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Biomedical subjects

D G Williams

Publications and source records attributed to D G Williams.

At least 73 records · Page 4Linked to original sources
PubMed1990

Antinuclear antibody determination methods.

Screening rheumatology patients for anti-nuclear and anti-cytoplasmic antibodies is easily done in a qualitative manner using the IF, CIE and ID assays. The immunoblot is of use for anti-La and anti-RNP assays but gives anomalous results for Sm binding by anti-RNP sera and is not easily quantitated. These deficiencies of the immunoblot do not apply to the ELISA. Advances in cloning of autoantigens will enable standardisation of antigen preparations used for these ELISAs. The quantitation of autoantibody appears significant since disease flares occur together with elevations in specific autoantibody. IgM anti-Sm autoantibody was detected with a different disease distribution to IgG anti-Sm but the prognostic implications for this remain to be determined.

Antibodies, Antinuclear↗
PubMed1990

A repeated proline-rich sequence in Sm B/B' and N is a dominant epitope recognized by human and murine autoantibodies.

Reactivity of a murine monoclonal anti-Sm B antibody was localized to a cDNA clone T3/2 encompassing codons 177-221 of Sm N and to a series of 10-residue synthetic peptides containing a proline-rich motif. Human sera containing anti-B antibodies also bound to this proline-rich motif in the form of a heptamer, PPGMRPP, and could distinguish the N/B sequence from similar sequences present in the RNP A and C polypeptides in a number of cases. Monoclonal antibodies binding to either this peptide or to a determinant present on both B and D polypeptides inhibited the majority of anti-B binding in 50% of anti-B sera. The region of N/B containing PPGMRPP also bears a second epitope, sterically blocked by monoclonal antibody KSm 5. This hotspot binds 40-60% of anti-B activity in 30% of anti-B sera. These data suggest that the anti-Sm B epitope recognition repertoire is restricted in SLE patients.

Amino Acid Sequence↗
PubMed1990

Genes encoding the beta-chains of HLA-DR7 and HLA-DQw2 define major susceptibility determinants for idiopathic nephrotic syndrome.

1. We have investigated the frequencies of the major histocompatibility complex class II alleles by restriction fragment length polymorphism analysis, using DR, DQ and DP complementary DNA probes, in 40 Caucasoid steroid-sensitive nephrotic children. 2. A significant association with HLA-DR7 was demonstrated (P = 2 x 10(-5); aetiological fraction 0.6). The DQB1 gene of HLA-DQw2 was present in 83% of our patients (P = 2 x 10(-4); aetiological fraction 0.7). We present evidence that it contributes a second susceptibility allele. 3. A weak association between the uncommon HLA-DP-Cp63 allele and the disease was also observed. 4. Our data suggest that the immune events in steroid-sensitive nephrotic syndrome are defined by a particular immunogenetic background involving the beta-chain genes of HLA-DR7 and HLA-DQw2.

Adolescent↗
PubMed1990

Regulated expression of the small nuclear ribonucleoprotein particle protein SmN in embryonic stem cell differentiation.

The SmN protein is a component of small nuclear ribonucleoprotein particles and is closely related to the ubiquitous SmB and B' splicing proteins. It is expressed in a limited range of tissues and cell types, including several undifferentiated embryonal carcinoma cell lines and undifferentiated embryonic stem cells. The protein declines to undetectable levels when embryonal carcinoma or embryonic stem cells are induced to differentiate, producing primitive endoderm or parietal endoderm or yielding embryonal bodies. This decline is due to a corresponding decrease in the level of the SmN mRNA. The potential role of SmN in the regulation of alternative splicing in embryonic cell lines and early embryos is discussed.

Actins↗
PubMed1990

Review of the teaching of medical ethics in London medical schools.

The study examined the influence of the Pond Report on the teaching of medical ethics in the London medical schools. A questionnaire was given to both medical students and college officers. All medical colleges reported that ethics was included in the curriculum. However, from students' replies, it seems that attendance of optional courses is low and that not all current final year medical students have had any formal teaching in medical ethics. Stronger guidelines are necessary to ensure appropriate ethical training in London medical schools.

Curriculum↗
PubMed1990

Recombinant autoantigens.

Highly specific serum autoantibodies directed at cellular macromolecules are detectable in the serum of many patients with autoimmune connective tissue diseases. This phenomenon has been useful in diagnosis and in identifying disease subsets. The mechanism whereby the immune system selects these specific targets, and their relation to the events of disease pathogenesis, remains unclear. The use of monoclonal autoantibodies has increased our knowledge of the molecular associations and components of the often complex heteropolymeric antigenic particles. The advent of antigen cDNA cloning now heralds the next stage in resolution of this understanding with the complete primary structure of the component proteins.

Autoantigens↗
PubMed1989

Isolation of cDNA clones encoding the human Sm B/B' auto-immune antigen and specifically reacting with human anti-Sm auto-immune sera.

A cDNA clone for the human SmB and B' auto-immune antigens has been isolated by antibody screening of a cDNA expression library. The cDNA clone hybridises with two distinct mRNAs, one of which is expressed in a tissue-specific manner. A fusion protein expressed from the cDNA clone was recognised by a number of sera from systemic lupus erythematosus (SLE) patients containing anti-Sm antibodies but not by sera reactive with other auto-immune antigens. The potential use of this clone in a diagnostic assay for SLE and in elucidating the processes regulating the expression of SmB and B' is discussed.

Amino Acid Sequence↗
PubMed1989

Expression of the SmB' splicing protein in rodent cells capable of following an alternative RNA splicing pathway.

The expression of the SmB and SmB' spliceosome proteins in a variety of cell types and tissues has been investigated. Although SmB is found in all cells studied, the SmB' protein is found only in a small number of rodent cell types. The presence of this protein is correlated with the ability to utilize an alternative pathway of RNA splicing which is not available in most cell types. This is the first demonstration of tissue specific expression of a protein component of the spliceo-some and suggests a role for SmB' in the regulation of some cases of alternative RNA splicing.

Animals↗
PubMed1989

A common anti-DNA antibody idiotype and anti-phospholipid antibodies in sera from patients with schistosomiasis and filariasis with and without nephritis.

The serum concentration of a public idiotype (16/6 ID), originally identified on a human hybridoma-derived monoclonal anti-DNA antibody, was raised in patients with S. mansoni and filariasis with or without nephritis, compared to patients with S. haematobium (in which nephritis does not occur) or idiopathic nephritis not associated with infection. There was no significant difference in 16/6 ID levels between patients with or without renal disease, whether associated with S. mansoni or filarial infection. The 16/6 ID-positive antibodies did not bind to native or denatured DNA, using competitive fluid-phase inhibition studies. Anti-cardiolipin antibody (ACA) concentration was increased in patients with either S. mansoni or filarial infection. In filariasis, both IgG and IgM ACA isotypes were elevated, irrespective of the presence of nephritis. In S. mansoni infection, IgA ACA were limited to patients with renal disease, and IgG ACA isotype to patients without overt nephritis. Both isotypes of anti-cardiolipin antibody correlated with levels of the 16/6 ID in patients with S. mansoni or filariasis. The 16/6 idiotype was therefore a feature of chronic helminthic infection, but was not related to anti-DNA antibody levels or specificity. The occurrence of nephritis as a complication of these infections was not related to the prevalence of the 16/6 idiotype.

Antibodies, Antinuclear↗
PubMed1989

Elevation of the levels of SmB, B' and D proteins but not that of the La (SS-B) antigen during HSV infections.

Three Sm proteins, B, B' and D, which are highly immunoreactive in systemic lupus erythematosus (SLE), increase in abundance in Vero cells infected with laboratory strains and clinical isolates of herpes simplex virus (HSV) types 1 and 2. The autoimmune antigen La (SS-B) does not accumulate in identical infections. The significance of the Sm antigen accumulation is discussed in terms of its possible role in HSV infection and in connection with the origin of autoantibodies in SLE.

Animals↗
PubMed1989

Increase in proteinuria and reduction in number of anionic sites on the glomerular basement membrane in rabbits by infusion of human nephrotic plasma in vivo.

1. Intraortic suprarenal infusion in vivo of New Zealand White rabbits with plasma from patients with the nephrotic syndrome reduced the number of anionic sites labelled by the cationic polymer polyethyleneimine in the lamina rara iterna to 14.0 +/- 2.7 per 1000 nm of lamina rara interna (mean +/- SD) compared with 18.7 +/- 2.1 (P less than 0.005) after infusion of plasma from normal subjects. 2. Proteinuria increased in all nine animals infused with nephrotic plasma and in two of seven infused with control plasma (P less than 0.01). The mean increase in proteinuria in the animals infused with nephrotic plasma was 246 mg/l (P less than 0.05), whereas in those infused with control plasma there was no increase. 3. We conclude that nephrotic plasma contains a factor(s) capable of neutralizing the charge of these anionic sites and concomitantly increasing proteinuria.

Animals↗
PubMed1989

Virus infection induces redistribution and membrane localization of the nuclear antigen La (SS-B): a possible mechanism for autoimmunity.

To investigate the possibility that anti-La (SS-B) antibodies in Sjögren's syndrome were induced by virus infection we studied the distribution of La in virus-infected human cell lines. Three monoclonal antibodies to La were used with monoclonal anti-Sm (derived from MRL/lpr lupus mice) and anti-rat immunoglobulin antibodies as controls. In uninfected cells La was predominantly in the nucleus. Twenty-four hours after infection of HEp-2 cells with adenovirus 2, the La and Sm antigens appeared to aggregate and accumulate in the periphery of the nucleus and, after 48 h, La was seen in the cytoplasm and cell membrane. No cytoplasmic or membrane expression of Sm was seen. Infection with adenovirus or cytomegalovirus caused a 2-13-fold increase in the concentration of La in three cell lines. Treatment of HE--2 cells with interferon-gamma (IFN-gamma) and infection with Epstein-Barr virus and cytomegalovirus caused cytoplasmic, but no definite membrane expression of La. The appearance of La on the surface of virally infected epithelial cells together with IFN-gamma induced class II expression could form the basis of a T cell dependent mechanism for anti-La autoantibody induction.

Adenoviridae Infections↗
PubMed1989

Rapid clearance of the lupus antigen Sm is delayed by autoantibody: a possible mechanism of autoimmunity perpetuation.

Sm ribonucleoprotein complex was immunopurified and labelled with 125I. After i.v. injection into normal mice 125I-Sm was cleared with a half life of less than 3 min, mainly to the liver (54% at 15 min). With time there was a progressive reduction in liver uptake (13.3% at 1 h), and this was associated with the appearance of increasing amounts of trichloroacetic acid soluble 125I in serum, suggesting complete Sm catabolism. Injection of 125I-Sm as a preformed immune complex with human anti-Sm antibody was associated with slower antigen removal from the circulation (half life 15 min), more gradual liver uptake (27% at 1 hr), and less degradation products in the serum than after injection of antigen alone. These data suggest that release of 125I-Sm into the circulation is followed by specific organ uptake and antigen degradation. In the form of an immune complex, the rapid removal mechanism is impaired, and antigen persists in the circulation in an undegraded form. Simultaneous production of anti-Sm antibody and Sm antigen release following tissue destruction could lead to amplification of any primed immune response as a result of autoantigen drive in systemic lupus erythematosus.

Animals↗
PubMed1989

Charge distribution of plasma IgA in IgA nephropathy.

The spectrotype of plasma IgA in patients with IgA nephropathy was studied by isoelectric focussing. Densitometry of the gels showed a significant increase in the anionic region at isoelectric points (pI) 4.7-5.1 (P = 0.02) and a reduction in the cationic region pI 5.8-6.0 (P = 0.03) in patients (n = 15) compared with controls (n = 8). Measurement of the IgA concentration in eluates of sequential slices of the gels showed that the ratio of anionic-to-cationic IgA, using pI 5.6 as the dividing point, was significantly greater in patients (n = 10) than in controls (n = 10) (P = 0.03). Two different methods of analysis have therefore demonstrated an increased proportion of anionic and decreased proportion of cationic IgA in the plasma of patients with IgA nephropathy.

Adolescent↗
PubMed1988

High-performance liquid chromatography separations of nitrosamines. III. Conformers of N-nitrosamino acids.

The separation of a selected group of N-nitrosamino acids and their syn and anti conformers by high-performance liquid chromatography using an alpha-cyclodextrin bonded silica gel column and a mobile phase of acetonitrile-triethylammonium acetate was achieved. The effects of mobile phase pH and concentration of acetonitrile on resolution and elution times are also reported.

Chromatography, High Pressure Liquid↗