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Mechanisms of aire control of immuno...

Venanzi, Emily Suzanne.

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Mechanisms of aire control of immunological tolerance.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Mechanisms of aire control of immunological tolerance./
Author:	Venanzi, Emily Suzanne.
Description:	129 p.
Notes:	Source: Dissertation Abstracts International, Volume: 67-12, Section: B, page: 6997.
Contained By:	Dissertation Abstracts International67-12B.
Subject:	Biology, Cell. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3245207

Mechanisms of aire control of immunological tolerance.
Venanzi, Emily Suzanne.

Mechanisms of aire control of immunological tolerance. - 129 p.

Source: Dissertation Abstracts International, Volume: 67-12, Section: B, page: 6997.

Thesis (Ph.D.)--Harvard University, 2006.

Patients with mutations in the autoimmune regulator (AIRE) gene have autoimmune-polyendocrinopaty-candidiasis-ectodermal dystrophy (APECED), a multiorgan autoimmune disease.{09}Mice deficient in the mouse aire protein develop disease similar to that of APECED patients, with lymphocytic tissue infiltrates and autoantibodies against peripheral targets. Aire, a putative transcriptional regulator, is expressed most highly by thymic medullary epithelial cells (MECs), a thymic stromal subset that expresses proteins otherwise produced only by specific peripheral tissues, such as the pancreas, liver, and eye. Because of aire's predicted transcriptional regulatory ability and elevated expression in MECs, we speculated that it might control the transcription of peripheral antigens. I showed that this was indeed the case, by performing microarray analysis comparing the gene expression profiles of aire +/+ and aire-/- MECs. It was suggested that aire and peripheral antigen gene expression was controlled by the lymphtoxin pathway, which includes the lymphotoxin beta receptor (LTbetaR), expressed on MECs, and its ligand LTalpha1beta 2, produced by thymocytes. Conversely, others showed that the LT pathway controlled MEC development and organization, but not aire expression. By performing microarray analysis comparing the gene expression profiles of wild-type and LTalpha-/-, LTbetaR-/- , and aire-/- MECs, I attempted to clear up this discrepancy. I observed a lower amount of MECs in LTbetaR -/- thymi. I found that expression of both aire and most aire-controlled peripheral antigens was unchanged in LTalpha-/- and LTbetaR -/- MECs, in agreement with the conclusion that the LT pathway controls MEC differentiation but not aire expression. Aire was previously shown to regulate clonal deletion of self-antigen-specific thymocytes, and deletion was impaired in aire-/- thymi. We demonstrated that this deletion defect occurred even when the cognate self-antigen was expressed normally, revealing that aire played another role in thymocyte clonal deletion, in addition to regulating peripheral antigen expression. By performing antigen-presentation assays using MECs as antigen-presenting cells, I found that aire-/- MECs are inferior presenters, which may account for the observed thymic clonal deletion defect. Finally, I used microarray analysis to show that aire does not regulate gene expression in peripheral dendritic cells (DCs), and also demonstrated that aire -/- DCs functioned normally in an antigen-presentation assay.Subjects--Topical Terms:

1017686
Biology, Cell.

Mechanisms of aire control of immunological tolerance.
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100 1 $a Venanzi, Emily Suzanne. $3 1917980
245 1 0 $a Mechanisms of aire control of immunological tolerance.
300 $a 129 p.
500 $a Source: Dissertation Abstracts International, Volume: 67-12, Section: B, page: 6997.
500 $a Advisers: Diane Mathis; Christophe Benoist.
502 $a Thesis (Ph.D.)--Harvard University, 2006.
520 $a Patients with mutations in the autoimmune regulator (AIRE) gene have autoimmune-polyendocrinopaty-candidiasis-ectodermal dystrophy (APECED), a multiorgan autoimmune disease.{09}Mice deficient in the mouse aire protein develop disease similar to that of APECED patients, with lymphocytic tissue infiltrates and autoantibodies against peripheral targets. Aire, a putative transcriptional regulator, is expressed most highly by thymic medullary epithelial cells (MECs), a thymic stromal subset that expresses proteins otherwise produced only by specific peripheral tissues, such as the pancreas, liver, and eye. Because of aire's predicted transcriptional regulatory ability and elevated expression in MECs, we speculated that it might control the transcription of peripheral antigens. I showed that this was indeed the case, by performing microarray analysis comparing the gene expression profiles of aire +/+ and aire-/- MECs. It was suggested that aire and peripheral antigen gene expression was controlled by the lymphtoxin pathway, which includes the lymphotoxin beta receptor (LTbetaR), expressed on MECs, and its ligand LTalpha1beta 2, produced by thymocytes. Conversely, others showed that the LT pathway controlled MEC development and organization, but not aire expression. By performing microarray analysis comparing the gene expression profiles of wild-type and LTalpha-/-, LTbetaR-/- , and aire-/- MECs, I attempted to clear up this discrepancy. I observed a lower amount of MECs in LTbetaR -/- thymi. I found that expression of both aire and most aire-controlled peripheral antigens was unchanged in LTalpha-/- and LTbetaR -/- MECs, in agreement with the conclusion that the LT pathway controls MEC differentiation but not aire expression. Aire was previously shown to regulate clonal deletion of self-antigen-specific thymocytes, and deletion was impaired in aire-/- thymi. We demonstrated that this deletion defect occurred even when the cognate self-antigen was expressed normally, revealing that aire played another role in thymocyte clonal deletion, in addition to regulating peripheral antigen expression. By performing antigen-presentation assays using MECs as antigen-presenting cells, I found that aire-/- MECs are inferior presenters, which may account for the observed thymic clonal deletion defect. Finally, I used microarray analysis to show that aire does not regulate gene expression in peripheral dendritic cells (DCs), and also demonstrated that aire -/- DCs functioned normally in an antigen-presentation assay.
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