Synovial dendritic cells and T cells in rheumatoid arthritis.
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Biomedical subjects
Publications and source records attributed to V Bergroth.
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We report a case of acute transverse myelopathy in a patient with primary Sjögren's syndrome of 3 years duration. Our patient's acute transverse myelopathy developed within 1 week and resulted in complete paraparesis below the mamillary level. Extensive laboratory investigation ruled out viral, bacterial, and fungal etiology, Guillain-Barré syndrome, poliomyelitis, and multiple sclerosis. At diagnosis, treatment was initiated immediately with prednisone (80 mg/day) and plasmapheresis, which was performed as a first-aid measure. Improvement was noted as early as 10 days after the start of therapy. Within 5 1/2 months of the first symptoms of paralysis, the patient walked without difficulty and returned to her normal activities. A causal relationship between plasmapheresis/prednisone therapy and recovery has not been proven but merits further consideration.
The immunomodulatory T4/T8 ratio was studied in the total and activated lymphocyte populations by a method combining visualisation of 3H-thymidine incorporating blasts with autoradiography (AR) with simultaneous identification of the respective lymphocyte subsets using monoclonal antibodies in avidin-biotin-peroxidase complex (ABC) staining. In rheumatoid arthritis synovial fluid the activated T4/T8 ratio (calculated from T cells in the S phase of the cell cycle) was significantly different from the total T4/T8 ratio (calculated for all the T cells) (0.45 +/- 0.05 versus 0.69 +/- 0.05, P less than 0.01). Similarly, the activated and total T4/T8 ratios were also significantly different in the phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cell cultures at days 3 and 5.
Activation state and proliferation of lymphocytes of 6 patients with definite multiple sclerosis in clinical remission were studied. Lymphocytes carrying MHC class II coded Ia antigen, glycoprotein gp 40/80 and interleukin-2 receptor were significantly higher in patients with MS in remission than in normal healthy controls. The entrance of T cells into the G1 and S phase of the cell cycle was studied using [3H]thymidine autoradiography in combination with immunocytochemistry (cell markers). The proportion of T cells in the S phase of the cell cycle in the peripheral blood was similar in the MS patient and in the control group.
Skin biopsies from 6 patients with Jessner's lymphocytic infiltration (JLI) were studied using monoclonal antibodies in peroxidase staining, on some occasions combined with [3H]thymidine incorporation visualized by autoradiography. Ninety-one +/- two percent of all inflammatory mononuclear cells in situ were T11-positive T lymphocytes, whereas B lymphocytes were few. Forty-nine +/- nine percent of cells were Ia-positive, suggesting involvement of T cells in the local pathogenetic mechanisms, but interleukin-2 receptor-carrying cells as well as [3H]thymidine-incorporating cells accounted for less than 2% of all inflammatory cells, suggesting that T blasts account for only a small minority. Similarly, PCA-1 plasma cells were few in situ, there was no immunoglobulin or complement deposition at the dermal-epidermal junction and serum antinuclear and anti-DNA antibodies as well as complement levels were normal, and no visceral involvement was revealed during the survey period. According to our findings, JLI of the skin seems to be sufficiently distinctive to be appreciated as an entity. T lymphocytes in JLI do not seem to proliferate in the site of inflammation but are merely accumulated from the circulation.
Local lymphoplasmacytoid infiltration of the diseased exocrine glands is a cardinal sign of Sjögren's syndrome (SS). The state of T lymphocyte activation present in these local infiltrations was studied by three different techniques: determination of interleukin 2 (IL2) receptor (Tac) on cell surface membrane; autoradiography combined with immunoperoxidase staining of T cell epitopes; and electron microscopic analysis of the lymphoblast subclasses. Although 64 (SEM 4)% of the local inflammatory cells expressed Ia antigen, only 4 (SEM 1)% of them displayed the T cell activation antigen Tac. Autoradiography-immunoperoxidase double labelling showed that less than 1% of all T cells in situ were [3H]thymidine incorporating blasts. This finding suggests that although T lymphocyte is the dominant cell in situ, only a few of these cells have passed the G0/G1 interphase, and even fewer have been pushed to the S phase of the cell cycle by IL2. Transmission electron microscopy showed that few T blasts were present, even though there were many plasma cells. This result further confirms the impression that only a minor T cell subpopulation in situ is blast transformed despite the fact that many of the local T lymphocytes in the diseased salivary glands in SS are Ia positive.
The state of lymphocyte activation in tuberculous pleural effusions was studied. The proportion of cells at and beyond the G1 phase of the cell cycle displaying interleukin-2 receptor, transferrin receptor or gp 40/80 glycoprotein in avidin-biotin-peroxidase complex (ABC) staining was 6 +/- 2 percent, 8 +/- 3 percent, and 14 +/- 4 percent of all pleural fluid mononuclear cells, respectively. These findings imply that only a fraction of pleural fluid lymphocytes is activated in tuberculosis. The proportion of autoradiographically visualized 3H-thymidine incorporating blasts at the S phase of the cell cycle was 1.2 +/- 0.3 percent. This phenomenon further confirms the impression that, in spite of activation, most of the pleural fluid mononuclear cells are resting cells. The T4/T8 ratio in the functionally active blast cell population determined by a double labeling method combining ABC staining with autoradiography was similar to the total T4/T8 ratio (2.3 +/- 0.7 vs 2.7 +/- 0.8, p greater than 0.05) calculated for all pleural fluid mononuclear cells.
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We analyzed lymphocyte activation state in vivo in lamina propria by applying a panel of monoclonal antibodies for cellular activation markers and by identifying different subsets of 3H-thymidine incorporating lymphoblasts by combining autoradiography with immunoperoxidase staining. In focal lymphoblastoid infiltrates 75 +/- 8% of all inflammatory cells displayed Ia, but lymphoid cells expressing 4F2 (40 +/- 6%) and T9 (14 +/- 3%) activation markers were less frequent. The expression of receptors for interleukin-2 (Tac) was particularly low (4 +/- 1%). There were very few 3H-thymidine incorporating cells (labeling index approx. 1%) and most of them belonged to the T cell series. T4+ blasts outnumbered T8+ blasts, and in this numerically minor subpopulation the activated T4/T8 ratio was 2.9 +/- 0.7. Our results suggest that, although a big part of the local inflammatory lymphocytes in Crohn's disease may be activated according to the expression of Ia and 4F2 activation markers, only a fraction of them possess interleukin-2 receptor and have been pushed to the S-phase of the cell cycle.
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The inflammatory involvement of cervical spine ligaments in patients with rheumatoid arthritis (RA) with atlantoaxial subluxation was studied. Biopsy specimens were obtained from the ligament structures between the posterior arch of the atlas and the spinous process of C2 during atlantoaxis stabilizing operations. Inflammatory cells in cryostat sections were stained in situ using monoclonal hybridoma antibodies applied in a sensitive avidin-biotin-peroxidase complex (ABC) method. In 4 of 8 ligament specimens, focal inflammatory cell infiltrates consisting mainly of T11 + T lymphocytes (77 +/- 9%) and M1 + monocytes (21 +/- 6%) were found. The occurrence of lymphocyte activation markers Ia, 4F2 and T9, 46 +/- 8%, 38 +/- 10% and 14 +/- 5%, respectively, suggests active involvement of the lymphocytes in the local immune inflammation. Our findings suggest a mechanism eventually leading to slackening of the cervical spine ligamentous apparatus and atlantoaxial subluxation in RA.
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Deformity and instability of the cervical spine is quite frequently recordable from patients with chronic rheumatoid arthritis. More than 70 per cent of patients who had been suffering this rheumatoid disease for more than ten years with mutilating peripheral joint lesions exhibited radiologically visible and clinically recordable cervical spine disorders. Anterior atlanto-axial subluxation has proved to be the most common rheumatic deformity of the cervical spine and was found to cause severe, even intolerable occipito-cervical headache. The authors have obtained good results from posterior C1-C2 fusion operation on patients in whom headache had been invalidising and resistant to conservative treatment.
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The histopathology of arthroscopic biopsy material from the knees of 8 patients with monarticular juvenile rheumatoid arthritis (JRA) of recent onset and of 4 control patients was examined using a histochemical method for acid alpha-naphthyl acetate esterase and an avidin-biotin-peroxidase complex method for different cell subtype-specific surface antigens. According to results of our prospective, single-blind study, nonspecific synovitis was observed in those biopsy samples obtained early in the course of disease. The samples were also characterized by cellular changes that are quite distinct from those described in patients with chronic rheumatoid synovitis. JRA must be considered the cause of symptoms if no orthopedic or infectious disease is found at arthroscopy in children with monarticular symptoms of recent onset and if nonspecific synovitis is observed in the histopathologic specimen. This pathologic description, however, does not correspond to that of classic rheumatoid synovitis. In our studies, we found that mononuclear cells displaying diffuse cytoplasmic esterase and surface Ia formed a large proportion of all inflammatory cells in situ. There were comparatively few activated Ia+ T cells and plasma cells. These observations suggest that exudative features and nonspecific cellular inflammation are prominent at onset of JRA. The immune response, in the form of immunocompetent T and B cells, seems to be more extensively involved in chronic JRA and may represent secondary features of the disease.
Tritiated-thymidine incorporating cells in synovial tissue samples from ten patients with definite or classic rheumatoid arthritis (RA) were studied by combining two techniques. Tritiated-thymidine-labelled cells were seen in autoradiography and simultaneously the subtype of them was determined with immunoperoxidase staining using monoclonal antibodies. Tritiated-thymidine-labelled cells comprised 0.8 +/- 0.4% of all the inflammatory cells in RA synovial membrane. Of all 3H-thymidine-labelled cells 34 +/- 17% were positive for OKT8 and 19 +/- 8% for OKT4 monoclonal antibodies. OKM1-positive cells comprised 7 +/- 3% of all 3H-thymidine labelled cells, whereas only a few (3 +/- 4%) of them were positive for pan-B monoclonal antibody. This study emphasizes the importance of activated OKT8 lymphocytes in RA synovial membrane.
To evaluate the level of lymphocyte activation in reactive and rheumatoid arthritis, density gradient-isolated, synovial fluid mononuclear cells were stained with a panel of antisera directed at lymphocyte activation markers using an avidin-biotin-peroxidase complex (ABC) method. More specifically, we studied the expression of immune response-associated class II HLA antigen (Ia), of receptors for interleukin 2 (Tac) and transferrin (T9), as well as of gp 40/80 glycoprotein (4F2). Although Ia+ cells formed about 60% of all the synovial fluid mononuclear cells in both disease conditions, the proportion of Tac+ (33 +/- 4% vs 3 +/- 1%, P less than 0.001), T9+ (34 +/- 4% vs 5 +/- 2%, P less than 0.001), and 4F2+ (48 +/- 6% vs 3 +/- 2%, P less than 0.001) cells was high only in reactive arthritis. All the patients who had reactive arthritis followed a favourable clinical course during the 4-month-long prospective follow-up, whereas disease activity was stable in patients with rheumatoid arthritis. These findings suggest that the diseased joints in reactive arthritis are a site for an active, but normally down-regulated, cell-mediated immune response.