Cytochrome P450IA2 and aromatic <scp>l</scp>‐amino acid decarboxylase are hepatic autoantigens in autoimmune polyendocrine syndrome type I

Gebre-Medhin, Gennet; Husebye, ES; Gustafsson, Jan Åke; Winqvist, Ola; Goksøyr, Anders; Rorsman, Fredrik; Kämpe, Olle

doi:10.1016/s0014-5793(97)00797-7

Cited by 73 publications

(41 citation statements)

References 32 publications

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“…When we compare the self-antigens differentially regulated in Aire Ϫ/Ϫ mTECs 21 to previously identified autoantigens in APS I patients, 28 the only antigen in common is the liver enzyme CYP1A2, which was not recognized by sera from Aire Ϫ/Ϫ mice ( Figure S4). Furthermore, liver stainings with Aire Ϫ/Ϫ sera 20 do not correspond to the distribution of the CYP1A2 APS I autoantigen, 47 suggesting another identity of the liver antigen recognized by Aire Ϫ/Ϫ sera. The only autoantigen that has been identified in Aire Ϫ/Ϫ mice is ␣-fodrin, 23 but the ␣-fodrin transcript was normally regulated in Aire Ϫ/Ϫ mTECs.…”

Section: Discussionmentioning

confidence: 94%

Aire-deficient mice develop hematopoetic irregularities and marginal zone B-cell lymphoma

Hässler

Ramsey

Karlsson

et al. 2006

Blood

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Autoimmune polyendocrine syndrome type I (APS I) is an inherited recessive disorder with a progressive immunological destruction of many tissues including the adrenal cortex, the parathyroid glands, and the gonads. APS I is caused by mutations in the AIRE gene (autoimmune regulator), expressed in cells of the thymus and spleen, suggesting a role in central and peripheral tolerance. Aire ؊/؊ mice replicate the autoimmune features of APS I patients with the presence of multiple autoantibodies and lymphocytic infiltrates in various tissues, but young mice appear clinically healthy. We here report the investigation of 15-to 24-monthold Aire ؊/؊ mice. We did not observe any endocrinological abnormalities, nor did sera from these mice recognize known APS I autoantigens. Interestingly, however, there was a high frequency of marginal zone B-cell lymphoma in Aire ؊/؊ mice and liver infiltrates of B cells, suggesting chronic antigen exposure and exaggerated activation. Furthermore, increased numbers of monocytes in blood were identified as well as augmented numbers of metallophilic macrophages in the spleen. We propose that Aire, in addition to its function in the thymus, also has a peripheral regulatory role by controlling the development of antigen-presenting cells ( IntroductionIn autoimmune polyendocrine syndrome type I 1 (APS I, or autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy [APECED]; Online Mendelian Inheritance in Man [OMIM] no. 240300), an inherited autoimmune disorder without major histocompatibility complex (MHC) linkage, 2,3 patients progressively lose tolerance to various tissue-specific antigens, with ensuing endocrine and nonendocrine disorders. APS I patients suffer from multiple organ failures due to immunologic destruction of the adrenal cortex, the parathyroid glands, the liver, ␤-cells of the islets of Langerhans, and enterochromaffin cells of the small intestine. In addition, probably as a sign of immune dysfunction, the patients suffer from a chronic mucocutaneous candidiasis. 1 The prevalence of APS I is increased in Finland, Sardinia, and among Iranian Jews. [4][5][6] The disease-causing gene was localized to the long arm of chromosome 21 7 and has later been identified and named the autoimmune regulator (AIRE). 8,9 AIRE has been proposed to function as a transcription factor. [10][11][12][13][14] Aire is expressed in thymic medullary epithelial cells, in dendritic cells, [15][16][17][18] and in blood monocytes, 19 suggesting a role of Aire in both central and peripheral tolerance. To define the role of Aire in immunologic tolerance, we previously reported an Aire Ϫ/Ϫ mouse line engineered to reproduce the most common Finnish APS I mutation. 20 In analogy with APS I, Aire Ϫ/Ϫ mice display multiple organ-specific autoantibodies and lymphocytic infiltrates. 20,21 Since Aire is expressed in medullary epithelial cells of the thymus (mTEC), studies have so far focused on central tolerance and have addressed the role of Aire in negative selection. 21,22 Aire has been proposed to ac...

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Section: Discussionmentioning

confidence: 94%

Aire-deficient mice develop hematopoetic irregularities and marginal zone B-cell lymphoma

Hässler

Ramsey

Karlsson

et al. 2006

Blood

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“…Investigation of mRNA from mTEC revealed an under-representation of certain transcripts in the absence of Aire, implicating a mechanism for Aire in regulating ectopic expression of tissue-specific genes in the thymus [5]. Interestingly, in a recent report the thymic expression of mRNA encoding the self antigens insulin and cytochrome P4501A2 [51] in two patients with Omenn syndrome and one SCID patient was absent, and, in addition, mTEC from the patients lacked Aire expression [52], suggesting that the few T cells carrying a restricted TCR repertoire may escape negative selection and cause autoimmunity in the periphery. Conversely, Aire -/-mice were recently reported to target the salivary gland autoantigen afodrin in spite of normal a-fodrin mRNA levels in mTEC [28], suggesting additional factors or mechanisms determining the organ-specific autoimmunity caused by Aire deficiency, an idea which has recently been reviewed by Mathis et al [53].…”

Section: Discussionmentioning

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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“…Cytochromes P450 2A6 (CYP2A6), and mainly P450 1A2 (CYP1A2), are enzymes that have been reported as self-Ags in patients with autoimmune hepatitis (62,68); aromatic l-amino acid decarboxylase (AADC) has also been implicated (68). Other possible self-Ags are the enzymes TPH (16) and HDC (66), which are also associated with gastrointestinal dysfunction, as stated above.…”

Section: Self-antibodiesmentioning

confidence: 96%

Autoimmune polyendocrine syndrome type 1: case report and review of literature

Weiler

Silva

Lazaretti-Castro

2012

Arq Bras Endocrinol Metab

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SUMMARYAutoimmune polyendocrine syndrome type 1 (APECED) is a rare autosomal recessive disorder characterized by autoimmune multiorgan attack. The disease is caused by mutations in the autoimmune regulator gene (AIRE), resulting in defective AIRE protein, which is essential for selftolerance. Clinical manifestations are widely variable. Although the classic triad is composed by mucocutaneous candidiasis, hypoparathyroidism and adrenal failure, many other components may develop. Treatment is based on supplementation of the various deficiencies, and patients require regular follow-up throughout their lifespan. This article describes the case of a patient with the disease, and reviews literature data on the epidemiology, clinical course, immunogenetic aspects, diagnosis and treatment of the syndrome. Arq Bras Endocrinol Metab. 2012;56(1):54-66 SUMÁRIOSíndrome poliglandular autoimune tipo 1 é uma rara desordem autossômica recessiva caracterizada por ataque autoimune a diversos órgãos. A doença é causada por mutações no gene AIRE (autoimmune regulator), resultando em uma proteína AIRE defeituosa, proteína esta essencial para a manutenção da autotolerância. As manifestações clínicas são extremamente variáveis. A tríade clássica é composta por candidíase mucocutânea crônica, hipoparatiroidismo e insuficiência adrenal, porém diversos outros componentes podem estar presentes. A base do tratamento é a reposição das diversas deficiências, e os pacientes devem ser acompanhados por toda a vida. Este artigo descreve o caso de uma paciente com a síndrome e apresenta uma revisão sobre a epidemiologia, quadro clínico, aspectos imunogenéticos, diagnóstico e tratamento da desordem, de acordo com a literatura publicada. Arq Bras Endocrinol Metab. 2012;56(1):54-66

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Cytochrome P450IA2 and aromatic l‐amino acid decarboxylase are hepatic autoantigens in autoimmune polyendocrine syndrome type I

Cited by 73 publications

References 32 publications

Aire-deficient mice develop hematopoetic irregularities and marginal zone B-cell lymphoma

Aire-deficient mice develop hematopoetic irregularities and marginal zone B-cell lymphoma

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

Autoimmune polyendocrine syndrome type 1: case report and review of literature

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