Expression of Activation Antigens on T Cells in Rheumatoid Arthritis Patients (original) (raw)
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Rheumatology International, 1982
Analyses of the synovial tissue and fluid T lymphocytes obtained from patients with rheumatoid arthritis revealed multiple functional defects in the regulation of autologous blood B cell differentiation into cells secreting immunoglobulin. These abnormalities were not found in peripheral blood T lymphocytes from the same patients. Although the patients selected showed elevated levels of T cells expressing the T 8 differentiation antigen as well as Ia antigens there was little demonstrable suppression of the blood B cell differentiation. Furthermore, the synovial T cells exhibited only minimal helper or inducer activity when tested in the same system. In contrast, patient's blood T lymphocytes gave levels of help and suppression that we{e not distinguishable from that of normal individuals. Co-culture experiments of blood and synovial T lymphocytes did not reveal any evidence for enhanced suppression; indeed, in most patients these cocultures resulted in marked augmentation of helper function, a phenomenon designated "helper augmentation". These data provide evidence that rheumatoid synovial lymphocytes are characterized by marked abnormalities in immunoregulatory T cell function, including divergence of cellular activity from the immune function predicted by surface phenotype and a capacity for "helper augmentation", a novel T cell function in man.
Activated T Lymphocytes of the Synovial Membrane in Rheumatoid Arthritis and Other Arthropathies
Scandinavian Journal of Immunology, 1985
Immunohistological techniques were used to identify activated T lymphocytes within the synovial membrane of patients with rheumatoid arthritis, using the monoclonal antibody (MoAb) RFT2, which identifies a 40-k dalton molecule preferentially expressed by T blasts or activated cells. Using this reagent together with a monoclonal ‘cocktail’ that stains all T cells, cell counts on consecutive sections of rheumatoid synovium revealed that up to 50% T lymphocytes were RFT2+ (range 9.3-50.2%, mean 25.4). Subsequent analysis using combination immunofluorescence demonstrated that over 90% of these activated cells were of the T4+ subset. Furthermore all these cells appeared to be Leu8-. suggesting that the activated population were exclusively ‘true helpers’ and not suppressor inducers. Studies indicated that 50% of the RFT2+ cells were positive with anti-Tac MoAb. Comparisons with tissues from other arthropathies demonstrated that this relatively high proportion of RFT2+ cells was a feature restricted to rheumatoid arthritis, although biopsies from patients with psoriatic arthritis and ankylosing spondylitis also contained activated cells. Biopsies of Reiter's syndrome, osteo-arthritis, and pigmented villonodular synovitis contained no activated cells, no were any seen in sections of normal synovium. The presence in rheumatoid synovial membrane of activated T cells which are only of the T4+, Leu8+ subset adds weight to the suggestion that local immunoregulatory dysfunction contributes to the chronic inflammation of rheumatoid arthritis.
Clonal heterogeneity of synovial fluid T lymphocytes from patients with rheumatoid arthritis
Proceedings of the National Academy of Sciences, 1989
Although substantial evidence suggests that synovial T lymphocytes are critical in the pathogenesis of rheumatoid arthritis (RA), little is known regarding their antigenic specificities, antigen receptor gene rearrangements, and mechanisms of activation. To assess the extent ofexpansion of specific clones among RA synovial fluid T cells, Southern blot analyses of T-cell receptor (TCR) gene rearrangements were performed on 40 RA synovial fluid T-cell clones, as well as on both fresh and polydonally activated T cells from RA synovial fluid, RA peripheral blood, and normal peripheral blood. Two of the clones had identical TCR rearrangement patterns, but the remainder were unique. The nonclonal RA T-cell samples showed the same pattern of TCR fl-chain rearrangement that was observed among normal peripheral blood T cells, indicating no dominant clonal T-cell population in these samples. It was noted that with sufficient exposure of autoradiograms of the Southern blots, discrete TCR gene rearrangements, representing in some cases common DpJp (D, diversity; J, joining) rearrangements,. were evident in T cells from peripheral blood of normal individuals and patients with RA, as well as T cells from RA synovial fluid. Taken together, the findings indicate that only a minor degree of oligoclonality can be demonstrated among T lymphocytes from RA synovial fluid.
Ia+ T Cells in Synovial Fluid And Tissues of Patients with Rheumatoid Arthritis
Arthritis & Rheumatism, 1981
Human Ia antigens are expressed primarily on all B lymphocytes and most monocytes, on cells in the early stages of hematopoiesis, and on certain other cell types (1-3). In contrast, Ia antigens are demonstrable on a very small number of T lymphocytes in the blood of normal individuals (4). These la positive T cells are small, do not actively synthesize DNA. and are found predominantly in the T gamma fraction (4). The number of such cells rapidly increases upon immunization,
European Journal of Immunology, 1987
CD3'4-8-WT31-(T cell receptor r f ) cells and other unusual phenotypes are frequently detected among spontaneously interleukin 2-responsive T lymphocytes present in the joint fluid in juvenile rheumatoid arthritis. A clonal analysis* T lymphocytes (E rosetting cells) isolated from the joint fluid of four patients with juvenile rheumatoid arthritis (JRA) were first analyzed for surface antigen expression. Approximately 15% of cells were CD25' (interleukin, IL, 2 receptor positive), in addition, a remarkable proportion of cells expressed the CD2'3-phenotype. CD3' cells outnumbered the sum of CD4+ and CD8+ cells as well as the cells reactive with the WT31 monoclonal antibody (which recognizes a framework determinant of the a/p T cell receptor). Purified T cells were cloned under culture conditions (1% phytohemagglutinin, PHA plus IL2) which allow clonal expansion of most peripheral blood T lymphocytes. Under these conditions proliferating cells ranged from 25 to 65%; clones (derived from microcultures containing 0.5 or 0.25 cells/well) were tested for cytolytic activity against P815 cells (in the presence of PHA) or against the natural killer (NK)-sensitive K562 target cells. Fifty-four percent and 73% of clones obtained from the two patients with the polyarticular form of the disease displayed cytolytic activity in the lectin-dependent assay. Cytolytic clones were 22 and 29% in the two patients with single joint involvement. About half of all cytolytic clones displayed NK-like activity. Surface antigen analysis revealed that, in addition to conventional CD3'4'8-and CD3'4-8+, a noticeable fraction of clones (501202) displayed unusual surface phenotypes. In particular, 33/50 coexpressed CD4 and CD8 antigens; 7/50 were CD2'3-4-8-and displayed NK-like activity; 10/50 expressed CD3 but lacked both CD4 and CD8 antigen and did not react with the WT31 monoclonal antibody. In order to allow selective growth of ILZresponsive cells, T lymphocytes were also cloned directly in IL2. As much as 57% of all clones thus obtained (48184) displayed cytolytic activity. Moreover, about half expressed unusual surface phenotypes including CD2+3-4-8-, CD3' 4' 8'
Clinical Rheumatology, 1982
The number of T-lymphocytes and T-lymphocyte subsets was measured in peripheral blood of 51 patients with rheumatoid arthiritis. T-lymphocytes were counted by E-rosette tests and by the immunogold staining method with OKT3.PAN monoclonal antibody. Helper and suppressor T-lymphocytes were determined by the immunogold staining method with OKT4.IND and OKT8.SUP monoclonal antibody. The relative and absolute numbers of T-lymphocytes and helper T-lympohocytes in peripheral blood of patients with RA did not differ significantly from those in the blood of healthy subjects. However, the relative and absolute numbers of suppressor T-cells were significantly lower in patients with RA than in healthy subjects. The decrease of suppressor T-cells in the blood of patients with RA dit not correlate with the activity of the disease nor the presence of the rheumatoid factor.
Lymphocyte Activation in Rheumatoid Arthritis Synovial Fluid in Vivo
Scandinavian Journal of Immunology, 1985
Monoclonal antibodies were used in avidin-biotin-peroxidase complex staining for activation marker analysis of rheumatoid synovial fluid cells. Although Ia expression indicates T cell activation, cells displaying receptors for interleukin 2 (Tac)-and transferrin receptor (T9)-positive proliferating cells were relatively few. Similarly, activated terminal effector cells of suppressor/cytotoxic nature were scarce in rheumatoid synovial fluid, as suggested by a low expression of Tac and 4F2 markers. The in vivo situation in the rheumatoid arthritic (RA) joint does not seem to be due to the inability of synovial fluid lymphocytes to become activated, because mitogen stimulation in vitro, in spite of a low proliferative response, induced expression of all the activation markers studied. The relevance of the present observations to the down-regulation of the active, inflammatory-immune response in situ is speculative, but the data show that in spite of T-cell activation and Ia expression, activated terminal effector cells of suppressor/cytotoxic nature are few in the RA joint in vivo.
Scandinavian Journal of Immunology, 1989
We studied the expression of the Tac antigen, the transferrin receptor (Tfr-R), HLA class II antigens (DR, DQ, DP), CD30, and Act 1 on purified CD4+ and CD8+ cells isolated from synovial fluid (SF), synovial tissue (ST), and peripheral blood (PB) of patients with rheumatoid arthritis (RA) and with non-RA inflammatory arthritides (not ST). Subfractionated T cells of PB from healthy individuals served as controls. SF CD4+ cells from RA and non-RA arthritides expressed the Tac antigen much more frequently than corresponding CD8+ cells (54 and 58% versus 16 and 17%). In contrast, SF CD8+ cells of both patient groups expressed the HLA class II antigens rather more frequently than the corresponding CD4+ cells (88 and 68% versus 72 and 40%). Tfr-R expression was low on CD4+ and CD8+ SF T cells from both patient groups. SF T cells did not express CD30, and their expression of Act 1 did not differ from that of normal PB T cells. The RA ST findings were similar to those of RA SF. The overall expression of activation markers on PB T cells of patients was slightly higher than on those of normal controls, and the RA group was slightly higher than the non-RA group. The results show that intra-articular T cells in arthritis are activated and that CD4+ and CD8+ subsets differ in their expression of Tac antigen and HLA class II antigens. There were also similar patterns of activation markers on both CD4+ and CD8+ SF cells from RA and non-RA arthritis patients, suggesting that several types of arthritis display a similar immunopathogenesis in the joints.
RHEUMATOID ARTHRITIS: A DISEASE OF T-LYMPHOCYTE/MACROPHAGE IMMUNOREGULATION
The Lancet, 1981
In rheumatoid arthritis the synovial membrane has many ofthe characteristics of a hyperactive, immunologically-stimulated lymphoid organ. The basis of this hyperactivity is poorly understood. Highly specific antisera to human Ia-like (HLA-DR) antigens and monoclonal antibodies (OKT series) to various T-lymphocyte subsets were used to analyse both the normal and the rheumatoid synovium and to compare it with normal lymph nodes. In rheumatoid arthritis the synovium acquires an infiltrate with microanatomical similarities to the paracortical area of the lymph node. Large, very strongly HLA-DRpositive macrophage-like interdigitating cells form close contacts with the OKT4+ (inducer-type) T-cells, while the OKT8+ population (T-cells of suppressor-cytotoxic type) between the macrophage-OKT4+ cell clusters is scanty (T4/T8 ratio = 9:1). By contrast, in the lymph node there are more OKT8+ T-cells interspersed between the HLA-DR+ interdigitating cells and OKT4+ cells (T4/T8 ratio=2:1). The large interdigitating cells and the OKT4+ T-cell population may be mutually stimulatory. In the absence of efficient suppression this stimulation may lead to activation of B-lymphocytes and oligoclonal or polyclonal immunoglobulin synthesis, as is found in the synovial membrane in rheumatoid arthritis.