Activated T Lymphocytes of the Synovial Membrane in Rheumatoid Arthritis and Other Arthropathies (original) (raw)
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Cells of the synovium in rheumatoid arthritis. T lymphocytes
Arthritis research & therapy, 2007
Recent findings have substantiated the importance of T lymphocytes to the pathogenesis of rheumatoid arthritis (RA). Here, we review emerging data regarding genetic predisposition, spontaneous animal models of arthritis, and cell-cell interactions that implicate T cells as driving synovial inflammation and joint destruction. Information regarding the proinflammatory role of interleukin-17-producing T cells and the functional state of regulatory T cells both in animal models and in patients with RA is also discussed. In light of the overwhelming evidence that disrupted T-cell homeostasis greatly contributes to joint pathology in RA, the therapeutic potential of targeting activators of pro-inflammatory T cells or their products is compelling.
Clinical and Experimental Immunology, 2002
SUMMARY T-cell cytokines play a crucial role in the pathogenesis and progression of rheumatoid arthritis (RA). Their detection in the joint, however, is impaired by the complex network present in the synovium. Although many synovial T cells show signs of previous activation, only a few express interleukin (IL)-2 receptor, marker of recent activation. The aim of this study was to analyse the cytokine production by in vivo activated (IL-2R +) T cells from RA at different stages of the disease. For this purpose, T cells were isolated from peripheral blood and synovial fluid of four patients with active RA, two at the onset of the disease, one in the early phase during treatment, one in long-lasting chronic phase. One patient was studied at the onset of the disease and 52 months later. Cells were initially expanded with a low dose of IL-2, cloned and analysed for cytokine production. The results showed a strong predominance of T helper (Th) 1 clones in the blood and a slight prevalence ...
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.
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.
Cytokine production by synovial T cells in rheumatoid arthritis
Rheumatology, 1999
Objective. To investigate the production of cytokines by T cells in patients with rheumatoid arthritis (RA), reactive arthritis (REA) and osteoarthritis (OA). Methods. The lymphokines interleukin (IL)-2, IL-4, interferon gamma (IFN-c) and tumour necrosis factor beta (TNF-b), as well as the monokines IL-1, IL-6 and TNF-a, were measured by immunoassays in sera and synovial fluid (SF) from patients with RA, REA and OA. In addition, cytokine expression was studied by immunohistochemistry in synovial membrane tissue sections from patients with RA and OA. Results. Almost 60% of RA sera contained at least one of the cytokines investigated, though in low concentrations, whereas cytokines were generally not detectable in sera from REA and OA patients. In contrast, cytokines were found in virtually all SF; thus, the majority of SF from RA patients contained IFN-c (median level 17 pg/ml) in addition to the monokines IL-6 (4700 pg/ml) and TNF-a (157 pg/ml). IFN-c and IL-6 (but not TNF-a) were also frequently measured in SF from REA patients, whereas OA samples typically contained only IL-6. Immunohistochemical analysis of tissue sections from RA patients revealed lymphokine expression in 0.1-0.3% of T cells, particularly IL-2 and IFN-c, and to a lesser extent also IL-4. Interestingly, the expression of TNF-a and IL-6 by synovial T cells was also observed. The majority of cytokine-expressing T cells were CD4-positive T-helper cells typically found in perivascular areas, whereas cytokine-producing CD8-positive T cells were found distributed throughout the synovium. As expected, in specimens from OA patients, T cells were much less abundant and expression of cytokines could not be detected. Conclusion. These data clearly demonstrate production of cytokines by T cells in RA synovial tissue, indicating that activated T cells play a role in the pathophysiological events of RA.
Clinical and experimental …, 1982
We have used monoclonal antibodies of the orthoclone (OKT) series to identify T cell subsets in an immunohistological analysis of the synovial membranes obtained from normal individuals and patients with osteoarthritis or rheumatoid arthritis. T cells of the inducer and the suppressor/cytotoxic subsets were identified by the OKT4 and OKT8 antibodies respectively while HLA-DR (Ia-like) antigens were recognized by a conventional antiserum. In the normal and osteoarthritic synovial membranes, virtually no lymphocytes were identified whereas the mononuclear cell infiltrates of the rheumatoid synovial membranes were composed predominantly of T cells expressing the OKT4 inducer phenotype with few OKT8+ suppressor/cytotoxic cells. The OKT4+ cells were found to be intimately related to B cells and strongly HLA-DR+ cells which morphologically resembled the interdigitating cells of lymph nodes. The micro-anatomical arrangement of these different cell types in the mononuclear infiltrates of the rheumatoid synovial membranes closely resembled that of the paracortical or T cell dependent area of normal lymph nodes except few OKT8+ lymphocytes were present. These findings are explained in terms of rheumatoid arthritis as a disease of altered T lymphocyte/macrophage immunoregulation.
Synovial biology and T cells in rheumatoid arthritis
Pathophysiology, 2005
Events that occur in rheumatoid arthritis synovial tissues are responsible for the signs and symptoms of joint inflammation and for the eventual destruction of articular and periarticular structures that lead to joint dysfunction and disability. The three most abundant cell populations in RA synovium are synovial macrophages (type A synoviocytes), synovial fibroblasts (type B synoviocytes) and infiltrating T lymphocytes. Other important cell populations include B lymphocytes, dendritic cells, plasma cells, mast cells and osteoclasts. Our current understanding of rheumatoid arthritis is moving beyond previous concepts that view this disease as the consequence of a specific and focused humoral or cellular autoimmune response to a single autoantigen. Rather, a new view of rheumatoid arthritis is emerging, which seeks to understand this disease as the product of pathologic cell-cell interactions occurring within a unique and defined environment, the synovium. T lymphocytes in rheumatoid arthritis synovium interact closely with dendritic cells, the most potent antigen-presenting cell population in the immune system. T cells also interact with monocytes and macrophages and cytokine-activated T cells may be, especially, suited to trigger production of the important cytokine TNF␣ by synovial macrophages. Recent evidence also suggests a potent bidirectional interaction between synovial T cells and synovial fibroblasts, which can lead to activation of both cell types. An important role for synovial B lymphocytes has been emphasized recently, both by experimental data and by results of clinical interventions. B cells in synovium can interact with fibroblasts as well as with other cells of the immune system and their potential role as antigen-presenting cells in the joint is as yet underexplored. Rheumatoid arthritis synovium may be one of the most striking examples of pathologic, organ-specific interactions between immune system cells and resident tissue cell populations. This view of rheumatoid arthritis also leads to the prediction that novel approaches to treatment will more logically target the intercellular communication systems that maintain such interactions, rather than attempt to ablate a single cell population.
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.
Arthritis & Rheumatism, 1992
Our understanding of the immunopathogenesis of rheumatoid arthritis (RA) has undergone a major revolution if we compare the concepts propounded 30 years ago with those proposed today. Synovitis is no longer conceived as an antibody-mediated process involving rheumatoid factors and immune complexes, but rather as a cell-mediated process involving T cells, antigen-presenting cells (APC), macrophages, synoviocytes, and cytokines. Recently, Firestein and Zvaifler have proposed that the pathogenesis of RA is predominantly based on macrophages (1). This hypothesis stems from their observations, and those by other groups, that the rheumatoid synovium (SM) expresses messenger RNA (mRNA) and protein products for a whole host of macrophage monokines, while it is d a c u l t to detect T cell products. These differences between the T cell and the macrophage "schools" may only be quantitative; nevertheless,