Dysregulated lymphocyte proliferation and differentiation in patients with rheumatoid arthritis.
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 CD45RB(bright)CD45RA(+)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.
Ponchel
Frederique
F
Molecular Medicine Unit, The University of Leeds, St James's University Hospital, United Kingdom.
Morgan
Ann W
AW
Bingham
Sarah J
SJ
Quinn
Mark
M
Buch
Maya
M
Verburg
Robert J
RJ
Henwood
Judy
J
Douglas
Susan H
SH
Masurel
Aurelie
A
Conaghan
Philip
P
Gesinde
Moji
M
Taylor
Julia
J
Markham
Alexander F
AF
Emery
Paul
P
van Laar
Jacob M
JM
Isaacs
John D
JD
D000328:Adult; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002097:C-Reactive Protein / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019070:Cell Lineage; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007156:Immunologic Memory; D016130:Immunophenotyping; D007249:Inflammation / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D008297:Male; D018448:Models, Immunological; D010835:Phytohemagglutinins / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D013950:Thymus Gland / Q000473:pathology
D010835:Phytohemagglutinins; D011948:Receptors, Antigen, T-Cell; D002097:C-Reactive Protein