Search PubMed⌕ Search

Biomedical subjects

J H Vaughan

Publications and source records attributed to J H Vaughan.

At least 19 recordsLinked to original sources
PubMed1990

Altered immune response to glycine-rich sequences of Epstein-Barr nuclear antigen-1 in patients with rheumatoid arthritis and systemic lupus erythematosus.

Prior studies have shown that patients with rheumatoid arthritis (RA) have an increased number of circulating Epstein-Barr virus-infected B lymphocytes and elevated titers of antibody to Epstein-Barr nuclear antigen-1 (EBNA-1), the major nuclear antigen expressed in latently infected B cells. However, it is not known whether antibodies from RA patients recognize the same epitopes as antibodies from normal subjects. are directed at the glycine-alanine repeating region of the molecule. Antibodies specific for this region are also somewhat more prevalent in RA patients than in normal subjects. A panel of synthetic peptides derived from EBNA-1 was used to analyze the immune response to antigenic epitopes outside the glycine-alanine region, using the peptides as solid-phase antigen. Sera from RA patients and from systemic lupus erythematosus patients contained elevated levels of IgG antibodies to 2 non-glycine-alanine peptide and to 3 non-glycine-alanine peptides, respectively. Two of the 3 peptides are glycine-rich, but antibodies that react with them are distinct from each other, as well as from those that react with the glycine-alanine epitope. Eight other peptides from the C-terminal portion of EBNA-1 either do not react with sera or show no difference between normal subjects and patient groups. The antibodies to the glycine-alanine peptide are enriched with kappa light chains, whereas antibodies to epitopes outside the glycine-alanine region are not so restricted among kappa and lambda light chains. Thus, RA patients and systemic lupus erythematosus patients have different antibody responses than do normal subjects, both quantitatively and qualitatively.

Amino Acid Sequence↗
PubMed1990

Occurrence of two germline-related rheumatoid factor idiotypes in rheumatoid arthritis and in non-rheumatoid seropositive individuals.

Human rheumatoid factor (RF) paraproteins express two distinct light chain cross-reactive idiotypes defined by the monoclonal antibodies 17.109 and 6B6.6. These germline gene-related cross-reactive idiotypes are both carried on VK3 light chains and are each present on about one-third of IgM RF paraproteins. We assessed the degree to which these idiotypes are represented in polyclonal RFs. We used rheumatoid arthritis (RA) and non-RA RF-positive sera selected from a large cross-sectional population study (the Mini-Finland Health Survey), and sera from a community-based follow-up study of recent-onset RA patients from Heinola, Finland. In the Mini-Finland Health Survey, elevated levels of the 17.109 RF idiotype were seen in sera of 13% of the RA and 19% of the non-RA group; 6B6.6 RF was seen in 26% of the RA and 28% of the non-RA group. In sera of the Heinola follow-up study, 17.109 RF was seen in 12% initially, but in only 3% at 8 years. Similarly, 6B6.6 RF was detected in 25% initially, but in only 7% at 8 years. Ten sera positive for RF prior to the onset of clinical RA were identified from individuals of a second large population study from Finland (North Karelia project); two of these sera exhibited the 6B6.6 idiotype; none exhibited the 17.109 idiotype. The data are consistent with the concept that these germline gene-related cross-reactive RF idiotypes occur frequently in the polyclonal RF of non-RA as well as RA sera, and that in RA the idiotypes may sometimes be reduced or lost as a consequence of somatic diversification of the RF through somatic mutation, usage of new germline genes, or both.

Arthritis, Rheumatoid↗
PubMed1990

Antibodies to synthetic peptides from Epstein-Barr nuclear antigen-1 in sera of patients with early rheumatoid arthritis and in preillness sera.

We studied IgG antibody levels to synthetic peptides (p62, E11 and E3) from Epstein-Barr nuclear antigen-1 (EBNA-1) protein sequence in sera of patients with rheumatoid arthritis (RA), in pre-RA and in rheumatoid factor (RF) positive non-RA sera from Finland. Anti-E11 and anti-E3 antibody levels were significantly elevated in RA sera, compared with both RF negative and RF positive nonrheumatoid controls. The concentrations of anti-E11 and anti-E3 antibodies in the preillness sera were lower than those in RA sera. Eight-year followup samples of patients with RA had slightly decreased levels of anti-E3 and anti-E11 antibodies compared with samples taken within 6 months of the disease onset. Anti-p62 antibody levels did not differ significantly between any of the groups studied. Thus, elevated levels of antibodies to 2 of the glycine containing EBNA-1 peptides were associated with clinical RA.

Adult↗
PubMed1989

Human T cell responses to the Epstein-Barr nuclear antigen-1 (EBNA-1) as evaluated by synthetic peptides.

A panel of synthetic peptides derived from Epstein-Barr virus (EBV) nuclear antigen 1 (EB-NA-1) was used to examine human T cell responses to this antigen. In six of seven normal persons with past EBV infection, T cell precursors specific for five peptides (P27, amino acid residues 83-101;P62, 148-166;E31, 353-367;E41, 368-381; and E11, 461-474) were detectable. The precursor frequencies were in the range of 1:20,000 to less than 1:100,000 peripheral blood mononuclear cells as determined by limiting dilution analyses. Only two of these peptides were predicted as alpha-helices; all peptides were glycine-rich. Four other peptides were not reactive in the seven individuals tested. T cell responses were not detectable in donors without prior EBV infection. Infectious mononucleosis patients investigated 4-6 weeks after diagnosis had likewise no detectable peptide-specific T cell precursors. Thus, it appears that T cells recognizing peptides from EBNA-1 arise and persist in people with past EBV infection.

Amino Acid Sequence↗
PubMed1989

Impairment in T-lymphocyte responses during early infection with the human immunodeficiency virus.

Uncertainty has existed as to whether a T-cell deficiency exists in human immunodeficiency virus (HIV) infection different from that inherent in the reduced T-cell numbers characteristic of the disease. Heretofore, methods for measuring T-cell responses in patients have been carried out with systems requiring monocytes as accessory cells. In the presence of high concentrations of interleukin-2, however, highly purified T cells respond in a monocyte-independent fashion to antibody reactive with the CD3 component of the antigen receptor complex Ti/CD3. Highly purified T cells of HIV-infected patients responded subnormally in this anti-CD3/IL-2 system, even in the case of patients who were asymptomatic or had only lymphadenopathy. The defective T-cell responses occurred over a wide range of concentrations of the anti-CD3. Neither poor IL-2 receptor function as reflected by responses to limiting dilutions of IL-2 nor IL-1 receptor function as defined by incremental proliferation when IL-1 is added accounted for this defect, which also correlated poorly with T4 and T8 numbers. These results suggested that the T-cell abnormality was closely related to Ti/CD3 function, was not specifically or restrictively associated with T4 cells, and was not due to defective IL-2- or IL-1-receptor functions. The amount of HIV RNA in 10(5) T lymphocytes from the patients amounted to less than that found in one cell of a standard HIV infected laboratory cell line (CEM), using slot-blot hybridization. Thus the T-cell deficiency we have observed was not likely to be due directly to cell killing by HIV resident in the T4 cells. Other factors may be important in inducing the immunodeficiency, some of which are discussed.

AIDS-Related Complex↗
PubMed1989

Synovium as a source of interleukin 6 in vitro. Contribution to local and systemic manifestations of arthritis.

Synovial inflammation is often associated with systemic changes, such as increased levels of acute phase proteins and hypergammaglobulinemia, which cannot be explained by the cytokines described in synovial fluids and synoviocyte secretions. Interleukin 6 (IL-6) has recently been characterized as a mediator of multiple inflammatory responses. This cytokine promotes T and B lymphocyte growth and differentiation, and acute phase protein synthesis. We therefore examined IL-6 production by human synoviocytes and its presence in synovial fluids. In vitro, synoviocytes spontaneously released IL-6, which was increased by IL-1 and tumor necrosis factor-alpha. Synoviocyte-derived IL-6 activity was able to induce hybridoma-plasmacytoma proliferation, and immunoglobulin and acute-phase protein synthesis. The synovial fluids from patients with diverse arthropathies contained IL-6 activity, but higher levels were present in inflammatory arthropathies than in osteoarthritis. These results demonstrate that synoviocytes are a potent source of IL-6, which can contribute to important manifestations of inflammatory arthropathies.

Acute-Phase Proteins↗
PubMed1988

Effect of neuropeptides on production of inflammatory cytokines by human monocytes.

Two groups of mediators, the neuropeptides substance P and K and the monocyte-derived cytokines, interact in the neural regulation of immunological and inflammatory responses. Substance P, substance K, and the carboxyl-terminal peptide SP(4-11) induce the release of interleukin-1, tumor necrosis factor-alpha, and interleukin-6 from human blood monocytes. The neuropeptide effects occur at low doses, are specific as shown by inhibition studies with a substance P antagonist, and require de novo protein synthesis. Since monocyte-derived cytokines regulate multiple cellular functions in inflammation and immunity and since neuropeptides can be released from peripheral nerve endings into surrounding tissues, these findings identify a potent mechanism for nervous system regulation of host defense responses.

Cells, Cultured↗
PubMed1987

Autoantibodies in infectious mononucleosis have specificity for the glycine-alanine repeating region of the Epstein-Barr virus nuclear antigen.

Viruses have been postulated to be involved in the induction of autoantibodies by: autoimmunization with tissue proteins released by virally induced tissue damage; immunization with virally encoded antigens bearing molecular similarities to normal tissue proteins; or nonspecific (polyclonal) B cell stimulation by the infection. Infectious mononucleosis (IM) is an experiment of nature that provides the opportunity for examining these possibilities. We show here that IgM antibodies produced in this disease react with at least nine normal tissue proteins, in addition to the virally encoded Epstein-Barr nuclear antigen (EBNA-1). The antibodies are generated to configurations in the glycine-alanine repeat region of EBNA-1 and are crossreactive with the normal tissue proteins through similar configurations, as demonstrated by the effectiveness of a synthetic glycine-alanine peptide in inhibiting the reactions. The antibodies are absent in preillness sera and gradually disappear over a period of months after illness, being replaced by IgG anti-EBNA-1 antibodies that do not crossreact with the normal tissue proteins but that are still inhibited by the glycine-alanine peptide. These findings are most easily explained by either a molecular mimicry model of IgM autoantibody production or by the polyclonal activation of a germline gene for a crossreactive antibody. It also indicates a selection of highly specific, non-crossreactive anti-EBNA-1 antibodies during IgM to IgG isotype switching.

Alanine↗
PubMed1987

Substance P activation of rheumatoid synoviocytes: neural pathway in pathogenesis of arthritis.

Several clinical features are consistent with nervous system involvement in the pathogenesis of rheumatoid arthritis. The neuropeptide substance P is one possible mediator of this interaction, since it can be released into joint tissues from primary sensory nerve fibers. The potential effects of the peptide on rheumatoid synoviocytes were examined. The results show that substance P stimulates prostaglandin E2 and collagenase release from synoviocytes. Furthermore, synoviocyte proliferation was increased in the presence of the neuropeptide. Similar effects were observed with a truncated form of substance P. Synoviocytes were sensitive to very small doses of the neuropeptide (10(-9) M), and its effects were inhibited by a specific antagonist. Thus, the specific stimulation of synoviocytes by the neuropeptide substance P represents a pathway by which the nervous system might be directly involved in the pathogenesis of rheumatoid arthritis.

Arthritis, Rheumatoid↗
PubMed1987

The glycine-alanine repeating region is the major epitope of the Epstein-Barr nuclear antigen-1 (EBNA-1).

The Epstein-Barr nuclear antigen-1 (EBNA-1) is a protein containing a large glycine-alanine repeat that has been shown to be antigenic. Antibodies to EBNA-1 can be detected by means of immunoblotting. Preincubation of antisera with purified EBNA-1 protein inhibits the binding of IgG antibodies in this system, indicating that those epitopes detected by immunoblots are also accessible on the native molecule. A number of synthetic peptides the sequences of which were derived from the glycine-alanine repeating region of EBNA-1 and from regions adjacent to it also inhibited antibody binding to EBNA-1. These showed, however, a 1000-fold variation in their inhibitory activities. Peptides containing only glycine and alanine were the most effective inhibitors. The anti-EBNA-1 antibodies did not react with several other peptides representing sequences from unrelated proteins. At saturating concentrations of peptide 85 to 100% of anti-EBNA-1, antibody binding was inhibited in all sera tested with one exception. Similar results are obtained when antibody binding is assayed by an enzyme immunosorbent assay by using partially purified EBNA-1 to coat the plates. Thus the glycine-alanine region, either through its primary structure or through conformations assumed by this region, forms the major epitope(s) of the EBNA-1 molecule.

Alanine↗
PubMed1985

Characterization of human rheumatoid factors with seven antiidiotypes induced by synthetic hypervariable region peptides.

Recently, we have used synthetic peptides corresponding to the complementarity-determining regions (CDR) of Ig molecules to induce antiidiotypic antisera. Peptide PSH3, representing the third CDR of the IgM rheumatoid factor (RF) Sie heavy (H) chain, induced a private antiidiotype that reacted with only one out of five IgM-RF. Peptide PSL2, corresponding to the second CDR of Sie light (L) chain, induced an antibody against a crossreactive idiotype (CRI), expressed by 10 out of 12 human IgM-RF analyzed. Herein, we report that five additional antiidiotypic antibodies were generated by immunization with synthetic peptides identical to the third L chain CDR of IgM-RF Sie (PSL3), the second and third H chain CDR of IgM-RF Wol, and the second and third CDR of IgM-RF Pom. As analyzed by immunoblot assay, both anti-PSL3 and anti-PSL2 reacted with the majority of 16 IgM-RF. In contrast, all five antiidiotypes induced by the H chain peptides reacted only with the parent proteins, except anti-PSH3, which reacted weakly with one additional RF. These results suggest that one (or very few) VL gene(s), but a larger number of VH genes, are used to encode IgM-RF autoantibodies.

Antibodies, Anti-Idiotypic↗
PubMed1985

Regulation of Epstein-Barr virus infection by recombinant interferons. Selected sensitivity to interferon-gamma.

Interferons (IFN) are antiviral proteins that may be important in mediating cellular defenses against Epstein-Barr virus (EBV) infection. However, the means by which IFN-alpha, -beta and -gamma modify EBV infectivity are not clear. We have evaluated the effects of purified recombinant preparations of all three classes of IFN on EBV-induced B lymphocyte proliferation and Ig secretion. When added early after EBV infection, all three recombinant IFN reduced B cell outgrowth and Ig secretion. IFN-gamma exerted a 7-10-fold more potent antiviral effect than IFN-alpha or -beta. All three types of IFN act directly on B cells. Monocytes and natural killer cells are not necessary for the anti-EBV activity. Of the three recombinant IFN, only IFN-gamma reduced EBV-induced proliferation and Ig secretion when added 3-4 days after virus infection; IFN-alpha/beta were only effective up to 24 h. B lymphoblastoid lines already transformed by EBV are insensitive to the anti-proliferative actions of all three types of IFN. On the basis of these findings, we propose three phases of regulation during EBV infection. In the early phase, EBV-infected cells can be regulated by all IFN. Subsequently, there is an intermediate period where only IFN-gamma is capable of directly affecting EBV-induced B cell responses. In the third phase, B lymphocytes become insensitive to direct actions of all IFN and are now subject to regulation only by cytotoxic cells.

B-Lymphocytes↗
PubMed1979

Antibodies to Epstein-Barr virus-determined antigens in normal subjects and in patients with seropositive rheumatoid arthritis.

Prior studies have shown that patients with seropositive rheumatoid arthritis (RA) have an increased frequency of precipitating antibody against a nuclear antigen, the RA nuclear antigen, detected in human B lymphoblastoid cell lines infected by Epstein-Barr virus. The present investigations demonstrate that patients with seropositive RA also have specifically elevated titers of antibodies to another, better-characterized Epstein-Barr virus-associated B cell antigen, the Epstein-Barr nuclear antigen, which is detected by anti-complement immunofluorescence. Titers of these two antibodies were not affected by absorption of rheumatoid factor from serum. Furthermore, patients with RA did not have elevated titers of antibodies against the Epstein-Barr virus capsid antigen or to three other species of human herpesviruses: herpes simplex type 1, varicella-zoster virus, and cytomegalovirus. In both normal individuals and RA patients there was a significant association between the presence of antibodies to RA nuclear antigen and the titers of antibody to Epstein-Barr nuclear antigen. Thus, normal subjects with antibody to RA nuclear antigen had titers of antibody to Epstein-Barr nuclear antigen equivalent to those of patients with RA and significantly higher than normal subjects lacking antibody to RA nuclear antigen. One interpretation of these results is that patients with seropositive RA derive from a larger population with enhanced immune responsiveness to B lymphocyte nuclear antigens determined by the Epstein-Barr virus.

Antibodies, Antinuclear↗