Cartilage-reactive T cells in rheumatoid synovium (original) (raw)
Related papers
Arthritis & Rheumatism, 1999
Objective. To analyze the CD4؉ ؉ ؉ T cell responses to the human cartilage antigen glycoprotein-39 (HCgp-39) in the context of rheumatoid arthritis (RA)-associated (DR␣1*0401) and nonassociated (DR␣1*0402) HLA class II molecules. Methods. Large numbers of HCgp-39-specific T cell hybridomas were generated following immunization of HLA-DR4/human CD4 transgenic, murine major histocompatibility complex class II deficient mice with native HCgp-39. Fine epitope mapping of DR␣1*0401and DR␣1*0402-restricted T cell hybridomas was performed using overlapping synthetic peptides. Antigenspecific cytokine production by lymph node T cells was evaluated after immunization with native antigen. Proliferative T cell responses of healthy human subjects were compared with the T cell responses of patients with active RA using HCgp-39 epitopes defined in HLA-DR4 transgenic mice. Results. CD4؉ ؉ ؉ T cells from DR␣1*0401 and DR␣1*0402 transgenic mice identified completely different immunodominant peptide epitopes of HCgp-39, and this was not explained by known DR4-binding motifs or direct peptide-binding studies. DR␣1*0401restricted, antigen-specific T cells produced significantly more interferon-␥ and tumor necrosis factor ␣ in response to HCgp-39 than did T cells from DR␣1*0402 transgenic mice. Finally, HCgp-39 peptides defined in DR␣1*0401 transgenic mice stimulated T cells from HLA-DR4 positive human subjects and RA patients, but not T cells from HLA-DR4 negative individuals. Conclusion. T cell epitopes of HCgp-39 that were defined in HLA-DR4 transgenic mice stimulated T cells from human subjects carrying RA-associated HLA-DR4 alleles. HLA-DR4 molecules may influence the disease process in RA both by presentation of selected peptide epitopes and by promoting the production of proinflammatory cytokines in synovial joints. Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovial joints that affects ϳ1% of the Caucasian population (1). Although the pathogenesis of RA is multifactorial, the major histocompatibility complex (MHC) in humans accounts for one-third to one-half of the total genetic contribution to disease susceptibility (2). A consensus motif encoded by the third hypervariable region of the HLA-DRB1 sequence of RA-associated alleles (DRB1*0401, *0404, *0405, *0408, and *0101) has been identified as one of the critical genetic elements of RA susceptibility (3-6), and the baseline frequency of expression of this diseaselinked "shared epitope" motif correlates very closely with the prevalence of RA in a given population (7). RA patients carrying 2 copies of disease-associated HLA-DRB1 alleles may have both an earlier disease onset and more severe erosive disease (8). Despite these strong
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,
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.
Seminars in arthritis and rheumatism, 2001
To review the role of T lymphocytes in the pathogenesis of rheumatoid arthritis (RA) and discuss the relevance of the components of the trimolecular complex (synovial T cells, autoantigens, and antigen presenting cells) in the pathogenic autoimmune response in RA. Currently available experimental data are combined into a hypothetical pathway that may explain some of the events in the RA process. The literature regarding the potential therapeutic strategies that interfere with specific components of the trimolecular complex and other mediators are discussed briefly. T cells are activated in the peripheral blood, cross the endothelial cell wall, and migrate into the joints. Once in the synovial joints, T cells are reactivated by cross-reactive antigens and clonally expand. Clonally expanded T cells accumulate in the diseased joint and secrete proinflammatory cytokines that attract and activate other cells, such as monocytes and macrophages. Treatment with anti-CD4 monoclonal antibodie...
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.
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.