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G R Harvey

Publications and source records attributed to G R Harvey.

18 recordsLinked to original sources
PubMed1999

Clinical and serological associations with anti-RNA polymerase antibodies in systemic sclerosis.

There are three classes of RNA polymerase enzyme (RNAPs I, II and III). In systemic sclerosis (SSc), three main groups of anti-RNAP sera have been characterized by radioimmunoprecipitation techniques: anti-RNAP I/III sera, anti-RNAP I/II/III sera, and a group precipitating both RNAP II and topoisomerase I (topo I). Some sera in this third group precipitate the phosphorylated (IIO) form of RNAP II in the absence of the unphosphorylated (IIA) form. Certain other antinuclear antibodies (ANA) have also been detected in anti-RNAP IIO/IIA/topo I and anti-RNAP IIO/topo I sera. In the present study of 155 SSc patients, clinical features of individuals from each of these antibody groups were assessed and compared with those of patients from other autoantibody-defined groups. The anti-RNAP I/II/III antibody specificity was closely associated with the presence of diffuse cutaneous SSc (dc-SSc) (77.8%; cf. remaining group, 12.4%; P < 0.001; relative risk (RR) 6.3). Patients with anti-RNAP I/III antibodies also had an increased incidence of dc-SSc, but this was not significant (42.9%; cf. remainder, 15.7%). Anti-RNAP+ patients had a significantly increased incidence of renal involvement (29.0%, cf. remainder, 11.3%; P < 0.05; RR 2.6), with 40% of anti-RNAP I/II/III patients having renal disease. Meanwhile, the presence of anti-centromere antibodies (ACA) was associated with limited cutaneous SSc (lc-SSc) (100.0%; cf. remainder, 75.3%; P < 0. 005), together with reduced incidences of both renal disease (2.4%, cf. remainder, 22.1%: P < 0.01) and pulmonary fibrosis (21.4%, cf. remainder, 52.3%; P < 0.005; RR 1.9). Anti-topo I antibodies were associated with the presence of pulmonary fibrosis (69.7%; cf. remainder, 32.6%; P < 0.001; RR 2.1). A majority of anti-topo I sera were from lc-SSc patients, regardless of whether anti-topo I antibodies occurred alone (75.0%) or together with anti-RNAP IIO + IIA antibodies (75.0%), and this was similar to the remainder (86. 5%; NS). However, when anti-topo I+ patients were compared with the ACA group, and then with all anti-RNAP I+ patients (37.5% lc-SSc), significant differences were found in the occurrence of dc- versus lc-SSc (P < 0.005 and P < 0.05, respectively). In conclusion, these results confirm that there are three main groups of SSc sera, each characterized by the presence of a mutually exclusive SSc-specific autoantibody (ACA, anti-topo I or anti-RNAP I), and distinguished by patterns of cutaneous involvement and specific clinical features. It appears that, in each of the three groups of SSc patients, distinct pathological processes are occurring, which are responsible for the characteristic symptoms, for the modification of particular autoantigens and, consequently, for the production of particular autoantibodies. Based on these data, together with our previous results, it is further hypothesized that anti-RNAP II antibodies may be produced in the context of two different immune response pathways.

Antibodies, Antinuclear↗
PubMed1999

Serologic abnormalities in systemic sclerosis.

Recent evidence has confirmed that sera from most systemic sclerosis (SSc) patients contain one of three mutually exclusive, SSc-associated autoantibodies (anti-RNA polymerase III, anti-topoisomerase I, or anti-centromere antibodies). Each is associated with the presence of particular clinical features and certain human lymphocyte antigen (HLA) alleles. Based on the available data the most likely model is for the existence of three distinct disease processes, each with certain key pathologic features. In turn, each pathologic state is responsible for characteristic symptoms, and leads to the production of a distinctive set of modified autoantigens. Certain cryptic epitopes are consequently produced by antigen-presenting cells, and are effectively presented according to the available HLA molecules, with subsequent HLA-restricted autoantibody production. Thus, while not directly involved in disease pathogenesis, SSc-associated autoantibodies appear to be reliable reporters of disease-specific pathologic phenomena, and may prove valuable pointers toward the etiopathogenesis of the different subtypes of SSc.

Autoantibodies↗
PubMed1996

Anti-RNA polymerase antibodies in systemic sclerosis (SSc): association with anti-topoisomerase I antibodies and identification of autoreactive subunits of RNA polymerase II.

The prevalence of autoantibodies to the three RNA polymerase (RNAP) enzymes in the sera of 249 SSc patients was measured using the technique of immunoprecipitation of 35S-methionine-labelled K562 cell extracts. Forty-six anti-RNAP sera were detected (18.5%) and three main groups were identified: anti-RNAP I/III sera (10; 4.0%), anti-RNAP I/II/III sera (15; 6.0%), and sera precipitating the phosphorylated (IIO) form of RNAP II (18; 7.2%). All sera in the third group also precipitated topoisomerase I (topo I), and six of them also precipitated the unphosphorylated (IIA) form of RNAP II. Although RNAP II/topo I multienzyme complexes may occur in cell extracts, autoreactive epitopes were shown to be located on both enzymes by a combination of antigen depletion studies, and in vitro assays which demonstrated functional inhibition of topo I activity. Furthermore, immunoblotting experiments using affinity-purified extracts demonstrated that all sera with anti-RNAP II antibodies recognized the largest RNAP II subunit in its phosphorylated form (IIo; 240 kD), whereas the unphosphorylated subunit (IIa; 220 kD) was only recognized by sera which also precipitated RNAP IIA. Therefore at least two different sites on the largest subunit of RNAP II are recognized by SSc sera, and one of these sites is unique to the phosphorylated (IIO) form.

Antigen-Antibody Reactions↗
PubMed1995

Segregation of autoantibodies with disease in monozygotic twin pairs discordant for systemic sclerosis. Three further cases.

OBJECTIVE: To study the serologic status of 3 previously unreported monozygotic twin pairs discordant for systemic sclerosis (SSc). METHODS: Autoantibodies were measured by indirect immunofluorescence, immunodiffusion, and immunoprecipitation of 35S-labeled cell lines. Major histocompatibility complex (MHC) class II allele typing and DNA fingerprinting were used to confirm monozygosity. RESULTS: Anti-PM-Scl, anti-threonyl transfer RNA synthetase, and anti-topoisomerase I antibodies, respectively, were found in each of the twins with SSc. None of the unaffected twin siblings had an identifiable autoantibody, although serum from 1 unaffected twin precipitated several unknown proteins. The MHC class II genotype in each twin was the genotype expected for the autoantibody that was present. CONCLUSION: Autoantibodies of certain defined specificities are intimately linked with the development of SSc, because they segregate with SSc in individuals who start life with identical germline genes.

Autoantibodies↗
PubMed1991

The modulation of the expression of IL-6 and its receptor in human osteoblasts in vitro.

Interleukin 6 (IL-6) probably plays a central role in the acute phase response and in haemopoiesis and may be involved in the control of bone turnover. We have studied the release of IL-6 from human trabecular bone cells treated with a variety of stimuli using a specific bioassay. In serum free medium, unstimulated human osteoblast-like cells produced IL-6 in the range of 1000-2050 pg/ml/24 h. Recombinant human interleukin 1 (IL-1 alpha) (10(-13)-10(-11) M), tumor necrosis factor alpha (TNF alpha) (10(-9)-10(-7) M) and lipopolysaccharide (5-500 ng/ml) all stimulated release of IL-6 from human bone cells. Maximal levels of 17,000 pg/ml were observed using the highest concentration of IL-1. 1,25(OH)2D3 and PTH did not stimulate IL-6 release. Using a specific sheep antihuman IL-6 antibody, all IL-6 activity could be neutralized. In parallel studies, ROS 17/2.8 rat osteosarcoma cells released around 50 pg/ml of IL-6 under basal conditions which were increased to a maximum of 900 pg/ml by treatment with PTH (10(-9) M). The cytokines were less effective and 1,25(OH)2D3 again had no effect. Modulation of expression of IL-6 mRNA in human osteoblast cells was examined using a human complementary deoxyribonucleic acid probe. The mRNA was constitutively expressed, and IL-1 (10(-11) M) and TNF (10(-7) M) induced further mRNA expression within 2 h, which was sustained over 24 h. 1,25(OH)2D3 (10(-7) M), IL-6 (2000 pg/ml), and PTH (10(-9) M) exerted no effects at any time point. Dexamethasone (10(-6) M) suppressed both basal and IL-1- and TNF-induced IL-6 mRNA expression. IL-6 receptor mRNA was constitutively expressed but was not regulated by any of the above agents. It is clear that rodent and human osteoblasts differ in their production of IL-6 and its modulation. These data support the hypothesis that IL-6 is produced locally in human bone by osteoblasts under the direction of other cytokines. This could have implications in bone remodeling, haemopoiesis, and systemic responses to local injury.

Blotting, Northern↗
PubMed1973

Polychlorobiphenyls in North Atlantic ocean water.

Concentrations of polychlorobiphenyls (PCB's) have been measured at the surface and at various depths in the water of the North Atlantic Ocean between 26 degrees N and 63 degrees N. The concentrations average about 20 parts per trillion and amount to an estimated 2 x 10(4) metric tons of PCB's in the upper 200 meters of water. The average concentrations of PCB's in the surface water of the Sargasso Sea are lower than those in the northern North Atlantic.

Polychlorinated Biphenyls↗
PubMed1972

Polystyrene spherules in coastal waters.

Polystyrene spherules averaging 0.5 millimeter in diameter (range 0.1 to 2 millimeters) are abundant in the coastal waters of southern New England. Two types are present, a crystalline (clear) form and a white, opaque form with pigmentation resulting from a diene rubber. The spherules have bacteria on their surfaces and contain polychlorinated biphenyls, apparently absorbed from ambient seawater, in a concentration of 5 parts per million. White, opaque spherules are selectively consumed by 8 species of fish out of 14 species examined, and a chaetognath. Ingestion of the plastic may lead to intestinal blockage in smaller fish.

Animals↗