Two different cytochrome P450 enzymes are the adrenal antigens in autoimmune polyendocrine syndrome type I and Addison's disease.

Winqvist, Ola; Gustafsson, Jan Åke; Rorsman, Fredrik; Karlsson, F. Anders; Kämpe, Olle

doi:10.1172/jci116843

Cited by 181 publications

(103 citation statements)

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“…It has been found that the adrenal cytochrome p450 enzyme 21 hydroxylase (which converts 17-␣-progesterone and progesterone into 11-deoxy- (191,192), either in the form of isolated adrenal failure or associated with hypothyroidism (type II APGS). In type I APGS it is thought that autoantibodies are directed to other members of the cytochrome p450 enzyme family, namely to the p450 side-chain cleavage enzyme (p450-scc) and to 17-␣-hydroxylase (17-␣-OH) (192)(193)(194)(195)(196), and to an ill-defined 51-kDa protein (197). However, there is some confusion on this subject, and not all investigators could confirm the presence of these autoantibodies in type 1 APGS [negative results: p450-scc (198); 17-␣-OH (198,199)].…”

Section: A Antibodies In Pof Patients With Adrenal Autoimmunity And/mentioning

confidence: 99%

“…In type I APGS it is thought that autoantibodies are directed to other members of the cytochrome p450 enzyme family, namely to the p450 side-chain cleavage enzyme (p450-scc) and to 17-␣-hydroxylase (17-␣-OH) (192)(193)(194)(195)(196), and to an ill-defined 51-kDa protein (197). However, there is some confusion on this subject, and not all investigators could confirm the presence of these autoantibodies in type 1 APGS [negative results: p450-scc (198); 17-␣-OH (198,199)]. Of the steroidogenic p450 enzymes 21-hydroxylase is adrenal-specific, 17-␣-OH is expressed in both adrenals and gonads, whereas p450-scc is present in adrenal, gonads, and placenta.…”

Section: A Antibodies In Pof Patients With Adrenal Autoimmunity And/mentioning

confidence: 99%

See 1 more Smart Citation

Premature Ovarian Failure and Ovarian Autoimmunity

Hoek¹

1997

Endocrine Reviews

212

221

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Section: A Antibodies In Pof Patients With Adrenal Autoimmunity And/mentioning

confidence: 99%

Section: A Antibodies In Pof Patients With Adrenal Autoimmunity And/mentioning

confidence: 99%

Premature Ovarian Failure and Ovarian Autoimmunity

Hoek¹

1997

Endocrine Reviews

212

221

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“…APS I patients develop a progressive loss of tolerance against self antigens and suffer from multiorgan failures due to the immunological destruction of adrenals, parathyroid glands and b cells of the islets of Langerhans [11]. Many of the APS I organ-specific autoantigens have been identified and characterized [12,13]. In addition, as a sign of immune dysfunction, these patients have difficulties clearing Candida albicans infections in mucosal membranes [14].…”

Section: Introductionmentioning

confidence: 99%

“…Many of the APS I organ-specific autoantigens have been identified and characterized [12,13]. In addition, as a sign of immune dysfunction, these patients have difficulties clearing Candida albicans infections in mucosal membranes [14].…”

Section: Introductionmentioning

confidence: 99%

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

et al. 2006

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Patients with autoimmune polyendocrine syndrome type I (APS I)suffer from endocrine and non-endocrine disorders due to mutations in the autoimmune regulator gene (AIRE). Mouse Aire is expressed both in thymic medullary epithelial cells and in peripheral antigen-presenting cells, suggesting a role in both central and peripheral tolerance. We here report that Aire -/-dendritic cells (DC) activate naive T cells more efficiently than do Aire +/+ DC. Expression array analyses of Aire -/-DC revealed differential regulation of 68 transcripts, among which, the vascular cell adhesion molecule-1 (VCAM-1) transcript was up-regulated in Aire -/-DC. Concurrently, the expression of the VCAM-1 protein was up-regulated on both Aire -/-DC and monocytes from APS I patients. Blocking the interaction of VCAM-1 prevented enhanced Aire -/-DC stimulation of T cell hybridomas. We determined an increased number of DC in spleen and lymph nodes and of monocytes in the blood from Aire -/-mice, and an increased number of blood monocytes in APS I patients. Our findings imply a role for Aire in peripheral DC regulation of T cell activation, and suggest that Aire participates in peripheral tolerance.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/35240_s.pdf IntroductionInactivation of the autoimmune regulator gene (AIRE) [1][2][3] causes autoimmunity in patients with autoimmune polyendocrine syndrome type I (APS I, APECED, OMIM 240300) and in a gene targeted mouse model [4,5]. APS I is a rare monogenic autosomal recessive disease without HLA association [6,7], which is prevalent in isolated populations [8][9][10]. APS I patients develop a progressive loss of tolerance against self antigens and suffer from multiorgan failures due to the immunological destruction of adrenals, parathyroid glands and b cells of the islets of Langerhans [11]. Many of the APS I organ-specific autoantigens have been identified and characterized [12,13]. In addition, as a sign of immune dysfunction, these patients have difficulties clearing Candida albicans infections in mucosal membranes [14]. Functional studies of AIRE suggest a role as a transcription factor and in vitro transactivating studies support this notion [15][16][17][18]. Moreover, the PHD1 domain of AIRE has been suggested to have an E3 ubiquitin ligase activity in cell-free assays [19], findings in variance with a recent report [20]. Aire is highly expressed in a subset of the medullary thymic epithelial cells (mTEC) as well as in DC in the spleen and lymph nodes [21][22][23][24], indicating a potential role in immunological tolerance.To characterize the function of Aire, we previously engineered an Aire-deficient mouse targeting the most common APS I mutation [4]. Aire-deficient mice develop multiple organ-specific autoantibodies and lymphocytic infiltrates, thus mimicking some of the features of human APS I [4]. Subsequently, the role of Aire in negative selection was demonstrated [5]. These findings were further supported using TCR transgenic mic...

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“…Furthermore, CYP2D6 is a target of anti-liver kidney microsome type I (LKM-1), present in type II autoimmune hepatitis and in virus C hepatitis (12). Epitopes in CYP11A (cholesterol side-chain cleavage enzyme), CYP17 (steroid-17␣ hydroxylase), and CYP21A2 (steroid-21␣ hydroxylase) are also recognized by autoantibodies associated with autoimmune polyendocrine syndrome and autoimmune Addison's disease (13,14). For some of these autoantibodies, extensive epitope mapping studies have been performed to get a better understanding of the mechanisms leading to autoimmunity (15)(16)(17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

Use of Molecular Simulation for Mapping Conformational CYP2E1 Epitopes

Vidali

Hidestrand

Eliasson

et al. 2004

Journal of Biological Chemistry

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The identification of the epitopes recognized by autoantibodies against cytochrome P450s (CYPs) associated with drug-induced hepatotoxicity is difficult because of their conformational nature. In the present investigation, we used a novel approach based on the analysis of the whole molecule antigenic capacity following single amino acid substitutions to identify the conformational epitopes on CYP2E1. A molecular model of CYP2E1 was generated based on the CYP2C5 crystal structure, and potential motifs for amino acid exchanges were selected by computer simulation in the surface of ␣ helices and ␤ sheets. Fourteen modified, apparently correctly folded CYP2E1 variants were produced in Escherichia coli and evaluated in immunoprecipitation experiments using sera with anti-CYP2E1 autoreactivity from 10 patients with halothane hepatitis and 12 patients with alcoholic liver disease. Ala substitution of Glu-248 and Lys-251 as well as of Lys-324, Lys-342, Lys-420, and Phe-421 severely decreased or abolished CYP2E1 recognition by the majority of both the halothane hepatitis and alcoholic liver disease sera, whereas the other substitutions had only minor effects. Based on the structural model, these substitutions identified two distinct epitopes on the CYP2E1 surface corresponding to the G-helix and an area formed by juxtaposition of the J and K؆ helices, respectively. The combined use of molecular modeling and single amino acid mutagenesis is thus a useful approach for the characterization of conformational epitopes recognized by autoantibodies.

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Two different cytochrome P450 enzymes are the adrenal antigens in autoimmune polyendocrine syndrome type I and Addison's disease.

Cited by 181 publications

References 36 publications

Premature Ovarian Failure and Ovarian Autoimmunity

Premature Ovarian Failure and Ovarian Autoimmunity

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

Use of Molecular Simulation for Mapping Conformational CYP2E1 Epitopes

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