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M J Rowley

Publications and source records attributed to M J Rowley.

At least 91 records · Page 5Linked to original sources
PubMed1993

Anti-collagen autoantibodies are found in women with silicone breast implants.

There have been several anecdotal reports that silicone breast implants are associated with an increased incidence of autoimmune disease. Based upon these data as well as the theoretical potential of silicon and silicone immune interactions, we hypothesized that an immune response to a silicone breast implant would include host reactivity against components of the microenvironment within the implant milieu. To test this hypothesis, we obtained detailed histories and performed examinations of 57 consecutive, self-referred patients concerned about their breast implants. Eleven of these women were excluded for various reasons including previous exposure to bovine collagen. The remaining 46 women, as well as 45 normal women of approximately the same age and living in the same geographic region, were tested using a sensitive ELISA for the presence of autoantibodies to human native type I collagen, denatured type I collagen, native type II collagen and denatured type II collagen. Known positive and negative sera were included in all assays and the ELISA was performed and interpreted blindly. Positive sera were defined as an ELISA value of three standard deviations above the mean of the normal controls. Using these stringent criteria, there was a statistically significant incidence of antibodies to collagen in women with silicone breast implants. In fact, 35% of women with silicone breast implants had such antibodies; this is higher than we have observed in any other autoimmune disease and is similar to that of chronic erosive rheumatoid arthritis. We believe that silicone breast implants, in genetically susceptible hosts, may pose a significant risk for immunopathology.

Adult↗
PubMed1993

Intrasynovial levels of sulphated glycosaminoglycans and autoantibodies to type II collagen in rheumatoid arthritis: a correlative analysis.

It is uncertain whether the autoantibodies to type II collagen that occur frequently in the serum and synovial fluid of patients with rheumatoid arthritis (RA), but rarely in other articular diseases, are primary or secondary to cartilage damage. Hence, we measured antibodies in synovial fluid from patients with RA and other articular diseases and related these to the concentration of sulphated glycosaminoglycans, as a measure of ongoing cartilage catabolism. Synovial fluids from 42 patients with RA and 30 patients with other articular diseases were studied. We found that levels of antibodies to native and denatured collagen were significantly higher in RA than in all other articular diseases, whereas concentrations of sulphated glycosaminoglycans were similar. The absence of any correlation between levels of sulphated glycosaminoglycans and antibodies to collagen weighs against the occurrence of such antibodies in RA as a secondary effect of cartilage damage.

Adult↗
PubMed1993

HLA-DQ genotypes are associated with autoimmunity to glutamic acid decarboxylase in insulin-dependent diabetes mellitus patients.

This study has investigated the genetic basis of the heterogeneous autoimmune response to glutamic acid decarboxylase (GAD) in 179 Australian patients with IDDM. Antibodies to GAD have been correlated with HLA-DQB1 alleles and genotypes, as determined by sequence-specific oligonucleotide hybridizations after polymerase chain reaction was applied to exon 2 of the DQ beta 1 gene. HLA-DQ2 was significantly increased (p < 0.01) in IDDM patients with antibodies to GAD. Antibodies to GAD were detected in 64% of 72 DQ2.8 patients, in 55% of 29 DQ2.2 or DQ8.8 patients and in 41% of 78 patients with other HLA-DQB1 genotypes. HLA-DQ genotype association with autoimmunity to GAD was statistically significant (p = 0.02) and reflected early formation of antibodies to GAD, rather than an HLA association with persistence of antibodies to GAD, since the genotype effect was more evident (p = 0.02) in those with more recent onset (0-5 years) of IDDM. Also, the HLA-DQ genotype effect was more evident in patients with IDDM onset after the age of 14 years (p = 0.003). Multivariate analysis showed that HLA-DQB1 genotypes had a more significant impact on antibodies to GAD than either duration or age of onset of IDDM. In patients with IDDM in childhood, only a minority had low-risk HLA-DQB1 genotypes (37%) when compared with those with onset in adulthood (62%) (p = 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Antibody to two forms of dihydrolipoamide acetyltransferase (PDC-E2) in primary biliary cirrhosis.

Dihydrolipoamide acetyltransferase, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), is the major autoantigen in primary biliary cirrhosis. By immunoblotting with sera from patients with primary biliary cirrhosis, we observed a double band, of molecular weight 70 and 74 kD for PDC-E2, when a preparation of bovine heart mitochondria was not boiled prior to electrophoresis. This double band could also be detected using antisera raised in rats or rabbits against intact PDC or PDC-E2, but not in antisera raised against a synthetic decamer representing the lipoic acid binding sequence of PDC-E2; the latter reacted only with the 74 kD component. Antibody eluted from either the 70 or 74 kD component reacted with both 70 and 74 kD components. By ELISA, sera from patients with primary biliary cirrhosis reacted more strongly with a non-boiled than a boiled PDC-E2, whereas immune animal sera reacted equally with both preparations. Thus, according to whether preparations of PDC are boiled or not, two conformationally alternative forms of the PDC-E2 protein can be revealed by immunoblotting. The two forms in non-boiled preparations migrate at molecular weights corresponding to 70 and 74 kD.

Acetyltransferases↗
PubMed1993

Antibodies to glutamic acid decarboxylase in Australian children with insulin-dependent diabetes mellitus and their first-degree relatives.

Antibodies to glutamic acid decarboxylase (GAD), previously known as the 64-kD pancreatic islet cell autoantigen, are an important serologic marker of insulin-dependent diabetes mellitus (IDDM). Antibodies to GAD (anti-GAD) were examined in sera from Australian children with newly diagnosed IDDM (within 1 mo of diagnosis), IDDM of longer duration (mean +/- SD, 4.8 +/- 3.3 y), and in first-degree relatives, using a radioimmuno-precipitation assay with purified porcine brain GAD as antigen. Antibodies to islet cell cytoplasmic antigens (ICAb) were tested concurrently. The frequency of anti-GAD was not significantly different in children with newly diagnosed IDDM (31 of 42, 74%) and with IDDM of longer duration (14 of 21, 67%), whereas ICAb were present more frequently in children with newly diagnosed IDDM (64%) than in those with longer duration IDDM (14%). In all, 90% of children with newly diagnosed IDDM had either anti-GAD or ICAb, whereas only 48% had both. For the 77 first-degree relatives, the frequency of anti-GAD was 2% (one of 44) in parents and 6% (two of 33) in siblings; ICAb were not detected in any of these relatives. The presence of anti-GAD in the majority of children with IDDM, irrespective of the duration of their disease, represents a useful diagnostic marker for IDDM, and should be of value in ascertaining individuals at risk for developing IDDM.

Adolescent↗
PubMed1993

Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease.

The classification of adults with diabetes mellitus can be invalidated by patients who initially present as NIDDM but who later become frankly insulin dependent. In some of these, the pathogenesis could be similar to that in IDDM, namely autoimmune destruction of the pancreatic beta-cells. We studied 102 patients > 35 yr of age at diabetes onset who had initially been nonketotic and non-insulin-dependent for > or = 6 mo. They were classified according to glucagon-stimulated C-peptide levels into an insulin-deficient group (n = 33) and a non-insulin-deficient group (n = 69). We measured antibodies to GAD, islet cell cytoplasm, thyroid antigens, and gastric parietal cells in both groups. Anti-GAD was significantly higher in the insulin deficient group, 76% (25 of 33), than in the non-insulin deficient group, 12% (8 of 69), and this difference was substantially greater than that shown for ICAs. Thus, in a proportion of adults who present with NIDDM, a slowly evolving autoimmune insulitis can be revealed by testing for anti-GAD. This could have important connotations not only for early intervention, but also for the correct classification of diabetes.

Adult↗
PubMed1992

Epitope specificity of antibodies to type II collagen in rheumatoid arthritis and systemic lupus erythematosus.

Antibodies to human type II collagen were examined in the sera of 105 patients with rheumatoid arthritis (RA), 44 patients with systemic lupus erythematosus (SLE) and 11 patients who fulfilled the criteria of both diseases (RA-SLE overlap), using a solid-phase radioimmunoassay (RIA). The frequencies of antibodies to native and denatured human type II collagen were 20% and 27% in RA, 14% and 16% in SLE, and 45% and 36% in RA-SLE overlap. The specificity of the antibodies was further examined by inhibition with native and denatured type II collagen, by immunoblotting on native and denatured type II collagen, and by immunoblotting on cyanogen-bromide derived polypeptides of type II collagen. We could not identify any disease-specific patterns of reactivity. Thus, in the three disease groups the antibody response was polyclonal; there were antibody populations that reacted with native and/or denatured collagen, and epitopes could be assigned to at least three CB peptides, CB10.5, CB11 and CB8.

Antibodies↗
PubMed1992

Antibodies to glutamic acid decarboxylase are associated with HLA-DR genotypes in both Australians and Asians with type 1 (insulin-dependent) diabetes mellitus.

Antibodies to glutamic acid decarboxylase, previously known as the 64 kD antigen, appear to be more predictive of Type 1 (insulin-dependent) diabetes mellitus in Caucasoids than other autoantibodies to islet cell antigens. However, seropositivity to glutamic acid decarboxylase is not universal at the onset of Type 1 diabetes and the prevalence in Asians is low compared to Caucasoid patients. This suggests the involvement of multiple pancreatic autoantigens in the Type 1 diabetes autoimmune process or, genetic differences within and between ethnic groups that contribute to the heterogeneous autoimmune response to glutamic acid decarboxylase or both. Alternatively some cases of Type 1 diabetes could have an aetiology unrelated to autoimmunity. This study examined the differential response to glutamic acid decarboxylase according to HLA-DR and -DQ genotypes, as determined by RFLP, in 49 white Australian and 44 Asian patients with Type 1 diabetes. Among Australians heterozygous for HLA-DR3, DR4, 85% were positive for antibodies to glutamic acid decarboxylase, significantly different (p = 0.039) from the prevalence of 48% in patients with at least one HLA-DR antigen other than DR3 or DR4. Also, among Australians, the presence of "low risk" HLA-DQ antigens, namely DQw5, DQw6 or DQw7, reduced the prevalence of antibodies to glutamic acid decarboxylase by 40% (p = 0.064). Among Asians with Type 1 diabetes and with antibodies to glutamic acid decarboxylase, HLA-DR9 was significantly (p = 0.037) increased in frequency, at 63% compared with 22% in those without glutamic acid decarboxylase antibodies, and the presence of a "low risk" HLA-DQ allele reduced the antibody rates by 87% (p = 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Differing epitope selection of experimentally-induced and natural antibodies to a disease-specific autoantigen, the E2 subunit of pyruvate dehydrogenase complex (PDC-E2).

Naturally-occurring autoantibodies to a family of mitochondrial enzymes, the 2-oxoacid dehydrogenase complexes (2-OADC), characterize the human liver disease primary biliary cirrhosis. The immunodominant epitope for these autoantibodies is associated with the lipoyl-binding domain of the E2 subunit of the enzymes. The reactivity of these disease-associated autoantibodies was compared with that of antibodies raised in rats and rabbits, by immunization with various preparations derived from the 2-OADC enzymes, using immunization protocols that have successfully induced various organ-specific autoimmune diseases in animals. The immunogens included the intact pyruvate dehydrogenase complex (PDC) from bovine heart, human recombinant PDC-E2, and short synthetic peptides representing the immunodominant lipoic acid binding sequences of the 2-OADC enzymes. The techniques for antibody analysis included immunofluorescence, immunoblotting on mitochondrial extracts, ELISAs using entire PDC, PDC-E2, or synthetic peptides, epitope mapping by peptide scanning on overlapping octameric peptides representing the human PDC-E2 sequence, affinity purification on PDC-E2, and inhibition in vitro by sera of the catalytic function of PDC. Experimental immunization did not elicit any evidence of autoimmune disease. Moreover, the experimentally-induced antibodies in striking contrast to the natural autoantibodies showed preferential reactivity with PDC-E2 rather than with intact PDC, failed to inhibit in vitro the catalytic function of PDC, and, on peptide scanning, reacted with discrete epitopes, but at sites other than the lipoyl-binding region of PDC-E2. Our data indicate that 'multisystem' autoimmune diseases including primary biliary cirrhosis may not be elicitable experimentally because a critical disease-relevant autoepitope is not engaged by the immune system.

Amino Acid Sequence↗
PubMed1992

Coexistent rheumatoid arthritis and systemic lupus erythematosus: clinical, serological, and phenotypic features.

The clinical and serological features and HLA phenotypes are reported for 11 patients with coexistent features of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). All patients had a symmetrical small joint polyarthritis and features of SLE such as rash, photosensitivity, oral ulceration, serositis, cytopenia, and biopsy proved lupus nephritis. Eight had hypocomplementaemia. Autoantibodies were characteristic of the two diseases: all patients had rheumatoid factor and antibodies to double stranded DNA, eight (73%) had antibodies to collagen, and five (46%) had antibodies to Ro (SS-A). There was also an overlap of HLA phenotypes. Six patients were DR4 and seven were DR2 or DR3 positive, and of the five patients who were DR4 negative, four shared class I alleles often associated with DR4. If RA and SLE share a common autoimmune dysfunction, those patients who have the two diseases do so because they have genetic determinants of both.

Antibodies, Antinuclear↗
PubMed1992

Antibodies to glutamic acid decarboxylase discriminate major types of diabetes mellitus.

Insulin-dependent diabetes mellitus (IDDM) is marked by circulating antibodies to a 64,000-M(r) islet cell antigen identified as glutamic acid decarboxylase (GAD). We describe a radioimmunoprecipitation assay with GAD isolated from pig brain. The sera tested were from 80 patients with IDDM including 26 with disease of recent onset and 54 with disease of longer duration (3-42 yr), 20 with non-insulin-dependent diabetes mellitus (NIDDM), and 55 nondiabetic subjects. Conventional assays for islet cell cytoplasmic antibodies were performed concurrently. The level of antibody in serum was expressed in units based on percentage reactivity of a standard reference serum. The frequency of antibody to GAD in IDDM was 69% in short-duration cases and 59% in long-duration cases. The latter was substantially higher than the frequency of islet cell cytoplasmic antibody. Antibodies to GAD were elevated (means +/- 3 SD) in 5% NIDDM cases and in none of the nondiabetic subjects. A simple laboratory test with a defined autoantigen has substantial implications for population screening and early diagnosis of IDDM and for better understanding of its pathogenesis.

Adolescent↗
PubMed1992

Selective production of interferon-alpha subtypes by cultured peripheral blood mononuclear cells and lymphoblastoid cell lines.

The biological significance of the existence of multiple interferon-alpha (IFN-alpha) subtypes is unknown but may represent a finely tuned mechanism whereby different subtypes are produced in response to different stimuli. To investigate the expression of individual IFN-alpha subtypes, polyclonal antipeptide antisera designed to react with all IFN-alpha subtypes, or with a particular subtype, IFN-alpha 2 or IFN-alpha 4, have been produced. In this study we demonstrate the utility of these antisera for the detection, using indirect immunofluorescence staining, of intracellular IFN-alpha produced by human peripheral blood mononuclear cells (PBMC) and lymphoblastoid cells. Secreted IFN-alpha was also investigated by bioassay and a sandwich radioimmunoassay (RIA), using two monoclonal antibodies (mAb) and specific for IFN-alpha 4. The PBMC were shown to produce IFN reactive with all three polyclonal antisera, after stimulation with Sendai virus. The lymphoblastoid cells also produced IFN, including IFN-alpha 2, but IFN-alpha 4 was not detected either intracellularly, by immunofluorescence, or in the medium, by sandwich RIA. The immunofluorescence studies also demonstrate that in the absence of viral stimulation IFN-alpha is found in the cytoplasm of PBMC and lymphoblastoid cells but not secreted in detectable levels. The finding that two lymphoblastoid cell lines do not produce the subtype IFN-alpha 4 raises important questions as to whether other cell lines and cell types produce IFN-alpha subtypes selectively, and whether individual IFN-alpha subtypes have different roles in human physiology and pathology.

Biological Assay↗
PubMed1992

Elephantiasis nostras.

Elephantiasis nostras is characterized by edema, skin fibrosis, and massive enlargement of a body part. Lymphatic obstruction, most commonly due to surgery, radiation, infection, or neoplasms, is important in its pathogenesis. The diagnosis of elephantiasis nostras can often be made based on the clinical findings, but examination of tissue may be helpful to rule out associated conditions, especially malignancies. Mainstays of therapy are elevation, use of pressure devices, and administration of antibiotics. Although medical and surgical treatments are limited in their value, pneumatic pumps are effective in refractory cases.

Adult↗
PubMed1991

Islet cell antibodies and other markers of autoimmunity and diabetes mellitus in Nauruans.

Among the population of Nauru there is a high prevalence of diabetes with onset in early adult life. To ascertain whether autoimmunity to islet cell antigens contributes to this diabetes, a population survey of serum autoantibodies was performed. Subjects were grouped into euglycaemic control subjects, those with impaired glucose tolerance, and those with diabetes subdivided according to duration of disease. No subject was positive by immunofluorescence for islet cell autoantibodies. Various other autoantibodies to nuclear, thyroid and gastric autoantigens were detectable, at comparable frequencies in the three groups. This population study on Nauruan subjects selected to include those in the early phases of disease negates a contribution from islet cell autoimmunity, and thus supports the concept that the disease is the Type 2 (non-insulin-dependent) type.

Animals↗
PubMed1991

Inhibitory autoantibody to a conformational epitope of the pyruvate dehydrogenase complex, the major autoantigen in primary biliary cirrhosis.

The mitochondrial autoantibodies present in primary biliary cirrhosis (PBC) react with the 2-oxoacid dehydrogenase enzymes that include the pyruvate dehydrogenase complex (PDC). All epitopes so far demonstrable, including the inner lipoyl domain of PDC-E2, have been revealed by immunoblotting. To identify other epitopes, advantage was taken of the capacity of PBC sera to inhibit in vitro the catalytic function of the PDC enzyme. PBC sera were analyzed by affinity chromatography, using columns containing either recombinant PDC-E2 or intact PDC. Fractions that bound to the column (B) and nonbinding effluent fractions (NB) were tested by immunoblotting and ELISA and for their capacity to inhibit enzyme function. After separation on the PDC-E2 column the B fractions were reactive with PDC-E2 and intact PDC, whereas the NB fractions did not react by immunoblotting or ELISA with PDC-E2 but did react strongly by ELISA with PDC and did strongly inhibit the enzyme function. After separation of sera on the PDC column, the B fractions reacted more strongly with PDC than PDC-E2 by ELISA and strongly inhibited the enzyme function, whereas the NB fractions were nonreactive. Thus we describe a hitherto undetected population of autoantibodies in PBC sera that react only with intact PDC but not with the recombinant PDC-E2 subunit that contains the lipoyl epitope, are demonstrable by ELISA but not by immunoblotting, and notably, inhibit enzyme function. These nonblotting inhibitory autoantibodies in PBC are presumed to react with an exclusively conformational determinant perhaps presented by the tertiary structure of the entire enzyme complex.

Autoantibodies↗
PubMed1991

Reliability of prognostic models in malignant melanoma. A 10-year follow-up study.

Certain histologic and clinical features of malignant melanoma have been shown to be indicators of prognosis, both collectively and individually. Even though the predictive value of these features is well established, long-term survival is occasionally seen in individuals with multiple poor prognostic factors. To further examine this phenomenon, histologic sections from 53 patients with malignant melanoma excised between the years 1977 and 1980 in whom reliable clinical follow-up data were obtained were evaluated for the presence of features associated with a poor prognosis (thickness greater than 1.7 mm, Clark level greater than or equal to III, vertical growth phase, high mitotic index, marked cytologic atypia, minimal tumor inflammatory infiltrate, presence of regression, presence of plasma cells, male sex, age greater than or equal to 45 years, and axial anatomic location). Sixty-eight percent of the patients survived for greater than or equal to 10 years. Of these, 26% had lesions greater than or equal to 1.7 thick. Multivariate discriminant analysis of all features provide a model that was 76% accurate in predicting outcome over a 10-year period. Although the predictive value of these prognostic variables is generally reliable, there is a significant population of long-term survivors in whom prognosis could not be accurately predicted using these features.

Adult↗