Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ultrastructural location of in vivo bound immunoglobulins in a case of bullous pemphigoid was determined by coupling peroxidase to antihuman gamma globulin. Immunoglobulin deposits were found exclusively in the space between the basal cells and the basal lamina. The location of the immunoglobulin in bullous pemphigoid thus differs from that in lupus erythematosus where immunoglobulins are found mainly below the basal lamina.
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PMID:Ultrastructural localization of in vivo bound immunoglobulins in bullous pemphigoid--a preliminary report. 4 29

Two immunohistochemical methods, using the enzyme horseradish peroxidase, the direct immunoperoxidase (DIP) and the immunoglobulin-enzyme bridge (IEB) method were applied on 129 skin specimens of 81 patients with lupus erythematosus, bullous pemphigoid, pemphigus vulgaris and rosacea. These methods were compared with each other and with the immunofluorescence (IF) method. The DIP method was preferred to the IEB method because of the greater contrast between the specific staining and the nonspecific staining of the former. The results obtained with both peroxidase methods were comparable with those of the IF method.
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PMID:Cutaneous immunohistochemistry. The direct immunoperioxidase and immunoglobulin-enzyme bridge methods compared with the immunofluorescence method in dermatology. 13 Mar 88

Conjugates of horseradish peroxidase with antibodies (anti-human IgG (H + L)) or their Fab' fragments were prepared according to the newest modification of the periodate (P-) method or the two-step glutaraldehyde (G-) method. The conjugates were analysed by gel chromatography and subsequently tested in three different applications. For tissue immunohistochemistry on sections of lupus erythematosus skin, G-conjugates were preferred to polymeric P-conjugates. In ELISA for detection of human antibodies against penicillin P-conjugates were superior to G-conjugates. For the detection of surface Ig on lymphoid cells both types of conjugate were more or less equally suitable. A scheme for the most suitable combinations of method of preparation and field of application is given.
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PMID:Periodate or glutaraldehyde for preparing peroxidase conjugates? 22 64

The principle of immunoelectronmicroscopic studies using horseradish perpoxidase is described. This method, especially the peroxidase-antiperoxidase multistep technique, reveals more details about the exact localization of immunophenomena in different dermatological diseases. The results of immunological investigations performed on the ultra-structural level in bullous diseases, lupus erythermatosus, vasculitis, and psoriasis are summarized and compared with the immunofluorescent and classical electromicroscopic findings.
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PMID:[Immunoelectron microscopy in dermatology]. 34 50

In 27 patients with lupus erythematodes diseminatus the determinations of the LE-cells according to the macromethod (Zimmer and Hargraves) and the micromethod (Mudrik and co-workers) were compared with the demonstration of antinuclear factors according to the indirect immunofluorescence and immune enzyme technique. The sensitiveness of the two last-mentioned immunomorphological methods is somewhat larger. In these cases the size of the titre of the antinuclear factor almost always correlates positively with the number of the LE-cells. For the purpose of the initial diagnostics and the judgment of the course a morphological method cannot be renounced, since in the acute episode a high consumption of the antinuclear factor the immunological methods negatively correlate with the number of the LE-cells. The immune enzyme technique is to be recommended on account of the smaller expenditure, permanence of the preparations and high sensitiveness as alternative method of the immunofluorescence technique. In the micromethod the large variation is opposite to the advantage of the slight quantity of blood and to an always existing evaluability. Investigations of the lymphocytes of patients with lupus erythematodes disseminatus by means of the lymphocyte transformation test and the determination of the B-cells with the help of the direct immune peroxidase technique refer to the close pathogenetic connections of cellular and humoral immune reactions in this disease.
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PMID:[Immunodiagnostic methods in lupus erythematosus disseminatus]. 77 10

Activated neutrophils and monocytes were found to metabolize procainamide to a reactive hydroxylamine. In contrast, there was little or no metabolism by lymphocytes or platelets. Therefore, it appears that only leukocytes that contain myeloperoxidase can metabolize procainamide to a significant degree. There was no difference in the degree to which neutrophils from males or females metabolized procainamide; however, monocytes from males formed significantly more hydroxylamine than did monocytes from females. By use of radiolabeled procainamide, covalent binding of procainamide to leukocytes was detected, and the degree of binding correlated with the cells' ability to oxidize procainamide. These findings suggest that myeloperoxidase is the major enzyme involved in the formation of reactive metabolites by leukocytes, a pathway that we propose may be responsible for procainamide-induced lupus and agranulocytosis.
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PMID:Comparative metabolism and covalent binding of procainamide by human leukocytes. 134 86

The tuberculostatic agent isoniazid has been implicated in inducing various idiosyncratic reactions including drug-induced lupus. The mechanism is unknown but may involve a reactive metabolite of the drug. Isoniazid was oxidized by activated leukocytes to isonicotinic acid. Myeloperoxidase is likely the enzyme in the leukocyte involved, since the oxidation was inhibited by azide, which inhibits myeloperoxidase, and by catalase, which catalyzes the breakdown of hydrogen peroxide. The same metabolic profile was observed when isoniazid was incubated with purified myeloperoxidase and hydrogen peroxide. The rate of the reaction was increased in the presence of chloride. Hypochlorous acid was also able to oxidize isoniazid to isonicotinic acid. Isoniazid, or an oxidative product, inhibited the reaction when high initial substrate concentrations were used. Isoniazid is oxidized by activated leukocytes, possibly to a reactive intermediate, which may have implications for isoniazid-induced lupus.
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PMID:Metabolism of isoniazid by activated leukocytes. Possible role in drug-induced lupus. 135 11

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)
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PMID:The role of leukocyte-generated reactive metabolites in the pathogenesis of idiosyncratic drug reactions. 162 36

A long-term side effect of therapy with a variety of drugs is a syndrome resembling the idiopathic autoimmune disease, systemic lupus erythematosus. Essentially all patients with drug-induced lupus display autoantibodies to nuclear histone components whose specificity appears to be related to the higher order structure of histones existing in chromatin. IgG antibodies to H1 and the (H2A-H2B)-DNA complex were observed in most patients with lupus induced by procainamide, hydralazine, and quinidine, whereas the H3-H4 tetramer, comprising half the mass of the nucleosome core particle, was largely nonantigenic. IgM antibodies to (H2A-H2B)-containing chromatin subunits were common also. IgM reactivity was observed with the DNA-free H3-H4 tetramer and with H1, especially in hydralazine-induced lupus. These results suggest that IgM antihistone antibodies may result from autoimmunization with a nonnative form of chromatin, whereas IgG antibodies may be selected for reactivity with H1 and a native form of the (H2A-H2B)-DNA subunit of the nucleosome. The chemical basis for induction of autoimmunity by drugs is unclear because lupus-inducing drugs do not have a common structural feature or biological activity nor are they capable of specific reactions with histones, the principal target antigen. However, in the presence of activated neutrophils, procainamide is transformed metabolically to the cytotoxic procainamide-hydroxylamine. Mixing experiments and cell-free studies demonstrated that procainamide was cooxidized with H2O2 by myeloperoxidase released when neutrophils undergo the respiratory burst and degranulation reactions. Preliminary results indicate other lupus-inducing drugs are also biotransformed by this mechanism suggesting that a common denominator linking these drugs may be the capacity to be oxidized to reactive metabolites by the action of activated phagocytic cells.
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PMID:Autoantibody specificity in drug-induced lupus and neutrophil-mediated metabolism of lupus-inducing drugs. 163 38

In previous studies we had shown that procainamide is metabolized to reactive metabolites by activated leukocytes, and evidence pointed to involvement of myeloperoxidase (MPO). In this study we examine the metabolism of procainamide by MPO/H2O2, in the presence and absence of chloride ion. In the absence of chloride ion, the metabolism was very similar to that seen with activated leukocytes. The major metabolite was formed by oxidation of the arylamine group to a hydroxylamine. In the presence of chloride ion, a much greater degree of metabolism occurred, and the major product (40% of the starting procainamide) was a reactive species that could not be isolated. This metabolite spontaneously rearranged to 3-chloroprocainamide, and from its mass spectrum and chemical reactions, we deduce its structure to be N-chloroprocainamide. The N-chloroprocainamide metabolite reacted very rapidly with reducing agents, such as ascorbate, and also reacted with protein such as albumin, the major product in both cases being procainamide. This metabolite also chlorinated phenylbutazone. When radiolabeled procainamide was oxidized by MPO/H2O2 in the presence of albumin, covalent binding of the radiolabel to albumin occurred, and binding was greater under conditions in which N-chloroprocainamide was formed. It is probable that the failure to observe N-chloroprocainamide, when procainamide is oxidized by activated leukocytes, is due to its rapid reaction with the cells. We propose that modification of neutrophils (or neutrophil precursors in the bone marrow) by these reactive metabolites is responsible for procainamide-induced agranulocytosis. In a similar manner, procainamide-induced lupus could be due to modification of monocytes by monocyte-generated reactive metabolites.
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PMID:N-Chlorination and oxidation of procainamide by myeloperoxidase: toxicological implications. 166 58


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