Survival and clonal expansion of mutating "forbidden" (immunoglobulin receptor-deficient) Epstein-Barr virus-infected B cells in angioimmunoblastic Tcell lymphoma

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is a peculiar T cell lymphoma, as expanding B cell clones are often present besides the malignant T cell clones. In addition, large numbers of Epstein-Barr virus E BV)-infected B cells are frequently observed. To analyze the differentiatio n status and clonal composition of EBV-harboring B cells in AILD, single EB V-infected cells were micromanipulated from lymph nodes of six patients wit h frequent EBV cells and their rearranged immunoglobulin (Ig) genes analyze d. Most EBV-infected B cells carried mutated Ig genes, indicating that in A ILD, EBV preferentially resides in memory and/or germinal center B cells. E BV+ B cell clones observed in all six cases ranged from small polyclonal to large monoclonal expansions and often showed ongoing somatic hypermutation while EBV- B cells showed little tendency for clonal expansion. Surprising ly, many members of expanding B cell clones had acquired destructive mutati ons in originally functional V gene rearrangements and showed an unfavorabl e high load of replacement mutations in the framework regions, indicating t hat they accumulated mutations over repeated rounds of mutation and divisio n while not being selected through their antigen receptor. This sustained s election-free accumulation of somatic mutations is unique to AILD. Moreover . the survival and clonal expansion of "forbidden" (i.e., Ig-deficient) B c ells has not been observed before in vivo and thus represents a novel type of viral latency in the B cell compartment. It is likely the interplay betw een the microenvironment in AILD lymph nodes and the viral transformation t hat leads to the survival and clonal expansion of Ig-less B cells.