Survival and Clonal Expansion of Mutating “Forbidden” (Immunoglobulin Receptor–Deficient) Epstein-Barr Virus–Infected B Cells in Angioimmunoblastic T Cell Lymphoma

Abstract

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 (EBV)-infected B cells are frequently observed. To analyze the differentiation status and clonal composition of EBV-harboring B cells in AILD, single EBV-infected cells were micromanipulated from lymph nodes of six patients with frequent EBV+ cells and their rearranged immunoglobulin (Ig) genes analyzed. Most EBV-infected B cells carried mutated Ig genes, indicating that in AILD, EBV preferentially resides in memory and/or germinal center B cells. EBV+ 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. Surprisingly, many members of expanding B cell clones had acquired destructive mutations in originally functional V gene rearrangements and showed an unfavorable high load of replacement mutations in the framework regions, indicating that they accumulated mutations over repeated rounds of mutation and division while not being selected through their antigen receptor. This sustained selection-free accumulation of somatic mutations is unique to AILD. Moreover, the survival and clonal expansion of “forbidden” (i.e., Ig-deficient) B cells 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 between the microenvironment in AILD lymph nodes and the viral transformation that leads to the survival and clonal expansion of Ig-less B cells.

Small Bowel Perforation Caused by Epstein-Barr Virus-Associated B Cell Lymphoma in a Patient with Angioimmunoblastic T-Cell Lymphoma

“…It has been reported that EBV genomes are found in most of the AITL cases 5 and almost all of the cells infected by EBV are B cells showing normal histological findings. 18 In the majority of cases, EBERpositive cells were scattered, but there were sheets of EBVpositive cells in some cases. 19 In spite of such a background, the complication of B cell lymphomas in AITL has been reported to be rare.…”

Epstein-Barr virus–associated lymphoproliferative disorders

“…The latency pattern for EBV is not known as well, although some have assumed a restricted latency II program similar to that seen in other EBV-associated T-cell lymphoproliferative disorders [93]. This postulation can also be supported by the fact that most of the subsequent EBVassociated B-cell proliferations that follow AILT in few occasions express LMP1 and the EBERs, which is consistent with type II latency [92].…”

“…These crippling mutations are almost restricted to the EBVinfected cells and not detected in EBV-negative cells, which assumes a potential influence of EBV on these proliferating cells [93]. Although crippling mutations are also seen in classic Hodgkin lymphoma, HRS cells lack the intraclonal diversity because of the shutdown of the ongoing somatic mutations, in contrast to the EBV-infected B cells in AILT that continue to undergo somatic mutations even with the presence of crippling mutations [94].…”

“…The EBV-positive B cells have been determined to have ongoing somatic hypermutation, a hallmark of GC cells; however, these mutations are nonfunctional [93]. These crippling mutations are almost restricted to the EBVinfected cells and not detected in EBV-negative cells, which assumes a potential influence of EBV on these proliferating cells [93].…”

Powerful strategy for polymerase chain reaction-based clonality assessment in T-cell malignancies Report of the BIOMED-2 Concerted Action BHM4 CT98-3936

“…Incidence of Ig clonality was highest in AILT (32%), close to the frequencies identified by Smith et al 28 and Lome-Moldonado et al, 35 but higher than reported by Frizzera. 27 In this entity, Ig clonality most likely corresponds to expanded B-cell clones 28,[35][36][37][38] in line with the occurrence of secondary Epstein-Barr viruspositive B-cell lymphoma after AILT. 38,39 Also in T-LGL the association with B-cell proliferations is described.…”