東華大學圖書館 |

語系: 繁體中文

說明(常見問題)

回圖書館首頁

手機版館藏查詢

登入

回首頁

切換: 標籤 | MARC模式 | ISBD

Maintaining Tolerance to Nucleic Aci...

Stanbery, Alison Gayle.

FindBook

Google Book

Amazon

博客來

Maintaining Tolerance to Nucleic Acids and the Microbiota Early in Life.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Maintaining Tolerance to Nucleic Acids and the Microbiota Early in Life./
作者:	Stanbery, Alison Gayle.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
面頁冊數:	81 p.
附註:	Source: Dissertations Abstracts International, Volume: 80-10, Section: B.
Contained By:	Dissertations Abstracts International80-10B.
標題:	Physiology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13423021
ISBN:	9781392035917

Maintaining Tolerance to Nucleic Acids and the Microbiota Early in Life.
Stanbery, Alison Gayle.

Maintaining Tolerance to Nucleic Acids and the Microbiota Early in Life. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 81 p.

Source: Dissertations Abstracts International, Volume: 80-10, Section: B.

Thesis (Ph.D.)--University of California, Berkeley, 2018.

This item must not be added to any third party search indexes.

Throughout life the immune system is faced with the challenging task of appropriately responding to both self- and nonself-derived ligands. The innate immune system utilizes pattern-recognition receptors, such as Toll-like receptors (TLR), to identify specific features of microbes, while the adaptive immune system employs T cells and antibodies (IgA, IgG) to generate robust secondary responses to invasive microorganisms. However, this poses the potential for inappropriate recognition of self-derived ligands or symbiotic bacteria. Therefore, the balance between recognition of non-self while preserving tolerance to self is necessary to prevent autoimmunity and detrimental infections. To better understand this balance, I first examined how the innate immune system prevents recognition of self-nucleic acids. In this study, I explored the consequences of dysregulating compartmentalized activation of a nucleic acid sensing receptor, TLR9. By inducing in vivo expression of a TLR9 mutant (TLR9™) that bypasses the need for intracellular activation, I discovered that dysregulated TLR9 activation early in life drives a fatal inflammatory disease, driven by type II interferon. In contrast, induced expression of TLR9™ late in life led to a milder, systemic autoinflammatory disease. This study demonstrates that compartmentalized activation of TLR9, especially early in life, is necessary to prevent deleterious recognition of self-nucleic acids. Early in life the naive immune system must be able to differentiate pathogenic microbes from symbiotic, beneficial microbes. The naive immune system receives some instruction through acquisition of maternal-derived microbiota-reactive antibodies, such as IgG2b and IgG3. These antibodies are anti-inflammatory and help to suppress inappropriate immune responses to commensal bacteria in the neonatal gut. However, the exact mechanism(s) by which maternal-derived IgG2b and IgG3 instruct the naive immune system remain relatively unknown. To better understand the role of microbiota-reactive IgGs in tuning the immature immune system, I generated mice that produce pro-inflammatory microbiota-reactive IgG2c (termed IgG32c/2c mice). Examination of the IgG3 2c/2c mice revealed that acquisition of maternal-derived microbiota-reactive IgG2c leads to fatal disease. This disease was characterized by weight loss and intestinal inflammation as measured by an increase in fecal lipocalin-2, an increase in intestinal myeloperoxidase, and an expansion of CD11b + myeloid cells in the spleen. In contrast, neonates that acquire maternal-derived microbiota-reactive IgG3 do not experience weight loss, inflammation, or fatality. This study establishes that effector functions elicited by maternal-derived microbiota-reactive antibodies help dictate neonatal fitness by fine-tuning the responses generated by the naive immune system to symbiotic gut bacteria. The work in this dissertation establishes how the innate immune system regulates nucleic-acid sensing TLRs to prevent inappropriate recognition of self-derived ligands. In addition, the work in this dissertation reveals how maternal-derived antibodies instruct the naive immune system in how to respond to beneficial microbes early in life.

ISBN: 9781392035917Subjects--Topical Terms:

518431
Physiology.

Maintaining Tolerance to Nucleic Acids and the Microbiota Early in Life.
LDR:04411nmm a2200337 4500 001 2207258
005 20190916101809.5
008 201008s2018 ||||||||||||||||| ||eng d
020 $a 9781392035917
035 $a (MiAaPQ)AAI13423021
035 $a (MiAaPQ)berkeley:18450
035 $a AAI13423021
040 $a MiAaPQ $c MiAaPQ
100 1 $a Stanbery, Alison Gayle. $3 3434220
245 1 0 $a Maintaining Tolerance to Nucleic Acids and the Microbiota Early in Life.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2018
300 $a 81 p.
500 $a Source: Dissertations Abstracts International, Volume: 80-10, Section: B.
500 $a Publisher info.: Dissertation/Thesis.
500 $a Advisor: Barton, Gregory.
502 $a Thesis (Ph.D.)--University of California, Berkeley, 2018.
506 $a This item must not be added to any third party search indexes.
506 $a This item must not be sold to any third party vendors.
520 $a Throughout life the immune system is faced with the challenging task of appropriately responding to both self- and nonself-derived ligands. The innate immune system utilizes pattern-recognition receptors, such as Toll-like receptors (TLR), to identify specific features of microbes, while the adaptive immune system employs T cells and antibodies (IgA, IgG) to generate robust secondary responses to invasive microorganisms. However, this poses the potential for inappropriate recognition of self-derived ligands or symbiotic bacteria. Therefore, the balance between recognition of non-self while preserving tolerance to self is necessary to prevent autoimmunity and detrimental infections. To better understand this balance, I first examined how the innate immune system prevents recognition of self-nucleic acids. In this study, I explored the consequences of dysregulating compartmentalized activation of a nucleic acid sensing receptor, TLR9. By inducing in vivo expression of a TLR9 mutant (TLR9™) that bypasses the need for intracellular activation, I discovered that dysregulated TLR9 activation early in life drives a fatal inflammatory disease, driven by type II interferon. In contrast, induced expression of TLR9™ late in life led to a milder, systemic autoinflammatory disease. This study demonstrates that compartmentalized activation of TLR9, especially early in life, is necessary to prevent deleterious recognition of self-nucleic acids. Early in life the naive immune system must be able to differentiate pathogenic microbes from symbiotic, beneficial microbes. The naive immune system receives some instruction through acquisition of maternal-derived microbiota-reactive antibodies, such as IgG2b and IgG3. These antibodies are anti-inflammatory and help to suppress inappropriate immune responses to commensal bacteria in the neonatal gut. However, the exact mechanism(s) by which maternal-derived IgG2b and IgG3 instruct the naive immune system remain relatively unknown. To better understand the role of microbiota-reactive IgGs in tuning the immature immune system, I generated mice that produce pro-inflammatory microbiota-reactive IgG2c (termed IgG32c/2c mice). Examination of the IgG3 2c/2c mice revealed that acquisition of maternal-derived microbiota-reactive IgG2c leads to fatal disease. This disease was characterized by weight loss and intestinal inflammation as measured by an increase in fecal lipocalin-2, an increase in intestinal myeloperoxidase, and an expansion of CD11b + myeloid cells in the spleen. In contrast, neonates that acquire maternal-derived microbiota-reactive IgG3 do not experience weight loss, inflammation, or fatality. This study establishes that effector functions elicited by maternal-derived microbiota-reactive antibodies help dictate neonatal fitness by fine-tuning the responses generated by the naive immune system to symbiotic gut bacteria. The work in this dissertation establishes how the innate immune system regulates nucleic-acid sensing TLRs to prevent inappropriate recognition of self-derived ligands. In addition, the work in this dissertation reveals how maternal-derived antibodies instruct the naive immune system in how to respond to beneficial microbes early in life.
590 $a School code: 0028.
650 4 $a Physiology. $3 518431
650 4 $a Immunology. $3 611031
690 $a 0719
690 $a 0982
710 2 $a University of California, Berkeley. $b Molecular and Cell Biology. $3 3174725
773 0 $t Dissertations Abstracts International $g 80-10B.
790 $a 0028
791 $a Ph.D.
792 $a 2018
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13423021