The importance of T cell interactions with macrophages in rheumatoid cytokine production (original) (raw)
Related papers
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.
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.
Cytokine regulation in RA synovial tissue: role of T cell/macrophage contact-dependent interactions
Arthritis research, 2002
Several groups have documented the expression of cytokines in rheumatoid arthritis synovial tissue over the past 15 years or so. These studies have indicated that most cytokines examined are expressed at the mRNA levels at least, and many other cytokines are found in abundance as proteins. Our attention has recently focused on the mechanisms that induce and regulate tumour necrosis factor and IL-10. Other workers and ourselves have found that cell-cell contact is an important signal for the induction of cytokines, and our work has demonstrated that tumour necrosis factor and IL-10 production in rheumatoid arthritis synovial joint cells cultures is dependent on T cell/macrophage interaction. In this chapter, we review recent advances in this area and also highlight areas where new therapeutic intervention opportunities arise.
Constitutive production of inflammatory and mitogenic cytokines by rheumatoid synovial fibroblasts
Journal of Experimental Medicine, 1991
Conditioned media obtained from fibroblasts cultured from rheumatoid and certain other inflammatory synovia were observed to stimulate [3H]thymidine incorporation in an indicator murine fibroblast line. Synovial fibroblasts derived from thejoints of patients with osteoarthritis did not display this property. This effect persisted in culture for many weeks and occurred in the absence of co-stimulatory immune cells. Antibody neutralization studies implicated a role for basic fibroblast growth factor (bFGF), transforming growth factor Q (TGF-a), granulocyte/ macrophage colony-stimulating factor (GM-CSF), and interleukin 10 (IL1)3) in the increased proliferative activity of synovial fibroblast-conditioned media . Synovial cell synthesis of bFGF, TGFa1, GM-CSF, IL10, and 11,6 was confirmed by 31 S-methionine labeling and immunoprecipitation . The constitutive production of inflammatory and mitogenic cytokiries by synovial fibroblasts may represent the result of long-term, phenotypic changes that occurred in vivo. Persistent cytokine production by synovial fibroblasts may play an important role in the continued recruitment and activation of inflammatory cells in chronic arthritis and in the formation of rheumatoid pannus.
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,
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.