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Biomedical subjects

A C Horsfall

Publications and source records attributed to A C Horsfall.

16 recordsLinked to original sources
PubMed1992

Cross-reactive maternal autoantibodies and congenital heart block.

Epitopes with linear sequences recognized by anti-La autoantibodies from seven mothers of children with congenital heart block were recently defined. Eight of these epitopes share sequence identity with three other proteins in addition to the original autoantigen, La. The three proteins are human cardiac myosin beta heavy chain, laminin B1 chain and the M6 protein of Streptococcus pyogenes. Affinity purified anti-La antibodies from a further three mothers bound to the La antigen and also to human cardiac myosin and mouse laminin. Affinity purified antibodies from three mothers of healthy children bound to the La antigen but showed minimal binding to either human cardiac myosin or mouse laminin. Cardiac myosin inhibited the binding of CHB-related anti-La antibodies to both La and myosin. These data support a role for maternal autoantibodies crossing the placenta and recognizing foetal cardiac antigens accessible at a critical developmental stage during gestation. We suggest that this would lead to complement fixation, inflammation and the subsequent pathology associated with congenital heart block.

Amino Acid Sequence↗
PubMed1991

Epitope mapping.

The immune response to extrinsic and intrinsic antigens involves specific antigen receptors on T and B cells. The precise antigenic determinants, or epitopes, recognized by these receptors are discrete sequences within the native antigen. The ability to identify and manufacture key epitopes in the immune response has important implications for disease diagnosis and immunointervention. Consequently, increasingly sophisticated technologies are being applied to epitope mapping. This report from a recent workshop gives a balanced view of progress to date and the challenges ahead.

B-Lymphocytes↗
PubMed1991

Ro and La antigens and maternal anti-La idiotype on the surface of myocardial fibres in congenital heart block.

Congenital complete heart block (CCHB) is a rare but potentially fatal disease of infants born to mothers with autoimmune disease where maternal autoantibodies to Ro (SS-A) are thought to cross the placenta and damage fetal cardiac tissue. We have adopted a novel approach to demonstrate the localization and specificity of maternal autoantibodies deposited in fetal heart. We raised an anti-idiotype against maternal anti-La antibodies, which reacted strongly with the surface immunoglobulin on the myocardial fibres from a CCHB heart but not a control fetal heart of the same age. Maternal immunoglobulin eluted from the CCHB heart reacted with La (SS-B) by ELISA. Using monoclonal and affinity-purified antibodies to La and affinity-purified anti-Ro antibodies, both antigens were identified on the surface of the fibres of the affected heart. Surface co-expression of immunoglobulin, complement and Class II antigen, consistent with a local immune response, was also found. This is the first definitive demonstration of Ro and La antigens and specific maternal anti-La antibody and idiotype on the surface of myocardial fibres in CCHB. It suggests that induction of Ro and La antigens on the surface of myocardial fibres during fetal development may be critical in the localization of the specific autoantibodies and subsequent evolution of congenital complete heart block.

Antibodies, Antinuclear↗
PubMed1989

The response to Epstein-Barr virus infection in Sjögren's syndrome.

To assess the response to Epstein-Barr virus (EBV) infection in patients with primary Sjögren's syndrome (SS), the frequency of detection of EBV DNA was studied in salivary gland biopsies and the antibody and idiotypic response to the virus was compared with healthy controls and infectious mononucleosis (IM). Viral DNA, detected by in-situ hybridization, was found in biopsies from two out of 12 patients with SS and six out of 10 controls. IgG, IgA and IgM antibodies to the virus, measured by ELISA using synthetic peptides (early antigen and EBNA-1) and a cloned fusion protein (EBNA-1), were normal in sera from 20 patients with SS, whereas infectious mononucleosis patients showed an increase in IgM antibodies to EBNA-1 and IgG antibodies to early antigen. One similarity between infectious mononucleosis and Sjögren's syndrome was a significant increase in the germline heavy chain idiotype G6 in both diseases, suggesting activation of similar B-cell subsets. It is possible that this is due to EBV, though the low frequency of EBV DNA in biopsies and the normal levels of EBV antibodies in SS does not lend any evidence that the virus itself is the causative agent.

Antibodies, Viral↗
PubMed1989

Autoantibody synthesis in salivary glands of Sjögren's syndrome patients.

We investigated the possibility that autoantibodies are locally synthesized and secreted within salivary glands of patients with Sjögren's syndrome by measuring specific autoantibody as a proportion of the total immunoglobulin present both in serum and saliva. Of 25 patients studied, 21 showed salivary enrichment of IgA anti-La, in three cases IgA anti-La being detected in saliva when IgG anti-La was negative (by ELISA) in serum. Twenty-four showed enrichment of salivary rheumatoid factors and IgA and/or IgM carrying the 17-109 idiotype, a marker of kappa IIIb light chains. These data suggest that autoantibodies, especially of the IgA class, are synthesized primarily in salivary gland and that they can be detected in saliva before they become apparent in the peripheral circulation. The subsequent deposition of these antibodies within salivary glands may be a contributory factor to the pathogenesis of Sjögren's syndrome.

Antibodies↗
PubMed1988

Co-existent anti-La antibodies and rheumatoid factors bear distinct idiotypic markers.

This study describes the distribution of isotypes and idiotypes of two autoantibody populations, anti-La and rheumatoid factor, which co-exist in both the sera and saliva of patients with primary Sjögren's syndrome. The two autoantibodies are distinguished not only by their antigenic specificity but also by the nature of their idiotypic markers. IgA anti-La antibodies bearing restricted idiotypes are specifically enriched in saliva compared to serum suggesting their local synthesis. In contrast, rheumatoid factors bear cross-reactive idiotypes and may arise as a direct consequence of the secondary immune response.

Antibodies↗
PubMed1988

Anti-idiotypic induced suppression of Sjögren's syndrome associated anti-La autoantibody secretion in vitro.

Peripheral blood mononuclear cells from patients with Sjögren's Syndrome spontaneously secrete autoantibodies to the La antigen when cultured in vitro. This paper reports that specific IgG autoantibody production in vitro is suppressed by pre-treatment of CD8+ enriched T cells with rabbit polyclonal antibodies to idiotypes borne by circulating autologous anti-La antibodies. Treatment of this T cell subpopulation with anti-idiotypes specific for circulating anti-La antibodies from other patients or for anti-DNA antibodies was without effect on anti-La antibody production. Similarly anti-La anti-idiotypes had no effect on the production of autoantibodies to other ribonucleoprotein antigens such as nRNP/Sm. These data show that CD8+ T cells are the main targets for anti-idiotypic control in vitro. We suggest that the relative deficit of these cells, plus a surfeit of CD4+ T cells at the site of the pathological lesion within the salivary gland permits localized production of autoantibodies. Thus, dysregulation of the idiotypic network could contribute to the pathogenesis of Sjögren's Syndrome.

Antibodies, Antinuclear↗
PubMed1987

Purification of human autoantibodies from cross-linked antigen immunosorbents.

A method is described whereby autoantibodies to the Sjögren's syndrome antigen La (SS-B) can be purified from re-usable immunosorbent columns constructed from covalently linked human autoantibodies to which the antigen is cross-linked. Previous attempts to link the antigen directly to CNBr-Sepharose beads resulted in loss of biological activity and thus each purification of antibody required fresh batches of antigen. The present technique is a significant improvement since the cross-linked immunosorbents prepared from a single batch of antigen can be re-used several times over a 6 month period. Furthermore F(ab')2 fragments of anti-La antibodies can be purified from pepsin-digested serum samples. These antibodies react in ELISA, Western blot and immunofluorescence in an identical way to serum and murine monoclonal anti-La antibodies and show no reaction with the Ro antigen. However, being of human origin the affinity-purified anti-La antibodies have the advantages of bearing the same idiotypes and reacting with the same antigenic epitopes as naturally occurring serum autoantibodies.

Autoantibodies↗
PubMed1986

Anti-C1q affinity isolated circulating immune complexes correlate with extra-articular rheumatoid disease.

Circulating immune complexes (CIC) were isolated from sera of 35 patients with rheumatoid arthritis (RA) by a two-step method using 2% polyethylene glycol precipitation and anti-C1q affinity chromatography. By this method CIC were exclusive to 19 patients with vasculitis, nodules, or Sjögren's syndrome. Levels of CIC did not correlate with the severity of synovitis but reflected the extent of extra-articular disease. Furthermore, in four patients with persistent severe synovitis observed over a period of 4 to 16 months, the levels of CIC paralleled changes in extra-articular disease. Despite such additional evidence, whether the relationship between CIC and tissue injury is causative or consequential remains unresolved.

Aged↗
PubMed1986

Idiotypes on antibodies to the La (SS-B) antigen are restricted and associated with the antigen binding site.

Rabbit anti-idiotypic antibodies were prepared against affinity purified autoantibodies to the ribonucleoprotein La (SS-B) antigen from the sera of three unrelated patients. Each anti-idiotype recognized private idiotypes expressed only on the immunizing anti-La antibody. In each case they were conformationally dependent and related to the antigen binding site. This demonstration of immunodominant private idiotypes on human autoantibodies to ribonucleoproteins is in direct contrast to the cross-reactive idiotypes described on rheumatoid factors and autoantibodies to DNA. We discuss the possibility that anti-La antibodies, unlike anti-DNA, arise as a result of autoantigenic stimulation.

Adult↗
PubMed1978

Nuclei of cultured synovial fibroblasts studied by immunofluorescence and microdensitometry.

Two techniques which might be expected to detect alterations in DNA have been used in a comparison of cultured non-rheumatoid and rheumatoid synovial fibroblasts. Microdensitometry showed no alteration in staining affinity for methyl green when two pairs of cultures were compared. There was, however, a minor difference in the predominant staining pattern to a fluorescein conjugated anti-IgM serum when five rheumatoid cultures were compared with five non-rheumatoid cultures after exposure to a serum containing anti-nuclear antibodies.

Cell Nucleus↗
PubMed1976

The fractionation of isolated liver cells from normal and carcinogen treated rats.

Suspensions of isolated cells were obtained from livers of normal rats and rats treated with the hepatocarcinogen N,N-dimethyl-4-aminoazobenzene. Differential centrifugation of dispersed cells yielded a large parenchymal cell fraction and a small non-parencymal cell fraction. By means of rate sedimentation through different concnetrations of Ficoll, parenchymal cells were separated into cells with fast, intermediate and slow rates of sedimentation. Periods of sedimentation were brief and centrifugal forces low in order to retain the best possible state of preservation of cells. DNA, RNA and protein contents, acid phosphatase activity, cell size and nucleocytoplasmic ratios of parenchymal cells sedimenting at fast, intermediate and slow rates were measured. Cell fractions from normal livers had properties suggesting that faster sedimenting cells were derived from the centre and middle of the lobule whereas slowly sedimenting cells were periportal; however, much of the periportal cell population remained in a residue of undissociated tissue. Compared with normal cells, carcinogen treated cells appeared to fractionate according to different physical and chemical criteria and could not be related to their origin within the liver lobule. They were smaller, slower sedimenting, lower in protein and RNA content and acid phosphatase activity. The tissue residue contained abnromal histological structures.

Acid Phosphatase↗