The APECED polyglandular autoimmune syndrome protein, AIRE-1, contains the SAND domain and is probably a transcription factor.
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Amino Acid Sequence↗
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Two novel mutations of the AIRE protein affecting its homodimerization properties.
We report two novel mutations, c.230T>C (p.F77S) and c.64_69del (p.V22_D23del) within the HSR domain of the AIRE protein in two patients of Italian descent affected by APECED. Both mutations were found in the compound heterozygous state respectively with c.994+5G>T and c.232T>A (p.W78R). With the two-hybrid assay in the yeast system we found that constructs containing the two mutations fail to interact with the wild-type protein. These findings indicate that both mutations negatively affected the homodimerization properties of the AIRE protein, thereby leading to a defective function.
Adult↗
Projection of an immunological self shadow within the thymus by the aire protein.
Humans expressing a defective form of the transcription factor AIRE (autoimmune regulator) develop multiorgan autoimmune disease. We used aire- deficient mice to test the hypothesis that this transcription factor regulates autoimmunity by promoting the ectopic expression of peripheral tissue- restricted antigens in medullary epithelial cells of the thymus. This hypothesis proved correct. The mutant animals exhibited a defined profile of autoimmune diseases that depended on the absence of aire in stromal cells of the thymus. Aire-deficient thymic medullary epithelial cells showed a specific reduction in ectopic transcription of genes encoding peripheral antigens. These findings highlight the importance of thymically imposed "central" tolerance in controlling autoimmunity.
Aging↗
Determination of surface tensions of proteins. II. Surface tension of serum albumin, altered at the protein-air interface.
Serum albumin, which itself has a surface tension of congruent to 70.3 erg/cm2, when dissolved in water lowers the surface tension of water from 72.5 to congruent to 50 erg/cm2, as measured by a variety of means, including the pendant drop, the Wilhelmy plate and the platinum ring methods. Equally low and even lower surface tensions are found with the contact angle method, on a thin layer of albumin that had been adsorbed onto a low energy surface and subsequently exposed to air. Surface tensions of drops of albumin solutions varying in concentration from 0.01 to 5.5% (w/v) yielded, with a contact angle method, values that only varied between 67 and 61 erg/cm2. With the pendant drop, the Wilhelmy plate and the platinum ring methods, one essentially measures the surface tension at the air-liquid interface, at which proteins tend to adsorb, and where reversible or irreversible reorientation can be expected. The same holds for a thin layer of protein adsorbed onto a low energy surface, exposed to air. Thus, when through the very act of surface tension measurement, or after adsorbing protein onto a substrate, protein is exposed at the air-liquid interface, it apparently loses the pronounced hydrophilicity characteristic of its native hydrated state and manifests through reorientation a much more hydrophobic tertiary configuration.
Air↗
AIRE and APECED: molecular insights into an autoimmune disease.
Mutations in the autoimmune regulator (AIRE) protein are the causative factor in development of the human disease autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). In mice, the absence of the analogous protein aire influences ectopic expression of peripheral tissue antigens in thymic medullary epithelial cells (MECs), resulting in the development of an autoimmune disorder similar to APECED and establishing aire/AIRE as an important player in the induction of central tolerance. However, the molecular mechanism of AIRE's function, in particular its ability to specifically control the expression of peripheral tissue antigens in MECs, is still unclear. Here, we review current evidence relating to the molecular mechanism of AIRE.
Animals↗
RNA and protein expression of the murine autoimmune regulator gene (Aire) in normal, RelB-deficient and in NOD mouse.
Mutations in the putative transcription factor autoimmune regulator (AIRE) gene are responsible for autoimmune polyendocrinopathy-candidiosis-ectodermal dystrophy (APECED; OMIM#240300), a monogenic recessively inherited disease characterized by destructive autoimmune diseases of the endocrine organs, chronic candidiosis of mucous membranes and ectodermal dystrophies. In this study the expression of murine homolog for AIRE protein, Aire, was detected in a fraction of thymic medullary epithelial cells. Subcellularly, in thymus the protein appears as concentrated into nuclear dot-like structures, whereas in transfected cells the protein is also bound along a cytosolic fibrillar network. By RT-PCR Aire mRNA was detected in thymus, lymph node, spleen and testis although the second round PCR amplified Aire specific band from most mouse tissues analyzed. Furthermore, the Aire mRNA was detected in dendritic cell (DC) populations isolated from thymus and spleen, representing both myeloid- and lymphoid-related lineages of DC. We also demonstrate that the Aire protein is absent in the thymus of RelB-deficient mouse and in NOD thymus most of the Aire positive cells showed an abnormal morphology. These results suggest that the Aire protein is associated with the normal development and/or action of a subset of thymic medullary stromal cells involved in tolerance induction.
Alternative Splicing↗
Ice as a matrix for IR-matrix-assisted laser desorption/ionization: mass spectra from a protein single crystal.
Lasers emitting in the ultraviolet wavelength range of 260-360 nm are almost exclusively used for matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) of macromolecules. Reports about the use of lasers emitting in the infrared first appeared in 1990/1991. In contrast to MALDI in the ultraviolet, a very limited number of reports on IR-MALDI have since been published. Several matrices have been identified for infrared MALDI yielding spectra of a quality comparable to those obtained in the ultraviolet. Water (ice) was recognized early as a potential matrix because of its strong O-H stretching mode near 3 microm. Interest in water as matrix derives primarily from the fact that it is the major constituent of most biological tissues. If functional as matrix, it might allow the in situ analysis of macromolecular constituents in frozen cell sections without extraction or exchanging the water. We present results that show that IR-MALDI of lyophilized proteins, air dried protein solutions, or protein crystals up to a molecular mass of 30 kDa is possible without the addition of any separate matrix. Samples must be frozen to retain a sufficient fraction of the water of hydration in the vacuum. The limited current sensitivity, requiring at least 10 pmol of protein for a successful analysis needs to be further improved.
Animals↗
Alterations in lumbar cerebrospinal fluid protein during air encephalography.
A significant fall occurred in the protein content of successive specimens of lumbar cerebrospinal fluid (C.S.F.) withdrawn during the course of air encephalography in 57% of cases. No correlation was found between the fall in the protein concentration and the total volume of air injected or the total volume of C.S.F. withdrawn, but the size of the fall was greater when the initial lumbar C.S.F. protein concentration was raised. The importance of taking specimens for routine laboratory analysis before the injection of any air is emphasized.
Adolescent↗
Population genetics and functions of the autoimmune regulator (AIRE).
The autoimmune polyglandular syndrome type 1 (APS1), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APS1), is a monogenic autosomal disease with recessive inheritance. It is characterized by chronic mucocutaneous candidiasis, multiple autoimmune endocrinopathies, and ectodermal dystrophies. The defective gene responsible for this disease has been identified and named "autoimmune regulator" (AIRE). The AIRE gene is located on chromosome 21q22.3. At least 45 different disease-causing mutations in AIRE have been discovered. This review summarizes the global distribution of AIRE mutations and the relevance of major mutations to the clinical disorders associated with APS1. We also will review studies on the structure and DNA-binding ability of the AIRE protein and the possible malfunctions of the AIRE protein as a result of major disease-causing mutations.
Binding Sites↗
Functional analysis of SAND mutations in AIRE supports dominant inheritance of the G228W mutation.
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare disorder caused by mutations in the autoimmune regulator gene (AIRE) and characterized by a variable combination of organ-specific autoimmune diseases. Studies on AIRE-deficient mice suggest that AIRE is an important factor in the establishment and maintenance of self-tolerance. The AIRE protein contains several structural domains often found in transcriptional regulators and functions as a transcriptional transactivator in vitro. To date, more than 50 patient mutations have been identified in the coding region of the AIRE gene. So far, APECED has been reported to be inherited in an autosomal recessive manner. However, in contrast to all other AIRE mutations, a novel mutation c.682T>G (p.G228W) in the DNA-binding and/or multimerization domain SAND was recently described to be inherited in a dominant fashion. We analyzed the effects of mutant AIRE proteins containing the patient mutations c.682T>G (p.G228W) and c.755C>T (p.P252L) located in the SAND domain on the properties of the wild-type AIRE in a heterozygous situation in vitro. In addition to the patient mutations, we analyzed the effects of a double mutation [c.727A>G;c.728A>C;c.739C>G;c740G>C] (p.K243A;R247A) of positively charged amino acids in the SAND domain. Of the mutants studied, only c.682T>G (p.G228W) mutant changed the subcellular localization and in addition severely disrupted the transactivating capacity of the wild-type AIRE. Our results indicate that the c.682T>G (p.G228W) mutant AIRE protein acts with a dominant negative effect by binding to the wild-type AIRE, thus preventing the protein from forming the complexes needed for transactivation.
Animals↗
Dual intracellular localization and targeting of aminoimidazole ribonucleotide synthetase in cowpea.
De novo purine biosynthesis is localized to both mitochondria and plastids isolated from Bradyrhizobium sp.-infected cells of cowpea (Vigna unguiculata L. Walp) nodules, but several of the pathway enzymes, including aminoimidazole ribonucleotide synthetase (AIRS [EC 6.3.3.1], encoded by Vupur5), are encoded by single genes. Immunolocalization confirmed the presence of AIRS protein in both organelles. Enzymatically active AIRS was purified separately from nodule mitochondria and plastids. N-terminal sequencing showed that these two isoforms matched the Vupur5 cDNA sequence but were processed at different sites following import; the mitochondrial isoform was five amino acids longer than the plastid isoform. Electrospray tandem mass spectrometry of a trypsin digest of mitochondrial AIRS identified two internal peptides identical with the amino acid sequence deduced from Vupur5 cDNA. Western blots of proteins from mitochondria and plastids isolated from root tips showed a single AIRS protein present at low levels in both organelles. (35)S-AIRS protein translated from a Vupur5 cDNA was imported into isolated pea (Pisum sativum) leaf chloroplasts in vitro by an ATP-dependent process but not into import-competent mitochondria from several plant and non-plant sources. Components of the mature protein are likely to be important for import because the N-terminal targeting sequence was unable to target green fluorescent protein to either chloroplasts or mitochondria in Arabidopsis leaves. The data confirm localization of the protein translated from the AIRS gene in cowpea to both plastids and mitochondria and that it is cotargeted to both organelles, but the mechanism underlying import into mitochondria has features that are yet to be identified.
Amino Acid Sequence↗
Breathing air from protein foam.
Protein foams can be used to extinguish fires. If foams are to be used to extinguish fires where people are present, such as in high-rise buildings or ships, then a method for allowing people to breathe in a foam-filled environment is needed. It is proposed that the air, used to create the foam be used for breathing. A canister that will break incoming air-filled foam has been designed for attachment to a standard gas mask, in order to provide breathable air to a trapped person. Preliminary results for the modified mask indicate feasibility of breathing air from air-filled protein foam.
Antifoaming Agents↗
Role of the autoimmune regulator (AIRE) gene in alopecia areata: strong association of a potentially functional AIRE polymorphism with alopecia universalis.
Alopecia areata is characterized by a reversible form of patchy or complete hair loss associated with T-cell infiltration of hair follicles. The lifetime disease risk of approximately 1.4% in the general population is increased to more than 30% in autoimmune polyendocrinopathy candidiasis ectodermal dysplasia syndrome (APECED), a recessive condition resulting from a mutation of the autoimmune regulator (AIRE) gene on chromosome 21q22.3. Aire protein is thought to have transcriptional regulatory activity but its role is not well defined at present. In this study, we have examined the possible involvement of AIRE in the pathogenesis of alopecia areata. On screening the AIRE coding sequence, we identified 20 variants. Two of these at positions, G961C and T1029C, give rise to amino acid changes, S278R and V301A, located in the DNA-binding segment (SAND) and PHD1 zinc finger motif, respectively. We found no difference in the frequency of the AIRE T1029C polymorphism between the control and patient groups. We genotyped 202 alopecia areata patients and 175 matched Caucasian controls for the AIRE G961C alleles. The frequency of the rare allele (961G) was 0.08 in the controls and there was a significant increase to 0.13 in alopecia areata overall and 0.20 in severe disease (alopecia universalis). We found no association between the AIRE G961G variant and mild (patchy) alopecia areata or alopecia totalis. However, the AIRE 961G allele is a potent risk factor (> 3) for the severest form of alopecia areata, and for disease of early age at onset (at 30 years). The change from serine to arginine in the SAND domain of AIRE protein may have a significant effect on AIRE DNA-binding activity. Moreover, our results could provide a rational explanation of the unusually high frequency of AA in APECED patients, supporting the concept of AA as an autoimmune disease.
Adolescent↗
Induction of selected lipid metabolic enzymes and differentiation-linked structural proteins by air exposure in fetal rat skin explants.
The epidermal permeability barrier of premature infants matures rapidly following birth. Previous studies suggest that air exposure could contribute to this acceleration, because: (i) development of a structurally and functionally mature barrier accelerates when fetal rat skin explants are incubated at an air-medium interface, and (ii) occlusion with a water-impermeable membrane prevents this acceleration. To investigate further the effects of air exposure on epidermal barrier ontogenesis, we compared the activities of several key enzymes of lipid metabolism and gene expression of protein markers of epidermal differentiation in fetal rat skin explants grown immersed versus air exposed. The rate-limiting enzymes of cholesterol (HMG CoA reductase) and ceramide (serine palmitoyl transferase) synthesis were not affected. In contrast, the normal developmental increases in activities of glucosylceramide synthase and cholesterol sulfotransferase, responsible for the synthesis of glucosylceramides and cholesterol sulfate, respectively, were accelerated further by air exposure. Additionally, two enzymes required for the final stages of barrier maturation and essential for normal stratum corneum function, beta-glucocerebrosidase, which converts glucosylceramide to ceramide, and steroid sulfatase, which desulfates cholesterol sulfate, also increased with air exposure. Furthermore, filaggrin and loricrin mRNA levels, and filaggrin, loricrin, and involucrin protein levels all increased with air exposure. Finally, occlusion with a water-impermeable membrane prevented both the air-exposure-induced increase in lipid enzyme activity, and the expression of loricrin, filaggrin, and involucrin. Thus, air exposure stimulates selected lipid metabolic enzymes and the gene expression of key structural proteins in fetal epidermis, providing a biochemical basis for air-induced acceleration of permeability barrier maturation in premature infants.
Acyltransferases↗
Concentration of legume proteins by air classification.
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Fabaceae↗
Autoimmune regulator: from loss of function to autoimmunity.
The autoimmune regulator (AIRE) is a gene where mutations cause the recessively inherited disorder called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) or autoimmune polyendocrinopathy syndrome type 1 (APS1). Variable combinations of autoimmune endocrine diseases such as Addison's disease, hypoparathyroidism, and type 1 diabetes characterize APECED. The AIRE protein has several domains indicative of a transcriptional regulator. AIRE contains two PHD (plant homeodomain) type zinc fingers, four nuclear receptor binding LXXLL motifs, a putative DNA-binding domain named SAND and, in addition, a highly conserved N-terminal domain similar to the homogenously staining region domain of the Sp100 protein. At the subcellular level, AIRE is expressed in nuclear dots resembling promyelocytic leukemia nuclear bodies, which are associated with several transcriptionally active proteins. AIRE is primarily expressed in thymic medullary epithelial cells and monocyte-dendritic cells in the thymus but also in a rare subset of cells in the lymph nodes, spleen and fetal liver. The disease, caused by mutations in AIRE, its function as a protein involved in transcription, and its restricted expression in cells important in negative selection, all together suggest that AIRE is a central protein in the maintenance of immune tolerance. In this review of the recent literature we discuss the results of these studies with particular attention on the AIRE expression pattern and its function as a transcriptional regulator, as well as the effects of patient mutations on the molecular characteristics of the protein.
Animals↗
AIRE and immunological tolerance: insights from the study of autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy.
PURPOSE OF REVIEW: To review the clinical and molecular features of autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy and discuss recent advances in the function of the AIRE protein. We will summarize how AIRE contributes to immunological tolerance, and thus to the prevention of autoimmunity. RECENT FINDINGS: The organization of a well-structured thymic microenvironment and the interaction between nascent thymocytes and thymic epithelial cells have been shown to be essential for AIRE expression. AIRE is involved in the expression of ectopic proteins by medullary thymic epithelial cells. This allows the establishment of central tolerance and contributes to the prevention of organ-specific autoimmunity, as shown by findings in patients with autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy (a disease caused by AIRE gene mutations) and in aire (-/-) mice. SUMMARY: Autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy represents a unique model to investigate the cellular and molecular mechanisms that govern central tolerance and help prevent autoimmunity. Recent findings indicate that the compartmentalization of AIRE and interaction with other proteins are involved in this mechanism. The disturbance of AIRE expression may also be responsible for autoimmune manifestations in disorders with disrupted thymic structure other than autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy alone.
Candidiasis↗
Insulin-like growth factor binding proteins in air- and 85% oxygen-exposed adult rat lung.
Expression of insulin-like growth factor (IGF) I and its type I receptor is increased in the adult rat lung exposed to 85% O2. We hypothesized that there would be a parallel up- and downregulation of growth-stimulating and growth-inhibiting IGF binding proteins (IGFBPs), respectively. The normal adult rat lung expresses mRNAs for IGFBP-2, -3, -4, -5, and -6 but not for IGFBP-1. O2 exposure for 6 or 14 days reduced IGFBP-3 and -6 and increased IGFBP-4 mRNA abundance. IGFBP-5 mRNA was reduced at 6 days but increased at 14 days. IGFBP-4 mRNA was localized to perivascular and peribronchial interstitial cells and IGFBP-5 mRNA to airway and alveolar epithelial cells. IGFBP-2, -4, and -5 immunolocalized to airway epithelial cells in normal lung and to perivascular exudates after 6 days in 85% O2. IGFBP-2 was diffusely increased throughout the lung tissue only after a 6-day exposure. IGFBP-5 was reduced after a 6-day exposure but was increased and widely distributed after 14 days. IGFBP-4 increased over airway epithelium and subepithelial cells after 6 days and over perivascular interstitial cells after 14 days of 85% O2. These data are consistent with the predicted changes for IGFBPs on O2 exposure except that the generally growth-inhibitory IGFBP-4 was increased at sites of active cell proliferation.
Air↗