Biomedical subjects
Publications and source records attributed to O Duke.
Gastrointestinal involvement in systemic vasculitis occurs in up to 30% of patients. Fortunately intestinal infarction is a rare complication, but if present carries a high mortality, and swift management of the underlying vasculitis is crucial. Two such cases are described.
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Brachyolmia is a form of spondylodysplasia that has not to the authors' knowledge been described in the UK. It may be a cause of short stature that is currently unrecognised. A case of an 11 year old boy with clinical, radiographic, and eye findings consistent with Toledo type brachyolmia is reported.
A prospective study of 33 patients with polymyalgia rheumatica/giant cell arteritis (PMR/GCA) was undertaken, firstly, to monitor sequentially peripheral blood CD8+ lymphocyte levels and, secondly, to assess the expression of activation markers on T lymphocyte subsets. The results indicated that there was a significant decrease in absolute numbers and relative percentages of CD8+ T lymphocytes, which returned to normal ranges after approximately 24 months' treatment, and that there was an increased percentage of CD8+ lymphocytes in PMR/GCA which express HLA class II antigens.
A 56 year old man with ankylosing spondylitis and discovertebral destruction presented with signs of spinal cord compression that was the result of the soft tissue reaction occurring at the level of the discovertebral destruction. This case emphasises the importance of early recognition, use of appropriate imaging techniques (computed tomographic myelography or magnetic resonance), and operative intervention in the management of this rare complication of ankylosing spondylitis.
Serum specimens from 35 patients with polymyalgia rheumatica and giant cell arteritis (PMR/GCA) were obtained sequentially at variable time intervals up to a year from onset of disease. These were tested for antibodies to intermediate filaments by indirect immunofluorescence using HEp2 cells as substrate. Twenty four of 35 (68%) patients' sera at onset of disease were positive at an anti-intermediate filament antibody (AIFA) titre of greater than 1/40 compared with three outs of 19 (15%) control sera. AIFA were predominantly of IgM class, and there was no significant change in AIFA titres on follow up despite clinical remission of disease.
Frozen sections of pannus tissue taken from the joints of patients with rheumatoid arthritis have been investigated using immunohistological methods to determine the distribution of subsets of macrophage-like cells in this area. A panel of monoclonal antibodies including reagents specific in normal tissue for interdigitating cells (RFD1), macrophages (RFD7), epithelioid cells, (RFD9), monocytes (UCHMI), and osteoclasts (263C), were used. Indirect immunoperoxidase and combination indirect immunofluorescence procedures revealed the phenotypes of macrophage-like cells in four histologically distinct areas of the tissue: the synovial lining layers, the deeper stroma, areas of perivascular infiltration, and the articular cartilage junction where degeneration was occurring. It was discovered that 80% of the lining cells and a majority of macrophage-like cells of the stroma, express the phenotype RFD1+ RFD7+ UCHMI+. Cells with a typical 'dendritic cell' phenotype (RFD1+ RFD7-) were only present in the perivascular infiltrates, while 'classic macrophages' (RFD7+ RFD1-) were the cells accumulating at the cartilage junction. No significant numbers of RFD9+ epithelioid cells were seen. 263C+ osteoclasts were present in small numbers distributed throughout the stroma but did not appear to be involved in areas of cartilage degradation. This cellular distribution in the pannus is compared with previous studies on the rheumatoid synovium proper. It is concluded that a distinct inflammatory reaction occurs in the pannus and that classic activated macrophages are the cells involved in cartilage degradation.
We have tested the hypothesis that the spontaneous proliferation of synovial fluid mononuclear cells (SFMC) observed during in vitro culture is due to a mechanism analogous to the autologous mixed lymphocyte reaction (AMLR). Thus by observing the effect of addition of cyclosporin A, monoclonal anti-HLA-DR antibody, and recombinant interleukin 2 (rIL-2) on the spontaneous proliferation of SFMC from patients with rheumatoid arthritis (RA) and a wide range of seronegative spondyloarthritides (SN), we have demonstrated that this phenomenon is: (i) a T cell response, (ii) inhibited by the addition of cyclosporin A or monoclonal anti-HLA-DR antibody, (iii) enhanced by the addition of rIL-2 and (iv) the rIL-2 enhancement of the spontaneous proliferation is inhibited by a monoclonal anti-HLA-DR antibody. These observations suggest that the spontaneous proliferation of SFMC is at least in part an HLA-DR driven, IL-2 dependent event analogous to the AMLR, and support the concept derived from immunohistological studies of an important role for an antigen-presenting cell/T cell interaction occurring in the synovial membrane in inflammatory joint diseases such as RA.
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, nor 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.
In an attempt to define the immunoregulatory mechanisms operating in rheumatoid arthritis we have enumerated T cell subsets in the peripheral blood and synovial fluid of patients with this disease. The peripheral blood analysis revealed an elevation of the ratio of inducer T cells (OKT4 positive) to suppressor/cytotoxic T cells (OKT5 positive) in patients with clinically active rheumatoid arthritis when compared with normal persons. This was due to a reduction in the percentage of suppressor/cytotoxic T lymphocytes in these patients. The synovial fluid in rheumatoid arthritis differed from the peripheral blood in 2 respects. Firstly, synovial fluid was characterised by a lower helper: suppressor ratio due to an increased number of suppressor/cytotoxic cells, and, secondly, it contained an increased number of activated T cells bearing HLA DR antigens. The majority of these activated T cells belonged to the helper/inducer T cell subset.
Macrophage like cells expressing high concentrations of HLA-DR antigen have been identified in situ within the synovium of patients with rheumatoid arthritis. The characteristics of these cells have been determined using immunohistological analysis and combined cytochemical techniques. It was found that the majority (greater than 80%) of these cells were interspersed within the perivascular lymphocytic infiltrates occurring in the synovium. These cells did not stain with antisera against surface immunoglobulin or any Mc Abs to T lymphocyte markers. Further combined staining demonstrated that the HLA-DR + ve cells did stain with an anti-monocyte monoclonal (FMC-17), but could not be stained with a Mc Ab against C3b receptors. The interfacing of cytochemical reactions for acid phosphatase (ACP) and adenosine triphosphatase (ATPase) with immunofluorescence staining for HLA-DR demonstrated that these cells were ACP - ve ATPase + ve. This analysis led to the conclusion that the HLA-DR + ve cells found in abundance in the rheumatoid synovium expressed identical characteristics to the interdigitating cells of the normal lymph node paracortex. The possible significance of the presence of large numbers of such antigen presenting cells in the rheumatoid synovium is discussed.
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A combination of immunochemical staining for HLA-DR antigens and the histochemical demonstration of enzyme activity has been used to identify specific cell populations in the normal and arthritic synovial lining layers. Such combined staining has revealed that the normal synovial lining contains a proportion of HLA-DR + ve cells, all of which show strong lysosomal enzyme activity. This population is greatly expanded in biopsies from patients with osteoarthritis and these positive cells also express strong ATPase activity. In the rheumatoid synovium five distinct cell types can be identified; all of which are HLA-DR + ve but differ in their morphology and pattern of enzyme activity. Of special interest was the discovery that a small but significant proportion of these cells have the characteristics of the interdigitating cells of the lymph node paracortex. The relationship between the emergence of these heterogeneous populations and the immunological basis of this inflammatory response is discussed.
The authors review a large body of contemporary immunohistologic findings on the tissue distribution of T lymphocytes in normal and pathological conditions. The suggestions for technological advances in this field are: signal amplification using mixtures of monoclonal antibodies directed against different epitopes on the same antigen (e.g. OKT4A+B+D), triple layer amplification systems using hapten-labelled antibodies, and informative double staining methods with combinations of antibodies labelled with different fluorochromes or enzymes. Review of histological observations in a series of human diseases suggests that imbalances of OKT4+ and OKT8+ subsets of T lymphocytes may represent different types of immunoregulatory disorders. Rheumatoid arthritis and sarcoidosis appear to involve a high level of OKT4+ subpopulation response coupled with an associated appearance of a special type of HLA-DR+ macrophages. It remains to be seen whether normal or self-limited immunological responses (early stages of bacterial infection or delayed-type hypersensitivity reactions) produce OKT4+ and macrophage responses that are characteristically different. Meanwhile, excessive levels of OKT8+ cells have been found in a wide range of recognized or presumed immunoregulatory disorders including: graft-vs.-host reaction and viral infections. These disorders, as well as primary biliary cirrhosis and lichen planus, appear to possess both overlapping and disparate clinical characteristics, and the immunohistological observations may reflect the functional heterogeneity of OKT8+ populations in these diseases. These studies show that histologically meaningful heterogeneity can already be demonstrated for the OKT8+ lymphocyte group.
We have used monoclonal antibodies of the orthoclone (OKT) series to identify T cell subsets in an immunohistological analysis of the synovial membranes obtained from normal individuals and patients with osteoarthritis or rheumatoid arthritis. T cells of the inducer and the suppressor/cytotoxic subsets were identified by the OKT4 and OKT8 antibodies respectively while HLA-DR (Ia-like) antigens were recognized by a conventional antiserum. In the normal and osteoarthritic synovial membranes, virtually no lymphocytes were identified whereas the mononuclear cell infiltrates of the rheumatoid synovial membranes were composed predominantly of T cells expressing the OKT4 inducer phenotype with few OKT8+ suppressor/cytotoxic cells. The OKT4+ cells were found to be intimately related to B cells and strongly HLA-DR+ cells which morphologically resembled the interdigitating cells of lymph nodes. The micro-anatomical arrangement of these different cell types in the mononuclear infiltrates of the rheumatoid synovial membranes closely resembled that of the paracortical or T cell dependent area of normal lymph nodes except few OKT8+ lymphocytes were present. These findings are explained in terms of rheumatoid arthritis as a disease of altered T lymphocyte/macrophage immunoregulation.
In rheumatoid arthritis the synovial membrane has many of the 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-DR-positive 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.
Fifty-nine patients were entered into a double-blind, parallel comparison of the efficacy and side-effects of naproxen sodium (825 mg daily) and indomethacin (100 mg daily) in the treatment of periarthritis of the shoulder joint. Assessments were made on entry to the study, at two weeks, and at the end of four weeks when objective and subjective recordings of mobility, loss of function, pain and the presence of absence of side-effects were noted. The two treatment groups were found to be matched for age, sex and duration of disease, and an assessment at the start of the study differed only in respect of the degree of active medial rotation of the shoulder joint and pain. There was an overall improvement from the time of admission to the study in both the naproxen sodium and the indomethacin treatment groups but there was no significant difference between the efficacy of the two groups. One patient from the naproxen sodium group and three patients from the indomethacin group withdrew from the trial because of side-effects which in each case involved the gastro-intestinal tract.
The results of recent immunohistological studies and ex vivo and in vitro experiments in rheumatoid arthritis (RA) are presented. These findings are used as the basis for a unifying concept of the pathogenesis of RA which serves to explain many clinical and laboratory features of this disease. This hypothesis, which may be regarded for experimental purposes as being analogous to the in vitro AMLR, provides a rational basis for the further analysis of the cellular immune mechanisms operating in RA and the development of effective therapeutic regimens. The ultimate goal is the early diagnosis and cure of RA before the development of irreversible joint damage.