SEARCH · Search PubMed

Results for “Mediator Complex”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 415 records · Page 23Linked to original sources

PubMed1989

C1q binding to human vascular smooth muscle cells mediates immune complex deposition and superoxide generation.

Evidence was obtained for the binding of C1q to the membrane of cultured vascular smooth muscle cells derived from human umbilical cord veins. C1q was fixed to the cell membrane at 4 degrees C, whereas it was ingested into the cytoplasm, as a cytoplasmic inclusion, when tested at 37 degrees C. The addition of C1q in advance inhibited the subsequent binding of C1q. Neither fibronectin nor laminin was detected on the cell membrane. Aggregated IgG bound to vascular smooth muscle cells in the case of preincubation with C1q at 4 degrees C, whereas aggregated IgG did not bind to the cells in the absence of C1q. The addition of C1q molecules to the cells in suspension enhanced superoxide generation by vascular smooth muscle cells. There was no effect of C1q on superoxide generation by the cells in monolayer. These results suggest that C1q binds on the membrane of vascular smooth muscle cells via its specific receptor that mediates immune complex binding to the cells and superoxide generation. These properties elucidate the mechanisms by which circulating immune complexes deposit in the vascular wall, and subsequent degradation of tissue components surrounding vascular smooth muscle cells occurs through oxidative burst of the cells.

Antigen-Antibody Complex↗

PubMed2026

Mechanisms of Transcriptional Regulation by Salicylic Acid Receptors.

Salicylic acid (SA) is a key phytohormone that activates plant defense responses 1-3. In Arabidopsis, NPR1 (also known as NIM1) and NPR3/NPR4 have been identified as dual SA receptors responsible for perceiving SA 4-6. However, the mechanisms of how SA binding to the NPR proteins leads to induction of defense gene expression remain unclear. Here, we elucidate how SA triggers transcriptional activation via NPR1 and relieves transcriptional repression mediated by NPR3/NPR4. We identified Mediator Complex Subunit 15A (MED15A) as a bridge between NPR1 and the Mediator complex governing transcription. SA induces direct interaction of NPR1 with MED15A. Structural and functional analysis showed that the binding of NPR1 to MED15A is essential for NPR1-mediated transcriptional activation. Meanwhile, SA relieves transcriptional repression mediated by NPR3/NPR4. NIM1-interacting 1 (NIMIN1) interacts with NPR3/NPR4 and the Topless (TPL) co-repressor, connecting them to Polycomb Repressive Complex 2 (PRC2) to mediate H3K27 trimethylation of SA-responsive genes. SA inhibits the interactions between NPR3/NPR4 and NIMIN1, reduces H3K27 trimethylation levels and increases histone acetylation of the target genes to release NPR3/NPR4-mediated repression. Our study offers a comprehensive view of SA-mediated defense gene activation. These findings lay a foundation for designing more effective SA analogs as agrochemicals and for engineering crop resistance by manipulating SA perception and signaling.

Journal Article↗

PubMed2000

Activation of Rho is required for ligand-independent oncogenic signaling by a mutant epidermal growth factor receptor.

Mutations in the epidermal growth factor receptor have been identified in several human tumor types, including gliomas. These receptor mutants have deletions in their extracellular ligand-binding domains and are, therefore, no longer regulated by ligand, resulting in constitutive activation of the receptor kinase. These mutants have been proposed to transduce oncogenic signals via ligand-independent signaling pathways. Avian viral homologues of these oncogenic epidermal growth factor receptors exhibit structurally homologous deletions and form tumors in chickens. One such mutant, S3v-ErbB, transforms fibroblasts in vitro, and transformation has been correlated with the formation of a novel tyrosine phosphoprotein complex. V-ErbB-mediated complex formation and transformation have been shown to occur independently of Ras activation. The major aims of this study are to further characterize this ligand-independent v-ErbB oncogenic signaling pathway. Here we show that both v-ErbB-mediated phosphoprotein complex formation and transformation are inhibited by a dominant negative mutant of Rho. This inhibition is specific for dominant negative Rho; dominant negative mutants of Rac and Cdc42 have no effect on transformation or on tyrosine phosphorylation of the phosphoprotein complex. Based on these observations, we propose that S3v-ErbB stimulates a Rho-dependent tyrosine kinase, resulting in complex formation and ultimately oncogenic transformation.

Animals↗

PubMed1994

Subunit interaction in the CCAAT-binding heteromeric complex is mediated by a very short alpha-helix in HAP2.

We dissected the domain of HAP2 that mediates subunit association in the heteromeric CCAAT-binding complex, first by genetic mutational analysis and then by structural studies. The mutational data suggest that a very short region in HAP2 mediates protein-protein association and that the structure of this domain is likely to be an alpha-helix. The CD analyses of a 15-residue synthetic oligopeptide covering this region confirm this surmise. The oligopeptide indeed formed an unusually thermal stable alpha-helix in aqueous solution. Eight amino acids that lie along one face of this helix, including three arginines, are found to be critical for protein-protein association. The partner that interacts with this helical motif is likely to be another subunit in the HAP complex, since the CCAAT-binding factor is shown to contain one molecule of HAP2. Our results suggest that very short regions in proteins can encode precise structures and mediate stable and specific protein-protein recognition and interactions.

Amino Acid Sequence↗

PubMed1992

Internalization of the urokinase-plasminogen activator inhibitor type-1 complex is mediated by the urokinase receptor.

The role of the urokinase receptor (uPAR) in the internalization of the urokinase-plasminogen activator inhibitor type-1 (uPA.PAI-1) complex has been investigated. First, exploiting the species specificity of uPA binding, we show that mouse LB6 cells (that express a mouse uPAR) were unable to bind or degrade the human uPA.PAI-1 complex. On the other hand, LB6 clone 19 cells, which express a transfected human uPAR, degraded uPA.PAI-1 complexes with kinetics identical to the human monocytic U937 cells. We also show by immunofluorescence experiments with anti-uPA antibodies that in LB6 clone 19 cells, the uPA.PAI-1 complex is indeed internalized. While at 4 degrees C uPA fluorescence was visible at the cell surface, shift of the temperature to 37 degrees C caused a displacement of the immunoreactivity to the cytoplasmic compartment, with a pattern indicating lysosomal localization. If uPA.PAI-1 internalization/degradation is mediated by uPAR, inhibition of uPA.PAI-1 binding to uPAR should block degradation. Three different treatments, competition with the agonist amino-terminal fragment of uPA, treatment with a monoclonal antibody directed toward the binding domain of uPAR or release of uPAR from the cell surface with phosphatidylinositol-specific phospholipase C completely prevented uPA.PAI-1 degradation. The possibility that a serpin-enzyme complex receptor might be primarily or secondarily involved in the internalization process was excluded since a serpin-enzyme complex peptide failed to inhibit uPA.PAI-1 binding and degradation. Similarly, complexes of PAI-1 with low molecular mass uPA (33 kDa uPA), which lacks the uPAR binding domain, were neither bound nor degraded. Finally we also show that treatment of cells with uPA.PAI-1 complex caused a specific but partial down-regulation of uPAR. A similar result was obtained when PAI-1 was allowed to complex to uPA that had been previously bound to the receptor. The possibility therefore exists that the entire complex uPA.PAI-1-uPAR is internalized. All these data allow us to conclude that internalization of the uPA.PAI-1 complex is mediated by uPAR.

Amino Acid Sequence↗

PubMed2006

Neutralized adenovirus-immune complexes can mediate effective gene transfer via an Fc receptor-dependent infection pathway.

Neutralization of adenovirus (Ad) by anti-Ad neutralizing antibodies in serum involves formation of Ad-immune complexes that prevent the virus from interacting with target cells. We hypothesized that Ad-immune complexes likely contain viable Ad vectors which, although no longer capable of gaining access to receptors on target cells, may be able to express transgenes in cells bearing Fc receptors for immunoglobulins, i.e., that antibody-based "neutralization" of Ad vectors may be circumvented by the Fc receptor pathway. To test this hypothesis, we expressed the Fcgamma receptor IIA (FcgammaR) in A549 lung epithelial cells or human dermal fibroblasts and evaluated gene transfer in the presence of human neutralizing anti-Ad serum. FcgammaR-expressing cells bound and internalized copious amounts of Ad, with a distinct population of internalized Ad trafficking to the nucleus. The dose-response curves for inhibition of gene transfer revealed that FcgammaR-expressing cells required a more-than-10-fold higher concentration of anti-Ad serum to achieve 50% inhibition of Ad-encoded beta-galactosidase expression compared with non-FcgammaR-expressing cells. The discrepancy between neutralization of Ad during infection of FcgammaR-expressing cells and neutralization of Ad during infection of non-FcgammaR-expressing cells occurred with either heat-inactivated or non-heat-inactivated sera, was blocked by addition of purified Fc domain protein, and did not require the cytoplasmic domain of FcgammaR, suggesting that immune complex internalization proceeded via endocytosis rather than phagocytosis. FcgammaR-mediated infection by Ad-immune complexes did not require expression of the coxsackie virus-Ad receptor (CAR) since similar data were obtained when CAR-deficient human dermal fibroblasts were engineered to express FcgammaR. However, interaction of the Ad penton base with cell surface integrins contributed to the difference in neutralization between FcgammaR-expressing and non-FcgammaR-expressing cells. The data indicate that complexes formed from Ad and anti-Ad neutralizing antibodies, while compromised with respect to infection of non-FcgammaR-expressing target cells, maintain the potential to transfer genes to FcgammaR-expressing cells, with consequent expression of the transgene. The formation of Ad-immune complexes that can target viable virus to antigen-presenting cells may account for the success of Ad-based vaccines administered in the presence of low levels of neutralizing anti-Ad antibody.

Adenoviridae↗

PubMed1998

Isolated necrotizing arteritis of the female genital tract: a clinicopathologic and immunohistochemical study of 11 cases.

Isolated necrotizing arteritis (INA) of the polyarteritis-nodosa type localized to the female genital tract is rare. Approximately 30 case reports have been published to date. Eleven additional patients are described here, all with a favorable follow-up. INA is usually localized in the uterine cervix, but, when multifocal lesions are present, the latter is almost always involved. Patients most frequently report menorrhagia or postmenopausal bleeding. With immunohistochemical studies, immune-complex deposits (IgM, IgG, and C'3) in 7 of 11 patients with INA of the female genital tract were demonstrated for the first time. The inflammatory cells were composed mainly of T-lymphocytes with macrophages and scarce B-lymphocytes also present. These results suggest that INA is primarily an immune complex-mediated disease, implicating humoral and cellular mediator systems. Possible pathogenetic factors of INA are immune complex-mediated hypersensitivity reactions to drugs, foreign materials (after cone biopsy or curettage), and cancers, or an autoimmune reaction against constituents of the vessel walls caused by tissue injury after local surgical intervention through in situ immune-complex formation.

Adult↗

PubMed2000

Hrs1/Med3 is a Cyc8-Tup1 corepressor target in the RNA polymerase II holoenzyme.

The Srb/Mediator, a multisubunit subcomplex of the RNA polymerase II (RNA pol II) holoenzyme has been proposed to function as a control panel regulating transcription in response to gene-specific activator proteins. In this report, we identify the Mediator subunit Hrs1/Med3 as a physical target for Cyc8-Tup1, a yeast transcriptional corepressor. Two-hybrid and glutathione S-transferase interaction assays show that Hrs1 can associate directly with Cyc8-Tup1. Moreover, affinity chromatography experiments, using yeast protein extracts, reveal that Cyc8-Tup1 co-purifies with Hrs1 and with additional Mediator subunits in a Hrs1-dependent manner. These observations suggest that Cyc8-Tup1 contacts the Mediator complex via its interaction with the Hrs1 subunit. Further on, genetic analysis indicates that increased Hrs1 dosage can alleviate Cyc8-Tup1-mediated repression, suggesting that Hrs1/Mediator's function is inhibited upon its interaction with Cyc8-Tup1. Finally, artificial holoenzyme recruitment assays support a model by which the contact between the corepressor and the Hrs1/Mediator may prevent pol II holoenzyme recruitment to the core promoter. These data, together with previous genetic evidence, establish a functional and physical interaction between the Cyc8-Tup1 corepressor and the RNA pol II holoenzyme and support a central role of the Mediator complex in transcriptional repression.

Chromatography, Affinity↗

PubMed2002

Pharmacology of nicotinic receptors in preBötzinger complex that mediate modulation of respiratory pattern.

Nicotine regulates respiratory pattern by modulating excitatory neurotransmission affecting inspiratory neurons within the preBötzinger Complex (preBötC). The nicotinic acetylcholine receptor (nAChR) subtypes mediating these effects are unknown. Using a medullary slice preparation from neonatal rat, we recorded spontaneous respiratory-related rhythm from the hypoglossal nerve (XIIn) and patch-clamped inspiratory neurons in the preBötC simultaneously. The alpha7 nAChR antagonists alpha-bungarotoxin or methyllycaconitine (MLA) had little effect on the actions of low concentrations of nicotine (0.5 microM), which included an increase in respiratory frequency; a decrease in amplitude of XIIn inspiratory bursts; a tonic inward current associated with an increase in membrane noise; an increase in the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), and; a decrease in the amplitude of inspiratory drive current in voltage-clamped preBötC inspiratory neurons. These nicotinic actions were completely reversed by dihydro-beta-erythroidine (DH-beta-E) or hexamethonium and reduced by D-tubocurarine. Comparable concentrations of RJR-2403 (0.5-1 microM), an agonist selective for alpha4beta2 nAChRs, increased respiratory frequency to 186% and decreased the amplitude of XIIn inspiratory bursts to 83% of baseline. In voltage-clamped preBötC inspiratory (including pacemaker) neurons, RJR-2403 induced a tonic inward current of -15.2 pA associated with an increase in membrane noise, increased the frequency to 157% and amplitude to 106% of spontaneous EPSCs, and decreased the amplitude of inspiratory drive current to 80% of baseline. MLA had little effect on RJR-2403 actions, while DH-beta-E completely reversed them. These results suggest that the predominant subtype of nAChRs in preBötC in neonatal rats that mediates the modulation of respiratory pattern by low concentrations of nicotine is an alpha4beta2 combination and not an alpha7 subunit homomer. We do not exclude the possibility that co-assembly of alpha4beta2 with other subunits or other nAChR subtypes are also expressed in preBötC neurons. The parallel changes in the cellular and systems level responses induced by different nicotinic agonists and antagonists support the idea that modulation of excitatory neurotransmission affecting preBötC inspiratory neurons is a mechanism underlying the cholinergic regulation of respiratory pattern (). This study provides a useful model system for evaluating potential therapeutic cholinergic agents for their respiratory effects and side effects.

Animals↗

PubMed1996

The YTA10-12 complex, an AAA protease with chaperone-like activity in the inner membrane of mitochondria.

The mitochondrial members of the highly conserved AAA family, Yta10p and Yta12p, constitute a membrane-embedded complex of about 850 kDa. As an ATP dependent metallopeptidase (AAA protease), the YTA10-12 complex mediates the degradation of nonassembled inner membrane proteins. In contrast to nucleotide-dependent complex formation and substrate binding, proteolysis of bound polypeptides depends on the hydrolysis of ATP and the metallopeptidase activity of both subunits. Independent of its proteolytic function, the chaperone-like activity of the YTA10-12 complex is required for assembly of the membrane-associated ATP synthase. We propose that proteolytic and chaperone-like activities in the YTA10-12 complex mediate assembly and degradation processes of membrane protein complexes and thereby exert key functions in the maintenance of membrane integrity.

Adenosine Triphosphatases↗

PubMed1986

The IIb-IIIa glycoprotein complex that mediates platelet aggregation is directly implicated in leukocyte adhesion.

Evidence is presented that the IIb-IIIa glycoprotein complex, which functions as the receptor for fibrinogen on platelets and is central to platelet aggregation, is expressed on the surface of leukocytes where it may function as a receptor for fibronectin. F(ab')2 fragments of a monoclonal antibody, 25E11, raised against activated large granular lymphocytes, inhibited killing by natural killer cells, blocked the binding of fibronectin-coated particles by monocytes, and stimulated neutrophils to exhibit increased antibody-dependent killing. Immunoprecipitation studies of leukocytes and platelets, and the ability of 25E11 to inhibit platelet aggregation, identified the antigen as an epitope on the IIb-IIIa complex. This glycoprotein thus constitutes the first example of a receptor mediating both platelet aggregation and leukocyte adhesion.

Adult↗

PubMed2001

Recruitment of an RNA polymerase II complex is mediated by the constitutive activation domain in CREB, independently of CREB phosphorylation.

The cAMP response element binding protein (CREB) is a bifunctional transcription activator, exerting its effects through a constitutive activation domain (CAD) and a distinct kinase inducible domain (KID), which requires phosphorylation of Ser-133 for activity. Both CAD and phospho-KID have been proposed to recruit polymerase complexes, but this has not been directly tested. Here, we show that the entire CREB activation domain or the CAD enhanced recruitment of a complex containing TFIID, TFIIB, and RNA polymerase II to a linked promoter. The nuclear extracts used mediated protein kinase A (PKA)-inducible transcription, but phosphorylation of CRG (both of the CREB activation domains fused to the Gal4 DNA binding domain) or KID-G4 did not mediate recruitment of a complex, and mutation of the PKA site in CRG abolished transcription induction by PKA but had no effect upon recruitment. The CREB-binding protein (CBP) was not detected in the recruited complex. Our results support a model for transcription activation in which the interaction between the CREB CAD and hTAFII130 of TFIID promotes the recruitment of a polymerase complex to the promoter.

Animals↗

PubMed2005

Yeast mediator and its role in transcriptional regulation.

Activated eukaryotic transcription requires the components of the Mediator complex, which can act as both a positive and negative regulator of transcription. This review of the yeast Saccharomyces cerevisiae Mediator complex describes the role of Mediator and its effects on transcriptional regulation. One focal point of the review is to summarize new information regarding the negative effect of Mediator on transcription and suggest a possible mechanism that encompasses the latest results.

Gene Expression Regulation, Fungal↗

PubMed2001

Differential recruitment of the mammalian mediator subunit TRAP220 by estrogen receptors ERalpha and ERbeta.

Estrogen receptors (ERs) associate with distinct transcriptional coactivators to mediate activation of target genes in response to estrogens. Previous work has provided multiple evidence for a critical role of p160 coactivators and associated histone acetyltransferases in estrogen signaling. In contrast, the involvement of the mammalian mediator complex remains to be established. Further, although the two subtypes ERalpha and ERbeta appear to be similar in regard to principles of LXXLL-mediated coactivator binding to the AF-2 activation domain, there are indications that the context-dependent transcriptional activation profiles of the two ERs can be quite distinct. Potentially, this could be attributed to differences with regard to coregulator recruitment. We have here studied the interactions of the nuclear receptor-binding subunit of the mammalian mediator complex, referred to as TRAP220, with ERalpha and ERbeta. In comparison to the p160 coactivator TIF2, we find that TRAP220 displays ERbeta preference. Here, we show that this is a feature of the binding specificity of the TRAP220 LXXLL motifs and demonstrate that the ER subtype-specific F-domain influences TRAP220 interaction. Such differences with regard to coactivator recruitment indicate that the relative importance of individual coregulators in estrogen signaling could depend on the dominant ER subtype.

Amino Acid Motifs↗

PubMed1997

The duplex DNA is very underwound in the three-stranded RecA protein-mediated synaptic complex.

BACKGROUND: The RecA protein is a central player in bacterial homologous recombination. It promotes two key events: the search for homology between two DNA molecules and the subsequent formation of the synaptic complex composed of RecA and three DNA strands (two from one duplex and one single strand). In spite of numerous studies, the architecture of the synaptic complex is still far from clear. RESULTS: We have exploited two approaches to study the structure of Escherichia coli RecA protein-mediated DNA synapsis: chemical modification with potassium permanganate and treatment of synaptic complexes of different lengths with topoisomerase I. The linking number difference values, obtained after separation of the individual sets of topoisomers in an agarose gel, were used to determine the number of bases per helical turn. We were able to show that the topology of the three-stranded complexes containing RecA is quite different from that expected for deproteinized D-loops. The original duplex in the synaptic complex is unwound, but not necessarily unpaired, to a structure topologically equivalent to DNA with approximately 27 bp per turn. Despite the fact that the patterns of reactivity towards potassium permanganate cannot be interpreted unambiguously, the results of chemical footprinting can be explained in terms of a synaptic complex as an extended and unwound three-stranded helical structure. CONCLUSIONS: This work provides the first quantitative topological parameters for the RecA protein-mediated three-stranded synaptic complex. Furthermore, the structure of synaptic complexes is different from that of a simple D-loop.

Base Sequence↗

PubMed2005

Genetic interactions between mediator and the late G1-specific transcription factor Swi6 in Saccharomyces cerevisiae.

Swi6 associates with Swi4 to activate HO and many other late G(1)-specific transcripts in budding yeast. Genetic screens for suppressors of SWI6 mutants have been carried out. A total of 112 of these mutants have been identified and most fall into seven complementation groups. Six of these genes have been cloned and identified and they all encode subunits of the mediator complex. These mutants restore transcription to the HO-lacZ reporter in the absence of Swi6 and have variable effects on other Swi6 target genes. Deletions of other nonessential mediator components have been tested directly for suppression of, or genetic interaction with, swi6. Mutations in half of the known subunits of mediator show suppression and/or growth defects in combination with swi6. These phenotypes are highly variable and do not correlate with a specific module of the mediator. Mutations in tail module components sin4 and pgd1 showed both growth defects and suppression when combined with swi6, but a third tail component, gal11, showed neither. A truncated form of the essential Srb7 mediator subunit also suppresses swi6 mutations and shows a defect in recruitment of the tail module components Sin4, Pgd1, and Gal11 to the mediator complex.

Deoxyribonucleases, Type II Site-Specific↗

PubMed1999

Assembly of urokinase receptor-mediated plasminogen activation complexes involves direct, non-active-site interactions between urokinase and plasminogen.

The binding of the zymogenic form of urokinase-type plasminogen activator (pro-uPA) to its specific cellular receptor, uPAR, leads to a large potentiation of plasmin generation. This is dependent on the concurrent cellular binding of plasminogen, and is completely abrogated by the plasminogen lysine-binding site ligand, 6-aminohexanoic acid. Previous data have provided circumstantial evidence for the formation of specific complexes to mediate the kinetically favorable reciprocal interactions between the protease and zymogen components [Ellis, V., and Dano, K. (1993) J. Biol. Chem. 268, 4806-4813]. To further investigate the formation of these putative complexes, we have studied the effect of various lysine-binding site ligands on the binding and activation of plasminogen on U937 cells. Lysine-binding site ligands resembling internal lysine residues, such as Nalpha-acetyl-L-lysine methyl ester, were found to specifically inhibit uPAR-mediated cell-surface plasminogen activation at concentrations up to 40-fold lower than those inhibiting the cellular binding of 125I-labeled plasminogen (IC50s 300 microM vs 8.5 mM). By contrast, 6-aminohexanoic acid, resembling a C-terminal lysine residue, did not display this disparity (IC50s 25 vs 30 microM). These lysine analogues were also found to compete a non-active-site interaction between uPA and plasminogen, detected by surface plasmon resonance (Kd 50 nM), at concentrations correlating with their effect on cell-surface plasminogen activation, suggesting that this interaction is part of the kinetic mechanism. Consistent with this, synthetic peptides corresponding to the sequence uPA149-158 (GQKTLRPRFK) and uPA149-157 (GQKTLRPRF) specifically abolished the amplification of cell-surface plasminogen activation. These data demonstrate that a novel non-active-site interaction between uPA and plasminogen is necessary for the assembly and efficiency of cell-surface plasminogen activation complexes.

Aminocaproic Acid↗

PubMed1986

Persistent local insulin allergy in a diabetic with chronic lymphatic leukaemia.

A 75 year old maturity-onset diabetic developed persistent local allergy to insulin. She had coexistent asymptomatic chronic lymphatic leukaemia. All species of insulin provoked a recurrence of the allergy and attempts at hyposensitization and treatment of the leukaemia produced only marginal benefit. Administration of subcutaneous steroids with insulin relieved the problem, but could not be stopped without relapse. Immunological investigations suggested an immune complex-mediated hypersensitivity reaction to insulin. The later development of immune complex-mediated arthropathy tended to support this suggestion. The lack of histological and immunological evidence of an IgE-mediated reaction suggested that in this case the mechanism of insulin allergy and arthralgia was IgG mediated. We suggest that the chronic leukaemia was implicated in both processes by interfering with homeostatic mechanisms that normally prevent the development of autoallergic disorders.

Aged↗