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The Role of β2-Glycoprotein I-Reactive T Cells in the Development of Systemic Lupus Erythematosus.

Record Type:	Electronic resources : Monograph/item
Title/Author:	The Role of β2-Glycoprotein I-Reactive T Cells in the Development of Systemic Lupus Erythematosus./
Author:	Salem, David.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
Description:	160 p.
Notes:	Source: Dissertations Abstracts International, Volume: 82-06, Section: B.
Contained By:	Dissertations Abstracts International82-06B.
Subject:	Cellular biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28248315
ISBN:	9798698519836

The Role of β2-Glycoprotein I-Reactive T Cells in the Development of Systemic Lupus Erythematosus.
Salem, David.

The Role of β2-Glycoprotein I-Reactive T Cells in the Development of Systemic Lupus Erythematosus. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 160 p.

Source: Dissertations Abstracts International, Volume: 82-06, Section: B.

Thesis (Ph.D.)--McGill University (Canada), 2019.

This item must not be sold to any third party vendors.

This thesis examines the role of β2-glycoprotein I (β2GPI)-reactive T cells in the development of systemic lupus erythematosus (SLE). SLE is a prototypic model for B cell epitope spread in autoimmunity. Autoantibodies to numerous molecularly distinct self-antigens emerge in a sequential manner over several years, leading to disease manifestations. Among the earliest autoantibodies to appear are those targeting phospholipids and phospholipid-binding proteins, particularly β2-glycoprotein I (β2GPI). Our laboratory has developed a model of SLE in which mice immunized with β2GPI and lipopolysaccharide (LPS) display a remarkably similar pattern of autoantibody emergence to that seen in human SLE, as well as SLE-like kidney disease. Here we use this model to investigate whether epitope spread to SLE autoantibodies is associated with a unique or limited β2GPI-reactive T cell response. We ask whether MHC class II haplotype, and its associated T cell epitope restriction, impacts epitope spread to SLE autoantibodies. Furthermore, we investigate the origin of β2GPI-reactive T cells initiating this epitope spread. We hypothesize that binding of β2GPI to necroptotic cells presents the immune system with a "scaffold" of cellular self-antigens in a pro-inflammatory and immunogenic context, leading to a robust β2GPI-reactive T cell response. Splenocytes from β2GPI/LPS-immunized mice with different MHC class II haplotypes were used to determine β2GPI-reactive T cell epitopes, using a peptide library spanning the entire sequence of human β2GPI. One β2GPI-reactive T cell epitope (LYRDTAVFECLPQHAMFG) in Domain III appeared to be a dominant epitope, since it was recognized in β2GPI/LPS-immunized mice with different MHC class II haplotypes, as well as in SLE-prone MRL/lpr mice. We next showed that β2GPI binds to necroptotic, as well as apoptotic, L929 cells but that necroptotic, not apoptotic, cells enhance pro-inflammatory cytokine (TNF-α) secretion by activated macrophages and dendritic cells in vitro. Necroptotic cells promoted MHC class II and costimulatory molecule expression in immature dendritic cells, leading to an enhanced CD4 T cell response to β2GPI in vitro. Finally, we show that mice deficient in Ripk3 (receptor-interacting serine/threonine-protein kinase 3), and hence necroptosis, show poor induction of SLE. In summary, we propose that factors enabling a β2GPI-reactive T cell response may predispose individuals to the development of SLE autoantibodies independent of their MHC class II haplotype. Furthermore, our findings suggest that necroptotic cells provide both self-antigens and pro-inflammatory signals that may be sufficient to overcome immune tolerance and induce SLE.

ISBN: 9798698519836Subjects--Topical Terms:

3172791
Cellular biology.
Subjects--Index Terms:

β2-glycoprotein I-reactive T cells

The Role of β2-Glycoprotein I-Reactive T Cells in the Development of Systemic Lupus Erythematosus.
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245 1 4 $a The Role of β2-Glycoprotein I-Reactive T Cells in the Development of Systemic Lupus Erythematosus.
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300 $a 160 p.
500 $a Source: Dissertations Abstracts International, Volume: 82-06, Section: B.
500 $a Advisor: Rauch, Joyce.
502 $a Thesis (Ph.D.)--McGill University (Canada), 2019.
506 $a This item must not be sold to any third party vendors.
520 $a This thesis examines the role of β2-glycoprotein I (β2GPI)-reactive T cells in the development of systemic lupus erythematosus (SLE). SLE is a prototypic model for B cell epitope spread in autoimmunity. Autoantibodies to numerous molecularly distinct self-antigens emerge in a sequential manner over several years, leading to disease manifestations. Among the earliest autoantibodies to appear are those targeting phospholipids and phospholipid-binding proteins, particularly β2-glycoprotein I (β2GPI). Our laboratory has developed a model of SLE in which mice immunized with β2GPI and lipopolysaccharide (LPS) display a remarkably similar pattern of autoantibody emergence to that seen in human SLE, as well as SLE-like kidney disease. Here we use this model to investigate whether epitope spread to SLE autoantibodies is associated with a unique or limited β2GPI-reactive T cell response. We ask whether MHC class II haplotype, and its associated T cell epitope restriction, impacts epitope spread to SLE autoantibodies. Furthermore, we investigate the origin of β2GPI-reactive T cells initiating this epitope spread. We hypothesize that binding of β2GPI to necroptotic cells presents the immune system with a "scaffold" of cellular self-antigens in a pro-inflammatory and immunogenic context, leading to a robust β2GPI-reactive T cell response. Splenocytes from β2GPI/LPS-immunized mice with different MHC class II haplotypes were used to determine β2GPI-reactive T cell epitopes, using a peptide library spanning the entire sequence of human β2GPI. One β2GPI-reactive T cell epitope (LYRDTAVFECLPQHAMFG) in Domain III appeared to be a dominant epitope, since it was recognized in β2GPI/LPS-immunized mice with different MHC class II haplotypes, as well as in SLE-prone MRL/lpr mice. We next showed that β2GPI binds to necroptotic, as well as apoptotic, L929 cells but that necroptotic, not apoptotic, cells enhance pro-inflammatory cytokine (TNF-α) secretion by activated macrophages and dendritic cells in vitro. Necroptotic cells promoted MHC class II and costimulatory molecule expression in immature dendritic cells, leading to an enhanced CD4 T cell response to β2GPI in vitro. Finally, we show that mice deficient in Ripk3 (receptor-interacting serine/threonine-protein kinase 3), and hence necroptosis, show poor induction of SLE. In summary, we propose that factors enabling a β2GPI-reactive T cell response may predispose individuals to the development of SLE autoantibodies independent of their MHC class II haplotype. Furthermore, our findings suggest that necroptotic cells provide both self-antigens and pro-inflammatory signals that may be sufficient to overcome immune tolerance and induce SLE.
520 $a Cette these examine le role des lymphocytes T reactifs specifiques a la β2-glycoproteine I (β2GPI) dans le developpement du lupus erythemateux dissemine (LED). LED est une maladie auto-immunitaire et un modele pour la propagation des epitopes des cellules B dans le contexte auto-immunitaire. Les auto-anticorps diriges contre de nombreux auto-antigenes apparaissent de maniere sequentielle pendant plusieurs annees, menant a des manifestations pathologiques. Parmi les premiers auto-anticorps a apparaitre sont ceux qui ciblent contre les phospholipides et aussi les proteines qui se lient aux phospholipides, particulierement la β2-glycoproteine I (β2GPI). Notre laboratoire a developpe un modele de LED ou les souris sont immunisees avec la β2GPI et le lipopolysaccharide (LPS) qui presente un profil d'emergence des auto-anticorps remarquablement similaire a celui observe dans le LED chez les humains, ainsi qu'une maladie renale similaire. Pour nos recherches, nous utilisons ce modele pour determiner si la propagation des epitopes aux auto-anticorps LED est associee a une reponse de lymphocytes T reactifs specifiques a la β2GPI est unique ou limitee. Nous cherchons a determiner si l'haplotype du CMH de classe II (MHC II), et la restriction d'epitope des lymphocytes T associee a celui-ci, affectent la propagation des epitopes aux auto-anticorps LED. De plus, nous etudions l'origine des lymphocytes T reactifs specifiques a la β2GPI dans l'initiation de cette propagation des epitopes. Nous emettons l'hypothese que la liaison de la β2GPI aux cellules necroptotiques presente au systeme immunitaire une "plateforme" d'auto-antigenes cellulaires dans un contexte pro-inflammatoire et pro-immunitaire, menant a une reponse vigoureuse des lymphocytes T reactifs specifiques a la β2GPI. Nous avons d'abord isole des splenocytes de souris immunisees qui possedent des haplotypes du CMH de classe II differents, et puis determine la specificite des epitopes des lymphocytes T reactifs specifiques a la β2GPI en utilisant une banque de peptides couvrant la sequence entiere de la β2GPI humaine. Un epitope dans la β2GPI (LYRDTAVFECLPQHAMFG) dans le troisieme domaine semble etre un epitope dominant, car il est reconnu chez des souris immunisees ayant des haplotypes du CMH de classe II differents, ainsi que chez des souris MRL/lpr sujettes au LED. Nous montrons ensuite que la β2GPI peut se lier aux cellules necroptotiques et que les cellules necroptotiques, mais non pas apoptotiques, ameliorent la secretion de cytokines pro-inflammatoires (TNF-α) par des macrophages et des cellules dendritiques (DCs) actives in vitro. De plus, les cellules necroptotiques augmentent l'expression de la molecule du CMH de classe II et les molecules de la costimulation par les DCs immatures, ce qui mene a une reponse accrue des lymphocytes T CD4 reactifs specifiques a la β2GPI. Enfin, nous montrons que les souris deficientes en Ripk3, et donc la necroptose, possedent une induction defectueuse de LED. En resume, nous proposons que les facteurs permettant une reponse des lymphocytes T reactifs a la β2GPI peuvent predisposer des individus au developpement d'auto-anticorps LED independamment de leur haplotype CMH de classe II. Ces etudes suggerent egalement que les cellules necroptotiques fournissent a la fois des auto-antigenes et aussi des signaux pro-inflammatoires qui peuvent etre suffisants pour surmonter la tolerance immunitaire et induire le LED.
590 $a School code: 0781.
650 4 $a Cellular biology. $3 3172791
650 4 $a Immunology. $3 611031
653 $a β2-glycoprotein I-reactive T cells
653 $a Systemic lupus erythematosus
690 $a 0379
690 $a 0982
710 2 $a McGill University (Canada). $3 1018122
773 0 $t Dissertations Abstracts International $g 82-06B.
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791 $a Ph.D.
792 $a 2019
793 $a English
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