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PMID: 11581315 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Survival and clonal expansion of mutating "forbidden" (immunoglobulin receptor-deficient) epstein-barr virus-infected b cells in angioimmunoblastic t cell lymphoma.

The Journal of experimental medicine ·Vol. 194 ·No. 7 ·2001-10-01 ·Pages 927-40

Bräuninger A, Spieker T, Willenbrock K, Gaulard P, Wacker HH, Rajewsky K, Hansmann ML, Küppers R

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.

MeSH Terms
Adult Aged Aged, 80 and over Antigens, CD20 B-Lymphocytes/virology Cell Differentiation Clone Cells Female Gene Rearrangement, B-Lymphocyte Genes, Immunoglobulin Genes, T-Cell Receptor gamma Herpesvirus 4, Human/isolation & purification Humans Immunoblastic Lymphadenopathy/immunology,virology Lymph Nodes/cytology,immunology,virology Lymphocyte Activation Lymphoma, T-Cell/immunology,virology Male Micromanipulation Middle Aged Mutation RNA, Viral/isolation & purification Virus Latency
Chemicals
Antigens, CD20 RNA, Viral
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Bräuninger A
Department of Pathology, University of Frankfurt, 60590 Frankfurt, Germany. braeuninger@em.uni-frankfurt.de
Spieker T
Willenbrock K
Gaulard P
Wacker H H
Rajewsky K
Hansmann M L
Küppers R
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.194.7.927
Email
braeuninger@em.uni-frankfurt.de
Published
2001-10-01
Pages
927-40
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2193480
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.194.7.927 PMC Full Text View journal details
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