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Prepublished online as a Blood First Edition Paper on August 8, 2002; DOI 10.1182/blood-2002-03-0671.
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Blood, 15 December 2002, Vol. 100, No. 13, pp. 4550-4556
IMMUNOBIOLOGY
Dysregulated lymphocyte proliferation and differentiation in
patients with rheumatoid arthritis
Frederique Ponchel,
Ann W. Morgan,
Sarah J. Bingham,
Mark Quinn,
Maya Buch,
Robert J. Verburg,
Judy Henwood,
Susan H. Douglas,
Aurelie Masurel,
Philip Conaghan,
Moji Gesinde,
Julia Taylor,
Alexander F. Markham,
Paul Emery,
Jacob M. van Laar, and
John D. Isaacs
From the Molecular Medicine Unit, The University of
Leeds, St James's University Hospital, United Kingdom;
Rheumatology and Rehabilitation Research Unit, The University of Leeds,
United Kingdom; Department of Rheumatology, Leiden
University Medical Centre, The Netherlands; and National
Blood Transfusion Service, Seacroft Hospital, Leeds, United
Kingdom.
Rheumatoid arthritis (RA) is a chronic, inflammatory disease of the
synovium of uncertain pathogenesis. A number of phenotypic and
functional T-cell defects have been described in RA, including abnormal
clonal expansions and suppressed proliferative responses, which suggest
a defect in T-cell differentiation. Here, we show that RA patients
possess fewer naive CD4+ T cells than healthy controls.
Furthermore, a smaller proportion of these cells contains a T-cell
receptor excision circle (TREC). Patients with RA also have unusual
populations of T cells. These include immature cells characterized as
CD45RBbrightCD45RA+CD62L by flow
cytometry and a large population that coexpresses CD45RA and CD45RO.
These cells are hyperresponsive to mitogen and TCR stimulation when
compared to naive cells. Additionally, an unusual putative
central memory subset expressing CD62L, but not CD45RA, appears
in RA patients at the expense of more typical cells. Levels of
C-reactive protein correlate inversely with the TREC content of naive T
cells and positively with the sizes of naive and immature atypical
T-cell subsets. These data suggest that inflammation drives
proliferation of naive T cells in RA and encourages their differentiation into atypical, hyperresponsive progeny. TREC content of
individual naive and atypical T-cell subsets suggests an ontogeny consistent with this hypothesis. These studies provide further evidence
of a T-cell differentiation defect in RA, which could explain some of
the well-characterized immunologic features of the disease.
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