Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite their importance, little is known about the mechanism of idiosyncratic reactions, many such reactions have characteristics that suggest an immune-mediated mechanism. This is particularly true of drug-induced lupus which is an autoimmune syndrome. Certain functional groups are associated with a high incidence of idiosyncratic reactions, probably reflecting the ease with which they are metabolized to reactive metabolites. Although the liver is the principal organ of drug metabolism, most reactive metabolites generated in the liver would not reach other organs in significant concentrations. Because of the function of leukocytes, especially monocytes, in the induction of an immune response, the generation of reactive metabolites by monocytes would seem likely to lead to an immune-mediated adverse reaction. We have found that drugs that are associated with drug-induced lupus are oxidized to reactive metabolites by the myeloperoxidase system of monocytes. The initial step in drug-induced lupus could be haptenization of a protein on the surface of monocytes by these reactive metabolites. Other types of idiosyncratic drug reactions may involve a similar mechanism and the same drugs that induce lupus are usually associated with a high incidence of other types of idiosyncratic reactions. for example, procainamide, which causes the highest incidence of drug-induced lupus, also causes a relatively high incidence of agranulocytosis. Even some of the therapeutic effects of drugs may involve the production of reactive metabolites by myeloperoxidase or thyroid peroxidase.
 ...
PMID:Metabolism of drugs by activated leukocytes: implications for drug-induced lupus and other drug hypersensitivity reactions. 206 78

This review presents a unifying hypothesis that provides a connection between several types of hypersensitivity reactions associated with several types of drugs and explains some of the therapeutic effects (antiinflammatory activity and antithyroid effects) of these same drugs. This hypothesis centers on the oxidation of these drugs to chemically reactive metabolites by peroxidases. The drugs of interest have functional groups that are easily oxidized. The major peroxidase involved in this hypothesis is MPO because of its critical location in leukocytes which play a key role in the function of the immune system. However, thyroid peroxidase can probably also oxidize many of the same drugs to reactive metabolites, and this may be responsible for the thyroid autoimmunity observed in connection with some hypersensitivity reactions. Peroxidases have also been described in the skin and in platelets, and their presence may be responsible for the high incidence of skin reactions in the hypersensitivity response and the occurrence of immune-mediated thrombocytopenia, respectively. Involvement of other peroxidases, such as prostaglandin peroxidase, may also be important for antiinflammatory effects of drugs. In addition, leukocytes contain prostaglandin synthetase, and the activation of leukocytes leads to the release of arachidonic acid and the production of prostaglandins. This process may also lead to the metabolism of drugs to reactive metabolites. In studies of the metabolism of procainamide and dapsone, aspirin and indomethacin did not inhibit the formation of the hydroxylamine by neutrophils and mononuclear leukocytes. This is evidence against the involvement of prostaglandin synthetase in these oxidation; however, preliminary studies with other drugs suggest that prostaglandin synthetase may contribute to the metabolism of some drugs by leukocytes. Furthermore, the metabolism of phenylbutazone, phenytoin, and tenoxicam, as well as our preliminary work with other drugs such as carbamazepine, suggests that the range of drugs that are metabolized to reactive metabolites by peroxidases may be broader than initially suspected. There are several other drugs that do not fit into the functional group classes covered in this review but have similar properties. A good example is alpha-methyldopa, which is associated with drug-induced lupus, immune-mediated hemolytic anemia, and other hypersensitivity reactions. Such drugs may also be metabolized to reactive metabolites by peroxidases. Another aspect of the hypothesis is that an infection, or other inflammatory condition, may be an important risk factor for a hypersensitivity reaction because such a stimulus leads to activation of leukocytes which can lead to formation of reactive metabolites from certain drugs.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Drug metabolism by leukocytes and its role in drug-induced lupus and other idiosyncratic drug reactions. 217 25

This study describes an assay for the detection of cytotoxicity for thyroid cells in serum of patients with autoimmune thyroiditis. Quantitative measurement may be performed by DNA or [3H] leucine incorporation determinations. The cytotoxic effect is localized in the gamma-globulin fraction, and is complement-mediated. It is thyroid specific i.e. it is not observed with fibroblasts and patients with other autoimmune diseases (patients with lupus erythematosis or glomerulonephritis) do not have cytotoxic antibodies directed against thyroid cells. The thyroid cytotoxicity is related to the presence of antimicrosomal antibodies and the effect of circulating antibodies is inhibited by human thyroid peroxidase. These results strengthen the possible implication of circulating antithyroid peroxidase antibodies in thyroid damage observed in autoimmune thyroiditis.
 ...
PMID:Cytotoxic assay of circulating thyroid peroxidase antibodies. 249 49

Although patients with SLE have autoantibodies to thyroid peroxidase (TPO), IgG from sera of SLE patients does not inhibit TPO activities, in contrast with IgG from sera of patients with thyroid disorders. This finding suggests that the specificities of anti-TPO autoantibodies in SLE are different from those in cases of thyroid disorders. These autoantibodies to TPO should be considered when searching for associations between SLE and autoimmune thyroid disorders.
 ...
PMID:Anti-thyroid peroxidase antibody activity in sera of patients with systemic lupus erythematosus. 270 76

MRL-lpr/lpr mice are genetically predisposed to develop a systemic lupus erythematosus-like syndrome that is clinically very similar to the human disease. The results presented here demonstrate, for the first time to our knowledge, that MRL-lpr/lpr mice also develop thyroiditis as part of their systemic autoimmune disorder. The thyroid gland was infiltrated by immunocomponent cells with defined lymphoid follicular centers and extensive interstitial lymphocytes dispersed throughout the thyroid epithelium. All the diseased mice were hypothyroid with reduced, relative levels of thyroid hormone (free T4) and elevated levels of thyroid-stimulating hormone (TSH). They also had high concentrations of circulating IgG class autoantibodies directed against thyroglobulin, thyroperoxidase and double-stranded DNA. The MRL-+/+ age-matched allelic counterpart mice had relatively few lymphocytes in their thyroid tissue, and normal levels of thyroxine and TSH. The non-diseased mice also had undetectable levels of thyroid reactive autoantibodies tested for by enzyme-linked immunosorbent assays. Collectively these findings document that the MRL-lpr/lpr mice spontaneously develop autoimmune thyroiditis and can be used as a model for the study of thyroid-specific autoimmunity.
Lupus 1995 Jun
PMID:Characterization of autoimmune thyroiditis in MRL-lpr/lpr mice. 765 88

An EIA for measuring anti-TPO autoantibodies (rhTPO-EIA) was developed using recombinant human TPO expressed in CHO cells and was compared with MC-HA generally used in laboratory routine work. rhTPO-EIA showed a satisfactory reproducibility in the intra-assay test and did not have an accidental error of lots. Almost equal number of healthy females and males were measured for their IgG binding to TPO to define a normal range of anti-TPO autoantibodies. After setting 20 IU/ml as an upper limit of normal range, sera from patient with thyroid disorders were measured for their anti-TPO autoantibodies. Chronic thyroiditis and Graves' disease were highly positive, while adenoma, thyroid cancer, SLE, and RA were low in their positivity. The positive rate of anti-TPO autoantibodies was compatible to those of previous reports in each disorder. Seventy-two sera from patients with chronic thyroiditis or Graves' disease were measured for their autoantibodies by both rhTPO-EIA and MC-HA and the results were compared between both methods. A correlation coefficient was 0.486. Following absorption with thyroglobulin, sera were measured again and as the results, the correlation coefficient increased to 0.723. Therefore, MC-HA was thought to be influenced in the presence of anti-thyroglobulin autoantibodies. Since rhTPO-EIA is excellent in quality and not affected by anti-thyroglobulin antibodies, it is useful and applicable to clinical diagnosis and observation of thyroid disorders.
 ...
PMID:[Measurement of human thyroid peroxidase autoantibodies by enzyme immunoassay using recombinant human TPO]. 815 66

TPO is a major antigen corresponding to thyroid-microsomal autoantibodies. Anti-TPO autoantibodies are very important to diagnose autoimmune thyroid disease and to estimate its clinical course. An EIA for measuring anti-TPO autoantibodies (rhTPO-EIA) was developed using recombinant human TPO expressed in CHO cells and was compared with MCHA generally used in routine laboratory work. Sera from patients with various disorders were measured for their anti-TPO autoantibodies. Chronic thyroiditis and Graves' disease were highly positive, while thyroid cancer, adenoma, SLE, and RA were low in their positivity. The positive rate of anti-TPO autoantibodies were compatible with those of previous reports of each disorder. In the comparison between rhTPO-EIA and MCHA, the correlation coefficient was 0.486. Following absorption with thyroglobulin, sera were measured again and as a result, the correlation coefficient increased to 0.723. Therefore, MCHA was thought to be influenced in the presence of anti-thyroglobulin autoantibodies. The characteristics of TPO antigen and anti-TPO autoantibodies were also summarized.
 ...
PMID:[Clinical application of recombinant thyroid peroxidase]. 829 53

Patients treated with natural human interferon alpha develop anti-interferon antibodies (IFN-AB) only in very rare cases. By contrast, patients with autoimmune disorders are able to generate high-titered IFN-AB against endogenous interferon alpha. One explanation for the development of auto-IFN-AB could be cross-reactivity with typical autoimmune antigens. We investigated the cross-reactivity of 3 high-titered IgG IFN-AB of female autoimmune patients (aged 32, 36, 74 years; two severe cases of SLE, one case of autoimmune thyroiditis) as well as 25 low-titered natural IgM IFN-AB of healthy blood donors (aged 19-48 years). Typical autoimmune antigens including dsDNA, ENA, as well as natural interferon beta and recombinant interferon gamma are not able to inhibit binding of IFN-AB to interferon alpha in an ELISA test system. Preincubation of sera containing either dsDNA antibodies (dsDNA-AB) (24 patients), thyroid peroxidase (TPO-AB) (9 patients) or thyroglobulin (TG-AB) (12 patients) with interferon alpha resulted in no change in the respective autoantibody titer. These data suggest that there is no cross-reactivity between IFN-alpha-AB and dsDNA-AB, TPO-AB or TG-AB. Thus, an explanation for the occurrence of IFN-AB in autoimmune disorders cannot be found in a cross-reaction between interferon alpha with typical autoimmune antigens.
 ...
PMID:[Interferon alpha antibodies show no cross reactions with typical autoantibodies]. 834 95

Thyroid microsomal antibodies (Ms-Ab) are recently proved to be directed to thyroid peroxidase (TPO). The aim of this study was to investigate whether the sera of patients with systemic lupus erythematosus (SLE) contain anti-TPO antibodies (TPO-Ab) and whether these antibodies influence enzyme activity. Sera from patient with Hashimoto's thyroiditis was also studied. Serum samples were obtained from 37 patients with SLE, 20 patients with Hashimoto's thyroiditis and 20 healthy subjects. TPO-Ab were detected by immunoprecipitation using crude microsomal preparations or enzyme-linked immunoabsorbent assay (ELISA) with recombinant TPO. Positive TPO-Ab by ELISA were found in 11 (61%) of 18 patients with lupus whose serum contained Ms-Ab. Low levels of TPO-Ab also were found in three (16%) of 19 lupus sera that did not contain Ms-Ab. All patients with Hashimoto's thyroiditis had high levels of TPO-Ab in serum. When measured by ELISA, TPO-Ab were highly correlated with the results of a TPO immunoprecipitation assay and with the titers of Ms-Ab in patients with lupus (r = 0.83, n = 18, P < 0.01; r = 0.63, n = 18, P < 0.01) and in Hashimoto's thyroiditis (r = 0.89, n = 20, P < 0.01; r = 0.75, n = 20, P < 0.01). When evaluating the direct influence of TPO-Ab on the activity of TPO, we found no significant inhibition of enzymatic activity in both guaiacol and iodide assays by lupus sera in contrast with sera from Hashimoto's thyroiditis.(ABSTRACT TRUNCATED AT 250 WORDS)
Lupus 1995 Aug
PMID:Thyroid peroxidase autoantibodies and their effects on enzyme activity in patients with systemic lupus erythematosus. 852 24

The involvement of autoantibodies in the extrathyroidal manifestations of Graves' disease has been the subject of extensive investigation, with fairly inconclusive results to date. We investigated the presence of immunoglobulin A (IgA) and IgG antibodies in patients with Graves' disease and pretibial myxedema (PTM; n = 21) as well as those with Graves' disease with thyroid-associated ophthalmopathy (TAO; n = 10), Graves' disease with no clinical evidence of extrathyroidal manifestations (n = 11), Hashimoto's thyroiditis (n = 9), type 1 diabetes mellitus (n = 10), systemic lupus erythematosus (n = 9) and normal individuals (n = 17). We looked for antibodies to both retroocular muscle and dermal fibroblasts as well as to thyroid peroxidase, thyroid microsomal antigen, thyroglobulin, and human eye muscle membranes. IgA class antibodies to microsomal antigen (30-50% of patients), thyroid peroxidase (5-20%), and human eye muscle membrane (0-26%) antigens were found in the various groups of patients with Graves' disease. With each of these antigens, serum from patients with PTM showed the greatest binding. Highly significant IgA binding was shown by PTM serum to both dermal (P < 0.001) and retroocular muscle (P < 0.001) fibroblasts from 12 different donors. Serum from Graves' patients with and without TAO and that from Hashimoto's thyroiditis patients reacted significantly with 4 of the 12 fibroblasts lines. In contrast, IgG binding was only found for 3 of the 12 fibroblast lines using patient serum. The IgA binding to fibroblasts shown by PTM patients was predominantly of the IgA2 subclass. The activity was absorbed out by both fibroblasts and thyroid cells. In immunoblotting studies, PTM patient serum reacted with a 54-kilodalton dermal fibroblast antigen and a 66-kilodalton retroocular fibroblast antigen. No binding to these antigens was seen with serum from normal controls or patients without PTM. Further elucidation of the nature of this fibroblast antigen will help to determine the role of IgA autoantibodies in the extrathyroidal manifestations of Graves' disease.
 ...
PMID:Immunoglobulin A class fibroblast antibodies in patients with Graves' disease and pretibial myxedema. 853 May 78


1 2 3 4 Next >>