Serum antibodies to human Pneumocystis carinii antigens were measured in greater than 400 specimens from different population groups by the immunoblotting technique. Serologic responses varied during the first 2 years of life, but in children greater than or equal to 2 1/2 years and in adults antibodies to a 40-kDa band were found in greater than 85% of the specimens; antigens to bands of 66, 92, and 116 kDa were also detected frequently. The prevalence of serum antibodies in immunosuppressed patients varied at different institutions and was usually lower than that of healthy controls. Seven (41%) of 17 patients with single episodes of pneumocystosis and 13 (93%) of 14 patients with recurrent episodes followed sequentially developed active serum IgM and/or IgG antibody responses to the 40-kDa antigen. Serologic responses to P. carinii were also detected, though less frequently, by immunofluorescence. These data suggest that the 40-kDa antigen is a major marker of P. carinii infection and that immunoblotting is useful in measuring serum antibody responses to the organism in both normal and immunocompromised hosts.

Serologic Responses to Pneumocystis carinii Antigens in Health and Disease

Evidence strongly suggests that many adverse drug reactions, including idiosyncratic drug reactions, involve reactive metabolites. Furthermore, certain functional groups, which are readily oxidized to reactive metabolites, are associated with a high incidence of adverse reactions. Most drugs can probably form reactive metabolites, but a simple comparison of covalent binding in vitro is unlikely to provide an accurate indication of the relative risk of a drug causing an idiosyncratic reaction because it does not provide an indication of how efficiently the metabolite is detoxified in vivo. In addition, the incidence and nature of adverse reactions associated with a given drug is probably determined in large measure by the location of reactive metabolite formation, as well as the chemical reactivity of the reactive metabolite. Such factors will determine which macromolecules the metabolites will bind to, and it is known that covalent binding to some proteins, such as those in the leukocyte membrane, is much more likely to lead to an immune-mediated reaction or other type of toxicity. Some reactive metabolites, such as acyl glucuronides, circulate freely and could lead to adverse reactions in almost any organ; however, most reactive metabolites have a short biological half-life, and although small amounts may escape the organ where they are formed, these metabolites are unlikely to reach sufficient concentrations to cause toxicity in other organs. Many idiosyncratic drug reactions involve leukocytes, especially agranulocytosis and drug-induced lupus. We and others have demonstrated that drugs can be metabolized by activated neutrophils and monocytes to reactive metabolites. The major reaction appears to be reaction with leukocyte-generated hypochlorous acid. Hypochlorous acid is quite reactive, and therefore it is likely that many other drugs will be found that are metabolized by activated leukocytes. Some neutrophil precursors contain myeloperoxidase and the NADPH oxidase system, and it is likely that these cells can also oxidize drugs. Therefore, although there is no direct evidence, it is reasonable to speculate that reactive metabolites generated by activated leukocytes, or neutrophil precursors in the bone marrow, could be responsible for drug-induced agranulocytosis and aplastic anemia. This could involve direct toxicity or an immune-mediated reaction. These mechanisms are not mutually exclusive, and it may be that both mechanisms contribute to the toxicity, even in the same patient. In the case of drug-induced lupus, a prevalent hypothesis for lupus involves modification of class II MHC antigens.(ABSTRACT TRUNCATED AT 400 WORDS)

The role of leukocyte-generated reactive metabolites in the pathogenesis of idiosyncratic drug reactions

Pneumocystis carinii is an extracellular organism which is thought to require attachment to alveolar epithelial cells for its growth and replication in humans. Fibronectin (Fn) binding to P. carinii is essential for optimal P. carinii attachment. This study demonstrates that gp120, a 110-120-kD membrane glycoprotein on P. carinii, mediates attachment of the organism to cultured lung cells and is the site of Fn binding to P. carinii. A 51Cr-labeled P. carinii binding assay was used to quantify attachment of the organism to the alveolar epithelial cell line A549. Addition of free gp120, purified from whole P. carinii organisms, caused a significant decrease in attachment of P. carinii to A549 cells from 44.2 +/- 5.5% to 22.4 +/- 4.2% (P less than 0.01). Preincubation of the P. carinii organisms with a polyclonal antibody to gp120 also resulted in a marked decrease in P. carinii attachment to A549 cells from 46.8% +/- 5.2% to 21.3 +/- 4.8% (P less than 0.01). Furthermore, addition of free gp120 to P. carinii organisms caused a significant reduction in specific binding of 125I-Fn to P. carinii (from 83.3 +/- 8.5 ng to 47.1 +/- 5.9 ng, P less than 0.01). Similarly, anti-gp 120 antibody decreased specific Fn binding to P. carinii from 74.3 +/- 8.4 ng to 25.5 +/- 5.3 ng (P less than 0.001). Solubilized P. carinii organisms separated by gel electrophoresis and blotted with 125I-Fn demonstrated specific binding of the 125I-Fn to gp120. In addition, a specific anti-beta 1-integrin antiserum reacted with gp120 by Western blot, suggesting structural homology between gp120 and the beta-subunit of integrins. Thus, the data suggest that the P. carinii membrane glycoprotein gp120 functions as a Fn binding protein and is required for optimal P. carinii attachment to alveolar epithelial cells.

/pdf/pneumocystis-carinii-attachment-to-cultured-lung-cells-by-5fpf36f0vs.pdf

Pneumocystis carinii attachment to cultured lung cells by pneumocystis gp 120, a fibronectin binding protein.

Subnucleosome structures as substrates in enzyme-linked immunosorbent assays.

The sequence of the coding region of the rRNA operon of rat-derived Pneumocystis carinii has been completed, including the genes for 5.8S and 26S rRNA. These genes show homology to the rRNA genes of yeast, and an apparent group I self-splicing intron is present in the 26S rRNA gene. Like a similar intron in the 16S rRNA gene, this intron is in a phylogenetically conserved region. Variation in the 26S rRNA sequence was noted between P. carinii organisms isolated from two different sources.

Sequence and variability of the 5.8S and 26S rRNA genes of Pneumocystis carinii.

Radioiodination of rat-derived Pneumocystis carinii obtained from an in vitro culture demonstrated the presence of a major surface glycoprotein (gp120). The glycoprotein was of the high mannose type. It exhibited adherence properties similar to those observed in the intact organism. Under nonreducing conditions, it existed as an aggregate with a molecular weight in excess of 2 x 10(6). Surface aggregating behavior and adherent quality prevented isolation of the glycoprotein by conventional methods. The glycoprotein was purified by chromatography on hydroxyapatite in the presence of sodium dodecyl sulfate under reducing conditions.

https://iai.asm.org/content/iai/57/7/2149.full.pdf

Identification and isolation of a major cell surface glycoprotein of Pneumocystis carinii.

Using the technique of immunoblotting, we assessed the ability of sera from 19 patients with drug-induced lupus to bind individual histones and specific histone fragments. The pattern of histone epitopes bound by sera from 9 patients with procainamide-induced lupus was very similar to that described previously in spontaneous systemic lupus erythematosus. In contrast, sera from 10 patients with hydralazine-induced lupus bound a broader array of individual histones and recognized a different set of histone epitopes. We conclude that these 2 drugs induce antihistone antibodies through somewhat different mechanisms, which possibly involve differences in their ability to structurally alter chromatin.

Autoantigenic histone epitopes: a comparison between procainamide- and hydralazine-induced lupus.

Rat-derived Pneumocystis carinii lysed with sodium deoxycholate catalysed the incorporation of uridine diphosphoglucose into an insoluble polymer. This enzyme activity was present in both the pellet and the supernatant when the P. carinii preparations were centrifuged. The polymer whose production was catalysed by the supernatant was examined by mass spectrometry and found to be an alpha 1----4 glucan, which is either unbranched or has relatively few branches. Polymer formation was completely inhibited by the addition of alpha amyloglucohydrolase to the supernatant. Polymer formation in the pellet of deoxycholate P. carinii preparations, unlike that in the supernatant, was partially resistant to alpha amyloglucohydrolase. The soluble glucan synthase activity in the supernatant was stable for more than 30 h at room temperature and was approximately 50 times more active on a cell-to-cell basis than the supernatant from deoxycholate preparations of the yeast Saccharomyces cerevisae.

Glucan synthesis in Pneumocystis carinii.

Pneumocystis carinii is an opportunistic pathogen of man, carried as a commensal in healthy subjects. It frequently causes a fatal pneumonia in the immunosuppressed host. It is a major complication of HIV-1 infection in man (AIDS). Using surface radioiodination of rat-derived P. carinii trophozoites obtained from in vitro culture, a major surface glycoprotein (gp120) has been identified. The glycoprotein exhibits adherent behavior similar to that of the intact organism. Purification of gp120 by conventional methods was unsuccessful as the glycoprotein irreversibly bound to numerous column matrices. A combination of gel chromatography and hydroxyapatite chromatography in sodium dodecylsulfate was utilized to purify the glycoprotein. Some preliminary characterization of the glycoprotein is presented.

Surface labeling of Pneumocystis carinii from in vitro culture.

Characterization of Pneumocystis carinii monoclonal antibodies.

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