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Biomedical subjects

M Peakman

Publications and source records attributed to M Peakman.

At least 19 recordsLinked to original sources
PubMed1992

Naturally occurring soluble CD4 in patients with human immunodeficiency virus infection.

To investigate its use as a marker of disease severity, serum soluble CD4 (sCD4) was measured by ELISA in patients with human immunodeficiency virus (HIV) infection. Levels of sCD4 were higher in patients than in controls (P less than .001) but did not increase with disease severity. sCD4 release per CD4 lymphocyte showed a linear increase with disease severity and performed as well as beta 2-microglobulin, a widely used marker. To study the role of sCD4 in the pathogenesis of HIV infection, an ELISA to detect sCD4 complexed with glycoprotein 120 (gp120) HIV envelope protein was developed. Preformed sCD4-gp120 complexes were not detectable in patient serum, but addition of recombinant gp120 showed that circulating sCD4 is capable of binding HIV envelope proteins. This study indicates that the sCD4-to-CD4 lymphocyte ratio increases linearly with disease severity and may be a useful marker of CD4 lymphocyte damage. In addition, serum sCD4 can bind viral particles, which may have implications for the use of recombinant sCD4 as a therapy in HIV infection.

AIDS-Related Complex↗
PubMed1992

Elevation of activated gamma delta T cell receptor bearing T lymphocytes in patients with autoimmune chronic liver disease.

To study the possible role of T cells bearing the gamma delta T cell receptor (TCR) heterodimer in the pathogenesis of autoimmune chronic active hepatitis (AI-CAH) and primary sclerosing cholangitis (PSC) in children, we measured levels of gamma delta+ T cells in the peripheral blood, assessed the proportion of cells bearing the disulphide-linked (BB3+) and non-disulphide-linked (A13+) subtypes of the receptor, and studied the co-expression of TCR-gamma delta and the activation markers HLA-DR and IL-2 receptor (IL-2R), and the memory cell marker CD45RO. Percentage levels and absolute numbers of gamma delta +T cells were higher in both groups of patients than in controls (P less than 0.01), mainly as a result of an increase in both percentage levels and absolute numbers of the A13+ subtype (P less than 0.001). Co-expression of IL-2R and TCR-gamma delta was not found in controls but was present in some patients with AI-CAH (four out of 17) and PSC (six out of 12) at low levels (median 2.3%, range 1.7-5.0%). Expression of HLA-DR on gamma delta+ T cells was similar in both groups of patients and controls. The majority of gamma delta+ T cells in children with AI-CAH and PSC also expressed CD45RO (74.7 +/- 18.4% and 79.8 +/- 24.3%, respectively) at levels significantly higher than in controls (53.3 +/- 17.2%, P less than 0.01). These results suggest that autoimmune liver diseases in children are associated with an expansion and activation of gamma delta+ T cells in the peripheral blood, which may be important in the pathogenesis of these disorders.

Adolescent↗
PubMed1992

Analysis of lymphocyte phenotypes in cord blood from early gestation fetuses.

Using cord blood samples obtained from fetuses between 16 and 40 weeks gestation, we have used a lysed whole blood flow cytometric technique to study the natural history of lymphocyte phenotypes known to be highly represented in cord blood at birth. The majority (51.0 +/- 14.7%) of lymphocytes expressed CD45RA, a marker of 'virgin' cells and there was a correlation between increasing percentages of CD45RA+lymphocytes and gestational age (r = 0.44, P < 0.01). Few cells (8.5 +/- 4.2%) expressed the CD45RO marker of primed lymphocytes and very few (1.0 +/- 0.7%) co-expressed CD45RA and RO, indicating little traffic between the two maturation markers. The percentage of B lymphocytes co-expressing CD5 was high in the fetal circulation (55.5 +/- 10.5%) compared with healthy adults (23.2 +/- 14.3%; P < 0.00001) and the level of CD5+ B cells declined with gestational age in an exponential manner (r = -0.45, P < 0.05). Similarly, levels of T lymphocytes expressing the gamma delta T cell receptor (TCR) declined exponentially (r = -0.59, P < 0.005). These results demonstrate that lymphocytes remain almost entirely unprimed before birth. In addition, CD5+ B lymphocytes and TCR-gamma delta+ T lymphocytes decline exponentially towards birth, in a manner suggesting that they may be seeding peripheral sites such as the spleen, skin and mucosae.

Antigens, CD↗
PubMed1992

Complement activation in neonatal infection.

To investigate the usefulness of indices of complement activation in the diagnosis of infections in the neonatal period, activation products C4d, Ba, and C3d were measured in 42 babies with a putative diagnosis of infection based on clinical/laboratory criteria, and compared with conventional clinical and haematological criteria of infection and with C reactive protein. The diagnosis of sepsis was confirmed by culture and identification of organisms in 17. Fourteen babies in whom infection was not suspected formed the control group. In babies with proved infection, concentrations of the fragments C4d, Ba, and C3d were higher than in babies with suspected infection in whom microbiological tests were negative, and concentrations of Ba and C3d were higher than in controls. C reactive protein and the platelet count were not significantly different in babies with proved infection and those with negative microbiological tests, but in the latter, C reactive protein concentrations were higher than in controls. Of the indices studied, high concentrations of Ba predicted microbiologically proved infection with the highest sensitivity (47.1%) and specificity (92.0%). Ba thus seems to be useful as an early indicator of infection in the neonatal period.

Analysis of Variance↗
PubMed1992

A new ELISA measuring antibodies to islet cell membranes: levels are increased in type 1 diabetes.

Using purified rat islet cell membranes as the solid phase antigen we have established an ELISA to detect anti-islet cell membrane antibodies. Levels were increased in Type 1 diabetics compared to controls (p < 0.02). There was no relationship between the level of antibodies to the membrane and the presence of islet cell cytoplasmic antibody (ICA), suggesting that they are not the same. The assay offers the opportunity to study antibodies to human beta cell membranes, the target of the immune attack in type 1 diabetes.

Antibodies↗
PubMed1991

Alpha 1-antitrypsin deficiency, complement activation, and chronic liver disease.

Activation of the complement system, the main humoral mediator of inflammation, is restrained by the action of enzyme inhibitors including alpha 1-antitrypsin. Deficiency leads to chronic liver disease in about one in five children with this genetic defect. Complement activation was investigated in 34 children with alpha 1 AT deficiency (12 with minimal, 10 with moderate, and 12 with severe liver disease) and in 38 sex and age matched normal children by measuring the complement parent molecules C3, C4, the C3d fragment and by calculating the C3d:C3 ratio. C3 and C4 were lower in children with severe liver disease compared with controls, indicating impairment of hepatic protein synthesis or complement consumption. The C3d activation fragment was higher in all the patient groups when compared with controls while the C3d:C3 ratio, a measure of activation independent of the concentrations of the parent molecule, was higher in patients than in controls and increased with the degree of disease severity. These results suggest that complement may have a role in the pathogenesis of the chronic liver disease associated with alpha 1AT deficiency.

Adolescent↗
PubMed1990

Activation of the complement system in human immunodeficiency virus infection: relevance of the classical pathway to pathogenesis and disease severity.

In vitro studies implicate classical and alternative complement pathway activation in the pathogenesis of human immunodeficiency virus (HIV) infection. To ascertain their importance in vivo, activation fragments of the classical (C4d), alternative (Ba), and common (C3d) pathways were measured and fragment to parent molecule ratios derived in 74 HIV-infected individuals and related to circulating immune complex (CIC) levels, Centers for Disease Control (CDC) stage, and beta 2-microglobulin, neopterin, and CD4-positive (CD4+) lymphocyte levels. All fragments and ratios were significantly higher in patients (P less than .01) than controls. C4 conversion indices (C4d and C4d to C4) increased linearly with increasing CDC stage (P less than .001), while CD4+ lymphocytes decreased linearly (P less than .001). C4d, C3d, C4d to C4, and C3d to C3 correlated with increasing CIC and beta 2-microglobulin, and C4d and C4d to C4 correlated with decreasing CD4+ lymphocytes (P less than .05). The relationship of classical complement pathway activation to disease progression and CD4+ lymphocytes suggests its involvement in the pathogenesis of HIV infection.

Adult↗
PubMed1990

Effect of initiation of insulin therapy on T-lymphocyte activation in type 1 diabetes.

Levels of activated T-lymphocytes are characteristically increased in recently diagnosed patients with Type 1 diabetes and remain elevated up to 6 months after diagnosis. To determine whether insulin treatment has a role in initiating or maintaining this activation 12 patients were studied at diagnosis and again 1, 5, and 70 days after the start of insulin therapy. Levels of activated T-lymphocytes were found to be elevated at diagnosis (9.7 +/- 1.6% (+/- SD)) before insulin treatment compared with normal control subjects (4.2 +/- 1.1%; p less than 0.001). One day after starting insulin therapy, the level of activated T-lymphocytes had not changed but by day 5 it had fallen significantly (7.6 +/- 1.9%; p less than 0.05) compared with pre-treatment levels. By day 70, activated T-lymphocytes were returning towards the high levels found before treatment. Investigation of the phenotype of the activated T-lymphocytes showed that there was an increase in the percentage of activated cells expressing the CD8 (suppressor/cytotoxic) phenotype at 70 days compared with pre-treatment values (p less than 0.02). These results show that elevated levels of activated T-lymphocytes found in recently diagnosed Type 1 diabetes are not a result of insulin treatment. Treatment may, however, have a role in maintaining T-lymphocyte activation and modifying the distribution of functional subsets of the activated cells.

Adult↗
PubMed1990

Antireticulin antibody in systemic sclerosis.

The prevalence, immunoglobulin class, and IgG subclass of antireticulin antibody in the serum samples of 32 patients with systemic sclerosis were investigated by indirect immunofluorescence on unfixed rodent tissue. Antireticulin antibody was present in 22/32 (69%) of patients and belonged to the IgG class in 19/22 (86%), the IgA class in 13/22 (59%), and the IgM class in 6/22 (27%) of positive sera. IgG1 was the predominant subclass of IgG antireticulin antibody, occurring either alone or in association with IgG3 in 12/19 cases (63%). Thus antireticulin antibody of the IgG and IgA classes is found in most patients with systemic sclerosis. The finding of an autoantibody with reactivity for collagen-like fibres in systemic sclerosis indicates that the antibody has a potential role in the pathogenesis of the disease, and as it belongs to the IgA class this suggests that it arises in response to antigens presented to the immune system at the mucosal level.

Adolescent↗
PubMed1989

Double stranded DNA binding in autoimmune chronic active hepatitis and primary sclerosing cholangitis starting in childhood.

Autoimmune chronic active hepatitis (aCAH) and primary sclerosing cholangitis (PSC) are liver disorders occurring in childhood in which non-organ specific autoantibodies, such as anti-nuclear antibody (ANA) are frequently found. Antibodies to double stranded DNA (dsDNA), which are typically present in systemic lupus erythematosus (SLE), have been detected in both acute and chronic liver diseases in adults. In this study, using a radioimmunoassay technique widely employed to measure antibodies to dsDNA, we have demonstrated significantly increased levels (median and range; 11.9, 1.0-36.5 U/ml) in 21 children with aCAH compared with normal children (1.0, 0.7-2.1 U/ml; p less than 0.01). Five children with aCAH had levels in the range considered diagnostic for SLE (greater than 25 U/ml) and of these, three had ANA and two had anti-liver kidney microsomal antibody. In addition, one child had antibodies to dsDNA as detected by the Crithidia luciliae test. DNA binding in aCAH was correlated with serum aspartate-amino transferase levels (r = 0.68; p less than 0.001), suggesting a direct relationship with disease activity. In PSC, levels of antibodies to dsDNA were significantly increased compared to normal controls (median and range; 7.0, 5.6-10.2 U/ml; p less than 0.01) but were not as high as those found in aCAH.

Adolescent↗
PubMed1989

Increased activated T-lymphocytes and normal thyrotropin receptor antibody levels in Graves' disease in long-term remission.

The involvement of the immune system in the attainment and maintenance of carbimazole-induced remission in Graves' disease is poorly understood. We have investigated levels of T-lymphocytes expressing the HLA DR marker of activation and levels of thyrotropin receptor antibody (TRAb) in patients in sustained, carbimazole-induced, long-term remission from Graves' disease (median duration of remission 29 months, range 7-64). Levels of activated T-lymphocytes were increased in patients with long-term remission compared with controls (p less than 0.05) and were no different from the high levels found in patients with active Graves' disease. In contrast, levels of TRAb were normal in patients in long-term remission but high in patients with active disease (p less than 0.01). These results show that increased activated T-lymphocytes but normal levels of antibody to the thyrotropin receptor characterize patients in carbimazole-induced long-term remission of Graves' disease suggesting that activated T-lymphocytes may be important in the maintenance of remission.

Adult↗
PubMed1988

Characterization of islet cell antibody in insulin dependent diabetes: evidence for IgG1 subclass restriction and polyclonality.

Using an indirect immunofluorescence technique we have investigated the titre, immunoglobulin class, complement-fixing ability, light chain type and IgG subclass of islet cell antibodies (ICA) in the sera of 21 recently diagnosed insulin-dependent diabetics and four non-diabetics before they developed diabetes. In the recently diagnosed patients titres of ICA ranged from 1/10 to 1/640. ICA belonged to the IgG class in all cases and fixed complement in 14 (67%). In all patients tested both kappa and lambda light chains were found, indicating that the antibody is polyclonal. IgG subclasses of ICA were investigated using specific murine monoclonal antibodies. All patients had ICA of the IgG1 subclass and in 16 (76%) this was the only subclass detected. In the remainder, one or more of the other IgG subclasses were found in association with IgG1. In the four pre-diabetic patients ICA fixed complement, was polyclonal and in all cases was of the IgG1 subclass. These characteristics of ICA, therefore, precede the onset of diabetes. The titre of ICA in the pre-diabetics tended to be greater (range 1/320 to (1/1280) than in the recently diagnosed diabetics. These results demonstrate restriction of ICA to the IgG1 subclass.

Adolescent↗
PubMed1987

Quantification of C3d in biological fluids by an enzyme-linked immunosorbent assay.

Using a commercial source of peroxidase-labelled anti-C3d antibody (Dakopatts), an enzyme-linked immunosorbent assay (ELISA) has been developed to quantify the complement fragment C3d. The technique enables the detection of C3d in plasma, urine and cerebrospinal fluid (CSF). The C3d-ELISA therefore provides a very sensitive technique for the evaluation of complement activation in biological fluids. In both plasma and urine the technique is able to discriminate between samples from normal controls and patients with rheumatoid arthritis in whom complement activation is known to occur. A good correlation was found between results obtained by ELISA and those by laser nephelometry (r = 0.91, P less than 0.0001). Microtitre plates pre-coated with anti-C3d antibody and subsequently stored at -70 degrees C retained the ability to perform in this assay. The sensitivity, short assay time and use of commercial reagents and pre-coated plates give this technique numerous potential applications in the evaluation of complement activation.

Arthritis, Rheumatoid↗