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David E J Jones

Publications and source records attributed to David E J Jones.

At least 19 recordsLinked to original sources
PubMed2024

Network proximity analysis as a theoretical model for identifying potential novel therapies in primary sclerosing cholangitis.

Primary Sclerosing Cholangitis (PSC) is a progressive cholestatic liver disease with no licensed therapies. Previous Genome Wide Association Studies (GWAS) have identified genes that correlate significantly with PSC, and these were identified by systematic review. Here we use novel Network Proximity Analysis (NPA) methods to identify already licensed candidate drugs that may have an effect on the genetically coded aspects of PSC pathophysiology.Over 2000 agents were identified as significantly linked to genes implicated in PSC by this method. The most significant results include previously researched agents such as metronidazole, as well as biological agents such as basiliximab, abatacept and belatacept. This in silico analysis could potentially serve as a basis for developing novel clinical trials in this rare disease.

Cholangitis, Sclerosing↗
PubMed2006

Toll-like receptor interactions: tolerance of MyD88-dependent cytokines but enhancement of MyD88-independent interferon-beta production.

Toll-like receptors (TLRs) signal through two main pathways: a myeloid differentiation factor (MyD)88-dependent pathway that acts via nuclear factor kappaB (NF-kappaB) to induce proinflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha) and a MyD88-independent pathway that acts via type I interferons to increase the expression of interferon-inducible genes. Repeated signalling through TLR4 and a number of other TLRs has been reported to result in a reduction in the subsequent proinflammatory cytokine response, a phenomenon known as TLR tolerance. In this study we have shown that, whilst NF-kappaB activation and production of TNF-alpha and interleukin-12 by murine RAW264.7 and J774.2 cells in response to stimulation by TLR4, -5, -7 or -9, was reduced by prior stimulation with TLR4, -5, -7 or -9 ligands, the primary stimulation of TLR3, which does not use the MyD88 pathway, did not reduce the TNF-alpha or interleukin-12 responses to subsequent TLR stimulation. The response to TLR3 stimulation was not diminished by prior TLR ligand exposure. Furthermore, the production of interferon-beta (IFN-beta) following stimulation of TLR3 or -4, which is MyD88-independent, was increased by prior activation of TLR4, -5, -7 or -9. In contrast, TLR9 ligand-induced IFN-beta production, which is MyD88-dependent, was tolerized by prior TLR stimulation. These results are consistent with differential regulation of MyD88-dependent and MyD88-independent cytokine production following serial activation of TLRs.

Animals↗
PubMed2006

Characterisation of the associations and impact of symptoms in primary biliary cirrhosis using a disease specific quality of life measure.

BACKGROUND/AIMS: Primary biliary cirrhosis (PBC) patients experience significant impairment to quality of life (QOL). Studies to date examining relative contributions of different symptoms to QOL impairment in PBC, and biological associations have been limited by the unavailability of appropriate disease specific symptom quantification modalities. METHODS: We applied the PBC-40, a recently developed, multi-domain disease specific QOL measure, to 54 PBC patients to explore the inter-relationship of different symptoms, their biological associations, and correlation with physical functioning measured by accelerometry. RESULTS: Two discrete and unrelated symptom complexes in PBC were identified focused on fatigue (together with cognitive and emotional dysfunction and other symptoms) and itch, with social dysfunction associating with both complexes. We confirmed no correlation between symptom severity and biological parameters of disease severity. There was a strong inverse correlation between physical activity (assessed over 6 days) and fatigue (P<0.005), but not between physical activity and Itch. Patients averaging <7,500 steps per day had over 75% higher fatigue scores than patients averaging >7,500 steps. CONCLUSIONS: We have demonstrated two independent symptom complexes in PBC centred around fatigue and itch, neither is associated with biological parameters of activity, and the fatigue-centred complex is associated with objective impairment of physical functioning.

Aged↗
PubMed2006

HLA class II alleles, genotypes, haplotypes, and amino acids in primary biliary cirrhosis: a large-scale study.

Twin and family studies suggest there is a significant genetic component to primary biliary cirrhosis (PBC). However, the inability to replicate reported associations has been a recurring problem, with the only consistently reported genetic association that between PBC and HLA-DRB1*0801. However, recently even this has been questioned, and a number of novel associations have also been reported. We reinvestigated HLA class II DRB1, DQA1, and DQB1 alleles and haplotypes in a total of 492 well-characterized PBC patients, 412 from the United Kingdom and an additional 80 patients from northern Italy. There was a clear and significant association with HLA-DRB1*0801 in both groups of patients compared to population-specific healthy controls (12% versus 4% in the UK patients, P=.00087, OR=3.05; and 18% versus 6% in the Italian patients, P=.021, OR=3.15). There were also significant protective associations with DRB1*11 in the Italian patients (28% versus 47%, P=.0071, OR=0.42), but not in the UK patients (8% versus 8%) and a protective association with DRB1*13 in both series (14% versus 20%, P=.042, OR=0.65 in the UK patients; and 10% versus 31%, P=.00092, OR=0.25 in the Italian patients). In conclusion, a complex relationship exists between HLA and PBC, and some genetic associations may be population specific.

Alleles↗
PubMed2006

Reduced heart rate variability and baroreflex sensitivity in primary biliary cirrhosis.

BACKGROUND: Standardized mortality ratio for primary biliary cirrhosis (PBC) is 2.87. Even after accounting for liver and cancer-related deaths there is an unexplained excess mortality associated with PBC. We have assessed heart rate variability (HRV) and baroreflex sensitivity (BRS) risk factors associated with cardiovascular mortality, in 57 PBC patients and age- and sex-matched normal controls. METHODS: HRV and BRS were measured non-invasively in subjects and controls. Beat to beat RR interval and 'Portapres' blood pressure data were processed using power spectral analysis. Power was calculated in very low frequency (VLF), low-frequency (LF) and high-frequency (HF) bands according to international guidelines. BRS (alpha) was computed using cross-spectrum analysis. Patients also underwent fatigue severity assessment using a measure validated for use in PBC. RESULTS: PBC patients had significantly lower total HRV compared with controls (P=0.02), with the reduction occurring predominantly in the LF domain (P=0.03). BRS was also significantly reduced compared with controls (P=0.02). There were no significant differences in HRV or BRS between cirrhotic and non-cirrhotic patients. Within the PBC patient group HRV was significantly lower in fatigued than in non-fatigued patients (P<0.05). CONCLUSION: Abnormalities of HRV and BRS in PBC are not specific to advanced disease but are associated with fatigue severity. Abnormalities could be associated with increased risk of sudden cardiac death, potentially contributing to the excess mortality seen in PBC.

Aged↗
PubMed2006

PDC-E3BP is not a dominant T-cell autoantigen in primary biliary cirrhosis.

BACKGROUND: Autoantibody responses reactive with the E2 and E3BP components of pyruvate dehydrogenase complex (PDC), which characterise primary biliary cirrhosis (PBC) crossreact, precluding the identification, from serological studies, of the antigen to which the principal breakdown of tolerance occurs. Although autoreactive T-cell responses to PDC-E2 have been well characterised it is, at present, unclear whether T-cell tolerance breakdown also occurs to PDC-E3BP. The aims of this study were to characterise autoreactive T-cell responses to PDC-E3BP in PBC and potential factors regulating their expression. METHODS: Peripheral blood T-cell proliferative responses to purified recombinant human PDC-E2 and PDC-E3BP at a range of concentrations were characterised in PBC patients and control subjects. RESULTS: T-cell proliferative responses to both E2 and E3BP were absent from control subjects (median peak stimulation index (SI) to PDC-E2 1.2 [range 0.3-1.9], 0/10 positive (SI>2.32), median peak SI to PDC-E3BP 1.1 [0.7-2.1]], 0/10 positive). Significant responses to PDC-E2 were seen in the majority of patients (median peak SI 11.4 [0.4-24.4], 17/20 (85%) positive) but to PDC-E3BP in only a minority (median peak SI 1-9 [0.6-9.95], 8/20 (40%) positive). Where responses to PDC-E3BP were seen they were universally secondary to responses to PDC-E2. CONCLUSIONS: Despite the presence of antibodies reactive with PDC-E3BP in the majority of PBC patients this self-protein is not a dominant T-cell autoantigen in PBC.

Autoantigens↗
PubMed2006

Toll-like receptor (TLR) response tolerance: a key physiological "damage limitation" effect and an important potential opportunity for therapy.

Endotoxin tolerance is a well known phenomenon, described both in vivo and in vitro, in which repeated exposure to endotoxin results in a diminished response, usually characterised as a reduction in pro-inflammatory cytokine release. The mechanisms responsible for endotoxin tolerance have become clear in recent years as our understanding of the pathways through which endotoxin mediates its effects has increased. The principal cell surface receptor for the lipopolysaccharide (LPS) component of endotoxin is Toll-Like Receptor 4 (TLR-4), a member of a highly conserved family of receptors specific for highly conserved bacterial and viral components which play key roles in the early inflammatory response to pathogens. As our understanding of the part played by TLR-4 signalling in endotoxin has increased, so it has become clear that response tolerance occurs to other TLR ligands in addition to LPS/endotoxin. Clinically, endotoxin/TLR response tolerance is thought to play an important part in susceptibility to reinfection in patients treated for severe sepsis. Whilst this may have developed as a protective evolutionary mechanism to prevent death caused by overwhelming cytokine release in sepsis, in the modern era of antibiotics, vasopressors and organ support, undoing this downregulation or "re-booting" the immune system may be a useful therapeutic target in the post-septic patient. This should, however, be approached with caution as it is possible that endotoxin/TLR response tolerance is also a physiological regulatory mechanism in areas normally exposed to bacterial-derived TLR-ligands such as the gut and liver.

Humans↗
PubMed2005

A key role for autoreactive B cells in the breakdown of T-cell tolerance to pyruvate dehydrogenase complex in the mouse.

The key immunological event in the pathogenesis of the autoimmune liver disease primary biliary cirrhosis is breakdown of T-cell self-tolerance to pyruvate dehydrogenase complex (PDC). The mechanism resulting in this breakdown of tolerance remains unclear. Mice exposed to self-PDC mount no immune response; however, animals coexposed to self-PDC and PDC of foreign origin (which in isolation induces a cross-reactive antibody but not an autoreactive T-cell response) show breakdown of T-cell as well as B-cell tolerance. This observation raises the possibility that a cross-reactive antibody response to self-PDC can promote breakdown of T-cell tolerance. The aim of this study was to address the hypothesis that breakdown of T-cell tolerance to PDC can be driven by the presence of B cells and/or antibodies cross-reactive with this self-antigen. Naive female SJL/J mice were exposed to self-PDC alone and in the presence of purified splenic B cells from animals primed with foreign PDC (or controls) or purified immunoglobulin (Ig) G from the same animals. Breakdown of T-cell tolerance was assessed by splenic T-cell proliferative response to antigen at 5 weeks. CD4(+) T-cell proliferative responses indicative of breakdown of T-cell tolerance to self-PDC were seen in the majority (7 of 9, 78%) of animals receiving self-PDC together with purified PDC-reactive B cells. Tolerance breakdown was not seen in animals receiving self-PDC with purified anti-PDC IgG or with B cells from animals sensitized with an irrelevant antigen. In conclusion, breakdown of T-cell tolerance to the highly conserved self-antigen PDC may be mediated by high-level presentation of self-derived epitopes by activated cross-reactive B cells.

Animals↗
PubMed2004

Oxidative stress as a trigger for cellular immune responses in patients with alcoholic liver disease.

Serum antibodies reactive with neo-antigens generated during ethanol metabolism have been identified in patients with alcoholic liver disease (ALD), although their role in the pathogenesis of disease remains unclear. In this study, we characterized peripheral blood mononuclear cell (PBMC) T-cell and antibody responses to human serum albumin (HAS) adducted with acetaldehyde under reducing conditions (AcA-HSA) or with malondialdehyde (MDA-HSA) in patients with advanced ALD (AALD, n = 28), heavy drinkers with no liver disease (NALD, n = 14), and mild/moderate drinking controls (n = 22). Peak proliferative responses of PBMC were assessed in vitro by tritiated thymidine incorporation after the addition of optimized concentrations of antigen or OKT3. Antibody titers were determined by enzyme-linked immunosorbent assay (ELISA). MDA-HSA induced PBMC T-cell proliferation was significantly higher in ALD than in NALD or control patients. Moreover, 10 of 28 (36%) of ALD patients had significant T-cell proliferative responses to MDA-HSA compared to 0 of 14 (0%, P =.02) of the NALD group and 2 of 22 (9%, P <.05) of controls. No significant difference in PBMC T-cell response to Aca-HSA was seen between subject groups. Patients with positive cellular responses to MDA had higher serum anti-MDA antibody titers than those not exhibiting a positive cellular response (P <.005). In conclusion, the pattern of cellular and humoral responses to MDA adducts suggests that the development of these responses may be a susceptibility factor for the development of advanced alcoholic liver disease. The apparent importance of T-cell responses to MDA adducts suggests that oxidative stress may represent an important stimulus for the development of cellular immune responses associated with advanced ALD.

Acetaldehyde↗
PubMed2004

Covalent modification as a mechanism for the breakdown of immune tolerance to pyruvate dehydrogenase complex in the mouse.

The autoimmune liver disease primary biliary cirrhosis (PBC) is characterized by the breakdown of normal immune self tolerance to pyruvate dehydrogenase complex (PDC). How tolerance is broken to such a central and highly conserved self antigen in the initiation of autoimmunity remains unclear. One postulated mechanism is that reactivity arises to an altered form of self antigen with subsequent cross-reactivity to native self. In this murine study, we set out to examine whether sensitization with a covalently modified form of self PDC can give rise to the pattern of breakdown of B-cell and T-cell tolerance to self PDC seen in PBC patients. The notion that altered self can lead to tolerance breakdown was studied by sensitizing SJL/J mice with a covalently modified (biotinylated) preparation of self murine PDC (mP/O-B). Subsequently, antibody and T-cell reactivities to unmodified self mP/O were studied. Sensitization with mP/O-B elicited high-titre, high-affinity antibody responses reactive with both the mP/O-B immunogen and, importantly, native mP/O. In addition, significant MHC class II restricted splenic T-cell responses to native mP/O (i.e., true autoimmune responses) were seen in mP/O-B sensitized animals. The breakdown of T-cell self tolerance to mP/O was not seen in animals sensitized with irrelevant biotinylated antigens. In conclusion, this study provides evidence to support the concept that exposure to covalently modified self PDC can, in the correct proimmune environment, replicate the full breakdown of B-cell and T-cell immune tolerance to PDC seen in PBC. One potential etiological pathway in PBC therefore could be the breakdown of tolerance to self PDC occurring after exposure to self antigen covalently modified in the metabolically active environment of the liver.

Animals↗
PubMed2004

Assessing quality of life in primary biliary cirrhosis.

BACKGROUND AND AIMS: Assessment of health-related quality of life (HRQOL) is not routinely reported in the literature on chronic liver disease (CLD). Few studies have examined quality of life (QOL) in patients with primary biliary cirrhosis (PBC) despite its significant functional impact. One of the reasons for the lack of HRQOL measurement in patients with PBC may be the absence of a well-recognized and widely used measure that clinicians can use in ordinary clinical practice. The aim of this study is to evaluate HRQOL measures used in patients with PBC and examine the suitability of the measures for these patients. METHODS: A literature search identified reports that focused on any aspect of QOL in patients with PBC. Key texts were identified containing generic, domain-specific, and condition-specific measures. The identified measures were systematically evaluated for appropriateness, acceptability, reliability, validity, precision, and responsiveness. RESULTS: Twenty measures were identified from 9 key texts. Six of the measures were previously validated generic measures; 10 were domain-specific measures previously used to measure fatigue, depression, and psychological distress in general and psychiatric populations; and 4 measures had been developed in patients with CLD. Reporting of reliability and validity generally was consistent for all measures used. However, reporting of the remaining criteria was variable, particularly in relation to responsiveness over time and acceptability of the measures to patients with PBC. CONCLUSIONS: A clearer and more rigorous approach is needed in reporting the properties of HRQOL measures used in patients with PBC to help clinicians decide which measures are most suitable for these patients.

Clinical Trials as Topic↗
PubMed2003

Pain as a complication of use of opiate antagonists for symptom control in cholestasis.

Controlled trials have suggested that opiate antagonist therapy may be effective for the treatment of the symptoms of cholestasis. The oral opiate antagonist naltrexone in particular has started to enter into routine clinical use for amelioration of cholestatic itch. Attention regarding the side effects of opiate antagonist therapy has, to date, largely focused on an opiate withdrawal-type reaction (which can be controlled effectively by titrated therapy introduction regimens). Here we describe 3 cases of a further clinically important side effect, loss of control of pain resulting from other pathologies, which in each case necessitated the withdrawal of hitherto clinically effective opiate antagonist therapy. Of the 14 patients treated by our unit with opiate antagonist agents for the control of cholestatic symptoms, 13 (93%) showed resolution of, or significant improvement in, symptoms. Of the 13 patients showing a clinical response, 7 (54%) subsequently had to discontinue therapy because of side effects (including the 3 patients with uncontrolled pain). It is our experience that in the routine clinical setting, opiate antagonists are highly effective for the treatment of cholestatic symptoms. In practice, however, their usefulness is limited by their side-effect profile.

Adolescent↗
PubMed2003

Genetic factors in the pathogenesis of primary biliary cirrhosis.

Current knowledge of the genetic basis of PBC is at best incomplete and at worst poor. Studies so far may be used as a guide to the pitfalls that await unwary investigators and also in deciding where to look and which genes or systems are most likely to yield informative results. The Human Genome Project has revealed a vast array of polymorphism that is too much to contemplate even with the best of current techniques. The crucial processes are the selection of candidates and study design. The strong genetic associations so far in PBC are with chromosomes 6p21.3 and 2q and include; HLA DRBI*08 haplotypes, CTLA4* G and IL1RN-IL1B haplotypes, CASP8, and nramp1. Many of the latter should be considered with caution until confirmed in independent series. Other associations with MBL, APOE and VDR remain to be confirmed. There are also several informative negatives, MMP3 and IL10 for example. It is unlikely that the only genes that influence disease susceptibility and progression in PBC are immunoregulatory genes concerned with T cell immunity. Recent studies indicate a new era for immunogenetics, when genes encoding all immune active proteins may be considered as candidates. One should not concentrate solely on the immune response as recent investigations of mannose binding lectin and apolipoprotein-E testify. One is only just beginning to understand the genetic basis of complex diseases like PBC. The key issues for future investigators are: defining the mechanisms where by self tolerance is broken, defining the mechanisms that determine the rate of disease progression, and identifying genetic markers to predict progression and malignancy. Assessing the genetic basis of variability in disease progression. The significant variation in rate of progression of PBC has led to the hypothesis that genes, in addition to contributing to disease susceptibility, may also determine the rate of disease progression. Several of the studies mentioned earlier have suggested associations between alleles at polymorphic loci and rate of progression . All studies performed to date, however, have been retrospective in nature. One problem inherent in such studies is that of definition of disease progression. One simple definition, that of histological progression to Scheuer stage IV disease , requires liver biopsy. The need to perform repeat biopsies raises ethical problems in cases where there is no other clinical indication. Studies of histologic progression in patients in the control arm of therapeutic trials represent one scenario where repeat biopsy would be indicated. However, the typical time course of such trials is 2 years, insufficient for meaningful assessment of disease progression and natural history, particularly in PBC where there is marked heterogeneity and, as a result, tissue sampling error. Yet, alternative systems for assessing disease progression, such as the Mayo prognostic score, lack sensitivity in any scenario other than existing advanced disease. Outlook for the future. Clinical observations support a significant genetic component to disease susceptibility. Elucidating predisposing genetic associations will markedly assist in understanding the pathophysiology of disease. Investigations to date have been restricted to various community-based case-control association studies, with well-recognized limitations. In future SNP maps and haplotype maps from the Human Genome Project will be available. Studies will require the collection of several well-characterized patients. To meet the required statistical power this will necessitate collaboration on a national and international scale. It is essential that these studies address the relationship between genes and disease progression. The possibility of identifying, in the early stages of disease, patients who are at elevated risk for more rapid progression, would have obvious clinical benefit in terms of patient management and therapy.

Genetic Predisposition to Disease↗