T cell lessons from the rheumatoid arthritis synovium SCID mouse model: CD3-rich synovium lacks response to CTLA-4ig but is successfully treated by interleukin-17 neutralization (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.
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.
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.
Modern Rheumatology, 2014
Objective TNFα and IL-17 have been shown to be the major inflammatory cytokines involved in the pathogenesis of rheumatoid arthritis (RA). Here, we examined the effect of these cytokines on spontaneously occurring RA in our newly established arthritis-prone FcγRIIB-deficient C57BL/6 (B6) mice, designated KO1, by introducing genetic deficiency of TNFα and IL-17 into KO1 mice. Methods KO1.TNFα-/and KO1.IL-17-/mice were established by crossing KO1 with TNFα-deficient and IL-17-deficient B6 mice, respectively. The incidence and severity of RA, cartilage and bone destruction, immunological abnormalities, and transcription levels of receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) and inflammatory cytokines/chemokines in ankle joints were compared among KO1, KO1.TNFα-/-, and KO1.IL-17-/mice. Results The development of RA was completely inhibited in KO1.TNFα-/mice. In contrast, KO1.IL-17-/mice unexpectedly developed severe RA comparable to KO1. Compared with those in KO1 and KO1.IL-17-/mice, frequencies of peripheral monocytes, known to be containing osteoclast precursors, were significantly decreased in KO1.TNFα-/mice. Intriguingly, while RANKL expression levels in ankle joints did not differ among the three strains, OPG expression levels were drastically decreased in arthritis-prone, but not arthritis-free, mice. The expression levels of inflammatory cytokines/chemokines, such as MCP-1, IL-6, and TNFα, were up-regulated in arthritis-prone mice. Conclusion TNFα is indispensable while IL-17 is dispensable in the pathogenesis of RA in KO1 mice. In this model, TNFα may contribute to the development of arthritis, through mediating the increase in frequencies of osteoclast precursors in circulation and their migration into the joints, and the decrease in OPG expression, leading to the up-regulated osteoclastogenesis associated with severe cartilage and bone destruction.
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 ...
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.
Interplay between TNF and Regulatory T Cells in a TNF-Driven Murine Model of Arthritis
The Journal of Immunology, 2011
CD4 + CD25 + Foxp3 + regulatory T cells (Treg) are involved in several autoimmune diseases, including rheumatoid arthritis. TNF-a blockers induce therapeutic benefits in rheumatoid arthritis via a variety of mechanisms. We aimed to characterize the impact on Treg of TNF-a overexpression in vivo and of TNF-a inhibiting treatments. We used human TNF-a transgenic mice as a model of strictly TNF-a-dependent arthritis. Our study showed that initial Treg frequency was lower in TNF-a transgenic mice than in wild-type mice. However, the course of arthritis was marked by elevation of Treg frequency and a dramatic increase in expression of TNFR2. Antagonizing TNF-a with either the anti-human TNF-a Ab (infliximab) or active immunotherapy (TNF-kinoid) increased the Treg frequency and upregulated CTLA-4, leading to enhancement of suppressor activity. Moreover, both anti-TNF-a strategies promoted the differentiation of a CD62L 2 Treg population. In conclusion, in an in vivo model of TNF-a-driven arthritis, Treg frequency increased with inflammation but failed to control the inflammatory process. Both passive and active TNF-a-inhibiting strategies restored the suppressor activity of Treg and induced the differentiation of a CD62L 2 Treg population.