Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004364 (autoimmune disease)
 24,845 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autoimmune regulator (AIRE) is a transcriptional regulator that is believed to control the expression of tissue-specific genes in the thymus. Mutated AIRE is responsible for onset of the hereditary autoimmune disease APECED. AIRE is able to form nuclear bodies (NBs) and interacts with the ubiquitous transcriptional coactivator CBP. In this paper, we show that CBP and AIRE synergistically activate transcription on different promoter reporters whereas AIRE gene mutation R257X, found in APECED patients, interferes with this coactivation effect. Furthermore, the overexpression of AIRE and CBP collaboratively enhance endogenous IFNbeta mRNA expression. The immunohistochemical studies suggest that CBP, depending on the balance of nuclear proteins, is a component of AIRE NBs. We also show that AIRE NBs are devoid of active chromatin and, therefore, not sites of transcription. In addition, we demonstrate by 3D analyses that AIRE and CBP, when colocalizing, are located spatially differently within AIRE NBs. In conclusion, our data suggest that AIRE activates transcription of the target genes, i.e., autoantigens in collaboration with CBP and that this activation occurs outside of AIRE NBs.
 ...
PMID:Cooperative activation of transcription by autoimmune regulator AIRE and CBP. 1596 47

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy is a rare recessive autoimmune disorder caused by a defect in a single gene called AIRE (autoimmune regulator). Characteristics of this disease include a variable combination of autoimmune endocrine tissue destruction, mucocutaneous candidiasis and ectodermal dystrophies. The development of Aire-knockout mice has provided an invaluable model for the study of this disease. The aim of this review is to briefly highlight the strides made in APECED research using these transgenic murine models, with a focus on known roles of Aire in autoimmunity. The findings thus far are compelling and prompt additional areas of study which are discussed.
 ...
PMID:The development of mouse APECED models provides new insight into the role of AIRE in immune regulation. 1629 27

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, or APS1), is a monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. The three main components of APECED are chronic mucocuteaneous candidiasis, hypoparathyroidism and adrenocortical insufficiency. However, several additional endocrine or other autoimmune disease components, or ectodermal dystrophies form the individually variable clinical picture of APECED. An important feature of APECED is a spectrum of well-characterized circulating autoantibodies, reacting against tissue-specific autoantigens. Aire deficient mice develop some characteristics of APECED phenotype. In order to investigate whether the Aire deficient mice produce autoantibodies similar to human APECED, we studied the reactivity of Aire mouse sera against mouse homologues of 11 human APECED antigens. None of the APECED antigens indicated elevated reactivity in the Aire knock-out mouse sera, implying the absence of APECED associated autoantibodies in Aire deficient mice. These findings were supported by the failure of the autoantigens to activate mouse T-cells. Furthermore, Aire knock-out mice did not express increased levels of anti-nuclear antibodies compared to wt mice. This study indicates that spontaneous induction of tissue-specific autoantibodies similar to APECED does not occur in the rodent model suggesting differences in the immunopathogenic mechanisms between mice and men.
 ...
PMID:Aire deficient mice do not develop the same profile of tissue-specific autoantibodies as APECED patients. 1682 Feb 79

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal-recessive autoimmune disease caused by autoimmune regulator gene mutations. The aim of this study was to examine the mutation profile of Polish APECED patients, determine the carrier rate of the most frequent mutation(s) and estimate disease prevalence. While studying 14 unrelated patients, we identified three novel mutations (c.1A>T, affecting the start codon; [IVS1 + 1G>C; IVS1 + 5delG], a complex mutation affecting splice site; c. 908G>C, p.R303P, a missense mutation in plant homeodomain (PHD) and three previously reported mutations (c.769C>T, p.R257X; c.967_979del13bp, C322fsX372; c.931delT, p.C311fsX376). Eleven patients had mutations on both chromosomes, whereas in three patients only a single alteration with proven or likely pathogenic effect was detected. The most frequent was the p.R257X mutation (71% of chromosomes); its carriage rate was assessed in the background population. Analysis of 2008 samples showed eight heterozygotes, indicating the frequency of 0.40% (1:250) and the disease prevalence - 1:129,000 (95% confidence interval: 1:555,000 to 1:30,000). Comparison with an epidemiological estimate (1:619,000, derived for women) suggested that in Poland, APECED is underdiagnosed. Among the patients, no genotype/phenotype correlations were found, but we noted that women had earlier onset of hypoparathyroidism (p < 0.02) and were younger at diagnosis (p < 0.05) than men.
 ...
PMID:Molecular background of polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome in a Polish population: novel AIRE mutations and an estimate of disease prevalence. 1696 30

Patients with Autoimmune polyendocrine syndrome type I (APS I) present with multiple endocrine failures due to organ-specific autoimmune disease, thought to be T-cell-mediated. Paradoxically, APS I patients suffer from chronic mucocutaneous candidiasis. The mutated gene has been identified as the Autoimmune regulator (AIRE). Aire is expressed in medullary epithelial cells of the thymus and in antigen presenting cells in the periphery. T cells from Aire deficient mice and men displayed an enhanced proliferative response against Candida antigen in vitro, suggesting that Aire deficient T cells are competent in recognizing Candida albicans. In contrast, monocytes from APS I patients displayed a decreased and delayed internalization of zymosan. Furthermore, Candida antigen activated monocytes from APS I patients show decreased and altered phoshotyrosine kinase activation. In conclusion, Aire deficient APCs have a defect receptor mediated internalization of Candida which affects kinase activation, likely altering the innate Candida immune response.
 ...
PMID:Defect internalization and tyrosine kinase activation in Aire deficient antigen presenting cells exposed to Candida albicans antigens. 1698 13

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I, is a rare autosomal recessively inherited disorder characterized by variable combinations of endocrine and nonendocrine symptoms. In this report, we describe two 20- and 17-year-old Turkish siblings presenting with typical symptoms of APECED, including Addison disease, alopecia, vitiligo, and hypopituitarism, in whom electrocardiographic examinations demonstrated an abnormal prolongation of the QT interval. In both cases, excessive hypocalcemia due to primary hypoparathyroidism was identified as the underlying cause of the long QT syndrome. Sequencing the gene coding for the autoimmune regulator revealed a homozygous missense mutation in exon 14 with a C-to-T transition that resulted in the substitution of proline 539 for leucine in the carboxy-terminal protein molecule. Our data show that a single point mutation in the transcriptional active autoimmune regulator protein is associated with inherited alterations in calcium metabolism resulting from autoimmune reactions against the parathyroid glands. This finding defines a congenital autoimmune disease as a hereditary long QT syndrome.
 ...
PMID:Hereditary long QT syndrome due to autoimmune hypoparathyroidism in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. 1728 71

Isolated and acquired hypoparathyroidism occurs as an autoimmune disorder either alone or in association with other autoimmune diseases. Reduced PTH (parathyroid hormone) secretion due to disorder of Ca-sensing regulation in parathyroid gland is most commonly caused by activating mutations of the CaSR (Ca-sensing receptor) gene. There has been accumulating evidence that it also occurs as a result of activating autoantibodies directed to CaSR. Hypoparathyroidism is one of the most common endocrine manifestation in APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy) , which is also known as APS (Autoimmune Polyendocrinopathy Syndrome) type I . In APECED, the spectrum of epitope responsible for the hypoparathyroidism is presumably CaSR. It remains unclear how autoimmunity against CaSR occurs and how much patients caused by this disorder exist.
 ...
PMID:[Hypoparathyroidism associated with autoimmune disorder]. 1766 Jun 15

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomic autoimmune disease resulting from the defective function of a gene codifying for a transcription factor named autoimmune regulation (AIRE). The AIRE protein contains several domains among which two PHD fingers involved in the transcriptional activation. We investigated the function of the two PHD finger domains and the COOH terminal portion of AIRE by using several mutated constructs transfected in mammalian cells and a luciferase reporter assay. The results predict that the second PHD as well as the COOH terminal regions have marked transactivational properties. The COOH terminal region contains the fourth LXXLL and the PXXPXP motifs which play a critical role in mediating the transactivation capacity of the AIRE protein. Our study provides a definition of the role of the PHD fingers in transactivation and identifies a new transactivation domain of the AIRE protein localized in the COOH terminal region.
 ...
PMID:Role of PHD fingers and COOH-terminal 30 amino acids in AIRE transactivation activity. 1767 38

Autoimmune diseases constitute a heterogeneous group of disorders characterized by the loss of immune tolerance to self-antigens. Despite their distinct clinical picture, there is growing evidence that common molecular mechanisms may contribute to the whole spectrum of autoimmune diseases. This theory is strongly supported by the existence of the autoimmune polyendocrine syndromes (APS). Thus, the clinical diagnosis of APS1 is made in an individual who presents with at least two out of three cardinal symptoms, namely autoimmune Addison's disease, autoimmune hypoparathyroidism, and mucocutaneous candidiasis. APS1 is a rare autosomal recessive syndrome caused by mutations in the autoimmune regulator (AIRE) gene. APS2, which occurs at a much higher frequency, is classically defined as the coexistence of autoimmune Addison's disease, autoimmune thyroid disease, and/or type 1 diabetes. In contrast to APS1, the precise modes of inheritance and the genetic causes underlying APS2 remain unknown. Identification of genetic factors predisposing to this syndrome may contribute to our understanding of common mechanisms involved in autoimmunity.
 ...
PMID:Genetic dissection of autoimmune polyendocrine syndrome type 2: common origin of a spectrum of phenotypes. 1791 31

AIRE (autoimmune regulator) promotes the establishment of self-tolerance by regulating gene expression in the thymus. Mutations in AIRE lead to an autoimmune disease, APECED. Here we have identified PIAS proteins as novel AIRE interaction partners. Although PIAS proteins function as E3 SUMO ligases, AIRE is not sumoylated. We expressed AIRE, wt PIAS1, and PIAS1 mutants with deleted SP-RING domain or SUMO interaction motif (SIM) in different cell lines and demonstrate that AIRE and PIAS1 localize to adjacent nuclear bodies (NBs). The expression of AIRE enhances the formation of PIAS1 NBs. The ability of PIAS1 to localize into NBs and interconnect with AIRE is neither dependent on the SP-RING domain nor the SIM. Further, we show that PIAS1 is able to attract AIRE into SUMO1-containing complexes and that the process is dependent on the SIM of PIAS1. PIAS1 and AIRE concurrently activate the human insulin promoter, a known target gene of AIRE, and the SP-RING is required for this activation. Moreover, AIRE represses and PIAS1 activates the CSTB promoter, used as a model for a housekeeping promoter, and both the SP-RING and SIM are needed for its activation by PIAS1. Collectively, our data suggest that AIRE and PIAS1 interact functionally to regulate the activities of the target genes of AIRE.
 ...
PMID:Functional interaction of AIRE with PIAS1 in transcriptional regulation. 1808 34


<< Previous 1 2 3 4 5 Next >>