PubMed Health⌕ Search

Biomedical subjects

F C Hall

Publications and source records attributed to F C Hall.

16 recordsLinked to original sources
PubMed2005

Disease modification and cardiovascular risk reduction: two sides of the same coin?

Inflammatory rheumatic diseases are associated with a substantial increase in accelerated atherosclerosis, with complex interactions between traditional and disease-related risk factors. Therefore, cardiovascular risk reduction should be considered as integral to the control of disease activity in the care plans of patients with RA, SLE and, arguably any chronic inflammatory disease. Shared care structures, already established for the monitoring of DMARDs, could be adapted to communicate and monitor cardiovascular risk reduction objectives. We review the evidence for the efficacy of a range of therapeutic strategies, the majority of which impact on both disease activity and cardiovascular risk. The algorithm proposed here attempts to distil the latest advice from specialist panels at the National Cholesterol Education Program and the British Hypertension Society, as well as incorporating the existing data on SLE and RA patients. The algorithm is structured to minimize clinic time and resources necessary to stratify patients into groups for ROUTINE, SUBSTANTIAL or INTENSIVE risk management; the associated table summarizes optimal therapeutic objectives in each of these groups. The implication of this algorithm is that management of cardiovascular risk should be much more aggressive than is currently the norm in patients with chronic inflammatory diseases, such as RA and SLE. Long-term studies of such interventions are needed to further clarify the benefits of intensive cardiovascular risk management in these patients.

Algorithms↗
PubMed2005

Inflammatory arthritis and dermatitis in thymectomized, CD25+ cell-depleted adult mice.

OBJECTIVE: To investigate the effect of CD25+ or CTLA-4(+) cell depletion on the natural history of collagen-induced and spontaneous arthritis in male DBA1/J mice. METHODS: Male DBA/1J mice were treated with anti-CD25 depleting antibody (PC61) or isotype control (GL113), or with anti-CTLA-4 depleting antibody (4F10) at various time-points peri- and post-immunization with bovine collagen type II, emulsified in adjuvant. In order to develop a model system in which long-term depletion of CD25+ regulatory T cells can be achieved prior to immunization, adult male DBA/1J mice were thymectomized prior to administration of either PC61 or GL113. An ELISA demonstrated that PC61 and GL113 antibodies were undetectable by 21 days after administration and FACS analysis confirmed the long-term depletion of CD25+ cells in peripheral blood. RESULTS: In the thymectomized mice treated with PC61, the CD25+ population was depleted and a spontaneous arthritis developed (P = 0.03). In the non-thymectomized mice, administration of CTLA-4-depleting antibody prior to immunization exacerbated arthritis in mice immunized with bovine collagen type II emulsified in incomplete Freund's adjuvant (P < 0.01). However, no significant difference in the natural history of arthritis was evident in mice treated with CD25-depleting antibody (PC61) compared with control antibody (GL113). CONCLUSIONS: Two separate models implicate CD25+ CTLA-4(+) constitutive cells in suppression of arthritis in susceptible DBA/1 males: exacerbation of collagen-induced arthritis following CTLA-4 depletion at the start of induction and spontaneous arthritis in the thymectomy/CD25+ depletion model.

Animals↗
PubMed2004

The non-thiol angiotensin-converting enzyme inhibitor quinapril suppresses inflammatory arthritis.

OBJECTIVES: In addition to its vasoactive effects, angiotensin II has proinflammatory properties. Angiotensin-converting enzyme (ACE) inhibitors reduce the production of angiotensin II and could therefore act as anti-inflammatory agents. Here we investigated the capacity of the ACE inhibitor quinapril to modulate inflammatory arthritis. METHODS: We studied the effect of quinapril on disease activity in mice with collagen-induced arthritis (CIA). Mice received oral quinapril (10 mg/kg/day) at the time of arthritis induction (prophylaxis protocol) or at the onset of mild arthritis (therapy protocol). Concentrations of immunoglobulin G (IgG) subtypes specific for bovine Type II collagen and TNF-alpha were measured by enzyme-linked immunoassay. RESULTS: Quinapril significantly diminished the activity of CIA when given as prophylaxis or therapy (prophylaxis protocol, P<0.001; therapy protocol P=0.002). Antigen-specific IgG2a antibodies were reduced by 52% (P=0.02) in the quinapril prophylaxis protocol. Suppression of arthritis by quinapril was associated with reduced articular expression of TNF-alpha by 68% (P=0.01) in the prophylaxis protocol and 27% (P=0.06) in the therapy protocol. Quinapril therapy also inhibited expression of splenocyte TNF-alpha production following lipopolysaccharide (LPS) in vitro stimulation by 59% (P=0.02). In parallel human in vitro experiments, ACE inhibition suppressed LPS-stimulated production of TNF-alpha by monocytes. In order to confirm that the action of quinapril occurred predominantly through suppression of angiotensin II, parallel experiments with the angiotensin receptor antagonist candesartan cilexetil demonstrated that this agent also inhibited disease activity in CIA. CONCLUSIONS: These data suggest that angiotensin II is a mediator of chronic inflammation and that ACE inhibition may have therapeutic effects in human inflammatory arthritis.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2001

Autoantigenic HCgp39 epitopes are presented by the HLA-DM-dependent presentation pathway in human B cells.

It is hypothesized that autoimmune diseases manifest when tolerance to self-Ags fails. One possible mechanism to break tolerance is presentation of self-Ag in an altered form. Most Ags are presented by APCs via the traditional presentation pathway that includes "epitope editing" by intracellular HLA-DM, a molecule that selects for stable MHC-peptide complexes. We were interested in testing the hypothesis that autoreactive MHC-peptide complexes may reach the cell surface by an alternate pathway without being edited by HLA-DM. We selected a cartilage autoantigen human cartilage glycoprotein 39 to which T cell responses are observed in rheumatoid arthritis (RA) patients and some DR(*)04 healthy subjects. RA is genetically associated with certain DRB1 alleles, including DRB1(*)0401 but closely related allele DRB1(*)0402 is either neutral or mildly protective with respect to RA. We generated human B lymphoblastoid cell line cells expressing DR(*)0401 or DR(*)0402 in the presence or absence of intracellular HLA-DM and assessed their ability to present a candidate autoantigen, human cartilage glycoprotein 39. Our results show that the presence of intracellular HLA-DM is critical for presentation of this autoantigen to CD4(+) T cell hybridomas generated from DR(*)04-transgenic mice. Presentation of an autoantigen by the traditional HLA-DM-dependent pathway has implications for Ag presentation events in RA.

Adipokines↗
PubMed1999

HLA class II transgenic mice: models of the human CD4+ T-cell immune response.

This review examines the field of current HLA class II transgenic mouse models and the individual approaches applied in production of these mice. The majority of these mice have been created with the objective of obtaining a disease model with clinical features mimicking human autoimmune disease. The development process of a different type of HLA class II transgenic mice, which are designed to function as a substitute for a normal human immune system in studies of human autoantigens, is described. Several HLA-DR4 transgenic lines with normally expressed HLA-DR4 molecules have been produced. To obtain adequate positive selection of the HLA-DR4-restricted CD4+ T-cell repertoire in these mice it is essential both to introduce a human CD4 transgene, and to delete the murine major histocompatibility complex (MHC) class II molecules. These HLA-DR4 transgenic mice have been used to determine the immunogenic CD4+ T-cell epitopes of several human autoantigenic proteins.

Animals↗
PubMed1998

Autoreactivity versus autoaggression: a different perspective on human autoantigens.

Antigen-specific B and T cell responses against myelin basic protein, as well as responses against beta-islet-cells or joint tissue, are commonly found both in patients with autoimmune disease and in normal control subjects with disease-associated HLA-DR/DQ alleles. Thus, autoreactive immune responses are not disease-specific; however, the presence of certain autoantibodies may have prognostic value and may aid in disease management.

Animals↗
PubMed1998

A comparison of two techniques for the molecular tracking of specific T-cell responses; CD4+ human T-cell clones persist in a stable hierarchy but at a lower frequency than clones in the CD8+ population.

Oligoclonal or clonal T-cell expansions, presumed to be antigen driven, are frequently sought and followed for diagnostic and prognostic purposes, as well as to understand more about their natural history. Techniques based on conservation of T-cell receptor CDR3 length are increasingly widely used, often without assessment of sensitivity or specificity. We present a comparative evaluation of a novel modified heteroduplex technique and a CDR3-length-based assay. Dilution of a known clone in a mixed T-cell population shows that in our hands the heteroduplex technique is at least 10-fold more sensitive than the CDR3-length-based assay. However, even with this level of sensitivity, we do not detect clonal expansions in unstimulated CD4+ T cells. This contrasts with the frequent detection of CD8+ clones in fresh samples and suggests different mechanisms of clonal homeostasis in the two subsets. We show that both techniques detect functional expansions after in vitro stimulation with a recall antigen. The distinct molecular footprint seen with the heteroduplex technique allows reproducible follow up of specific clonal expansions. We have exploited this to demonstrate that the repertoire of clones expanded by in vitro tetanus toxoid stimulation shows stability within an individual, implying long-term maintenance of multiple CD4+ clones.

CD3 Complex↗
PubMed1998

TCR beta spectratyping in RA: evidence of clonal expansions in peripheral blood lymphocytes.

OBJECTIVE: To compare the TCR beta repertoire of peripheral blood CD8 enriched (CD8+) and depleted (CD8-) T cells in rheumatoid arthritis (RA) patients and controls using CDR3 length analysis (spectratyping). METHODS: CD8+ and CD8- T cells were separated from 14 RA patients and 12 controls, using magnetic beads coated with anti-CD8 monoclonal antibodies. cDNA was prepared as the template for amplification with 22 V beta-C beta primer pairs. The products were resolved by electrophoresis in an ABI373 sequencer using GENESCAN software. Expansions were identified as dominant CDR3 lengths, where the area underlying the corresponding peak exceeded the sum of the areas of the two adjacent peaks. This method was validated by sequencing 10 samples displaying dominant peaks. The expansion frequencies in RA patients and controls were compared using the chi 2 test statistic. RESULTS: Dominant peaks were evident in several V beta families. They were more frequent in RA patients in both the CD8+ subset (RA normalised frequency 10.6; control normalised frequency 8.0; p = 0.03) and the CD8- subset (RA normalised frequency 2.9; control normalised frequency 1.5; p = 0.02). Sequencing of 10 samples exhibiting dominant peaks revealed an unequivocal clonal expansion in nine (90%). CONCLUSIONS: RA patients exhibited a significantly increased frequency of T cell expansions both in the CD8+ and CD8- subsets. This phenomenon may reflect the proliferation of autoreactive cells, a nonspecific expansion of memory T cells in response to pro-inflammatory cytokines or a defect of T cell regulation that predates the onset of RA and may itself predipose to disease.

Adult↗
PubMed1997

A linkage study across the T cell receptor A and T cell receptor B loci in families with rheumatoid arthritis.

OBJECTIVE: To examine whether the T cell receptor (TCR) A or TCRB loci exhibit linkage with disease in multiplex rheumatoid arthritis (RA) families. METHODS: A linkage study was performed in 184 RA families from the UK Arthritis and Rheumatism Council Repository, each containing at least 1 affected sibpair. The microsatellites D14S50, TCRA, and D14S64 spanning the TCRA locus and D7S509, Vbeta6.7, and D7S688 spanning the TCRB locus were used as DNA markers. The subjects were genotyped using a semiautomated polymerase chain reaction-based method. Two-point and multipoint linkage analyses were performed. RESULTS: Nonparametric single-marker likelihood odds (LOD) scores were 0.49 (P = 0.07) for D14S50, 0.65 (P = 0.04) for TCRA, 0.07 (P = 0.29) for D14S64, 0.01 (P = 0.43) for D7S509, 0.0 (P = 0.50) for Vbeta6.7, and 0.0 (P = 0.50) for D7S688. By multipoint analysis, there was no evidence of linkage at TCRB (LOD score 0), and the maximum LOD score at the TCRA locus was 0.37 (at D14S50). The presence of a susceptibility locus (LOD score < -2.0) was excluded, with lambda > or = 1.8 at TCRA and > or = 1.4 at TCRB. CONCLUSION: These linkage studies provide no significant evidence of a major germline-encoded TCRA or TCRB component of susceptibility to RA.

Alleles↗
PubMed1996

Influence of the HLA-DRB1 locus on susceptibility and severity in rheumatoid arthritis.

We examined HLA-DR genotype risk in 288 patients with rheumatoid arthritis who were carefully categorized for disease severity. Five hundred ethnically-matched bone-marrow donors were controls. A hierarchy of positive allelic associations was noted with DRB1*0401 (p < 10(-38), *0404,8 (p < 10(-43), *0405 (p < 10(-8), *10 (p < 10(-3) and *0101,2 (p < 10(-2), while DRB1*0403 was negatively associated (p = 0.02). The DRB1 genotype relative risks (and 95% CIs) for RA were: *0404,5,8/*0404,5,8 = 36.2 (15-87), *0401/*0404,5,8 = 31.3 (18-55), *401/*0401 = 18.8 (11-35), *0101,2/*0404,5,8 = 6.0 (2-14), *0101,2/*0401 = 6.4 (3-12), *0101,2/*0101,2 = 1.3 (0.3-6), *10/*0404,5,8 = 27.8 (5-148), *10/*0401 = 20.8 (5-89), *10/*0101,2 = 22.3 (5-96), *0404,5,8/DRX = 5.0 (3-8), *0401/DRX = 4.7 (3-7), *0101,2/DRX = 2.3 (1.4-4), *10/DRX = 3.4 (0.8-14). No significant correlation of DRB1 genotypes was found with severity of RA as judged by nodules or articular erosions.

Arthritis, Rheumatoid↗
PubMed1995

Idiopathic eosinophilic myositis.

Eosinophilic myositis is a rare entity accompanying parasitic infection or other inflammatory disorders. Two cases are reported in which myalgia and eosinophilic infiltration of muscle occurred in the absence of associated disease, and twelve previously published cases of idiopathic eosinophilic myositis are reviewed. A classification system for idiopathic eosinophilic muscle disease is proposed, describing three distinct groups. Comparisons are drawn between these and other causes of eosinophilic muscle disease, outlining the differential diagnoses for each group.

Adult↗
PubMed1991

Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome.

OBJECTIVE: To study the association between coxsackie B virus infection and the postviral fatigue syndrome and to assess the immunological abnormalities associated with the syndrome. DESIGN: Case-control study of patients with the postviral fatigue syndrome referred by local general practitioners over one year. SETTING: General practitioner referrals in Dunbartonshire, Scotland. PATIENTS: 254 Patients referred with the postviral fatigue syndrome (exhaustion, myalgia, and other symptoms referable to postviral fatigue syndrome of fairly recent onset--that is, several months) and age and sex matched controls obtained from same general practitioner; 11 patients were rejected because of wrong diagnoses, resolution of symptoms, and refusal to participate, leaving 243 patients and matched controls. MAIN OUTCOME MEASURES: Detailed questionnaire (patients and controls) and clinical examination (patients) and blind analysis of blood sample at entry and after six months for determination of coxsackie B virus IgM and IgG antibodies and other variables (including lymphocyte protein synthesis, lymphocyte subsets, and immune complexes). RESULTS: Percentage positive rates for coxsackie B virus IgM at entry were 24.4% for patients and 22.6% for controls and for coxsackie B virus IgG 56.2% and 55.3% respectively; there were no significant differences between different categories of patients according to clinical likelihood of the syndrome nor any predictive value in a fourfold rise or fall in the coxsackie B virus IgG titre in patients between entry and review at six months. The rates of positive antibody test results in patients and controls showed a strong seasonal variation. Of the numerous immunological tests performed, only a few detected significant abnormalities; in particular the mean value for immune complex concentration was much higher in 35 patients and 35 controls compared with the normal range and mean value for total IgM was also raised in 227 patients and 35 controls compared with the normal range. CONCLUSIONS: Serological tests available for detecting coxsackie B virus antibodies do not help diagnose the postviral fatigue syndrome. Percentage positive rates of the antibodies in patients simply reflect the background in the population as probably do the raised concentrations of total IgM and immune complexes.

Adult↗