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)

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.
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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)
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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.
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PMID:Cytotoxic assay of circulating thyroid peroxidase antibodies. 249 49

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

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

A patient with a history of recurrent late fetal loss associated with multiple placental infarcts and cerebrovascular ischemia at the age of 36, followed a year later by a myocardial infarction, was referred for further investigation. Coronary angiography was normal. Antinuclear factor, lupus anticoagulant, anticardiolipin antibodies, and other thrombophilia parameters were negative, but there was moderate hyperthyroidism with positive thyroid peroxidase antibodies. Platelet numbers and von Willebrand factor (vWF) were normal. Her platelets showed spontaneous aggregation that disappeared with aspirin intake. However, aggregation still was induced by low levels of ristocetin (0.3 to 0.5 mg/mL). The low-dose ristocetin aggregation in patient platelet-rich plasma (PRP) was completely blocked by neutralizing antiglycoprotein Ib (GPIb) and anti-vWF antibodies. The monoclonal anti-Fc gamma RII receptor antibody IV.3 inhibited partly, which suggests that PRP aggregation by low-dose ristocetin was elicited by vWF-immunoglobulin (Ig) complexes. Upon addition to washed human platelets, with vWF (10 micrograms/mL), purified patient Igs dose-dependently enhanced ristocetin (0.15 mg/mL)-induced aggregation between 0 and 500 micrograms/mL, an effect that disappeared again above 1 mg/mL. Aggregation was dependent on the vWF concentration and was blocked by IV.3 or neutralizing anti-GPIb or anti-vWF antibodies. The spontaneous aggregation of normal platelets resuspended in patient plasma could be inhibited totally by IV.3 and partially by neutralizing anti-GPIb or anti-vWF antibodies. Perfusion with normal anticoagulated blood, enriched with 10% of control or patient plasma, over surfaces coated with vWF showed increased platelet adhesion and activation in the presence of patient antibodies. Treatment of the patient with the antithyroid drug thiamazol and temporary corticosteroids, aspirin, and ticlopidine did not correct the platelet hypersensitivity to ristocetin. These observations suggest that some autoantibodies to vWF may both enhance vWF binding to platelets and cause platelet activation through binding to the Fc gamma RII receptor, and thereby may be responsible for a new form of antibody-mediated thrombosis.
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PMID:Recurrent arterial thrombosis linked to autoimmune antibodies enhancing von Willebrand factor binding to platelets and inducing Fc gamma RII receptor-mediated platelet activation. 953 91

Autoimmune thyroid disease (AITD) is the most common organ specific autoimmune disorder usually resulting in dysfunction (hyperfunction, hypofunction or both) of the thyroid gland. The syndromes comprising autoimmune thyroid disease are many intimately related illnesses: Graves' disease with goitre, hyperthyroidism and, in many patients, associated ophthalmopathy, Hashimoto's thyroiditis with goitre and euthyroidism or hypothyroidism but also thyroid dysfunction occurring independently of pregnancy and in 5-6% of postpartum women and thyroiditides induced by different drugs and other environmental influences. The immunological mechanisms involved in these diseases are closely related, while the phenotypes probably differ because of the specific type of immunological response that occurs. The syndromes are connected together by their similar thyroid pathology, similar immune mechanisms, co-occurrence in family groups, and transition from one clinical picture to another within the same individual over time. In some patients, other organ specific and nonorgan specific autoimmune syndromes are associated with autoimmune thyroid disease, including pernicious anemia, vitiligo, myasthenia gravis, primary adrenal autoimmune disease, celiac disease, rheumatoid arthritis or lupus. Thyroid peroxydase, TPO, the primary enzyme involved in thyroid hormonogenesis, was initially identified in 1959 as the 'thyroid microsomal antigenn. It is uncertain whether TPO autoantibodies or TPO-specific T cells are the primary cause of thyroid inflammation, which can lead, in some individuals, to thyroid failure and hypothyroidism. TPOAbs are the hallmark of AITB and are present in almost all patients with Hashimoto's thyroiditis, in two-thirds of patients with postpartum thyroiditis and also in 75% of patients with Graves' hyperthyroidism. The antibodies are mainly produced by lymphocytic infiltrate in the thyroid gland and only to a small extent by regional lymph nodes or the bone marrow. Unlike antibodies against thyroglobulin (Tg), TPO antibodies are capable of inducing antibody-dependent cell-mediated cytotoxicity. Antibodies to TSH-R mimic the function of TSH, and cause disease by binding to the TSH-R and stimulating (or inhibiting) thyroid cells. The TSHR, a member of the G protein-coupled receptor family with seven membrane-spanning segments. Patients with autoimmune thyroid disease may have both stimulating and blocking antibodies in their sera, the clinical picture being the result of the relative potency of each species; blocking antibodies seem more common in Graves' patients with ophthalmopathy compared to those without this complication. The major T cell epitopes are heterogeneous and T cell reactivity against certain TSH-R epitopes has been present in high proportion in normal subjects. More diversified response to TSH-R, with heterogeneity of epitope recognition by TSAb, is predictive of likely remission after antithyroid drug treatment for Graves' disease.
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PMID:[Diagnosis of autoimmune thyroid disease]. 1640 53

Data on thyroid disease in Arabs with lupus is scarce. We conducted a cross-sectional and retrospective case-control study to report the prevalence of thyroid diseases in 110 Arabs with lupus who attended our Rheumatology Clinic between January 2002 and January 2007, and to delineate the clinical and immunological features of Arabs lupus patients with thyroid diseases. We found hypothyroidism in 15 (13.7%) patients. Overall, 25.6% had elevated thyroid peroxidase antibodies, 14.6% had elevated anti-thyroglobulin antibodies, and 13.7% were positive for both antibodies. Lupus patients with hypothyroidism had a significantly higher frequency of polyarthritis (OR = 9.3, CI: 2.0-41.7, P < 0.001), cutaneous manifestations (OR = 5.6, CI: 2.4-14.3, P < 0.0001), positive anti-thyroglobulin antibodies (OR = 19.9, CI: 8.38-47.4, P < 0.0001), and thyroid peroxidase antibodies (OR = 12.3, CI: 6.27-24.1, P < 0.0001) than lupus patients with normal thyroid function. Furthermore, neuropsychiatric (OR = 0.36, CI: 0.14-0.93, P < 0.05) and hematological (OR = 0.52, CI: 0.29-0.91, P < 0.05) manifestations were significantly lower in patients with hypothyroidism than in euthyroid patients. Surprisingly, the prevalence of anticardiolipin antibody immunoglobulin G (aCL IgG) (OR = 0.34, CI: 0.13-0.86, P < 0.05), lupus anticoagulant (OR = 0.02, CI: 0.001-0.35, P < 0.0001), and anticardiolipin syndrome (OR = 0.02, CI: 0.001-0.43, P < 0.0001) were significantly lower in lupus patients with hypothyroidism than in lupus patients with normal thyroid function. In conclusion, the prevalence of hypothyroidism in Arabs with lupus is comparable to that reported in the literature. Arab lupus patients with hypothyroidism have distinctive clinical and immunological features that differentiate them from euthyroid patients.
Lupus 2008 Mar
PMID:Hypothyroidism determines the clinical and immunological manifestations of Arabs with lupus. 1837 63

The aim of this study was to evaluate the frequency of thyroid dysfunction and thyroid antibodies in patients with juvenile onset Systemic Lupus Erythematosus (JOSLE) and its association with clinical and immunological features. Seventy-seven patients with JOSLE, 64 females, median age 19 years, were consecutively enrolled from March to December 2007. Clinical data related to thyroid dysfunction and lupus were obtained by chart review and patient interview. Serum levels of TSH, free T4, anti-thyroglobulin (TgAb), anti-thyroperoxidase (TPOAb), TRAb and lupus related autoantibodies were analyzed by standard techniques. Nine patients were diagnosed as hypothyroidism and 4 hyperthyroidism. 28% JOSLE patients had moderate/high titer of thyroid antibodies: 23% TgAb, 2.6% TPOAb and 3.9% TRAb. JOSLE patients with positive thyroid autoantibodies had higher frequency of anti-U1RNP antibodies than patients without these antibodies (40.9 vs. 14.5%, OR:0.25, CI:0.08-0.76, p = 0.017). Furthermore, renal/neurological/hematological involvement was less frequently observed in patients with hypothyroidism (55.6 vs. 87.5%, OR:0.18, CI:0.04-0.81, p = 0.035) and with thyroid antibodies (68.4 vs. 90.9%, OR:0.22, CI:0.06-0.82, p = 0.027) than in patients without these alterations. No association with PTPN22 polymorphism was found. In conclusion, JOSLE patients have high prevalence of subclinical hypothyroidism. The novel association of anti-thyroid antibodies with anti-U1RNP antibodies in JOSLE seems to identify a subgroup of patients with less life-threatening organ involvement.
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PMID:Juvenile onset Systemic Lupus Erythematosus thyroid dysfunction: a subgroup with mild disease? 1941 39

Autoimmune thyroid disease has been associated with several systemic autoimmune disorders. However, limited data are available regarding the prevalence and clinical associations of thyroid autoimmunity in antiphospholipid syndrome (APS). Seventy-five patients with APS, 75 patients with systemic lupus erythematosus (SLE) and 75 healthy controls were tested for the presence of antithyroid antibodies (ATAs) (anti-thyroglobulin and anti-thyroid peroxidase [anti-TPO]) using commercial ELISA. Clinical data were also recorded. Although no significant differences in the prevalence of ATAs were detected among APS, SLE patient groups and healthy controls, a significant increase of anti-TPO antibodies in patients with APS-SLE was found. An increased prevalence of ATAs in APS population with ischemic central nervous system (CNS) clinical manifestations was also detected. We present novel associations between thyroid autoimmunity and ischemic CNS clinical manifestations in the setting of APS.
Lupus 2009 Oct
PMID:Antithyroid antibodies in antiphospholipid syndrome: prevalence and clinical associations. 1976 85


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