lines (LCLs). In addition, viral proteins required for this EBV-mediated transformation have been identified. The presence of EBV in the neoplastic cells of specific lymphoid malignancies is quite consistent, further indicating an etiopathogenic role in their development. Nevertheless, it is clear that while important in the process of lymphomagenesis, infection by EBV is not sufficient. Important co-factors exist for the development of EBV-associated lymphomas, one of which is the lack of normal immune surveillance.
The production of high-affinity protective antibodies requires somatic hypermutation (SHM) of the antibody variable (V)-region genes. SHM is characterized by a high frequency of point mutations that occur only during the centroblast stage of B-cell differentiation. Activation-induced cytidine deaminase (AID), which is expressed specifically in germinal-centre centroblasts, is required for this process, but its exact role is unknown. Here we show that AID is required for SHM in the centroblast-like Ramos cells, and that expression of AID is sufficient to induce SHM in hybridoma cells, which represent a later stage of B-cell differentiation that does not normally undergo SHM. In one hybridoma, mutations were exclusively in G*C base pairs that were mostly within RGYW or WRCY motifs, suggesting that AID has primary responsibility for mutations at these nucleotides. The activation of SHM in hybridomas indicates that AID does not require other centroblast-specific cofactors to induce SHM, suggesting either that it functions alone or that the factors it requires are expressed at other stages of B-cell differentiation.