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Prepublished online as a Blood First Edition Paper on August 8, 2002; DOI 10.1182/blood-2002-03-0671.
Submitted March 6, 2002
Accepted July 18, 2002
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 Conagham, Moji Gesinde, Julia Taylor, Alexander F Markham, Paul Emery, Jacob M van Laar, and John D Isaacs*
Molecular Medicine Unit, University of Leeds, Leeds, United Kingdom; Rheumatology research unit, University of Leeds, Leeds, United Kingdom
Rheumatology research unit, University of Leeds, Leeds, United Kingdom
Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands
Molecular Medicine Unit, University of Leeds, Leeds, United Kingdom
Seacroft Hospital, National Blood Transfusion Service, Leeds, United Kingdom
* Corresponding author; email: rrrjdi{at}leeds.ac.uk.
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 T-cells than healthy controls. Furthermore, a smaller proportion of these cells contains a T-cell receptor excision circle (TREC). RA patients also possess unusual populations of T-cells. These include immature cells characterised as CD45RBbright CD45RA+ CD62L- by flow cytometry and a large population that co-expresses CD45RA and CD45RO. These cells are hyper-responsive 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 (CRP) correlate inversely with the TREC content of naive T-cells and positively with the size 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, hyper-responsive progeny. The 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 immunological features of the disease.
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