ライフサイエンスコーパス: Aire

1 gulated in part by the autoimmune regulator (AIRE).

2 EC expressing the autoimmune regulator gene (Aire).

3 rtly controlled by the autoimmune regulator (Aire).

4 may partake in delivering inactive P-TEFb to Aire.

5 (high) mTECs expressing Tnfrsf11a, Ctss, and Aire.

6 2(+) T cells was increased in humans lacking Aire.

7 n in expression of the autoimmune regulator (Aire), a critical mediator of central immune tolerance.

8 are controlled by the autoimmune regulator (AIRE), a key factor in central tolerance.

9 Here we showed that Autoimmune Regulator (Aire), a transcription coordinator involved in immune to

10 Autoimmune regulator protein (AIRE), a transcription factor located on chromosome 21,

11 We report that autoimmune regulator (Aire), a transcriptional regulator, is inducibly express

12 We show that Prdm1 acts independently of Aire, a crucial transcription factor implicated in medul

13 f APECED/APS1 patients, who are deficient in AIRE, a major regulator of central T cell tolerance (Mey

14 Aire, a transcription factor essential for central T cel

15 g a post-transcriptional level of control of Aire-activated expression in mTECs.

16 sayed 26 thymoma samples for transcripts for AIRE and 16 peripheral tissue-specific autoantigens (TSA

17 Whereas relative transcript levels for AIRE and 7 of 16 TSAgs showed the expected underexpressi

18 eed, mice with a dominant-negative allele of Aire and deficiency in LYN spontaneously developed organ

19 provide insight into the molecular action of AIRE and demonstrate that disease-causing mutations in t

20 In mice lacking Aire and gammadelta T cells, certain tissues typically t

21 How AIRE and its partners mediate these various effects at t

22 ation of AIRE, we assessed the expression of AIRE and of several peripheral tissue-restricted Ag gene

23 strong evidence for the fundamental role of AIRE and pGE, namely, central tolerance, in the predispo

24 ered a previously unappreciated function for Aire and provide new insights into the biology of stem c

25 We found that Aire and some of its partners, notably those implicated

26 orrespondence between those genes induced by Aire and those inhibited by a small-molecule bromodomain

27 uals contained significantly lower levels of AIRE and thyroglobulin, to which tolerance is typically

28 We investigated the expression of AIRE and TRAs in DS and control thymic tissue using quan

29 lockade selectively and transiently depletes Aire and TSA expression in the thymus to create a window

30 Twelve missense or nonsense mutations in AIRE and two chimeric AIRE constructs were generated.

31 CD70 was expressed on Aire(-) and Aire(+) medullary thymic epithelial cells (m

32 ol of transit-amplifying cells gives rise to Aire- and Ccl21a-expressing mTEC subsets.

33 In patients with APECED, loss of AIRE appears to cause an autoimmune response against ent

34 expression of the transcriptional regulator Aire are involved in the regulation of thymus medullary

35 BioID analysis showed that AIRE associates with spindle-associated proteins in mES

36 cells (mTECs) is controlled predominantly by Aire at the transcriptional level and possibly regulated

37 sulin-variable number of tandem repeats) and AIRE (autoimmune regulator) have been associated with th

38 Aire:Brd4 association was critical for tolerance inducti

39 Aire:Brd4 binding depended on an orchestrated series of

40 f2, as well as the transcriptional regulator Aire, but the entire picture of the transcriptional prog

41 ll, our results suggest that the presence of AIRE can trigger molecular events leading to an altered

42 Mutations in AIRE cause a monogenic autoimmune disease called autoimm

43 Mutations in AIRE cause a rare autosomal-recessive disease, autoimmun

44 copy analysis was performed for WT or mutant AIRE cellular localization.

45 nonsense mutations in AIRE and two chimeric AIRE constructs were generated.

46 Aire-containing complexes include 7SK RNA, the latter in

47 ng of super-enhancers to efficiently deliver Aire-containing complexes to local and distal transcript

48 lf commensal Ags in APECED and indicate that AIRE contributes to the regulation of gut homeostasis, a

49 nd trends toward increased expression of the AIRE-controlled genes INSULIN and CHRNA1 were found.

50 Aire controls immunologic tolerance by inducing a batter

51 The transcription factor Aire controls immunological tolerance by inducing the ec

52 AIRE decreases, via non-cell autonomous mechanisms, the

53 AIRE deficiency also affects B cell tolerance, but this

54 Together, our work showed how Aire deficiency can enhance immune responses against mel

55 In this study, we show that Aire deficiency decreases thymic expression of TRP-1 (TY

56 Aire deficiency in humans and mice manifests as spontane

57 Therefore, we hypothesized that Aire deficiency in mice may elevate immune responses to

58 suggesting that autoimmunity associated with Aire deficiency results from two failed tolerance mechan

59 ins are autoantigens in humans and mice with AIRE deficiency.

60 clude known targets of autoimmunity in human AIRE deficiency.

61 efect of thymic presentation associated with AIRE-deficiency and raises novel questions what other fa

62 Patients with AIRE-deficiency develop multiple autoimmune manifestatio

63 spectrum of autoantibodies in patients with AIRE-deficiency is much broader than previously apprecia

64 -methylation analysis of Aire-sufficient and Aire-deficient medullary epithelial cells (mTECs).

65 We found that Aire-deficient mice had expanded thymic and peripheral p

66 he multiorgan autoimmunity characteristic of Aire-deficient mice.

67 ctive elimination of self-reactive clones in Aire-deficient mice.

68 of wild-type mice and expanded very early in Aire-deficient mice.

69 For example, AIRE-deficient patients are predisposed to vitiligo, an

70 autoantibodies, which are typically found in AIRE-deficient patients.

71 ficient TSAg transcription in these aberrant AIRE-deficient tumors.

72 repertoires enriched in self-reactive cells (Aire-deficient) are transferred into cognate hosts.

73 tTreg development is predominantly AIRE dependent, with an AIRE-independent component.

74 MJ23 T(regs) underwent autoimmune regulator (Aire)-dependent thymic development in both male and fema

75 the commonalities and discrepancies between AIRE-dependent and -independent pGE, we analyzed the tra

76 We also found that AIRE-dependent and -independent TRA present several dist

77 Taken together, these results suggest that Aire-dependent central deletion and regulatory T cell-me

78 n Aire(+/+) mice, consistent with a role for Aire-dependent central deletion in establishing toleranc

79 Aire-dependent control of Il7 expression in mTECs regula

80 Approximately half of Aire-dependent deletion or Treg cell selection utilized

81 n structural alterations in conjunction with AIRE-dependent gene expression.

82 ire transactivation function, we screened an AIRE-dependent gene-expression system with a genome-scal

83 ty in a multiple sclerosis mouse model in an Aire-dependent manner.

84 We found that the impact of AIRE-dependent pGE is not limited to generation of TRA.

85 Aire-dependent processes are thought to promote both clo

86 us sequence in a relevant subset of K17- and Aire-dependent proinflammatory genes.

87 athological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs,

88 re1 mTEC) and a decrease in the diversity of Aire-dependent tissue-restricted peripheral selfantigens

89 ulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects.

90 Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antige

91 Furthermore, we report that AIRE-dependent versus -independent TRA project nonredund

92 By tracking a clonal population of Aire-dependent, prostate-specific Treg cells in mice, we

93 deficient in the autoimmune regulatory gene Aire develop a spontaneous T-cell and macrophage-mediate

94 Both humans and mice lacking Aire develop multiorgan autoimmunity.

95 -specific HIPK2 deletion only mildly affects AIRE-directed pGE in vivo.

96 In mature medullary TEC, AIRE-driven pGE upregulates non-TRA coding genes that en

97 Expression of Aire during a perinatal age window is necessary and suff

98 Thus, Aire enforces immune tolerance by ensuring that distinct

99 Thus, Aire exerts multi-faceted autoimmune control that extend

100 Recently, extrathymic Aire-expressing cells (eTACs) have been described in mur

101 , with only mTECs and peripheral extrathymic Aire-expressing cells (eTACs) known to express detectabl

102 of TOP2 religation activity by etoposide in AIRE-expressing cells had a synergistic effect on genes

103 T cell tolerance depends upon Aire-expressing cells to purge the T cell repertoire of

104 erimental techniques to show that within the Aire-expressing developmental branch, TSA expression pea

105 asal epithelia and type II taste cells to ex-Aire-expressing medullary thymic cells and small-intesti

106 B-dependent development of normal numbers of AIRE-expressing mTECs in the complete absence of SP thym

107 Thus, therapies to deplete Aire-expressing mTECs represent an attractive strategy t

108 nd RANK-Ligand (RANKL) in the development of Aire-expressing mTECs.

109 be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells.

110 Remarkably, in mouse mTEC, Aire expression alone positively regulates 3980 tissue-r

111 Led by the observation that genes induced by Aire expression are generally characterized by a repress

112 single mTEC indicates that genes induced by Aire expression are transcribed stochastically at low ce

113 velopmental branch, TSA expression peaked as Aire expression decreased, implying Aire expression must

114 ty, the cis-regulatory elements that control Aire expression have remained obscure.

115 ogen treatment resulted in downregulation of AIRE expression in cultured human TECs, human thymic tis

116 turn inhibits RANK signaling and facilitates AIRE expression in mTECs.

117 ry junction and subsequently fail to sustain AIRE expression in the medulla, escaping medullary negat

118 , we find that this element is essential for Aire expression in vivo and necessary to prevent spontan

119 JCI, Dragin and colleagues demonstrate that AIRE expression is downregulated in females as the resul

120 In mice and humans, thymic Aire expression is higher in males compared with females

121 We also demonstrated that AIRE expression is related to sexual hormones, as male c

122 eaked as Aire expression decreased, implying Aire expression must be established before TSA expressio

123 changes in the AIRE gene, leading to reduced AIRE expression under a threshold that increases female

124 show that nuclear PTEN most likely regulates Aire expression via its emerging role in splicing regula

125 Strikingly, despite the 21 trisomy, AIRE expression was significantly reduced by 2-fold in D

126 Furthermore, when present, Aire expression-dependent transcript levels were 16-fold

127 icient mice did not show a sex disparity for AIRE expression.

128 noncoding DNA element that is essential for Aire expression.

129 ng population of cycling mTECs that preceded Aire expression.

130 ymic deletion as a result of the hypomorphic Aire function and that these cells also escaped peripher

131 This study addresses the role of PHD2 in Aire function by comparing the behavior of wild-type and

132 e of central tolerance, and complete loss of AIRE function results in the development of autoimmune p

133 sight into keratin intermediate filament and Aire function, along with a molecular basis for the K17-

134 veals a new regulatory role of PML bodies in Aire function, and highlights the interplay between nucl

135 In conclusion, the increased AIRE gene dose in DS could contribute to an autoimmune p

136 The AIRE gene plays a key role in the development of central

137 Meyer et al. find that subjects lacking the AIRE gene, critical for self-tolerance in T lymphocytes,

138 , estrogen induces epigenetic changes in the AIRE gene, leading to reduced AIRE expression under a th

139 utoimmune disease caused by mutations in the AIRE gene.

140 The autoimmune regulator (AIRE) gene contributes to the maintenance of central tol

141 The autoimmune regulator (AIRE) gene is crucial for establishing central immunolog

142 ial cells (mTECs), the Autoimmune regulator (Aire) gene plays an essential role in this process by dr

143 ed by mutations in the autoimmune regulator (AIRE) gene, and myasthenia gravis (MG) with thymoma, sho

144 ed by mutations in the autoimmune regulator (AIRE) gene, located on chromosome 21, which regulates th

145 ed by mutations in the Autoimmune regulator (AIRE) gene, which promote thymic display of thousands of

146 ed by mutations of the autoimmune regulator (AIRE) gene.

147 cy accelerated neuropathy development in NOD.Aire(GW/+) mice, and Ab blockade of both B7-1 and B7-2 r

148 t of autoimmune peripheral neuropathy in NOD.Aire(GW/+) mice.

149 Interestingly, Aire has a highly tissue-restricted pattern of expressio

150 AIRE has been shown to promote DNA breaks via its intera

151 Using WT/mutant AIRE heterozygous forms to modulate the INS-VNTR target

152 on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to tar

153 Aire impacts immunological tolerance by regulating the e

154 ppressed gene expression driven by wild-type AIRE in a dominant-negative manner, unlike CARD or trunc

155 o and suppressed the coactivator activity of AIRE in a kinase-dependent manner.

156 g the behavior of wild-type and PHD2-deleted Aire in both transfected cells and transgenic mice.

157 HIPK2 partially colocalized with AIRE in nuclear bodies upon cotransfection and in human

158 Moreover, HIPK2 phosphorylated AIRE in vitro and suppressed the coactivator activity of

159 role of Hipk2 in modulating the function of AIRE in vivo, we compared whole-genome gene signatures o

160 e transcription factor autoimmune regulator (Aire) in these processes.

161 XO3) (SKP1-CUL1-F box) complex ubiquitylates AIRE, increases its binding to the positive transcriptio

162 ent is predominantly AIRE dependent, with an AIRE-independent component.

163 distinct Treg populations are age-dependent, Aire-independent differences in the processing and prese

164 In particular, relative to AIRE-induced TRA, AIRE-independent TRA are more numerous and show greater

165 (lo) mTEC subset and preferentially included AIRE-independent TRAs.

166 TECs and CD8alpha(+) DCs for presentation of Aire-induced self-antigens to developing thymocytes.

167 In particular, relative to AIRE-induced TRA, AIRE-independent TRA are more numerous

168 the effect of the splicing factor Hnrnpl on Aire-induced transcription.

169 Aire induces the expression of a large set of autoantige

170 ast two-hybrid screen, we searched for novel AIRE-interacting proteins and identified the homeodomain

171 Here we identified two Aire-interacting proteins known to be involved in gene r

172 Aire is a transcription factor that controls T cell tole

173 Aire is an important regulator of immunological toleranc

174 to analyze whether each functional domain of AIRE is critical for the activation of INS-VNTR in human

175 Thymopoiesis in the absence of AIRE is implicated in both syndromes.

176 We hypothesized that the level of AIRE is linked to sexual dimorphism susceptibility to au

177 AIRE is modified post-translationally by phosphorylation

178 AIRE is part of higher-order multiprotein complexes, whi

179 n AIH on a BALB/c mouse background, in which Aire is truncated at exon 2.

180 The autoimmune regulator (AIRE) is a transcription factor which is expressed in me

181 The autoimmune regulator (Aire) is essential for prevention of autoimmunity; its r

182 The autoimmune regulator (AIRE) is to date the only validated molecule known to re

183 mus, driven in part by autoimmune regulator (Aire), is critical for the protection of peripheral tiss

184 nd mononuclear infiltration of the retina in Aire knockout (KO) mice triggers the onset of uveitis fr

185 the three main TEC subsets in wild-type and Aire knockout mice.

186 Using the Aire KO mouse model, we demonstrated an essential role f

187 , certain tissues typically targeted in the "Aire-less" disease, notably the retina, were only minima

188 AIRE levels in human thymus grafted in immunodeficient m

189 strate that disease-causing mutations in the AIRE locus are more common than previously appreciated a

190 ssociation between estrogen and reduction of AIRE may at least partially account for the elevated inc

191 to an autoimmune phenotype through multiple AIRE-mediated effects on homeostasis and function of thy

192 Thus, Aire-mediated expression of peripheral tissue antigens d

193 ys a critical role in integrating Fezf2- and Aire-mediated gene induction to establish central immune

194 indings provide a mechanism by which loss of AIRE-mediated immune tolerance leads to intestinal disor

195 2-dependent genes, while contributing to the Aire-mediated induction of self-antigens via super-enhan

196 Here we show that androgen upregulates Aire-mediated thymic tolerance to protect against autoim

197 Thus, androgen control of an intrathymic Aire-mediated tolerance mechanism contributes to gender

198 AIRE-mediated transcription was not only enhanced by TOP

199 A model antigen specifically expressed in Aire(+) medullary TECs (mTECs) induced efficient deletio

200 CD70 was expressed on Aire(-) and Aire(+) medullary thymic epithelial cells (mTECs) and on

201 lls through RANK in a manner that depends on AIRE(+) medullary thymic epithelial cells.

202 in self-Ag-presenting, autoimmune regulator (AIRE)(+) medullary thymic epithelial cells (mTECs).

203 The high rate of apoptosis in pre-Aire MHCII(lo) mTECs points to a "quality control" step

204 henotypically overlapping pre- from the post-Aire MHCII(lo) stage has been lacking.

205 ed to include a third stage, namely the post-Aire MHCII(lo) subset as identified by lineage-tracing m

206 Aire (-/-) mice fail to express self-antigens in the thy

207 -/-) mice had more severe renal disease than Aire(+/+) mice, consistent with a role for Aire-dependen

208 entially expressed by Foxp3(+) Treg cells in Aire(+/+) mice.

209 We used Aire(-/-) mice as a model of APECED, and studied the eff

210 Aire(-/-) mice developed defensin-specific T cells that

211 Aire(-/-) mice developed defensin-specific T cells.

212 anti-glomerular basement membrane antibody, Aire(-/-) mice had more severe renal disease than Aire(+

213 emonstrating defective T cell development in Aire(-/-) mice is not because of a loss of CCR4-mediated

214 Here, examination of autoimmune lesions in Aire(-/-) mice revealed an unexpected third possibility.

215 The induction of Aire mRNA in keratinocytes depends on a functional inter

216 AIRE mRNA levels were elevated in thymic tissue from DS

217 man and mouse thymus, females expressed less AIRE (mRNA and protein) than males after puberty.

218 er, by mapping OPG expression to a subset of Aire(+) mTEC, our data show how cis- and trans-acting me

219 tal repertoire secondary to a decline in the Aire(+)mTEC(high) cell pool.

220 HD interfered with the capacity of recipient Aire(+)mTEC(high) to sustain TRA diversity.

221 s study reveals that distinct DC subsets and AIRE(+) mTECs contribute substantially to presentation o

222 athways are essential for differentiation of AIRE(+) mTECs.

223 nt-negative manner, unlike CARD or truncated AIRE mutants that lacked such dominant capacity.

224 Several loss-of-function Aire mutants, including those causing autoimmune polyend

225 This study supports the notion that AIRE mutation could specifically affect human insulin ge

226 systemic autoimmunity, could combine with an Aire mutation to provoke organ-specific autoimmunity.

227 nitiated by self-reactive T cells because of AIRE mutation-induced defective central tolerance.

228 ent of AIH in APS-1 is dependent on specific Aire mutations and genetic background genes.

229 ease manifestation was dependent on specific Aire mutations and the genetic background of the mice.

230 l. discovered heterozygous dominant-negative AIRE mutations in patients with certain forms of autoimm

231 We found that all of the AIRE mutations resulted in loss of transcriptional activ

232 ave described a variety of dominant-negative AIRE mutations that likely contribute to human autoimmun

233 erstand fertility defects in humans carrying Aire mutations.

234 AIRE nuclear localization in the human thymic epithelial

235 lso identified topoisomerase 1 as a cardinal Aire partner that colocalized on super-enhancers and was

236 Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease wit

237 r both T-cell and B-cell areas, distant from Aire(pos) and CD11c(pos) cells.

238 DS individuals with increased frequencies of AIRE-positive medullary epithelial cells and CD11c-posit

239 Autoimmune regulator (Aire) prevents autoimmunity by promoting self-antigen ex

240 c transcription factor autoimmune regulator (Aire) prevents autoimmunity in part by promoting express

241 Androgen recruits AR to Aire promoter regions, with consequent enhancement of Ai

242 ed the number of methylated CpG sites in the AIRE promoter.

243 sult of estrogen-mediated alterations at the AIRE promoter.

244 We report that Aire promotes the perinatal generation of a distinct com

245 Further, K17 colocalizes with Aire protein in the nucleus of tumor-prone keratinocytes

246 The autoimmune regulator (AIRE) protein is the key factor in thymic negative selec

247 tion, facilitated by decreased expression of Aire rather than impaired regulatory T cell generation,

248 -state postnatal thymus TPA(lo)MHCII(lo) pre-Aire rather than terminally differentiated post-Aire TPA

249 Although Aire regulates expression of the CCR4 ligands CCL17 and

250 th this, mTECs continue to express Fezf2 and Aire, regulators of intrathymic self-antigens, and suppo

251 his interaction ensures proper expression of AIRE-responsive tissue-specific antigens in the thymus.

252 lymphoid structures constitutes part of the Aire (-/-) retinal phenotype, 4) all major resident reti

253 er that 1) the dominant effector response in Aire (-/-) retinas is Th1-driven, 2) a subset of monocyt

254 (scRNA-seq), we characterized wild-type and Aire (-/-) retinas to define, in a comprehensive and unb

255 es of posttranslational modifications within Aire's caspase activation and recruitment domain.

256 We explored Aire's collaboration with the bromodomain-containing pro

257 ternal and zygotic knockout further revealed Aire's critical functions for spindle assembly in preimp

258 cript isoforms in mTECs, a feature preceding Aire's expression and correlated with the preferential s

259 Aire's functional allies were validated on transfected a

260 ng TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex

261 terminal LESLL motif as a critical motif for AIRE's mitotic function.

262 RNA processing; it also was not required for Aire's nuclear translocation or regional distribution.

263 Aire's primary mechanism of action is to regulate transc

264 or tissue-specific immune targets, mirroring AIRE's selectiveness for this category of genes.

265 To better understand Aire's specificity, we performed single-cell RNA-seq and

266 Each of Aire's target genes was induced in only a minority of mT

267 ion, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs.

268 Thus, Aire's two PHDs seem to play distinct roles in the scena

269 Aire-sensitive gene expression is influenced by several

270 We discovered that Aire-sensitive genes display a pronounced preference for

271 igher transcript stability and expression of Aire-sensitive genes, revealing a post-transcriptional l

272 llele-specific quantification of intrathymic AIRE showed that despite its lower expression, the three

273 cell RNA-seq and DNA-methylation analysis of Aire-sufficient and Aire-deficient medullary epithelial

274 er, CARD-mediated multimerization also makes Aire susceptible to interaction with promyelocytic leuke

275 and the exchange of histone H1 with HMGB1 at AIRE target gene promoters.

276 Our findings are consistent with AIRE targeting and inducing the promiscuous expression o

277 irst plant homeodomain (PHD1) zinc finger of AIRE that followed dominant inheritance, typically chara

278 ined by defects in the autoimmune regulator (AIRE) that mediates central T cell tolerance to many sel

279 cells, independently of their dependence on Aire, therefore indicating a general effect of Hnrnpl on

280 exual hormones, as male castration decreased AIRE thymic expression and estrogen receptor alpha-defic

281 PHD2 was required for Aire to interact with sets of protein partners involved

282 Directing Aire to PML bodies impairs the transcriptional activity

283 that mRNA processing factors cooperate with Aire to release stalled polymerases and to activate ecto

284 e transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance.

285 e rather than terminally differentiated post-Aire TPA(hi)MHCII(lo) mTECs were marked for apoptosis at

286 ctrum of molecular mechanisms underlying the Aire transactivation function, we screened an AIRE-depen

287 oter regions, with consequent enhancement of Aire transcription.

288 ator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown.

289 ersity of self-antigen expression, Fezf2 and Aire utilized completely distinct transcriptional mechan

290 Here we demonstrate that Aire utilizes its caspase activation recruitment domain

291 More importantly, decreased expression of AIRE was accompanied by a reduction of pGE because expre

292 Loss of function analysis revealed that Aire was important for centrosome number regulation and

293 e reduction of pGE owing to dysregulation of AIRE, we assessed the expression of AIRE and of several

294 SAs largely depends on autoimmune regulator (Aire), which is expressed in mature mTECs.

295 Aire, which induces tissue-specific antigen expression i

296 AIRE, which is phosphorylated on two specific residues n

297 ugh the activity of the autoimmune regulator AIRE, which promotes central T cell tolerance.

298 ed by mutations in the autoimmune regulator (AIRE, which regulates immune tolerance) that allow self-

299 dies impairs the transcriptional activity of Aire, while dispersing PML bodies with a viral antagonis

300 cers and was required for the interaction of Aire with all of its other associates.