Proliferation Of Synovial Lining Cells Research Articles

How complement activation influences the development of chronic synovitis in a mouse model of rheumatoid arthritis

Objectives: Chronic synovitis is the main characteristic of rheumatoid arthritis (RA), defined by the proliferation of synovial lining cells, an important source of chemokines and cytokines associated with inflammation. The aim of this study was to examine the influence of complement functional activity on the development of chronic synovitis.Method: The experiments were conducted in zymosan-induced arthritis (ZIA) provoked by intra-articular injection of 180 μg zymosan. Mice were treated with 10 ng/g body weight (bw) cobra venom factor (CVF) on days −3 and −2 or with 10 ng/g bw CVF on days 7, 12, and 17 of ZIA. The percentage of neutrophils (CD11b+Ly6G+), macrophages (F4/80), and complement 5 anaphylatoxin receptor (C5aR)-positive cells in the synovial fluid (SF) were determined by flow cytometry and the expression of C5aR and C3aR in the synovium was detected immunohistochemically.Results: The induction of ZIA in the absence of complement activity strongly inhibited the development of synovitis. By contrast, complement activation during ZIA exacerbated chronic synovitis through an increase in macrophage infiltration, C5aR and C3aR expression in the joints, and C5aR expression on SF cells. Levels of C5a and soluble receptor activator of nuclear factor kappa B ligand (sRANKL) in the SF were elevated whereas neutrophil infiltration and levels of tumour necrosis factor (TNF)-α and interleukin (IL)-6 in the SF were unchanged.Conclusions: Our findings indicate an important role for functional complement activity in the maintenance of chronic synovitis in a model of RA. Antagonizing complement activation represents new possibilities for the amelioration of synovitis symptoms.

Estradiol-potentiated cadherin-11 in synovial membrane involves in temporomandibular joint inflammation in rats

Estrogen is involved in inflammation/pain of temporomandibular joint (TMJ), but the underlying mechanisms are largely unknown. Cadherin-11 plays an essential role in synovial inflammation. This study examined whether estrogen could potentiate cadherin-11 in synoviocytes and contribute to TMJ inflammatory pain. Female rats were ovariectomized, treated with increasing doses of 17β-estradiol for 10 days, and injected intra-articularly with complete Freund’s adjuvant to induce TMJ inflammation. The expression of cadherin-11 in synovial membrane was evaluated. TMJ pain was blocked with intra-articular injection of anti-cadherin-11 antibody and evaluated by head withdrawal threshold. Primary TMJ synoviocytes were treated with estradiol and tumor necrosis factor (TNF)-α or blocked with anti-cadherin-11 antibody to assess the expression of cadherin-11, interleukin (IL)-6, cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS). We observed that estradiol potentiated the inflammation-induced expression of cadherin-11 in the synoviocytes of synovial membrane from inflamed TMJ. Estradiol induced cadherin-11 expression in a dose- and time-dependent manner in primary synoviocytes and further potentiated the induction of cadherin-11 by TNF-α in synoviocytes. Furthermore, an estrogen receptor antagonist or a NF-κB inhibitor partially blocked the effects of estradiol on cadherin-11 induction in the synovial membrane. Blocking cadherin-11 partially reversed the TMJ inflammatory pain and estradiol-potentiated proliferation of synovial lining cells accompanied with iNOS expression. In addition, blocking cadherin-11 reversed TNF-α-induced and estradiol-potentiated transcription of IL-6, COX-2, and iNOS in primary synoviocytes. These results suggest that estrogen aggravated TMJ inflammatory pain partially through cadherin-11-mediated release of proinflammatory cytokines and enzymes in the synoviocytes.

Light and Electron Microscopic Features of Synovium in Patients with Psoriatic Arthritis

Introduction: Few ultrastructural studies have been reported in psoriatic arthritis (PsA). The authors report a series of synovial biopsies with emphasis on patients with early disease to look for distinctive light (LM) and electron microscopic (EM) features of possible importance.Methods: The authors examined synovial biopsies obtained primarily by needle biopsy from 13 PsA patients using LM and/or EM. Sections from 12 patients were evaluated by LM for vascularity, synovial lining thickness, fibrin deposition, and inflammation via a semi-quantitative scale. Nine EM specimens were descriptively analyzed. Clinical, synovial fluid (SF), and radiographic characteristics were recorded.Results: Patients were mostly male, with mean disease duration before biopsy of 2.19 ± 2.60 years; 7 patients had arthritis for less than 1 year. All patients had peripheral arthritis, 2 had axial involvement. SFs disclosed predominance of polymorphonuclear leukocytes. LM demonstrated proliferation of synovial lining cells, lymphocyte and plasma cell infiltration, as well as dramatic clusters of small vessels in the superficial synovium. EMs showed more detailed vascular changes, including small, subendothelial, electron-dense deposits and scattered microparticles in vessel lumens and walls.Conclusions: Prominent vascularity is confirmed as an important feature of some PsA. Vascular changes and other features, including the first EM demonstration of microparticles in PsA (identified as potent factors in other inflammatory joint diseases), are potential targets for therapy.

Gene expression analysis of rheumatoid arthritis synovial lining regions by cDNA microarray combined with laser microdissection: up-regulation of inflammation-associated STAT1, IRF1, CXCL9, CXCL10, and CCL5

Objectives: The main histological change in rheumatoid arthritis (RA) is the villous proliferation of synovial lining cells, an important source of cytokines and chemokines, which are associated with inflammation. The aim of this study was to evaluate gene expression in the microdissected synovial lining cells of RA patients, using those of osteoarthritis (OA) patients as the control.Methods: Samples were obtained during total joint replacement from 11 RA and five OA patients. Total RNA from the synovial lining cells was derived from selected specimens by laser microdissection (LMD) for subsequent cDNA microarray analysis. In addition, the expression of significant genes was confirmed immunohistochemically.Results: The 14 519 genes detected by cDNA microarray were used to compare gene expression levels in synovial lining cells from RA with those from OA patients. Cluster analysis indicated that RA cells, including low- and high-expression subgroups, and OA cells were stored in two main clusters. The molecular activity of RA was statistically consistent with its clinical and histological activity. Expression levels of signal transducer and activator of transcription 1 (STAT1), interferon regulatory factor 1 (IRF1), and the chemokines CXCL9, CXCL10, and CCL5 were statistically significantly higher in the synovium of RA than in that of OA. Immunohistochemically, the lining synovium of RA, but not that of OA, clearly expressed STAT1, IRF1, and chemokines, as was seen in microarray analysis combined with LMD.Conclusions: Our findings indicate an important role for lining synovial cells in the inflammatory and proliferative processes of RA. Further understanding of the local signalling in structural components is important in rheumatology.

Cutaneous mucinous nodule in a patient with rheumatoid arthritis

We report a cutaneous mucinous nodule on the inflamed elbow joint in a patient with rheumatoid arthritis (RA). The lesion is clinically characterized by a continuous flow of mucinous exudates from the nodule, and histologically by an extensive mucin deposition and proliferations of the fibroblastic cells and mononuclear cells. The histological findings suggest the histogenesis of this unique nodule is related to extralesional proliferation of synovial lining cells consisting of monocyte-macrophage lineage cells and fibroblast-like cells which potentially produce synovial fluid. Four patients have been hitherto reported in the published work and all of them have been associated with RA. The condition may be one of the characteristic skin manifestations of RA.

Bisphosphonate: A Novel Treatment for Pigmented Villonodular Synovitis

Pigmented villonodular synovitis (PVNS) is an aggressive lesion occurring primarily within joint spaces, usually the knee. A combination of surgery and radiotherapy may be helpful in difficult cases. Recurrence after operation is common. Histologically, PVNS is characterised by the proliferation of synovial lining cells and a heavy diffuse subintimal infiltrate of mononuclear cells, largely macrophages, among which are scattered multinucleated giant cells. Also, it is shown that the giant cells in the PVNS express all the phenotypical features of osteoclasts, including the ability to carry out lacunar resorption. This may account for the bone destruction associated with this aggressive synovial lesion. The osteoclastic cells, which cause bony destruction, are thought to be recruited from normal monocytic pre-osteoclasts by stromal cell expression of the ligand for receptor activator of nuclear factor kappa B (RANKL). Osteoprotegerin acts as a decoy receptor for RANKL blocking the process of osteoclast differentiation. Bisphosphonates stimulate the osteoprotegerin production by osteoblasts, which can lead to a significant reduction in RANKL. Therefore, bisphosphonates can be considered an adjuvant therapy for pigmented villonodular synovitis. Pigmented villonodular synovitis (PVNS) is an aggressive lesion occurring primarily within joint spaces, usually the knee. However, other sites including the hip, temporomandibular joint and bursa have been described. A combination of surgery and radiotherapy may be helpful in difficult cases, although recurrence after operation is common. The outcome after surgical resection has been affected negatively by tumour recurrence and additional bone destruction. Histologically, PVNS is characterised by the proliferation of synovial lining cells and a heavy diffuse subintimal infiltrate of mononuclear cells, largely macrophages, among which are scattered multinucleated giant cells; both mononuclear and multinucleated cells may contain phagocytosed haemosiderin or lipid. It is not known whether this giant-cell-rich synovial proliferation is reactive or neoplastic in nature, but in about one-third of cases PVNS behaves aggressively, causing para-articular osteolysis with the formation of multiple cysts in the bone. Ultrastructural studies of both the villous and nodular forms of PVNS have shown the presence of synovial type A macrophage-like cells and synovial type B fibroblast cells; the multinucleated cells show similar features to type A mononuclear cells, suggesting that they are formed by the fusion of type A cells. Multinucleated giant cells similar to those seen in PVNS may be found in a wide variety of giant cell lesions of bone and extraskeletal soft tissues. The giant cells from these various lesions have all been shown to be capable of lacunar bone resorption, a characteristic feature of osteoclasts. In skeletal giant cell containing lesions, such as giant cell tumour of the bone and giant cell reparative granuloma of the jaw, the giant cells exhibit all the defining characteristics of the osteoclast phenotype. Also, it is shown that the giant cells in the PVNS express all the phePublished online January 23, 2008. Address correspondence and reprint requests to: Hamid Namazi; E-mail: namazih@sums.ac.ir

Paclitaxel selectively induces mitotic arrest and apoptosis in proliferating bovine synoviocytes.

Rheumatoid arthritis (RA) is characterized by chronic progressive destruction of joints involving several disease processes, such as villous hypertrophy, proliferation of synovial lining cells, and infiltration of inflammatory cells. Synovial cell activation and proliferation is thought to be a key step in the destruction of cartilaginous and bony tissues in RA joints. In view of the invasive properties of synoviocytes in RA, we conducted in vitro studies to determine the mechanism of action of paclitaxel (Taxol) on synoviocytes, which may account for the inhibition of joint destruction found when this agent is administered. Cultured synovial cells were treated with various concentrations of paclitaxel and were evaluated by cell viability, fluorescence microscopy, flow cytometry of DAPI-stained cells, and electron microscopy. The data indicated that paclitaxel inhibited synoviocyte proliferation by a G2/M phase block and was toxic to synoviocytes by inducing apoptosis. Confluent cells such as chondroyctes and synoviocytes were not affected by paclitaxel. Synchronization of synovioyctes at the G1/S boundary effectively abolished paclitaxel-induced apoptosis. The data indicate that induction of apoptosis in synoviocytes might be dependent on transit through the cell cycle, specifically through G2 and mitosis. Further, paclitaxel was selectively toxic to proliferating synoviocytes but spared nonproliferating synoviocytes and chondrocytes. These results demonstrate that paclitaxel can inhibit synovial cell proliferation and pannus formation in RA joints in vivo. We suggest that paclitaxel be considered as a prototypical compound for a new class of potential chondroprotective agents.

Immunohistochemical analysis of proliferating and antigen-presenting cells in rheumatoid synovial tissue.

We analysed the proliferative activity of synovial lining cells (SLCs), the distribution of proliferating B and T lymphocytes and the relationship of proliferating B and T lymphocytes to the pattern of antigen-presenting cells (APCs) within the rheumatoid synovial tissue (n = 21). The immunohistochemical detection of the proliferation-associated antigen Ki67 revealed low proliferative activity of SCL with and without expression of the Kim 8 (CD68) antigen. Ki67-positive B lymphocytes could be observed within secondary follicles (2/21), in small follicular dendritic reticulum cell (FDC)-containing follicle-like aggregates (7/21) and near the enlarged synovial intima (6/21). Ki67-positive T lymphocytes could be detected in T-lymphocyte aggregates (8/21), in the vicinity of blood vessels (18/21) and within the enlarged synovial intima (15/21). Semiquantitative analysis showed a strong correlation between the numbers of Ki67-positive B lymphocytes and FDCs and between the numbers of Ki67-positive T lymphocytes and interdigitating dendritic reticulum cells (IDC). There were significant differences in the number of Ki 67-positive B and T lymphocytes, IDCs and FDCs between the two groups of rheumatoid arthritis (RA) patients with different local clinical activity. These findings demonstrate a low proliferation of SLCs with and without expression of the monocyte-specific antigen Kim 8 and imply that B and T lymphocyte proliferation occurs in the presence of FDCs and IDCs. These results indicate that the RA synovial tissue is a site for antigen-dependent proliferation and maturation of B and T lymphocytes. The atypical pattern of FDC distribution within the rheumatoid synovial tissue "dysmorphic follicle" may be regarded as morphological substrate for a dysmaturation compartment of B lymphocytes leading to pathogenetic autoimmune phenomena in RA patients.

関節リウマチ滑膜組織におけるアポトーシス関連抗原の発現

We examined whether apoptosis-associated antigens were expressed in synovial tissues from nine patients with rheumatoid arthritis (RA) and five patients with osteoarthritis (OA) using immunohistochemical staining and DNA nick end labeling.Paraffin sections of synovial tissues were stained with various antibodies, such as anti-PCNA monoclonal antibody, anti-Fas monoclonal antibody, anti-Ley monoclonal antibody and anti-bcl-2 polyclonal antibody. DNA nick end labeling was also performed on each of the paraffin sections.In RA specimens, the PCNA positivity ratio and Fas positivity ratio of synovial lining cells were 16.85±4.28% and 1.97±0.99%, respectively. On the other hand, in OA the corresponding ratios were 4.25±0.66% and 1.58±1.24%, respectively. The degree of proliferation of synovial lining cells was significantly different between RA and OA, but Fas antigens on the synovial lining cells did not differ significantly. DNA nick end labeling and staining with anti-Fas monoclonal antibody were positive in synovial lining cells, macrophages and fibroblasts. Anti-Ley monoclonal antibody produced positive staining in inflammatory cells. On the other hand, antibcl-2 polyclonal antibody gave a positive reaction in synovial lining cells, macrophages, fibroblasts, inflammatory cells and vascular endothelial cells.We conclude that apoptosis-associated molecules (for enhancement and inhibition) are expressed in synovial tissues from patients with RA.

Initial Arthritic Lesions Induced by Immunization with Type II Collagen in Lewis Rats.

Lewis rats were immunized with an intradermal injection of type II collagen to study the time course of arthritic lesions. Serum type II collagen antibody was detected 9 days after immunization. Increased paw volume in the hind limbs was noted on day 11. Histopathologically, proliferation of synovial lining cells was observed on day 11 and typical lesions similar to those of human rheumatoid arthritis were noted on day 18.

Overexpression of zinc-finger transcription factor Z-225/Egr-1 in synoviocytes from rheumatoid arthritis patients.

In rheumatoid arthritis (RA) the proliferation of synovial lining cells appears to be one of the initial pathologic changes that contributes to the destruction of articular joints. To understand the pathomechanisms involved in these functional changes, we analyzed the transcriptional regulation of the zinc-finger gene 225 (Z-225/Egr-1), a transcription factor expressed in the immediate early events of cellular activation. We found that Z-225 transcripts were significantly up-regulated in RA synoviocytes. In primary and long term culture Z-225 was spontaneously transcribed at elevated levels. In situ hybridization of zinc-finger probe showed characteristic Z-225 transcripts in RA synovial tissues. Identity of these signals to the Z-225 gene product were confirmed in freshly isolated synovial tissue by enzymatic amplification of cDNA by the PCR technique. Z-225 transcripts were also detected and characterized in a cDNA library established from a RA synovial explant. We therefore conclude that RA synoviocytes spontaneously produce Z-225 gene products at elevated levels. Because early growth response gene Z-225 is involved in the regulation of expression of other genes such as proto-oncogenes c-ras and c-sis, which are also up-regulated in the RA synovium, activation of Z-225 transcription in RA may represent a key event in articular joint destruction.

Arthropathy in thalassaemia patients receiving deferiprone

The iron chelator deferiprone (L1) reduces tissue iron stores in iron-loaded patients. Three of sixteen patients treated with deferiprone developed joint pain and swelling without evidence of systemic lupus erythematosus (SLE). Articular cartilage, synovial hypertrophy and iron deposition, and synovial lining cell proliferation, with no inflammatory or allergic reaction, were observed on synovial exploration and biopsy. Symptoms resolved partly or completely during continued drug administration. We hypothesise that deferiprone-induced shifts of iron to synovium resulted in tissue damage, accelerated by free-radical formation during incomplete complexation of iron and this bidentate chelator. This deferiprone-associated symptom complex is not associated with drug-induced SLE, and does not progress in severity during continued therapy.

Local proliferation of fibroblast-like synoviocytes contributes to synovial hyperplasia. Results of proliferating cell nuclear antigen/cyclin, c-myc, and nucleolar organizer region staining.

To test the hypothesis that local proliferation contributes significantly to the hyperplasia of rheumatoid synovium. Immunohistologic and chemical staining was used to identify 3 markers of cell proliferation: proliferating cell nuclear antigen, c-myc proto-oncogene, and nucleolar organizer regions. Synovium from 21 patients with rheumatoid arthritis, 34 with degenerative joint disease, and 7 with joint trauma was examined. All 3 markers indicated substantial, active proliferation of synovial lining cells in synovium with hyperplasia. Proliferating cells showed type I procollagen immunoreactivity but were negative for CD68, a monocyte/macrophage marker. Proliferation was greater in rheumatoid arthritis than in the other conditions evaluated. In situ proliferation of fibroblast-like synoviocytes in the synovium lining contributes considerably to the increase in cell numbers in rheumatoid synovium.

ＲＡの病理組織像と単純Ｘ線関節骨破壊像の相関について

Histological features of the synovial membrane in eighty one knee and hip joints of rheumatoid arthritis patients were studied. The histological findings were then compared to radiographic changes.Each synovial membrane was classified histologically according to the degree of inflammatory cell infiltration and synovial lining cell proliferation.Radiographic changes in the same joint were evaluated independently using the Larsen system.Results showed that radiographic joint destruction is associated with a sparsity of inflammatory cells and synovial lining cell proliferation.

Histopathological observation of joint lesions of extremities in mice transferred genome.

Pathological examination of arthritic lesions in transgenic mice produced by the pX region of the human T-cell leukemia virus type-1 (HTLV-1) was carried out. Clinically, erythema, swelling and/or ataxia of the limb joints were observed in many transgenic mice about 1 month-old. Histopathologically, proliferation of synovial lining cells, infiltration of inflammatory cells with lymphoid structures and formation of pannus with cartilage and/or subchondral bone destructions were observed in various joints of transgenic mice. The frequency of abnormalities in the joints was higher in females than in males. These histopathological findings were very similar to those of human rheumatoid arthritis (RA). Present results indicate that the pX genome of the HTLV-1 is an etiological agent for the incidence of arthritic lesions in the transgenic mice.

Light and electron microscopic observations on the synovitis of ankylosing spondylitis

Light microscopic studies on synovium obtained from seven knees and three hips of patients with ankylosing spondylitis and peripheral arthritis showed surface fibrin, proliferation of synovial lining cells, moderate infiltration with lymphocytes, and sometimes striking numbers of plasma cells. There was some vascular congestion and obliteration, occasional bone and cartilage debris, and a tendency toward increased fibrous tissue. Although the intensity of some findings varies from those in rheumatoid arthritis, there were no consistent distinguishing features. Electron microscopy of eight synovial tissue specimens showed increased type B or synthetic lining cells. Structures that could possibly have been organisms were seen among synovial cells in two patients. Immune complex-like deposits were not seen in vessel walls, although there were other vascular alterations. Synovial fluid studies showed 2,200 to 16,500 white blood cells/mm 3 (mean, 8,236), 29% to 93% polymorphonuclear leukocytes (mean, 66%), and 0.5 to 32% lymphocytes (mean, 18%). The presence of at least some activated lymphocytes (lymphoblasts) in seven of nine patients in addition to the above findings in synovium suggest an immunological component to the driven process. No more than 32% lymphocytes was found in any synovial fluid despite the use of nonsteroidal antiinflammatory drugs. Thus no support for synovial fluid lymphocytosis, such as has been described in rheumatoid arthritis patients treated with nonsteroidal antiinflammatory drugs alone, is provided.

Mechanisms of Immune Injury in Rheumatoid Arthritis: Evidence for the Involvement of T Cells and Heat‐Shock Protein

Evidence for the involvement of T cells, especially CD4+ T cells, in the pathogenesis of RA is substantial and includes 1) the correlation between prolonged CD4+ T-cell depletion and improvement in joint disease in the absence of observable changes in the levels of autoantibodies (rheumatoid factors) in the blood and joints, 2) the infiltration of the inflamed synovial tissues with T cells and, 3) the increased susceptibility of individuals to RA with certain HLA-DR haplotypes. The most direct evidence for the involvement of CD4+ T cells is provided by recent studies which demonstrate rapid improvement in the joint disease manifestations of RA following the infusion of anti-CD4 monoclonal antibodies (Herzog et al. 1989, Walker et al. 1989). It is unlikely that T cells alone are responsible for the joint injury in RA. Autoantibodies (rheumatoid factors) in the joint which contribute to the release of complement breakdown products, and to the secretion of cytokines such as IL-1 by macrophages must also play an important role. Indeed, depletion of CD4+ cells after TLI or therapy with monoclonal antibody reduces, but does not eliminate, joint disease activity. The residual joint disease activity is probably influenced by the continued contribution of autoantibodies to joint injury. Production of these autoantibodies may not be dependent on help from CD4+ cells, since little change is observed in autoantibody levels after CD4+ cell depletion. The mechanisms by which T cells mediate to the joint disease in RA are not clear. Little or no direct evidence of cytotoxic effects of T cells on autologous joint cells has been reported. Considerable evidence suggests that at least some T-cell cytokines (i.e., TNF alpha, IL-6) can contribute to the proliferation of synovial lining cells which results in the marked build-up of inflammatory tissue (pannus) in the joints of patients with RA (Firestein et al. 1990). In addition, T cells may recruit other joint cells, such as macrophages, to secrete cytokines (i.e., IL-1) which both contribute to synovial cell proliferation, and cartilage and bone degeneration. The marked reduction in the spontaneous secretion of IL-1 by synovial biopsies, and improvement in disease activity after TLI support this notion. Interestingly, the CD4+ T-cell lymphokines, IL-2 and IFN-gamma, were not spontaneously secreted in detectable quantities by synovial biopsies. This suggests that the pattern of lymphokines secreted by T cells in the joint in RA are not typical of that in delayed-type hypersensitivity reactions.(ABSTRACT TRUNCATED AT 400 WORDS)

II型コラーゲン感作DBA/1 Jマウスの関節病変について

Eight male DBA/1J mice immunized twice by intradermal injection of type II collagen were autopsied 12 weeks after the first immunization and analyzed for anti-type II collagen antibody level, and the limb joints were examined radiologically and histopathologically. Clinical onset of swelling and erythema in the limb joints occurred about 5 weeks after the first immunization and deformity of the limbs was observed in a few animals about 5 weeks later. Although there were marked individual differences, serum anti-type II collagen antibody levels were elevated in all animals. Histopathologically, the changes were similar to those seen in human rheumatoid arthritis and were characterized by proliferation of synovial lining cells, formation of granulation tissue with destruction of cartilage and subchondral bone, and ankylosis. Systematic examination of various joints of the fore- and hind-limbs revealed definitely that the sequence of arthritic lesions was not uniform. The knee joint was involved most frequently, but smaller joints such as the phalangeal joints were involved less frequently but exhibited severe changes. The significance of histopathological examinations in the evaluation of effects of anti-rheumatic drugs was discussed with reference to this model.

Light and electron microscopic studies on the synovial membrane in Reiter's syndrome. Immunocytochemical identification of chlamydial antigen in patients with early disease.

Studies by light microscopy on synovium obtained from 11 patients with Reiter's syndrome during the first month of an episode showed proliferation of synovial lining cells, polymorphonuclear neutrophils among the synovial lining cells, increased surface fibrin, and vascular congestion. Biopsy specimens taken later showed vascular congestion and still proliferated synovial lining cells, fewer polymorphonuclear neutrophils in some, and a tendency toward increased infiltration with lymphocytes and plasma cells. Electron microscopy of samples from 8 patients during the first month of disease activity showed occlusion of vessels by platelets in 4, and fibrin or dense granular material in the vessel walls in 4. Five of the patients with arthritis of less than 4 weeks duration had unidentified intracellular and extracellular particles; some of these were highly suggestive of Chlamydia. No such particles were noted in samples from patients with more chronic cases. Using an antibody to Chlamydia trachomatis and the peroxidase-antiperoxidase technique, immunocytochemistry showed reaction product in synovial macrophages in 2 patients with arthritis of less than 4 weeks duration, but not in the 1 patient studied who had more chronic disease. These studies provide support for dramatic synovial vascular injury consistent with that caused by endotoxin and the presence of chlamydial antigen in synovial macrophages, at least in the early phases of synovitis.

Synovial microenvironment‐t cell interactions

Synovitis in rheumatoid arthritis is characterized by infiltration of the synovium by T and B lymphocytes and monocytes, as well as by the proliferation of synovial lining cells, fibroblasts, and endothelial cells. To study synovial cell-T cell interactions in vitro, we established cultures of fibroblast-like synovial cells, and used these cells in a synovial cell-T cell binding assay. Using T cells at various stages of differentiation and activation, we found that human thymocytes and mitogen-activated peripheral blood T cells bound to fibroblast-like synovial cells, whereas fresh peripheral blood T cells did not. Moreover, activated T cells from inflammatory synovial tissue or from synovial fluid also bound to fibroblast-like synovial cells cultured in vivo. Antibodies against certain epitopes of the T cell CD2 (35.1) and synovial cell lymphocyte function-associated antigen-3 (LFA-3) (TS2/9) molecules inhibited synovial cell-thymocyte binding. However, these same anti-CD2 and anti-LFA-3 antibodies only partially inhibited synovial cell binding to activated normal peripheral blood T cells. Moreover, T cells from inflammatory synovium from rheumatoid arthritis and psoriatic arthritis patients also bound to synovial cells in vitro. These findings demonstrate that fibroblast-like synovial cells are capable of binding to human T cells in vitro, and suggest that during the course of inflammatory synovitis, synovial fibroblast-T cell interactions may occur in vivo.