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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 610-617
Genetic defect in human X-linked agammaglobulinemia impedes a
maturational evolution of pro-B cells into a later stage of pre-B cells
in the B-cell differentiation pathway
Keiko Nomura,
Hirokazu Kanegane,
Hajime Karasuyama,
Satoshi Tsukada,
Kazunaga Agematsu,
Gyokei Murakami,
Satoru Sakazume,
Masahiro Sako,
Rieko Tanaka,
Yoshinori Kuniya,
Takuya Komeno,
Shigehiko Ishihara,
Keizo Hayashi,
Tadamitsu Kishimoto, and
Toshio Miyawaki
From the Department of Pediatrics at the Faculty of
Medicine, Toyama Medical and Pharmaceutical University, the Toyama Red
Cross Hospital, and the Kamiichi Welfare Hospital, Toyama, Japan; the
Department of Immunology, The Tokyo Metropolitan Institute of Medical
Science, Tokyo, Japan; the Department of Pediatrics, Dokkyo Medical
Koshigaya School, Saitama, Japan; the Department of Pediatrics at Osaka
City General Hospital and Kashiwara Municipal Hospital and the
Department of Molecular Medicine, Osaka University Medical
School, Osaka, Japan; the Department of Pediatrics, Shinshu
University School of Medicine, Matsumoto, Japan; the Japanese
Red Cross Society Wakayama Medical Center, Wakayama, Japan;
the Department of Pediatrics, NTT Sapporo Hospital, Sapporo,
Japan; and the Division of Hematology, Institute of Clinical Medicine,
University of Tsukuba, Tsukuba, Japan.
Surrogate light chains ( 5/VpreB) are selectively
expressed in early precursors of B cells. B-cell defects in
X-linked agammaglobulinemia (XLA) are caused by mutations in the
gene for Bruton's tyrosine kinase. To elucidate the nature of early
B-lineage cells in bone marrow (BM), samples from 13 XLA patients
and 24 healthy controls of different ages were comparatively
analyzed using an antihuman VpreB monoclonal antibody. Expression of
surrogate light (SL) and µ-heavy chains were examined after cell
membrane permeabilization because they are mainly expressed in the
cytoplasm of early B-lineage cells. A flow cytometric analysis of
normal BM identified 5 discrete cell types of B cells:
µ SL++ (pro-B [B-cell progenitor]),
µlowSL++ (pre-B1a),
µlowSL+ (pre-B1b),
µlowSL (pre-B2), and
µhighSL (B). The large cells,
presumably in cycling states, were enriched in pre-B1a cells. The
frequencies of B-lineage cells in BM were higher in young children, and
declined with advancing age. In contrast, XLA showed a profound
reduction in BM B-lineage cells. In XLA BM, an expansion of pro-B cells
with some small pre-B1a cells was marked, but other cells were
negligible. These observations illustrate a B-cell maturation defect in
XLA as well as a normal human B-cell differentiation pathway. The
results suggest that the genetic defect in XLA may impede the evolution
of pro-B cells beyond the earlier pre-B stage into the later stage of
pre-B cells in B-cell development.
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