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Blood, 15 September 2002, Vol. 100, No. 6, pp. 2145-2152
IMMUNOBIOLOGY
The immunophenotypic and immunogenotypic B-cell differentiation
arrest in bone marrow of RAG-deficient SCID patients corresponds to
residual recombination activities of mutated RAG proteins
Jeroen G. Noordzij,
Sandra de Bruin-Versteeg,
Nicole S. Verkaik,
Jaak M. J. J. Vossen,
Ronald de Groot,
Ewa Bernatowska,
Anton W. Langerak,
Dik C. van
Gent, and
Jacques J. M. van
Dongen
From the Department of Immunology, Erasmus MC,
University Medical Center Rotterdam, Rotterdam, The Netherlands;
Department of Pediatrics, Division of Immunology and Infectious
Diseases, Erasmus MC, University Medical Center Rotterdam, Rotterdam,
The Netherlands; Department of Cell Biology and Genetics, Erasmus MC,
University Medical Center Rotterdam, Rotterdam, The Netherlands;
Department of Pediatrics, Leiden University Medical Center, Leiden, The
Netherlands; and Department of Immunology, The Children's Memorial
Health Institute, Warsaw, Poland.
The protein products of the recombination activating genes
(RAG1 and RAG2) initiate the formation of
immunoglobulin (Ig) and T-cell receptors, which are essential for B-
and T-cell development, respectively. Mutations in the RAG
genes result in severe combined immunodeficiency disease (SCID),
generally characterized by the absence of mature B and T lymphocytes,
but presence of natural killer (NK) cells. Biochemically, mutations in
the RAG genes result either in nonfunctional proteins or in
proteins with partial recombination activity. The mutated RAG
genes of 9 patients from 7 families were analyzed for their
recombination activity using extrachromosomal recombination substrates,
rearrangement of endogenous Ig loci in RAG
gene-transfected nonlymphoid cells, or the presence of Ig gene
rearrangements in bone marrow (BM). Recombination activity was
virtually absent in all 6 patients with mutations in the RAG core
domains, but partial activity was present in the other 3 RAG-deficient
patients, 2 of them having Omenn syndrome with oligoclonal T
lymphocytes. Using 4-color flow cytometry, we could define the exact
stage at which B-cell differentiation was arrested in the BM of 5 RAG-deficient SCID patients. In 4 of 5 patients, the absence of
recombination activity was associated with a complete B-cell differentiation arrest at the transition from cytoplasmic (Cy) Igµ pre-B-I cells to CyIgµ+ pre-B-II
cells. However, the fifth patient showed low frequencies of
precursor B cells with CyIgµ and surface membrane IgM, in line with
the partial recombination activity of the patient's mutated RAG gene and the detection of in-frame Ig gene
rearrangements in BM.
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