Biomedical subjects

W D Reed

Publications and source records attributed to W D Reed.

At least 19 recordsLinked to original sources

PubMed1992

Mouse cytomegalovirus infection induces antibodies which cross-react with virus and cardiac myosin: a model for the study of molecular mimicry in the pathogenesis of viral myocarditis.

Mouse cytomegalovirus (MCMV) infection induces persisting myocarditis in the susceptible BALB/c strain. Autoantibodies to cardiac myosin are produced in both susceptible BALB/c and resistant C57BL/6 mice following MCMV infection. These affinity-purified anti-cardiac myosin antibodies cross-react with MCMV protein(s). The polypeptides of CMV which share immunological cross-reactivity with the 200,000 MW polypeptide, the heavy chain of myosin, were viral polypeptides of 83,000, 94,000 and 116,000 MW recognized by BALB/c post-infection sera and polypeptides of 66,000 and 94,000 MW recognized by C57BL/6 post-infection sera. Passive transfer of anti-cardiac myosin antibodies from Day 56 post-infection sera of the BALB/c strain induced inflammation and necrosis of the myocardium of uninfected BALB/c recipients. This late immune sera contains autoantibodies specific for the cardiac isoform of myosin. Furthermore, immunization with cardiac myosin induced myocarditis and high titres of cardiac myosin antibodies in uninfected mice of the susceptible BALB/c strain only. However, antibodies to myosin elicited in cardiac myosin-immunized BALB/c mice did not cross-react with MCMV by ELISA. We suggest that virus infection may modulate the immune recognition of the common-epitope(s) shared between MCMV protein(s) and the heavy chain of myosin. Of particular interest is the possibility that molecular mimicry of CMV with cardiac myosin may contribute to the pathogenesis of autoimmune myocarditis following virus infection.

Animals↗

PubMed1992

Carbamazepine hepatotoxicity: another cause of the vanishing bile duct syndrome.

Serious carbamazepine hepatotoxicity is being recognized more frequently and is usually manifest as an acute granulomatous hepatitis that is self-limiting if the drug is withdrawn. The case of a 59-year-old man who developed the vanishing bile duct syndrome after 2 months of treatment with carbamazepine for glossopharyngeal neuralgia is reported. The characteristic histological features of this syndrome may also be seen in primary biliary cirrhosis, primary sclerosing cholangitis, graft-vs.-host disease after allogeneic bone marrow transplantation, chronic liver allograft rejection, and other drug reactions. The progress of this patient to date suggests that irreversible liver injury resulting in chronic liver disease is likely, in keeping with the clinical course of the vanishing bile duct syndrome in most cases.

Bile Ducts↗

PubMed1991

Nodular regenerative hyperplasia of the liver: the importance of combined macroscopic and microscopic findings.

A 40-year-old man with rheumatoid arthritis, splenomegaly and mild thrombocytopenia presented with gross ascites and a history of excess alcohol consumption. Oesophageal varices were documented endoscopically. Alcoholic cirrhosis was suspected and laparoscopy revealed a macronodular liver surface. Liver biopsy disclosed subtle microscopic structural variations which together with the laparoscopic findings were consistent with the diagnosis of nodular regenerative hyperplasia. The importance in diagnosis of macroscopic appearance combined with histological findings is emphasised. Clinically significant portal hypertension may be present at a histologically early stage of this condition.

Adult↗

PubMed1991

Diclofenac hepatitis.

We report five cases of biopsy-proven hepatitis developing between six and 20 weeks after administration of diclofenac. In one patient jaundice had previously developed following use of ibuprofen. In another the clinical, biochemical and histopathological features were those of chronic active hepatitis and treatment with corticosteroids was required. All patients recovered from their liver injury without sequelae. Resolution of symptoms occurred between three and 12 weeks following cessation of the drug, while liver function tests returned to normal between seven and 16 weeks after drug withdrawal, except in the patient with chronic active hepatitis who remained biochemically abnormal for eight months. Three of the five patients developed transient circulating autoantibodies, suggesting immune mechanisms may be important in the pathogenesis of this injury. The incidence of severe hepatic dysfunction related to the use of diclofenac appears low and is probably in the order of one case per 50-100,000 prescriptions.

Aged↗

PubMed1991

Diarrhoea--an unrecognised hazard of coeliac plexus block.

Coeliac plexus block is a safe procedure with relatively few side-effects. We report two cases of persistent severe diarrhoea following coeliac plexus block and explore the possible reasons for this previously unrecognised side-effect. We postulate that somatostatin analogue may be useful as treatment for diarrhoea following neurolytic coeliac plexus block that is unresponsive to conventional anti-diarrhoeal agents.

Adult↗

PubMed1991

Confirmation of the efficacy of hepatic tissue iron index in differentiating genetic haemochromatosis from alcoholic liver disease complicated by alcoholic haemosiderosis.

The hepatic tissue iron index proposed by Bassett et al was evaluated in 35 patients with homozygous genetic haemochromatosis, 67 patients with alcoholic liver disease, and 18 patients with other forms of chronic liver disease with and without cirrhosis. In patients with cirrhosis hepatic tissue iron concentration reliably differentiated alcoholic liver disease from genetic haemochromatosis. Although mean iron concentration was greater in patients with prefibrotic haemochromatosis than in those with prefibrotic alcoholic liver disease, some overlap occurred and complete differentiation of the two conditions was not possible. This overlap was particularly evident in some young patients with haemochromatosis in whom the tissue iron concentration grade fell in the range commonly seen in alcoholic haemosiderosis. Inability to differentiate early genetic haemochromatosis from alcoholic liver disease complicated by haemosiderosis was also a problem with standard Perls's staining. When the hepatic tissue iron index was calculated (hepatic tissue iron concentration/patient's age in years), clear differentiation of genetic haemochromatosis from both alcoholic liver disease and other forms of chronic liver disease was obtained in both cirrhotic and precirrhotic patients. This study confirms that the hepatic tissue iron index is a useful means of differentiating patients with genetic haemochromatosis from those with alcoholic liver disease. We suggest that biochemical estimation of tissue iron concentration and calculation of the tissue iron index in all patients in whom genetic haemochromatosis is a possible diagnosis will reduce the likelihood of misdiagnosing this as alcoholic liver disease.

Aging↗

PubMed1991

Histological and immunohistochemical study of the gall bladder lesion in primary sclerosing cholangitis.

The histological features and type of mononuclear cell infiltrate in gall bladders from six patients with primary sclerosing cholangitis were studied using routine staining techniques and immunohistochemistry. Control studies were performed using the gall bladders from six patients (age and sex matched) with chronic cholecystitis and four with primary biliary cirrhosis. A range of histological abnormalities was present in gall bladders from patients with primary sclerosing cholangitis including a mild to moderate degree of epithelial hyperplasia, pseudogland formation, and mononuclear cell infiltrate of the epithelium; moderate to severe chronic inflammatory cell infiltrate and fibrosis affecting the superficial and deep layers of the gall bladder wall; and minimal smooth muscle hypertrophy. These abnormalities were non-specific and were also present in gall bladders from patients with chronic cholecystitis and primary biliary cirrhosis. Vasculitis and granulomas were not present in the patients with primary sclerosing cholangitis. Immunohistochemistry showed that the superficial and deep mononuclear cell infiltrate in primary sclerosing cholangitis gall bladders was composed predominantly of lymphocytes, in contrast to chronic cholecystitis where macrophages were found in similar or greater numbers. Moreover, T lymphocytes (activated and resting) were present throughout the lymphocytic infiltrate and were apposed to the base and interdigitated between the biliary epithelial cells in significantly greater numbers than in chronic cholecystitis gall bladders. B lymphocytes were present only in lymphoid follicles. Comparative studies using liver biopsy specimens from three of the primary sclerosing cholangitis patients showed a similar T lymphocyte portal tract infiltrate. We conclude that a number of non-specific chronic inflammatory histological abnormalities were present in primary sclerosing cholangitis gall bladders. Immunohistochemistry found other features that were present in this disease - a predominantly lymphocytic mononuclear cell infiltrate of the superficial and deep layers of the gall bladder wall and the presence of T lymphocytes that infiltrated the biliary epithelial cells. These findings support the hypothesis that aberrant cell mediated immune mechanisms may play a role in the pathogenesis of both the intrahepatic and extrahepatic lesions in primary sclerosing cholangitis.

Adult↗

PubMed1991

Murine anti-cytomegalovirus monoclonal antibodies with autoreactivity.

Certain murine monoclonal antibodies (mAb) raised against structural proteins of mouse cytomegalovirus (MCMV) display distinct patterns of multiple organ-autoreactivity in addition to their viral specificities. We analysed the autoreactivity of five such mAb by immunoperoxidase histochemistry, western immunoblot and enzyme-linked immunosorbent assay (ELISA). Four mAb recognized cellular autoantigens in the salivary gland, lung, heart, liver, kidney, ileum, striated muscle and brain, as detected by immunoperoxidase histochemistry. However, the mAb showed different specificities for nuclear, cytoplasmic and surface membrane antigens on various cell types in addition to common autoreactivities. Immunoblot analyses showed that some of the mAb recognized polypeptides of various molecular weights obtained from 100,000 g supernatants of normal BALB/c liver, brain, striated and cardiac muscle homogenates. Reactivity of the mAb with a 200,000 molecular weight (MW) polypeptide was similar to our previous finding of the reaction of late immune polyclonal sera with a 200,000 MW polypeptide, the heavy chain of myosin. The mAb reacted to the cardiac isoform of myosin as determined by ELISA and immunoblot. Reactivity of mAb with cardiac myosin, as detected by immunoblot, was removed by absorption with cardiac myosin and recovered in the eluate. However, cardiac myosin used in a competitive inhibition ELISA did not abrogate the reactivity of the mAb with MCMV antigens. These anti-MCMV mAb appear to be multispecific for both virus and self-antigens, including cardiac myosin, and possibly recognize these different antigens through partly similar or distinct antigen-binding sites.

Animals↗

PubMed1990

Does hepatitis C virus play a role in "non-viral" chronic liver disease?

It has recently been suggested that the hepatitis C virus may play a significant role in chronic liver diseases, such as autoimmune chronic active hepatitis, which are usually attributed to non-viral causes. We tested for antibodies to hepatitis C virus (anti-HCV) in sera from 140 patients with well characterised "non-viral" chronic liver diseases as well as sera from 51 patients thought to have chronic non-A, non-B (NANB) hepatitis (acting as positive controls) and 25 patients with non-hepatic autoimmune disorders. As expected, 45 of 51 patients (88%) diagnosed as having chronic NANB hepatitis were anti-HCV seropositive. Among 26 patients with cryptogenic cirrhosis, 8 were anti-HCV seropositive; in 5 patients (22%) there was no apparent risk factor for parenteral transmission. In the remaining 114 patients with chronic liver disease, 10 patients (9%) were seropositive for anti-HCV. However, 5 of these patients had a significant risk factor for parenteral transmission of hepatitis C virus, leaving only 5 of 106 (4.7%) with unexplained positive anti-HCV test results. Among patients with high titres of circulating autoantibodies but no liver disease, no positive results occurred. It is concluded that hepatitis C virus infection may account for some cases of cryptogenic cirrhosis. Although anti-HCV occurs more commonly in patients with other "non-viral" chronic liver diseases than has been reported in the community (0.5%-1.2%), the low prevalence of the antibodies indicates that hepatitis C virus infection is unlikely to be important in the aetiology or pathogenesis of autoimmune chronic active hepatitis and other poorly understood chronic liver diseases.

Autoimmune Diseases↗

PubMed1990

Autoantibodies to isolated human hepatocyte plasma membranes in chronic active hepatitis. II. Specificity of antibodies.

The fine specificity of autoantibodies to human hepatocyte plasma membranes in autoimmune chronic active hepatitis was determined by one-dimensional immunoblotting. Sera from 12 patients with "classical" autoimmune chronic active hepatitis contained autoantibodies recognizing many human hepatocyte plasma membrane polypeptides in the 15 to 220 kD range. Many of these autoantibodies titrated beyond 1:80,000 and some may be potentially "pathological." In particular, one band with an apparent molecular weight of 60 kD was a dominant and consistent finding in all patients with autoimmune chronic active hepatitis by immunoblotting. Serum absorption studies showed this band to be predominantly liver-specific. Control sera from patients with chronic persistent hepatitis, nonhepatic autoimmune disease and normal healthy subjects possessed low titer reactivity that most likely represented "natural" autoantibodies. Anti-human hepatocyte plasma membranes in autoimmune chronic active hepatitis consisted of all three immunoglobulin isotypes (G,M and A) and their presence was not caused by nonspecific reactions as a consequence of hypergammaglobulinemia. Autoantibodies were shown to be specific by virtue of their absorption and exhaustion on titration. Many were directed at species nonspecific determinants, however, some autoantibodies recognized human-specific polypeptides. The majority of anti-human hepatocyte plasma membranes appeared to be organ-specific as sera from patients with autoimmune chronic active hepatitis reacted only weakly with polypeptides of kidney plasma membranes. Of the activity detected, few bands corresponded with those obtained using polypeptides of human hepatocyte plasma membranes. Our results show that patients with autoimmune chronic active hepatitis possess an array of liver-specific autoantibodies to polypeptide subunits of human hepatocyte plasma membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1990

Familial hypocalciuric hypercalcaemia and pancreatitis: no causal link proven.

A case of a patient with pancreatitis and familial hypocalciuric hypercalcaemia is presented and the literature linking FHH and pancreatitis is reviewed. The case for a causal link between the two conditions is not proven and seems unlikely. In view of this we strongly challenge the recommendation of total parathyroidectomy in such cases.

Adult↗

PubMed1990

Validation of prognostic models in primary biliary cirrhosis.

Prognostic models in primary biliary cirrhosis have been validated for large population groups but the predictive value for individual patients has not been tested. We used data from ten deceased patients with primary biliary cirrhosis to test three prognostic models: the Shapiro model (bilirubin); the Christensen model (age, bilirubin, albumin, presence of cirrhosis or cholestasis, azathioprine treatment); and the Dickson model (age, bilirubin, albumin, prothrombin time, oedema). The predictive value of each model for individual patients was determined by assessing whether it would have accurately predicted appropriate timing of liver transplantation in patients prior to death. The Dickson model predicted that four of nine cases would have been considered for liver transplantation one year before death and one of seven cases two years before death. The Christensen model predicted that this procedure would have been considered in three of seven cases two years before death. The Shapiro model was demonstrated to be the least predictive of the three tested. Although none of the three models assessed was found to accurately predict survival, no model predicted a worse survival than actually occurred. Liver transplantation is indicated in those cases with a poor predicted survival.

Aged↗

PubMed1990

Bile duct antibodies crossreacting with blood group antigens in primary sclerosing cholangitis.

Indirect immunoperoxidase histochemistry was used to localise and determine the disease, species, and tissue specificity of bile duct antibodies in primary sclerosing cholangitis. Serum was collected from: 29 patients with primary sclerosing cholangitis, 18 patients with ulcerative colitis alone, 19 patients with extrahepatic biliary obstruction of other causes, and 42 healthy control subjects. Bile duct antibodies reacted with an antigen localised to the small and large intrahepatic bile ducts. When blood group A human liver was used they were detected in 34% of patients with primary sclerosing cholangitis. They were not detected when blood group O human liver was used. Bile duct antibodies that reacted with obstructed and normal rabbit liver were detected in 34% and 17% respectively of patients with primary sclerosing cholangitis but were also present in similar proportions of control subjects. Colon antibodies that reacted with human and rabbit colon were found in 52% and 24% respectively of patients with primary sclerosing cholangitis. Absorption studies using blood group substances A and B abolished the reactivity of bile duct antibodies with human and rabbit liver and that of colon antibodies' with rabbit colon. Colon antibodies that reacted with human colon were not absorbed. Absorption studies using isolated peripheral white blood cells did not affect reactivity of bile duct or colon antibodies. We conclude that bile duct antibodies are disease, species, and tissue non-specific and react with blood group A/B antigens present in human and rabbit bile ducts and rabbit colon. This suggests that they do not play a role in the pathogenesis of primary sclerosing cholangitis.

Antibody Specificity↗

PubMed1990

Genetic control of mouse cytomegalovirus-induced myocarditis.

Mouse cytomegalovirus (MCMV) infection of mice induced myocarditis, characterized by a mononuclear cell infiltrate with associated necrosis of myofibres. Myocarditis was observed in parallel with viral inclusion-bearing cells in the heart during the acute phase of the infection. Myocarditis also persisted after the acute phase when viral antigens were no longer detectable by immunoperoxidase histochemistry and infectious virus could not be cultivated from various organs. The influence of host genetic factors on the development of cytomegalovirus-induced myocarditis was investigated using H-2 congenic and recombinant inbred mouse strains. Analysis of congenic variants with C57BL/10 and BALB/c backgrounds and the A/J strain revealed that genes linked to the H-2 complex influenced susceptibility to peak levels of MCMV-induced myocarditis seen 7 and 10 days post-infection. In addition, non-H-2 genes of the BALB/c background were important in determining the severity of myocarditis. Analysis of the strain distribution pattern of the CXB recombinant inbred series did not disclose the identity of the BALB/c non-H-2-linked allele conferring susceptibility to MCMV-induced myocarditis. The level of myocarditis seen in the F1 hybrid between the high-responder BALB/c and low-responder C57BL/6 strains suggested dominant inheritance. The amount of viral replication in the major target organs did not correlate with the severity of myocarditis. In conclusion, at least two genes, one mapping to the H-2 complex and another non-H-2-linked gene, influenced the development of myocarditis in MCMV-infected mice.

Animals↗

PubMed1990

Autoantibodies to cardiac myosin in mouse cytomegalovirus myocarditis.

Myocarditis accompanies sublethal mouse cytomegalovirus (MCMV) infection in susceptible BALB/c mice and persists beyond the acute phase of infection, in the absence of demonstrable virus antigen but in the continuing presence of autoantibodies to cardiac muscle. Heart tissue autoantibodies of the IgG class were first detected by ELISA in sera at Days 3-5 post-infection (PI) and persisted to Day 100, in two strains of MCMV-infected mice which are susceptible (BALB/c) and resistant (C57BL/10) to MCMV-induced myocarditis. Analysis by immunoblot showed that autoantibodies in early immune sera (Day 10) from both mouse strains reacted with the contractile proteins troponin, tropomyosin and myosin, as well as with other unidentified polypeptides within normal mouse organ homogenates. However, the dominant reactivity of late immune sera (Day 100) was to a 200,000 molecular weight (MW) polypeptide in muscle homogenates identified as the heavy chain of myosin. Autoantibodies reacting with the cardiac or striated muscle isoforms of myosin were assessed by ELISA in BALB/c and C57BL/10 mice. At Days 28, 56 and 100 PI only the susceptible BALB/c strain had high titres of autoantibodies reacting with the cardiac isoform of myosin. Increasing the virus dose given to C57BL/10 mice resulted in slight increases in titres of anti-myosin antibody; however, the peak antibody titres did not approach those of BALB/c mice and persisting myocarditis did not develop. Absorption experiments showed that cardiac myosin-specific antibodies were present in immune sera from susceptible BALB/c mice at Day 100 but not in resistant C57BL/10 mice by ELISA and immunoblot. These results demonstrate that autoimmunity to myosin is a prominent feature of the humoral autoimmune response following MCMV infection, and that there are differences both in fine isoform specificity and titre of anti-myosin antibodies between strains of mice that develop persisting myocarditis and strains that do not. Cardiac myosin-specific autoantibodies may play an immunopathogenic role in CMV-induced myocarditis.

Animals↗

PubMed1989

Autoantibodies to isolated human hepatocyte plasma membranes in liver disease. I. Specificity for chronic active hepatitis.

Circulating autoantibodies reacting with human hepatocyte plasma membranes (HHPM) were quantitated in acute and chronic liver disease using an enzyme-linked immunosorbent assay (ELISA). Anti-HHPM were found most frequently in patients with chronic active hepatitis (CAH), a disease postulated to result from autoimmune processes directed at organ-specific antigens on the surface of hepatocytes. The high incidence of anti-HHPM in CAH (75%) contrasted significantly with all other groups assayed, including primary biliary cirrhosis (44%), alcoholic liver disease (21%), acute viral hepatitis (17%), and chronic persistent hepatitis (8%). The titers of anti-HHPM in CAH were significantly greater than in other liver disease and control groups. Anti-HHPM quantitated by ELISA correlated with hepatocellular membrane staining by indirect immunofluorescence. Autoantibodies to HHPM were found with an equivalent frequency in three etiological subgroups of CAH: autoimmune CAH, hepatitis B virus (HBV)-related CAH, and CAH associated with excess alcohol consumption. Anti-HHPM of the IgG and IgA isotypes were found in the highest frequency. There was a trend for patients with a histologically more severe disease to have higher titers of anti-HHPM. Immunoblots of SDS-PAGE-separated HHPM showed antibodies to react with a number of polypeptides, some of which appeared human specific. These data suggest that isolated HHPM are a source of relevant hepatocellular membrane antigens. Further studies of the different antigenic specificities of anti-HHPM are required to define which of these may be of pathogenetic importance in chronic active hepatitis.

Autoantibodies↗

PubMed1989

Evaluation of omeprazole in reflux oesophagitis.

In patients with reflux disease, pH monitoring has shown that omeprazole virtually eliminates oesophageal exposure to a pH of less than 4. Motility studies concurrent with pH monitoring have indicated that reflux continues on omeprazole, its effect on acid exposure being entirely dependent on elevation of gastric pH. Omeprazole and placebo have been compared in 64 patients with erosive or ulcerative oesophagitis; the 4-week healing rates were 81% with omeprazole, 20 mg or 40 mg daily, and 6% with placebo. The efficacies of omeprazole at doses of 20 mg and 40 mg daily, were then compared in 164 patients. At 4 weeks, oesophagitis was healed in 70% and 82% of patients for the 20 mg and 40 mg doses respectively (p = 0.05). Eight-week healing rates (79% for 20 mg and 85% for 40 mg) did not differ significantly. Symptom response was excellent for both doses. Relapse of oesophagitis was determined over 6 months for patients healed with omeprazole. Relapse was shown to occur in 88 of 107 patients by 6 months. Omeprazole is a highly effective treatment for erosive/ulcerative peptic oesophagitis, 40 mg daily being marginally superior to 20 mg. Relapse is almost inevitable within 6 months of cessation of therapy.

Dose-Response Relationship, Drug↗

PubMed1989

The role of T cells in mouse cytomegalovirus myocarditis.

BALB/c mice infected with murine cytomegalovirus (MCMV) developed myocarditis. Athymic nu/nu mice infected with the virus did not develop myocarditis, in contrast to heterozygous T-cell competent nu/+mice. MCMV-infected BALB/c mice given cyclosporin A(CsA) a drug which inhibits the activation of T cells, showed a delay in the development of myocarditis relative to CsA-untreated mice infected with MCMV. However, BALB/c mice infected with MCMV, regardless of CsA treatment, developed both anti-MCMV antibodies and autoantibodies. Nu/nu mice infected with MCMV did not produce the anti-MCMV antibody response or the multiple autoantibody response which was observed in nu/+ MCMV-infected mice. Both nu/nu and CsA-treated animals displayed greater organ distribution of viral antigen than control MCMV-infected animals. These results suggest that the presence of a thymus is required for both the development of myocarditis and the multiple autoantibody response, which includes autoantibodies to cardiac muscle, and that CsA immunosuppression does not abrogate either myocarditis or the antibody response in mice following MCMV infection.

Animals↗