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From the Molecular Immunology Group of the Wessex Immunology
Service*
and the Department of
Pathology,
Southampton University Hospitals
National Health Service Trust, Southampton; and the Department of
Pathology,
Cheltenham General Hospital,
Cheltenham, United Kingdom
The identification of clonal rearrangements of T cell
receptor (TCR) genes is central to the diagnosis of T cell
lymphomas. However, in angioimmunoblastic lymphadenopathy
(AILD), first described as a nonneoplastic proliferation
associated with immunodeficiency, the heterogeneity of TCR and
IgH gene rearrangements suggest that some cases may harbor multiple
lymphoid clones. In this study we have isolated DNA from archival
paraffin biopsy material from 22 cases of AILD identified on the basis
of classical histological and immunohistochemical features with the aim
of establishing the occurrence of clones and oligoclones, the
frequency of TCR and immunoglobulin heavy chain (IgH) variable (v) gene
use, and the relationship of these findings to the presence of
Epstein-Barr virus. DNA extracted from the biopsies was amplified using
the polymerase chain reaction (PCR) and sequenced to detect functional
and nonfunctional gene rearrangements. Epstein-Barr virus-encoded short
RNA species (EBERs) were detected using in situ
hybridization combined with immunochemistry to identify the phenotype
of the Epstein-Barr virus-infected cells. Fifty-seven clonal products
were found in 20/22 patients: TCR
clonal products were identified in
16/22, TCRß clonal products in 16/22 and IgH clonal products
in 6/22 cases. Oligoclonal PCR products were seen for TCR in 3/22 and
for IgH in 3/22 cases. In one biopsy PCR products from all reactions
were polyclonal. Sequence analysis revealed functional TCR,
TCRß, and IgH sequences in 6/12, 9/11, and
8/8 cases, respectively. Functional TCR and/or IgH oligoclones
were detected in 6/20 (30%) cases. In addition, nonfunctional
TCR and IgH sequences were found in 11 cases. EBERs were identified in
18/20 cases varying from occasional to 25 to 30% nuclei staining and
were associated with both T and B cells, although the majority
were of indeterminate phenotype. The presence of EBERs was not
associated with all clonal IgH gene rearrangements but was associated
with B cell oligoclones. Patterns of gene recombinations indicated that
the majority of TCR recombinations used GV1 and GJ1S3/2S3 genes. Six
out of eleven cases used TCR BV4S1 or BV2S1 genes associated with
various BJ and BD1/2 genes. No common IgH gene usage was
identified, but 8 clones had varying degrees of replacement and
silent mutations (0.6–10.1%), consistent with B cell clones
having undergone somatic mutation in the germinal center, and 3
clones harbored unmutated V genes, consistent with naive B
cells. Our data do not support the concept of AILD as a clearly defined
peripheral T cell lymphoma (PTCL). Rather, they suggest
that AILD as defined by histology and immunohistochemistry is either a
heterogeneous entity or represents a lymphoproliferation associated
with immunodeficiency in which clonal T cell or B cell proliferation
may occur.
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