Biomedical subjects
Publications and source records attributed to R B Clague.
In rheumatoid arthritis the mean platelet volume does not alter with the institution of parenteral gold therapy and with long term gold therapy. It appears to have no value in predicting the onset of thrombocytopenia. It may, however, predict a haemorrhagic diathesis once gold induced thrombocytopenia is established.
The frequencies of antibodies to the cartilage type IX and XI collagens and to type I collagen were determined in 188 patients with rheumatoid arthritis, of whom 76 were positive for antibodies to native type II collagen. A higher proportion of patients with antibodies to native type II collagen had antibodies to these other collagens, but about one third of patients without antibodies to native type II collagen had antibodies to one or more denatured collagens. The patterns of antibodies present in individual sera suggested that there was a selective response to the collagens in an individual patient. The incidence of patients having antibodies to these native and denatured collagens in a random group of patients with rheumatoid arthritis was calculated.
HLA antigens and immunoglobulin heavy chain allotypes (Gm) were determined in 166 unrelated patients with rheumatoid arthritis (RA), 44 of whom had circulating antibodies to native type II collagen. Collagen antibody positive patients showed an association with HLA-DR3 and DR7 (68% compared with 39% of collagen antibody negative RA, p less than 0.005), and with the Gm phenotype, Gm(zafngb). This contrasted with the collagen antibody negative RA patients where there was an association with HLA-DR4 and, in DR4 positive disease only, with the Gm allotype, G1m(x). The Gm(zafngb) phenotype was found in 26% of DR3 or DR7 positive patients overall and only 9% of RA patients negative for these DR antigens (p less than 0.005), suggesting an interaction between HLA-DR3/7 and Gm(zafngb). The differing Gm associations for collagen antibody positive and negative RA provide further evidence for genetic heterogeneity in susceptibility to RA.
HLA phenotypes were determined in 60 Caucasoid patients with rheumatoid arthritis (RA) and normal serum antibody levels to native type II collagen. Antigen frequencies were compared with 52 patients with RA who had elevated antibody levels to native type II collagen. Both RA groups were compared with 163 healthy controls. A clinical comparison of both RA groups yielded few differences, except a decreased incidence of rheumatoid factor and a positive family history of RA and radiologically, increased osteosclerosis in the RA group with elevated antibodies to native type II collagen. HLA-DR4 was increased and HLA-DR7 was decreased in the RA group with normal antibody levels to native type II collagen. A comparison of both RA groups showed an increased incidence of HLA-DR4 in the normal antibody group, whereas HLA-DR7 was increased in the elevated antibody group. In the elevated antibody group the majority of patients possessed either HLA-DR3 or DR7 both of which are in strong linkage disequilibrium with HLA-DQw2. This immunogenetic data suggests that RA patients with autoimmunity to native II collagen form a distinct genetic subset of RA.
Levels of IgG and IgM antibody to native type II collagen, a component of articular cartilage, were measured by a specific solid-phase radioimmunoassay, in 48 rheumatoid arthritis patients. Good correlations were found between the levels in sera and those in synovial fluids. Collagenase digestion caused a significant rise in specific antibody levels in synovial fluids, indicating the presence of intraarticular collagen-anticollagen complexes. These immune complexes may be one mechanism for perpetuation of inflammation in some rheumatoid arthritis patients.
Three patients with unexplained synovial inflammation were found to have an ulcerative, granulomatous synovitis on biopsy. Maize starch was identified in giant cells within the granulomata. Starch synovitis has clinical and histological similarities to starch peritonitis, which is thought to be an example of a cell mediated immune response.
A collaborative study of 75 selected patients with rheumatoid arthritis (RA) employing 6 different methods for the detection of antibodies to type II collagen showed highly significant correlations between all the assays. The radioimmunoassays showed a greater sensitivity than either the passive haemagglutination or immunofluorescent techniques, and when the native collagen molecule was heat-denatured a higher number of patients showed increased antibody levels. In 33 patients the measurement of serum antibody levels to human, bovine, and rat native type II collagen showed a lack of species specificity, indicating that heterologous collagens can be employed in these assays. A retrospective analysis of the clinical, laboratory, and radiological features in the 41 patients with raised antibody levels and the 34 patients with normal antibody levels showed very few differences, but there was a significantly lower incidence of subcutaneous nodules (24% versus 56%) in patients with raised antibody levels. This study emphasizes the need to standardize assays for the measurement of serum antibody levels to native type II collagen. More extensive studies will be required before the clinical significance of these antibodies can be fully established.
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Cellular immunity to native type II collagen as well as to rheumatoid and osteoarthritic synovial membrane homogenates was assessed in a leukocyte adherence assay (LAI) in patients with rheumatoid arthritis (RA). Eleven out of 14 RA patients (79%) were positive in the LAI assay, demonstrating increased reactivity to rheumatoid over osteoarthritic synovial extracts. Increased reactivity to native type II collagen was not noted in the LAI assay. Radioimmunoassay studies demonstrated that 3 out of 14 RA patients (22%) had circulating IgG rheumatoid factor. None of the 11 patients with osteoarthritic or seronegative arthritis had antibodies to native type II collagen or circulating IgG rheumatoid factor, although 2 subjects with ankylosing spondylitis yielded positive LAI results. Our results suggest that type II collagen is not the important constituent in rheumatoid synovial membrane extract responsible for the positive LAI results observed in rheumatoid arthritis patients.
Antibodies to native bovine type II collagen may be important in initiating arthritis in rats immunized with this antigen. The cross-reactivity of these antibodies with native rat type II collagen was higher in rats that developed arthritis than in those that did not. Depletion of serum C3 levels by cobra venom factor delayed the onset of arthritis until C3 levels were returning to normal; therefore, complement may be involved in initiation of the arthritis, and this arthritis may be an example of an immune complex--mediated disease.
Raised serum IgG and IgM antibody levels to native type II collagen were found in patients with rheumatoid arthritis and in patients with juvenile chronic arthritis. There was a good correlation between the serum IgG and the IgM antibody levels in rheumatoid arthritis and a weaker correlation in juvenile chronic arthritis. Raised serum IgM antibody levels to native type II collagen were found in only 1 patient each with ankylosing spondylitis and psoriatic arthritis, and in these groups here was no correlation between the serum IgG and the IgM antibody levels. The highest serum IgG and IgM antibody levels to native type II collagen were found in rheumatoid arthritis. These results, together with the results on serum antiglobulin levels, indicate that patients with rheumatoid arthritis produce antibodies of both IgG and IgM immunoglobulin class which may have pathogenetic significance in the more severe arthritis found in this condition.
Using a new solid-phase double-antibody radioimmunoassay we have determined the incidence of serum IgG antibodies to native bovine type I and type II collagens in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis. Raised serum IgG antibody levels to native type I collagen were present in 49% of patients with RA, 30% with AS, and none of the patients with psoriatic arthritis. Raised serum IgG antibody levels to native type II collagen were present in 42% of patients with RA, 30% with AS, and none of the patients with psoriatic arthritis. In rheumatoid arthritis there was a lack of correlation between IgG antibody levels to collagen and the erythrocyte sedimentation rate, IgG rheumatoid factor, and circulating immune complexes measured by the Clq-binding activity. In ankylosing spondylitis IgG antibody levels to native type II collagen were raised only in patients with peripheral joint involvement. The significance of IgG anticollagen antibodies is not certain, but parallels with rheumatoid factor are discussed.
An acute inflammatory arthritis has been induced in 76% of rats injected intradermally with native bovine type II collagen emulsified in Freund's complete (CFA) or incomplete (ICFA) adjuvant. The arthritis became chronic in 14 out of 31 rats, and ear and tail lesions were noted in some rats. No arthritis was induced by native type I collagen, denatured type II collagen, rabbit IgG, or buffer alone injected intradermally with adjuvant. Using a solid-phase radioimmunoassay for serum antibodies we have shown that IgM and IgG levels to native bovine type II collagen were significantly higher in arthritic than nonarthritic rats. Antiglobulin antibody levels were not raised in arthritic rats. Equivalent antibody levels to native type II collgen were obtained whether this antigen was emulsified in ICFA or CFA. However, native type I collagen produced high antibody levels only when emulsified in CFA, indicating a difference in the immunogenicity of these collagens. These studies suggest that native type II collagen possesses arthritogenic properties in the rat and that humoral immunity may play a role in the induction of this arthritis.
A solid-phase radioimmunoassay has been developed using polystyrene tubes for the detection of class-specific antibodies to collagen. The optimal conditions for the adsorption of collagen onto the tubes, followed by incubation with the antisera and finally the radiolabelled antibody to the class-specific antibody are described. Studies carried out on antisera raised in rats and rabbits using this assay confirm its sensitivity and applicability.
Circulating immune complexes have been measured using the (125I)C1q binding test in 216 sera from 135 children with acute lymphoblastic leukaemia. Increased circulating immune complexes were detectable in 10.7% of the sera and 10.4% of the children. There was no correlation between the presence of circulating immune complexes and prognosis, but a strong correlation with a history of recent infection.
Hypokalemic periodic paralysis occurring in thyrotoxicosis is rare in Caucasians and is not often highlighted as an endocrine emergency. Periodic paralysis, without familial background, manifests only in the thyrotoxic patient. Thyrotoxic periodic paralysis is a self-limiting disorder that is cured by the treatment of the underlying hyperthyroidism. We report an unusual case of acute onset weakness from thyrotoxic periodic paralysis in a young Chinese migrant who had a normal serum potassium level at the time of initial presentation, though on subsequent presentation one week later, he had the typically associated hypokalemia. We also review the literature on thyrotoxic periodic paralysis.
Immunisation of rats with native type II or type XI collagen produced an inflammatory arthritis in certain strains of rats. Antibodies to the native and denatured whole molecules, to the individual alpha chains and to the cyanogen bromide derived peptides of these chains were studied. Inter- and intra-strain variation in the specificity of the antibodies produced was seen and there were also changes with time, especially with the rats immunised with type XI collagen. Both collagen type-specific and cross-reacting antibodies were produced following immunisation with either type II or type XI collagen. Although no specific pattern of antibodies was unique to the presence or absence of arthritis in all rats, antibodies that bound to the CB-11 peptide or antibodies that bound to the CB-9,7 peptide of type II collagen occurred at the time of onset of arthritis in type II or type XI immunised, arthritic rats. Antibodies to these peptides occur in many patients with rheumatoid arthritis (RA) who also have antibodies to type II collagen. Therefore these findings suggest that epitopes on these peptides may be important in the continued production of antibodies to these collagens in patients with RA and that these antibodies may indeed be pathogenic.