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Biomedical subjects

J B Ziegler

Publications and source records attributed to J B Ziegler.

At least 73 records · Page 4Linked to original sources
PubMed1981

Glucocorticosteroid enhancement of immunoglobulin synthesis by pokeweed mitogen-stimulated human lymphocytes. III. Common variable immunodeficiency.

We studied the effect of glucocorticosteroids (GCS) on IgG synthesis by peripheral blood mononuclear cells from 19 patients with common variable immunodeficiency (CVID). Purified T and B lymphocyte subpopulations from patients and normal subjects were recombined at various T : B ratios and cultured for 8 days unstimulated, stimulated with pokeweed mitogen (PWM) and in the presence of prednisolone. IgG synthesis was measured in the culture supernatants by radioimmunoassay. Enhancement of PWM-stimulated IgG synthesis by prednisolone at high T : B ratios was found in nine patients, four of whom produced negligible amounts of IgG with PWM alone. In four patients, enhancement by prednisolone of IgG synthesis by purified B lymphocytes was noted. In three out of eight patients whose IgG synthesis was increased by normal allogeneic T lymphocytes with PWM and prednisolone, negligible amounts of IgG were produced by similarly treated autologous combinations. T lymphocytes from CVID patients provided less help compared with normal T lymphocytes for IgG synthesis by normal B lymphocytes at high T : B ratios even in the presence of prednisolone. GCS in vitro enhance IgG synthesis by lymphocytes from some but not all patients with CVID by a mechanism which appears independent of GCS action on regulatory T lymphocytes.

Adolescent↗
PubMed1980

Severe combined immunodeficiency and adenosine deaminase deficiency: failure of enzyme replacement therapy.

A first-born baby boy presented at age 3 months with persistent diarrhoea, failure to thrive, and recurrent bacterial and fungal infections. Severe combined immunodeficiency was demonstrated. A deficiency of adenosine deaminase (ADA) activity was suggested by the presence of extensive skeletal abnormalities, and the ADA activity in erythrocyte and leucocyte lysates was < 0.005 nmol/h per mg protein. Culture of ADA-negative peripheral blood mononuclear cells, together with purified calf ADA, did not alter the absent phytohaemagglutinin response. Treatment with immunoglobulin, pentamidine, and co-trimoxazole was started and a programme of ADA enzyme replacement, with infusions of plasma and frozen irradiated erythrocytes, was begun at age 4 months and achieved blood ADA levels in excess of 30 nmol/h per mg haemoglobin. Although resolution of the interstitial pneumonitis and skeletal abnormalities was observed, there was no evidence of immunological reconstitution. The patient died at age 17 months after a parainfluenza pneumonitis. Features of importance in predicting lack of benefit from enzyme replacement by erythrocyte infusion in ADA-negative severe combined immunodeficiency appear to be early clinical presentation with associated severe skeletal abnormalities, a very low level of residual ADA activity in peripheral blood mononuclear cells, and lack of effect of exogenous ADA on the absent in vitro mitogen response of ADA-negative blood mononuclear cells.

Adenosine Deaminase↗
PubMed1979

Family study on the kindred of an adenosine deaminase deficient child with severe combined immunodeficiency.

A study was performed on the family of a child with severe combined immunodeficiency and deficiency of the purine salvage pathway enzyme, adenosine deaminase (ADA). Sixteen relatives over three generations were studied. Erythrocyte ADA levels clearly indicated the heterozygous status of five members. A sixth member, whose erythrocyte ADA level of 48 nmol/hr/ml Hb was within two standard deviations (32) of the mean (76) was shown by ADA determination on platelets to be clearly heterozygous. Similarly, consideration of ADA data of either serum, platelets or lymphocytes only, would have failed to identify all heterozygotes. The survey shows that the identification of phenotype by the indirect means of enzyme level determination is enhanced by the simultaneous study of several tissues.

Adenosine Deaminase↗
PubMed1979

In vitro platelet abnormality in adenosine deaminase deficiency and severe combined immunodeficiency.

The platelets of an infant with severe combined immune deficiency and adenosine deaminase deficiency showed markedly diminished responses to ADP-induced aggregation in vitro. This abnormality was corrected by the addition of purified adenosine deaminase in vitro. Exogenous adenosine added to platelet-rich plasma caused markedly prolonged inhibition of ADP-induced aggregation. This was shown by isotopic studies to be due to slow clearance of adenosine and hence persistence of this nucleoside. Direct assay for adenosine deaminiase in plasma and platelet lysates of the patient confirmed the very low activity of this enzyme. Raised cAMP levels were demonstrated in his platelets. The deranged adenosine metabolism and raised cAMP in the platelets of this child with severe combined immunodeficiency may explain the altered response to ADP. Despite the in vitro platelet aggregation abnormality, the patient had no clinical evidence of impaired hemostasis.

Adenosine Deaminase↗
PubMed1977

Antifilarial agents. 1,2-Cyclobutanediamines as analogues of diethylcarbamazine. Status of structure-activity relationships among diethylcarbamazine analogues.

cis-and trans-1,2-cyclobutanediamines bearing appropriate N-methyl and N-acyl substituents were prepared as analogues of diethylcarbamazine (DEC). None displayed activity against Litomosoides carinii in the gerbil despite substantial structural and sterochemical similarities to the parent drug. The inactivity of these drugs is rationalized in terms of eclipsed pharmacophore configurations and the increased population of unfavorable rotational conformations made possible by the exocyclic position of both pharmacophores. To provide perspective for these conclusions, the literature on DEC analogues is briefly summarized and structure-activity data are discussed in terms of critical structural factors associated with microfilaricidal activity. Generalizations on structural principles governing activity are advanced which encompass test results for the large majority of DEC analogues.

Animals↗
PubMed1977

Heterogeneity of nephritic factor and its identification as an immunoglobulin.

Complement C3 nephritic factor (NeF) produces alternative pathway-meciated C3 cleavage by binding to and stabilizing the alternative pathway C3 convertase, C3bBb. Some studies have suggested that NeF is an immunoglobulin, while others conclude that it is a distinct serum protein. The heterogeneity of NeF was evaluated by electrophoresis and isoelectric focusing of NeF-containing serum followed by hemolytic demonstration of NeF activity in agar gel. With each method, diffuse cathodal zones or multiple bands of hemolysis developed, which revealed remarkable variations in patterns from patient to patient. NeF activity was absorbed by and eluted from insolubilized antibody to Fc and Fab fragments of IgG. Immunoabsorption of six NeF-containing sera with insolubilized anti-kappa and anti-lambda light chain antisera revealed that NeF had kappa antigenic determinants in three, lambda antigenic determinants in one, and both kappa and lambda antigenic determinants in two. These data indicate that NeF is an oligoclonal immunoglobulin. Because NeF binds to the alternative pathway C3 convertase, C3bBb, we suggest that it is an antibody to a conformational antigen of the C3-factor B complex, and thereby stabilizes this complex.

Complement C3↗
PubMed1976

Monitoring immune function during immunosuppressive therapy.

Twenty-nine patients with a variety of connective tissue disorders were studied for the effects of immunosuppressive therapy on non-specific parameters of immune function. Baseline studies prior to therapy showed a frequent incidence of anergy (13%) lymphopenia (31%) and abnormal PHA response (43%). Despite these abnormalities in untreated patients it was possible to show an even higher incidence of anergy (31%), lymphopenia (66%) and abnormal PHA response (77%) following immunosuppressive treatment. The changes in lymphocyte count and PHA response were found to be statistically significant. It was found, paradoxically, that delayed hypersensitivity responses improved following institution of therapy in three patients. Clinical efficacy of immunosuppression correlated with lymphopenia and depressed PHA responses; in particular in the five patients with uncontrolled disease, these parameters were normal. Lymphocyte counts and PHA responses are the most simple and informative procedures to monitor immunosuppression in patients.

Collagen Diseases↗
PubMed1976

Complement activation in semi-solid medium: Insolubilization of properdin and the third component of complement (C3) in agar gels.

Although the role of properdin in the alternative pathway of complement activation remains unclear, evidence has recently been obtained for the formation of complexes between properdin and other components, including C3. In this study such complexes have apparently been directly visualized. When normal human serum and properdin were allowed to diffuse toward each other in agar gel for 16 hr, a line of precipitation could be seen when stained with Coomassie brilliant blue. The reaction occured at pH 8.6 in 0.05 M Veronal buffer at room temperature but not under physiologic conditions of pH or tonicity. Like the alternative pathway, the reaction was Me++ dependent, occurred with C2- or C5-deficient or hypogammaglobulinemic serum, and did not occur with aged, 52 degrees C-inactivated, C3b inactivator-deficient, or C3-deficient serum. 125I-labeled C3 and properdin but not Factor B were incorporated in the precipitate. Eleven sera containing the C3 nephritic factor failed to produce a precipitate with properdin, but a line of precipitation occurred between seven of these sera and normal serum. This line showed identity with the line occurring between properdin and normal serum. The phenomenon appears to result from formation of insoluble complexes between proteins of the alternative pathway and agar.

Agar↗
PubMed1975

Leucocyte function in paraproteinaemia.

Cellular immunity has been studied by means of lymphocyte response to PHA, delayed hypersensitivity and skin window responses in 23 patients with myeloma (14 IgG, 9 IgA) and 14 patients with macroglobulinaemia. In the myeloma patients, 14% had abnormal PHA response and 29% were anergic. In those with macroglobulinaemia, 29% showed abnormal PHA response and 57% were anergic. In myeloma, the abnormal PHA response was due to a serum inhibitor. Abnormal skin window responses were present in 75% of the patients with myeloma, but only 22% of those with macroglobulinaemia. All the myeloma patients with anergy had abnormal skin windows but this correlation did not exist in macroglobulinaemia. No correlation was found between the paraprotein concentration and anergy, PHA response or skin window. The results support the conclusion that myeloma is predominantly associated with an abnormal skin window (inflammatory) response and macroglobulinaemia with intrinsic abnormalities of cellular immunity. When anergy and abnormal PHA response are present in myeloma, it appears to be attributable to an effect of the paraprotein and not an intrinsic abnormality of lymphocytes.

Adult↗
PubMed1975

Restoration by purified C3b inactivator of complement-mediated function in vivo in a patient with C3b inactivator deficiency.

In a patient with lifelong increased susceptibility to infection and multiple abnormalities in complement-mediated functions, the infusion of normal plasma had been seen to produce a prolonged partial correction of serum abnormalities. It was subsequently shown that the patient was genetically deficient in the C3b inactivator and that immunochemical depletion of C3b inactivator from normal serum resulted in abnormalities similar to those found in the patient's serum, including alternative pathway C3 activation. Highly purified C3b inactivator was obtained from the euglobulin fraction of normal human serum, sterilized by filtration, and infused intravenously. Partial or complete correction of almost all the known serum abnormalities was obtained. C3b almost disappeared from the serum within 4-5 h, as did Factor C activity. Native C3, C5, and serum hemolytic activity rose to normal or near-normal levels over 4 days and were sustained for another week. Factor B, properdin, opsonic activity, and bactericidal activity reached a level at least two-five times that found before the infusion within 24 h and fell over the next 5 days. These observations prove the primary role of C3b inactivator deficiency in the patient's disease and demonstrate clearly the curcial role in vivo of C3b inactivator in modulating alternative pathway activity.

Blood Proteins↗
PubMed1975

Metabolism of properdin in normal subjects and patients with renal disease.

Properdin deposition has been recognized in glomeruli of patients with acute and chronic nephritis and lupus nephritis, and low serum properdin levels have been found in these disorders. These findings suggest that properdin may be involved in the production of glomerular damage and that low properdin levels may be due to hypercatabolism. The study was designed to examine the metabolism of properdin in normal subjects and to look for an abnormality in five patients with systemic lupus erythematosus with renal involvement and in six patients with membranoproliferative glomerulonephritis or dense deposit disease (MPGN). Highly purified human properdin was prepared by elution from zymosan, followed by DEAE-cellulose and carboxymethyl-Sephadex chromatography, and labeled with 125I by the iodine monochloride method. Parameters of metabolism were determined by monitoring plasma and urinary radioactivity at frequent intervals after the intravenous injection of 1-2 muCi of labeled material. The fractional catabolic rate (FCR) of properdin in normal subjects was found to have a very narrow range of 0.78-1.0,% of the plasma pool per hour (mean 0.95%). In systemic lupus erythematosus, the FCR was regularly elevated with a range of 1.21-2.30% (mean 1.70%). In MPGN, FCR was elevated in three patients (1.22, 1.94, and 2.08%) and within or below the normal range in three (0.78, 1.00, and 1.00%). Properdin levels were reduced in two patients who had the highest FCR's noted in the study. Properdin synthetic rates in normals varied from 4.1 to 14.3 mug/kg per h (mean 9.1) and was not found to be reduced in any patient. Properdin catabolism was found to be normal in a patient deficient in the C3b inactivator. These studies show that properdin is hypercatabolized in patients with renal disease and that decreased properdin levels when they occur in these patients can be entirely explained on the basis of this hypercatabolism.

Adolescent↗
PubMed1975

Genetic polymorphism of properdin factor B in the rhesus: evidence for single subunit structure in primates.

Properdin Factor B shows genetic polymorphism in the human and the polymorphic patterns in agarose gel electrophoresis suggest a tetrameric structure. Factor B polymorphism in the rhesus monkey has been demonstrated in the present study to be genetically determined and under the control of a single autosomal locus, rhesus Bf. Six codominant alleles, Bf-F, Bf-G-1, Bf-G-2, Bf-S-1, Bf-S-2 have been recognized and the first five have been shown to have gene frequencies of 0.307,0.160,0.016,0.377, and 0.139. The electrophoretic appearance of the polymorphic patterns does not suggest a tetrameric structure in the rhesus. Structural studies show purified human factor B to exist as a single subunit of molecular weight 94,000 daltons so that a tetrameric structure appears highly unlikely.

Animals↗