Hodgkin's disease revisited: Reed-Sternberg cells as natural hybridomas

The formation of natural hybridomas during the course of malignant lymphoproliferative diseases was first observed in 1969, and many times thereafter. This natural phenomenon remains experimentally unexplored even though it exerts fundamental influence on the natural history and outcome of neoplastic cell proliferations. Instead, hybridomas artificially constructed in the laboratory from 1975 on are being extensively studied and utilized for the production of highly specific monoclonal antibodies in the diagnosis and treatment of infectious and malignant diseases. This review lists examples of natural hybridomas formed in murine and human neoplasms. Indirect evidence supports the notion that hybridomas are generated in African Burkitt's lymphoma (BL) in the form of large, immunoresistant tetraploid BL cells emerging in immunoreactive relapsed patients; and in Hodgkin's disease (HD) in the form of Reed-Sternberg (RS) cells. RS cells may be formed when retroviral antigens expressed by the mononuclear HD cell attract reactive B and T cells, and instead of an immune attack by reactive cells, fusion with reactive cells takes place. The resulting RS cells may further fuse with other reactive cells (e.g., with two B cells, one expressing kappa, the other lambda light chains) or with each other, forming quadromas. RS cells appear multinucleated and hyperploid; they express the products of activated genes of the interdigitating dendritic cell (the retrovirally infected mononuclear HD cell) and those of reactive B and/or T cells. Thus, RS cells present themselves with a great variety of marker expression. Molecular mediators and immunoglobulins released from RS cells are responsible for the activities of proliferating polyclonal reactive cells and/or for the depletion of these cells in HD lesions. Multinucleated giant RS cells in anaplastic lymphomas and the syncytial subtype of RS cells of nodular sclerosing HD should be studied first for retro- or herpes viral antigen expressions and for fusion with reactive cells or with other RS cells.