The Journal of Experimental Medicine
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Published online 1 October 2001. doi:10.1084/jem.194.7.927
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© The Rockefeller University Press, 0022-1007/2001/10/927/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 7, October 1, 2001 927-940

Original Article

Survival and Clonal Expansion of Mutating "Forbidden" (Immunoglobulin Receptor–deficient) Epstein-Barr Virus–infected B Cells in Angioimmunoblastic T Cell Lymphoma

Andreas Bräuningera, Tilmann Spiekera, Klaus Willenbrocka, Philippe Gaulardb, Hans-Heinrich Wackerc, Klaus Rajewskyd, Martin-Leo Hansmanna, and Ralf Küppersd,e
a Department of Pathology, University of Frankfurt, 60590 Frankfurt, Germany
b Department of Pathology, Centre Hospitalier Universitaire Henri Mondor, 94010 Créteil, France
c Department of Hematopathology, University of Kiel, 24118 Kiel, Germany
d Institute for Genetics, University of Cologne, 50931 Cologne, Germany
e Department of Internal Medicine I, University of Cologne, 50931 Cologne, Germany

Correspondence to: Andreas Bräuninger, Dept. of Pathology, University of Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt, Germany. Tel:49-069-6301-5440 Fax:49-069-6301-5241 E-mail:braeuninger{at}em.uni-frankfurt.de.

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.

Key Words: B lymphocytes, somatic hypermutation, EBV, immunoglobulin genes, single cell PCR


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