ABSTRACT
The function of the Laccase domain-containing 1 (LACC1) gene is unknown, but genetic variation at this locus has been reported to consistently affect the risk of Crohn's disease (CD) and leprosy. Recently, a LACC1 missense mutation was found in patients suffering from monogenic forms of CD, but also systemic juvenile idiopathic arthritis. We tested the hypothesis that LACC1 single nucleotide polymorphisms (SNPs), in addition to CD, are associated with juvenile idiopathic arthritis (JIA, non-systemic), and another major form of inflammatory bowel disease, ulcerative colitis (UC). We selected 11 LACC1 tagging SNPs, and tested their effect on disease risk in 3855 Swedish individuals from three case-control cohorts of CD, UC and JIA. We detected false discovery rate corrected significant associations with individual markers in all three cohorts, thereby expanding previous results for CD also to UC and JIA. LACC1's link to several inflammatory diseases suggests a key role in the human immune system and justifies further characterization of its function(s).
Subject(s)
Arthritis, Juvenile/genetics , Colitis, Ulcerative/genetics , Polymorphism, Single Nucleotide , Proteins/genetics , Case-Control Studies , Female , Humans , Intracellular Signaling Peptides and Proteins , Male , Middle Aged , Mutation, Missense , Proteins/metabolismABSTRACT
New direct-acting antivirals have the potential to transform the hepatitis C (HCV) treatment landscape, with rates of sustained viral response in excess of 90%. As these new agents are expensive, an important question is whether to focus on minimizing the consequences of severe liver disease, or reducing transmission via 'treatment as prevention'. A back-calculation model was used to estimate the impact of treatment of mild, moderate and compensated cirrhosis on incident cases of HCV-related end-stage liver disease/hepatocellular carcinoma (ESLD/HCC). In addition, a dynamic model was used to determine the impact on incidence and prevalence of chronic infection in people who inject drugs (PWID), the main risk group in England. Treating 3500 cirrhotics per year was predicted to reduce ESLD/HCC incidence from 1100 (95% CrI 970-1240) cases per year in 2015 to 630 (95% CrI 530-770) in 2020, around half that currently expected, although treating moderate-stage disease will also be needed to sustain this reduction. Treating mild-stage PWID was required to make a substantial impact on transmission: with 2500 treated per year, chronic prevalence/annual incidence in PWID was reduced from 34%/4.8% in 2015 to 11%/1.4% in 2030. There was little overlap between the two goals: treating mild stage had virtually no impact on ESLD/HCC within 15 years, but the long timescale of liver disease means relatively few PWID reach cirrhosis before cessation of injecting. Strategies focussing on treating advanced disease have the potential for dramatic reductions in severe morbidity, but virtually no preventative impact.
Subject(s)
Antiviral Agents/therapeutic use , Chemoprevention/methods , Disease Transmission, Infectious/prevention & control , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/prevention & control , England , Hepatitis C, Chronic/transmission , Humans , Incidence , Models, Statistical , Prevalence , Treatment OutcomeABSTRACT
BACKGROUND: Liver transplantation is an important and established treatment option for chronic hepatitis C virus (HCV) related end-stage liver disease (HCV-related ESLD). This study describes trends in elective liver transplantation among persons with HCV-related ESLD. STUDY DESIGN: Retrospective cohort. METHODS: Analyses of United Kingdom (UK) Transplant Registry data for the period 1994 to 2010, with follow-up information extending to 2011. RESULTS: Annual registrations for liver transplantation increased linearly and alcoholic liver cirrhosis (2075, 24%) and HCV-related ESLD (1213, 14%) were the most common indications. HCV-related ESLD patients were mainly aged 40-49 years (32%) and 50-59 years (43%); males (76%); and of white ethnicity (74%). Overall, 75% (956/1213) received a liver transplant with a linear increase over the period (OR 1.11, 95% CI 1.08, 1.13). Pre transplant mortality was unchanged (adjusted OR 1.0, 95% CI 0.96, 1.05) and post-transplant mortality decreased in both HCV-related (adjusted OR 0.77, 95% CI 0.68, 0.88) and non-HCV-related ESLD (adjusted OR 0.82, 95% CI 0.75, 0.89) patients. CONCLUSION: The increase in demand for and receipt of liver transplants among persons with HCV-related ESLD requires coordinated efforts to increase not only organ donation, but investment in HCV prevention programmes and improved access to hepatitis C treatment services.
Subject(s)
Elective Surgical Procedures/statistics & numerical data , End Stage Liver Disease/surgery , End Stage Liver Disease/virology , Hepatitis C, Chronic/complications , Liver Transplantation/statistics & numerical data , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Registries , Retrospective Studies , United Kingdom , Young AdultABSTRACT
PGE2 is a potent lipid mediator of pain and oedema found elevated in RA. Microsomal prostaglandin E synthase-1 (mPGES-1) is a terminal enzyme of the PGE2 pathway inducible by proinflammatory cytokines. mPGES-1 is markedly upregulated in RA synovial tissue despite antirheumatic treatments, suggesting that multiple inflammatory stimuli contribute to its induction. High-mobility group box chromosomal protein 1 (HMGB1) is known to induce inflammation both by direct interaction with TLR4 and by enhancement of other proinflammatory molecules signalling, through complex formation. The high expression of extracellular HMGB1 within the inflamed synovium, implies its pro-arthritogenic role in RA. We aimed to investigate the effects of IL-1ß/HMGB1 complexes on mPGES-1 and other enzymes of the PGE2 pathway in synovial fibroblasts (SFs) from patients with arthritis. Furthermore, we studied the effect of COX-2 inhibition and IL-1RI antagonism on prostanoid and cytokine production by SFs. Stimulation of SFs with HMGB1 in complex with suboptimal amounts of IL-1ß significantly increased mPGES-1 and COX-2 expressions as well as PGE2 production, as compared to treatment with HMGB1 or IL-1ß alone. Furthermore, NS-398 reduced the production of IL-6 and IL-8, thus indicating that IL-1ß/HMGB1 complexes modulate cytokine production in part through prostanoid synthesis. Treatment with IL-1RA completely abolished the induced PGE2 and cytokine production, suggesting an effect mediated through IL-1RI. IL-1ß/HMGB1 complexes promote the induction of mPGES-1, COX-2 and PGE2 in SF. The amplification of the PGE2 biosynthesis pathway by HMGB1 might constitute an important pathogenic mechanism perpetuating inflammatory and destructive activities in rheumatoid arthritis.
Subject(s)
Biosynthetic Pathways/drug effects , Dinoprostone/biosynthesis , Fibroblasts/drug effects , HMGB1 Protein/pharmacology , Interleukin-1beta/pharmacology , Interleukin-8/metabolism , Arthritis/metabolism , Arthritis/pathology , Blotting, Western , Cells, Cultured , Chemokines/metabolism , Cyclooxygenase 2/metabolism , Cyclooxygenase Inhibitors/pharmacology , Cytokines/metabolism , Drug Synergism , Fibroblasts/metabolism , Humans , Interleukin 1 Receptor Antagonist Protein/pharmacology , Interleukin-6/metabolism , Intramolecular Oxidoreductases/metabolism , Nitrobenzenes/pharmacology , Prostaglandin-E Synthases , Sulfonamides/pharmacology , Synovial Membrane/metabolism , Synovial Membrane/pathologyABSTRACT
In a cohort of 272 treatment-naive individuals with chronic hepatitis C infection acquired on a known date who were enrolled in the UK HCV National Register, a progressive improvement in response to treatment was found with the evolution of antiviral therapies from 20% (25/122) for interferon monotherapy to 63% (55/88) for pegylated interferon+ribavirin therapy. Multivariable analysis results showed increasing age to be associated with poorer response to therapy [odds ratio (OR) 0·84, 95% confidence interval (CI) 0·72-0·99, P=0·03] whereas time since infection was not associated with response (OR 0·93, 95% CI 0·44-1·98, P=0·85). Other factors significantly associated with a positive response were non-type 1 genotype (P<0·0001) and combination therapies (P<0·0001). During the first two decades of chronic HCV infection, treatment at a younger age was found to be more influential in achieving a sustained viral response than treating earlier in the course of infection.
Subject(s)
Antiviral Agents/administration & dosage , Hepatitis C, Chronic/drug therapy , Adult , Cohort Studies , Female , Humans , Interferons/administration & dosage , Male , Middle Aged , Ribavirin/administration & dosage , Treatment Outcome , United KingdomABSTRACT
A variety of factors have been associated with spontaneous loss of hepatitis C virus (HCV)-RNA from serum, including infecting HCV type, although results are conflicting. This study aimed to investigate further whether infecting HCV type was linked to spontaneous loss of HCV-RNA. Serum samples from 321 untreated HCV antibody positive patients presenting at the Hepatology clinic at Addenbrooke's Hospital, Cambridge between 2004 and 2007 were tested. These individuals were classified either as HCV antibody and HCV-RNA positive (viremic, n = 219) or HCV antibody positive and repeatedly HCV-RNA negative (non-viremic, n = 102). Infecting HCV type was identified by genotyping (viremic) or serotyping (non-viremic). Binomial regression analysis investigated the independent effect of HCV type on spontaneous loss of HCV-RNA from serum by comparing the two groups. Ninety-one percent of patients were found to be either genotype 1 or genotype 3. The prevalence of type 1 infection was greater among non-viremic (64.5%) than viremic individuals (45%). After controlling for the effects of potential confounding factors, multivariable analyses showed that individuals with type 1 infections were more likely to be non-viremic than genotype 3 infections (RR = 2.07; 95% CI: 1.25, 3.43; P = 0.005). Individuals infected at an older age were also less likely to become HCV-RNA negative spontaneously (RR = 0.42 comparing those infected at ≥20 years of age against those infected at <20 years of age, 95% CI: 0.25, 0.72; P = 0.002). In conclusion, the results suggest that HCV genotype 1 infections are more likely than genotype 3 infections to become spontaneously non-viremic, as are infections acquired at younger age.
Subject(s)
Hepacivirus/isolation & purification , Hepatitis C/virology , RNA, Viral/blood , Adult , Age Factors , Female , Genotype , Hepacivirus/classification , Hepacivirus/genetics , Humans , Male , RNA, Viral/genetics , Serum/virologyABSTRACT
Matching individuals reported to a sentinel surveillance scheme for hepatitis C between 2000 and 2005 to individuals with a hospital episode for hepatitis C-related liver disease in the same hospitals, we estimated that the number of cases of hepatitis C-related end-stage liver disease in these English hospitals was 42% (597/419) higher than Hospital Episode Statistics (HES) would indicate. Further, matching records of hepatitis C-related deaths in HES to death certificates, we estimated that, between 2000 and 2005, the true number of deaths from hepatitis C-related end-stage liver disease was between 185% (353/124) and 257% (378/106) higher than the number recorded in routine mortality statistics. We provide estimates of under-recording that can be used to modify existing models of disease burden due to hepatitis C and provide a simple approach to improve the monitoring of trends in severe hepatitis C-related morbidity over time.
Subject(s)
Hepatitis C/complications , Hepatitis C/mortality , Liver Failure/mortality , England/epidemiology , Female , Hepatitis C/epidemiology , Hospitalization/statistics & numerical data , Humans , Liver Failure/epidemiology , Liver Failure/etiology , Male , Middle Aged , Sentinel Surveillance , Time FactorsSubject(s)
Antibodies, Monoclonal/adverse effects , Antirheumatic Agents/adverse effects , Brain/pathology , Leukoencephalopathy, Progressive Multifocal/chemically induced , Lupus Erythematosus, Systemic/drug therapy , Antibodies, Monoclonal, Murine-Derived , Female , Humans , Leukoencephalopathy, Progressive Multifocal/diagnostic imaging , Lupus Erythematosus, Systemic/complications , Magnetic Resonance Imaging , Middle Aged , Radiography , RituximabABSTRACT
HMGB1 is a pro-inflammatory cytokine that together with TNF-alpha and IL-1beta is involved in the pathogenesis of spontaneously occurring skin lesions in lupus erythematosus. The purpose of the present study was to explore the sequence of events in HMGB1, TNF-alpha and IL-1beta expression under development and resolution of experimentally induced CLE lesions. The study involved investigation of 38 serial skin biopsies acquired from photoprovoked skin lesions of nine CLE patients, using immunohistochemical staining of tissue sections. In biopsies from the clinically most active phase of skin involvement extracellular, secreted HMGB1 and increased cytoplasmic HMGB1 were found, as compared with the late and fading lesions or non-lesional skin. Besides HMGB1, increased expression of TNF-alpha and IL-1beta was observed in dermal infiltrates of the induced CLE lesions. These cytokines were however not upregulated in all lesions, and increased expression of IL-1beta was seen predominantly in late biopsies.In conclusion, extracellular and cytoplasmic HMGB1 coincides with the clinically most active phase of photoinduced lesions of cutaneous lupus, and suggests that HMGB1 is an important factor in the inflammatory autoimmune process of CLE. HMGB1 can induce expression of TNF-alpha and IL-1beta, and formation of a pro-inflammatory loop between HMGB1, TNF-alpha, and IL-1beta may be responsible for the prolonged and sustained inflammation in CLE.
Subject(s)
HMGB1 Protein/metabolism , Lupus Erythematosus, Cutaneous/etiology , Cytokines/genetics , Cytoplasm/metabolism , Extracellular Space/metabolism , Gene Expression Regulation , Humans , Inflammation/etiology , Lupus Erythematosus, Cutaneous/immunology , Lupus Erythematosus, Cutaneous/pathology , Protein Transport , Skin/pathology , Ultraviolet Rays/adverse effectsABSTRACT
In England, a large number of individuals are infected with the hepatitis C virus (HCV) and may develop future liver complications, such as decompensated cirrhosis and hepatocellular carcinoma (HCC). Estimates of the magnitude of this future burden are required to plan healthcare resources. We have estimated past incidence of HCV infection in England and predict future burden of end-stage liver disease in the HCV-infected population. A model of the natural history of HCV as a series of disease stages was constructed. A back-calculation approach was performed, using the natural history model and data on annual HCC deaths in England from 1996 to 2004 with mention of HCV and hospital episode statistics for end-stage liver disease with HCV. The number of HCV-infected people living with compensated cirrhosis is predicted to rise from 3705 [95% credible interval (CrI): 2820-4975] in 2005 to 7550 (95% CrI: 5120-11,640) in 2015. The number of decompensated cirrhosis and/or HCC cases is also predicted to rise, to 2540 (95% CrI: 2035-3310) by 2015. HCV incidence increased during the 1980s, with an annual incidence of 12 650 (95% CrI: 6150-26,450) by 1989. HCV-related cirrhosis and deaths from HCC in England are likely to increase dramatically within the next decade. If patients are left undiagnosed and untreated, the future burden of the disease on healthcare resources will be substantial.
Subject(s)
Hepacivirus/growth & development , Hepatitis C, Chronic/epidemiology , Carcinoma, Hepatocellular/epidemiology , Carcinoma, Hepatocellular/virology , Disease Progression , England/epidemiology , Hepatitis C, Chronic/complications , Humans , Incidence , Liver Cirrhosis/epidemiology , Liver Cirrhosis/virology , Liver Neoplasms/epidemiology , Liver Neoplasms/virology , Models, StatisticalABSTRACT
Whether differences in the natural history of hepatitis C virus (HCV) can be explained by differences in the infecting HCV type is unknown. The aim of this study was to investigate whether the HCV type might influence the clinical outcome of infection. Study serum samples were assembled from 749 individuals enrolled into the UK HCV National Register from which data on clinical outcomes were extracted. HCV-RNA-positive specimens were genotyped and HCV-RNA-negative specimens serotyped. Logistic regression analysis was used to investigate the independent effect of HCV type on viral clearance by comparing patients who were HCV RNA negative (n = 86) with those who were HCV RNA positive (n = 508). The same method was used to investigate whether HCV type was associated with histological stage of liver disease. The prevalence of HCV type 1 among those who cleared infection was 69% and among those who remained HCV RNA positive was 51%: Type 1 infections were more likely to be HCV RNA negative than non-1 types (OR 0.47, 95% CI 0.29-0.78, P = 0.003). Type 1 infections were also more likely to be associated with histological stage scores above the median when compared with non-1 types (OR 2.03, 95% CI 1.07-3.83, P = 0.03). In conclusion, HCV type 1 infection was more often HCV RNA negative, suggesting that spontaneous clearance may occur more commonly with this type. Among the RNA-positive infections, type 1 infection may be more aggressive than types 2/3.
Subject(s)
Hepacivirus/classification , Hepacivirus/genetics , Hepatitis C/pathology , Hepatitis C/virology , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Disease Progression , Female , Genotype , Humans , Infant , Infant, Newborn , Liver/pathology , Logistic Models , Male , Middle Aged , Prognosis , RNA, Viral/blood , Serotyping , United KingdomABSTRACT
The aim of this study was to describe the natural history of HCV after 16 years of infection, in a cohort of individuals who acquired their infections on a known date in the United Kingdom. A total of 924 HCV-infected transfusion recipients (cases) and 475 anti-HCV negative transfusion recipients (controls) were eligible for inclusion in the study. Survival was compared between cases and controls to see if there was any excess mortality attributable to HCV. The results show that all-cause mortality was not significantly different between cases and controls (hazard ratio 1.17, 95% CI 0.92-1.49, P=0.21). However, the risk of death directly from liver disease was higher in cases than controls (hazard ratio 2.71, 95% CI 1.09-6.75, P=0.03). Nearly 30% of those HCV-infected cases who died directly from liver disease were known to have consumed excess alcohol.
Subject(s)
Hepatitis C, Chronic/mortality , Adolescent , Adult , Aged , Aged, 80 and over , Alcohol Drinking/adverse effects , Child , Child, Preschool , Cohort Studies , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Proportional Hazards Models , Time FactorsABSTRACT
The Hepatitis C Strategy and Action Plan for England recommend that all individuals testing positive for hepatitis C virus (HCV) should be referred to a specialist centre for assessment and care. One key aim is to reduce the number of people progressing to liver disease and therefore reduce the associated costs. The aims of this paper are to describe the care pathways and evaluate resource utilization in a cohort of 826 patients with transfusion-acquired hepatitis C enrolled in the HCV national register. We reviewed data extracted from patient notes to establish pathways of care since HCV-positive diagnosis through to May 2002, and to document all treatment, liver biopsy and hospital usage for each patient. Type of care was classified into specialist-interest in HCV-related care, other-hospital care or general practitioner (GP)-led care. Over 70% of patients were referred to specialist care following HCV diagnosis. Patients who were older or who had normal liver function were less likely to be referred to specialist-care. Between first diagnosis and May 2002, no patients were referred from GP to specialist-care. Less than half of this cohort had undergone liver biopsy and only 18% had been treated. Younger patients and those with abnormal liver function were more likely to have undergone liver biopsy and to have received treatment. Analysis of care histories of patients with transfusion-acquired hepatitis C suggest that changes are needed in the care and management of patients with HCV infection, if the recommendations of the HCV strategy and action plan are to be fully implemented.
Subject(s)
Delivery of Health Care/statistics & numerical data , Health Resources/statistics & numerical data , Hepatitis C , Transfusion Reaction , Adult , Aged , Female , Hepacivirus , Hepatitis C/diagnosis , Hepatitis C/drug therapy , Hepatitis C/mortality , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , Physicians, Family , Practice Patterns, Physicians' , Registries/statistics & numerical data , Specialization , United KingdomABSTRACT
Extracts of the leaves and roots from the tree Artocarpus tonkinensis A Cheval (family Moraceae) are used in traditional Vietnamese medicine in order to treat backache as well as rheumatic joint diseases. We prepared an ethyl acetate (EtOAc) extract from this plant and tested its anti-inflammatory properties in an experimental arthritis model, collagen-induced arthritis (CIA). CIA was induced in Dark Agouti rats by means of immunization with collagen type II (CII) emulsified in incomplete Freund's adjuvant. Starting at the day of immunization, the rats were treated daily with intraperitoneal injections of Artocarpus extract. Arthritis progression was measured by means of clinical scoring of paws and anti-CII antibody titres were measured by means of ELISA. In vitro, lymph node (LN) cell cultures were treated with Artocarpus extract and the apoptosis-inducing effect was determined with FACS staining by using annexin V and propidium iodide as well as the TUNEL method. Treatment of the rats with Artocarpus extract decreased arthritis incidence and severity and delayed disease onset. When treatment was started after the onset of arthritis, a tendency towards arthritis amelioration was observed. In vitro, Artocarpus extract acted as a T-cell modulator, inhibiting mitogen-induced T-cell proliferation and inducing apoptosis of activated LN-derived lymphocytes. Thus, we have demonstrated that an EtOAc extract of Artocarpus, a plant traditionally used in Vietnamese folk medicine for treating arthritic conditions, has beneficial effects in an experimental arthritis model. This effect is likely to be T cell-dependent and mediated through apoptosis induction in activated cells.
Subject(s)
Arthritis, Experimental/prevention & control , Artocarpus , Phytotherapy , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Apoptosis/drug effects , Arthritis, Experimental/immunology , Autoimmunity/drug effects , Female , In Vitro Techniques , Lymphocytes/cytology , Lymphocytes/drug effects , Male , Medicine, East Asian Traditional , Plant Extracts/pharmacology , Rats , Rats, Inbred Strains , VietnamABSTRACT
OBJECTIVE: To investigate if administration of CNI-1493, an inhibitor of the synthesis of proinflammatory cytokines and NO, protects against development of joint destruction in collagen induced arthritis (CIA) in rats. METHODS: In a placebo controlled experiment, CNI-1493 was given once daily intraperitoneally after onset of clinical arthritis in DA rats. Disease progression was studied by clinical scoring of arthritis, serial measurement of serum levels of COMP, and histological examination of joints. RESULTS: Clinical signs of arthritis were significantly reduced in the CNI-1493 treated group of rats in comparison with the placebo treated group. Histological examinations of paws demonstrated a significant reduction of cartilage destruction in the CNI-1493 treated group, but marked destruction of cartilage in the placebo group. Serum levels of COMP increased in the placebo group, whereas in the CNI-1493 treated group levels were low and decreased significantly during the observation time. CONCLUSIONS: Treatment with CNI-1493 provides efficient protection against synovial inflammation and cartilage destruction when used therapeutically in CIA. The protective effect against cartilage destruction can be monitored by measuring serum COMP. These observations make CNI-1493 an attractive candidate for therapeutic studies in human arthritis, and COMP an attractive serum marker for monitoring joint protective effects.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arthritis, Experimental/prevention & control , Cartilage, Articular/pathology , Cytokines/antagonists & inhibitors , Hydrazones/therapeutic use , Animals , Arthritis, Experimental/blood , Arthritis, Experimental/pathology , Biomarkers/blood , Cartilage Oligomeric Matrix Protein , Disease Progression , Extracellular Matrix Proteins/blood , Female , Glycoproteins/blood , Immunosuppressive Agents/therapeutic use , Matrilin Proteins , Rats , Statistics, NonparametricABSTRACT
Abstract High-mobility group box chromosomal protein 1 (HMGB1) is a protein with both intranuclear functions and extracellular cytokine-like effects. In this report, we study possible candidate receptors for HMGB1 on macrophages (Mphi) and define pathways activated by HMGB1 binding. Bone marrow Mphi were prepared from Dark Agouti (DA) rats and stimulated in vitro with HMGB1. The kinetics of tumour necrosis factor (TNF) production, NO production, activation of p38 mitogen-activated protein kinase (MAPK), p44/42 MAPK- and SAPK/JNK-signalling pathways, nuclear translocation of nuclear factor kappa B (NF-kappaB) and HMGB1-induced upregulation of major histocompatibility complex (MHC) class II and CD86 were analysed. Mphi from interleukin (IL)-1 receptor type I-/-, Toll-like receptor 2 (TLR2-/-) and RAGE-/- mice were used to investigate the role of these receptors in HMGB1 signalling. HMGB1 induced TNF and NO production by Mphi, phosphorylation of all investigated MAP kinase pathways and NF-kappaB translocation, and expression of MHC class II was increased. Mphi from RAGE-/- mice produced significantly lower amounts of TNF, IL-1beta and IL-6, while IL-1RI-/- and TLR2-/- Mphi produced cytokine levels comparable with wildtype controls in response to HMGB1 stimulation. We conclude that HMGB1 has the potential to induce a proinflammatory phenotype in Mphi, with RAGE as the major activation-inducing receptor.
Subject(s)
High Mobility Group Proteins/pharmacology , Inflammation Mediators/metabolism , Macrophages/drug effects , Macrophages/metabolism , Repressor Proteins/pharmacology , Animals , Cytokines/biosynthesis , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , HMGB1 Protein/metabolism , High Mobility Group Proteins/metabolism , Histocompatibility Antigens Class II/metabolism , In Vitro Techniques , Inflammation Mediators/pharmacology , Macrophage Activation/drug effects , Macrophages/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , NF-kappa B/metabolism , Nitric Oxide/biosynthesis , Phosphorylation , Rats , Receptor for Advanced Glycation End Products , Receptors, Cell Surface/deficiency , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Receptors, Immunologic , Receptors, Interleukin-1/deficiency , Receptors, Interleukin-1/genetics , Receptors, Interleukin-1/metabolism , Receptors, Interleukin-1 Type I , Recombinant Proteins/metabolism , Recombinant Proteins/pharmacology , Repressor Proteins/metabolism , Toll-Like Receptor 2 , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
Autoimmune diseases are characterized by chronic inflammation in target organs and immunoreactivity towards one or multiple autoantigens. Several potential mechanisms of tolerance breaking have been postulated, one being inflammation-associated events. We have investigated whether chlorination of an autoantigen can lead to disruption of self-tolerance. Chlorination of antigens might occur during inflammation via the granulocyte-specific, myeloperoxidase-catalysed conversion of hydrogen peroxide to hypochlorous acid (HOCl). HOCl, being a strong oxidant, reacts with proteins both within cellular phagosomes and in the immediate extracellular environment. By immunizing Lew.1AV1 rats with chlorinated or unmodified rat serum albumin (RSA), we could detect tolerance-breaking effects of chlorination. RSA is a systemic autoantigen in rat not inducing antibody production upon immunization in its unmodified form. Rats immunized with chlorinated RSA (RSA-Cl) developed high titres of immunoglobulin G (IgG) specific for RSA-Cl which cross-reacted with native RSA. T cells reactive with both RSA-Cl and RSA were detected by [(3)H]-thymidine incorporation. We hence speculated that immunological tolerance established for unmodified proteins, during certain circumstances such as inflammation, might be broken by induced protein chlorination. T cells specific for the chlorinated protein can confer help to B cells recognizing both the chlorinated and the native form of the protein, leading to the formation of high-affinity autoreactive antibodies and possibly autoimmune disease.
Subject(s)
Autoantigens/immunology , Chlorine/immunology , Immune Tolerance , Inflammation/metabolism , Oxidants/metabolism , Adjuvants, Immunologic , Animals , Autoantigens/chemistry , Electrophoresis, Polyacrylamide Gel , Hydrogen Peroxide/metabolism , Hypochlorous Acid/metabolism , Inflammation/immunology , Peroxidase/metabolism , Rats , Serum Albumin/chemistry , Serum Albumin/immunologyABSTRACT
HS 378 is a recently developed indolomorphinan with high selectivity and antagonist potency at the delta-opioid receptor. The present study was performed to characterize the opioid binding properties and pharmacological and immunological activity of HS 378 and to compare them with those of two well-known delta-opioid receptor antagonists, naltrindole (NTI) and naltriben (NTB). In vitro opioid receptor binding profiles were determined in rat brain homogenates. HS 378 showed 4.7- and 2.4-fold higher mu/delta selectivity compared to NTI and NTB, respectively. In the [35S]GTPgammaS functional assay carried out in cell lines expressing cloned human opioid receptors, HS 378 was found to be a pure delta-opioid receptor antagonist. In vitro, exposure of HS 378 resulted in an apparent dose-related suppression of concanavalin A induced rat T-lymphocyte proliferation with an IC50 value of 0.54 microM. NTI showed also immunosuppression with an IC50 value of 6.93 microM, whereas NTB had no effect. The IC50 of HS 378 was 13 times lower than that of NTI and 8 times higher than that of cyclosporin A. Taken together, our findings indicate that the small molecule HS 378 has properties that may be of therapeutic value in the setting of human inflammatory diseases.
Subject(s)
Lymphocyte Activation/drug effects , Naltrexone/analogs & derivatives , Naltrexone/metabolism , Naltrexone/pharmacology , Narcotic Antagonists/metabolism , Narcotic Antagonists/pharmacology , Receptors, Opioid, delta/antagonists & inhibitors , Animals , Brain/metabolism , Cells, Cultured , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Immunosuppressive Agents/metabolism , Immunosuppressive Agents/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Opioid, delta/metabolism , T-Lymphocytes/drug effects , T-Lymphocytes/immunologyABSTRACT
The aim of this paper is to describe the development of a national hepatitis C register and the completeness of the data it contains. This is a descriptive report of the structure and function of the register, including case definitions, registration and follow-up procedures, and methods used to maximize data quality and to obtain comparative data sources. The register contains data on HCV-infected individuals who acquired their infections on a known date and by a known route; to date all are transfusion recipients identified during the UK lookback exercise, who tested positive or indeterminate for anti-HCV after receiving 'infected' blood issued before the introduction of routine testing of the blood supply for anti-HCV. By 31 December 1999, 871 (87%) of 996 eligible transfusion recipients had been registered, and 984 (99%) flagged in the NHS Central Registers. Registered patients had been infected for an average of 11.1 years (SEM 0.1); around half were being cared for by clinicians with a specialist interest in liver disease. Except for the information on tobacco use, current alcohol use, and hepatitis B status, data were more than 80% complete, and for most variables, more than 90% complete. The consistency of data abstraction was found to be 98% (SEM 0.5). In conclusion, the Register contains high quality anonymised data on one of the largest cohorts of individuals with HCV infections acquired on a known date and by a known route. It could serve as a model for other chronic disease registers; developers may find the structure, design, and methodological issues addressed useful.
Subject(s)
Hepacivirus , Hepatitis C , Registries/statistics & numerical data , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Data Collection , Female , Hepatitis C/epidemiology , Humans , Infant , Male , Transfusion Reaction , United Kingdom/epidemiologyABSTRACT
STUDY OBJECTIVE: To assess the relative importance of heritable characteristics and lifestyle in the development of "maternal obesity" after pregnancy. SETTING: South east London, in the homes of mothers who had delivered their babies at either Guy's, Lewisham or St Thomas's hospitals. PARTICIPANTS: Seventy four mothers of low antenatal risk who had been enrolled in the Antenatal Care (ANC) Project (a previous trial of antenatal care) during the first trimester of pregnancy, and who had subsequently been followed up 2.5 years after delivery. DESIGN: Information on parental obesity, psychosocial and sociodemographic factors as well as lifestyle, was gathered during a semi-structured interview at each mother's home. Additional anthropometric and psychosocial data were taken from the existing ANC Project database. These data were used to assess the relative importance of heritable characteristics and lifestyle on changes in maternal body weight from the beginning of pregnancy to the follow up interview. MAIN RESULTS: After adjusting for the effects of potential confounders and known risk factors for maternal obesity, women who selected larger silhouettes to represent their biological mothers were significantly more likely to have higher long term weight gains than those who selected thinner maternal silhouettes (r = 0.083, p = 0.004). Women who were less satisfied with their bodies postpartum had significantly greater long term weight gains than those women who displayed no increase in dissatisfaction with their bodies after pregnancy (r = 0.067, p = 0.010). CONCLUSIONS: A heritable predisposition to gain weight together with changing attitudes to body size, both had an independent role in the development of maternal body weight after pregnancy. Differences in each woman's heritable predisposition to gain weight and any changes in body image that occur after pregnancy might explain why some women gain weight in association with pregnancy.