Rheumatoid Arthritis: Buch M

Emery P, Buch M. · No affiliation provided · BMJ. · Pubmed #11834544 links to  free full text

This publication has no abstract.

Ponchel F, Verburg RJ, Bingham SJ, Brown AK, Moore J, Protheroe A, Short K, Lawson CA, Morgan AW, Quinn M, Buch M, Field SL, Maltby SL, Masurel A, Douglas SH, Straszynski L, Fearon U, Veale DJ, Patel P, McGonagle D, Snowden J, Markham AF, Ma D, van Laar JM, Papadaki HA, Emery P, Isaacs JD. · Molecular Medicine Unit, University of Leeds, Leeds, UK. · Arthritis Res Ther. · Pubmed #15642146 links to  free full text

Abstract: We previously demonstrated prolonged, profound CD4+ T-lymphopenia in rheumatoid arthritis (RA) patients following lymphocyte-depleting therapy. Poor reconstitution could result either from reduced de novo T-cell production through the thymus or from poor peripheral expansion of residual T-cells. Interleukin-7 (IL-7) is known to stimulate the thymus to produce new T-cells and to allow circulating mature T-cells to expand, thereby playing a critical role in T-cell homeostasis. In the present study we demonstrated reduced levels of circulating IL-7 in a cross-section of RA patients. IL-7 production by bone marrow stromal cell cultures was also compromised in RA. To investigate whether such an IL-7 deficiency could account for the prolonged lymphopenia observed in RA following therapeutic lymphodepletion, we compared RA patients and patients with solid cancers treated with high-dose chemotherapy and autologous progenitor cell rescue. Chemotherapy rendered all patients similarly lymphopenic, but this was sustained in RA patients at 12 months, as compared with the reconstitution that occurred in cancer patients by 3-4 months. Both cohorts produced naive T-cells containing T-cell receptor excision circles. The main distinguishing feature between the groups was a failure to expand peripheral T-cells in RA, particularly memory cells during the first 3 months after treatment. Most importantly, there was no increase in serum IL-7 levels in RA, as compared with a fourfold rise in non-RA control individuals at the time of lymphopenia. Our data therefore suggest that RA patients are relatively IL-7 deficient and that this deficiency is likely to be an important contributing factor to poor early T-cell reconstitution in RA following therapeutic lymphodepletion. Furthermore, in RA patients with stable, well controlled disease, IL-7 levels were positively correlated with the T-cell receptor excision circle content of CD4+ T-cells, demonstrating a direct effect of IL-7 on thymic activity in this cohort.

Ponchel F, Morgan AW, Bingham SJ, Quinn M, Buch M, Verburg RJ, Henwood J, Douglas SH, Masurel A, Conaghan P, Gesinde M, Taylor J, Markham AF, Emery P, van Laar JM, Isaacs JD. · Molecular Medicine Unit, The University of Leeds, St James's University Hospital, United Kingdom. · Blood. · Pubmed #12393721 links to  free full text

Abstract: 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.