Immune Response to Erythrocyte-specific Antigens Pubblico

Hudson, Krystalyn E (2011)

Permanent URL: https://etd.library.emory.edu/concern/etds/5m60qs10n?locale=it
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Abstract

Abstract
Immune Response to Erythrocyte-specific Antigens

By
Krystalyn E. Hudson
Antibodies to red blood cell (RBC) antigens can occur spontaneously or as
a consequence of antigen exposure through infection, transfusion, transplantation, or
pregnancy. Some antibodies against RBC antigens are clinically insignificant, whereas
others are clinically relevant and can result in hemolysis, pose a barrier to future
transplants and complicate finding future compatible RBC units for transfusion. Defining
the underlying mechanisms that contribute to the breakdown of tolerance to RBC
antigens and factors that regulate the rates of alloimmunization are complex.
These data demonstrate that RBC-specific B cells escape both central and
peripheral tolerance mechanisms, encounter and present self-antigen, and are receptive of
CD4+ T cell help. Therefore, in the event that T cell tolerance is broken, autoimmunity
can be initiated. We have further demonstrated that molecular mimicry of CD4+ T cell
epitopes shared between a pathogen and an RBC antigen can enhance alloimmune
responses. As such, it is plausible that pathogen-elicited CD4+ T cells, through
molecular mimicry and/or linked recognition of cryptic (e.g. transmembrane or cytosolic)
peptides from RBCs could break T cell tolerance and lead to autoimmune pathology.
Maintenance of RBC structure and function is essential for sustaining life. As
such, RBC transfusions are life-saving therapies for persons with inherited or acquired
anemia and also those who suffer blood loss as a consequence of trauma, surgery or
childbirth. Thus, understanding the underlying mechanisms behind the breakdown of B
and/or T cell tolerance to RBC-specific self- and allo-antigens is important.

Immune Response to Erythrocyte-specific Antigens

By
Krystalyn E. Hudson
B.S., Georgia Institute of Technology, 2003
Advisor: James C. Zimring, M.D., Ph.D.
A dissertation submitted to the Faculty of the
James T. Laney School of Graduate Studies of Emory University
in partial fulfillment of the requirements for the degree of
Doctor of Philosophy
Graduate Division of Biological and Biomedical Sciences
Immunology and Molecular Pathogenesis
2011

Table of Contents

Table of Contents
Chapter 1 - Introduction

..............................................................................................1

The Importance of Red Blood Cells ..........................................................................2


Structure and Function ........................................................................................2

RBCs in Transfusion Medicine ..................................................................................4


Why Transfusions are Necessary .........................................................................4


Clinically Relevant Antigens ................................................................................4


Hemolytic Disease of the Fetus and Newborn .....................................................7


Adverse Reactions to Transfusions ......................................................................8

Tolerance to Self Erythrocyte Antigens ....................................................................10


Development and Maturation of RBCs ................................................................10


Lymphocyte Tolerance .........................................................................................11


Stages of B Cell Development (Making the B Cell Receptor) .............................11


Checkpoints During B Cell Development ............................................................13


Types of B Cells ...................................................................................................14


Conventional (B-2) B cells ...................................................................................14


Innate (B-1) B cells .............................................................................................16


Tolerance to Soluble and Membrane-bound Antigens .........................................19


A Murine Model of B Cell Tolerance to Erythrocyte Antigens ............................23


T Cell Tolerance ..................................................................................................25

Breaking Tolerance to Erythrocyte Antigens ............................................................26


The Effect of Antibodies Specific for RBC Antigens ............................................26


Mechanisms Hypothesized to Break Tolerance to RBC Antigens .......................27
References .......................................................................................................................30

Chapter 2 - Regulation of Primary Alloantibody Response through
Antecedent Exposure to a Microbial T cell epitope ....................................................50
Abstract ............................................................................................................................51
Introduction ......................................................................................................................52
Materials and Methods .....................................................................................................56
Results ............................................................................................................................61
Discussion ........................................................................................................................68
References ........................................................................................................................72
Figure Legends.................................................................................................................76

Chapter 3 - Patterns of Deletion of RBC Antigen Specific Autoreactive B cells
in a Murine Model ........................................................................................................92
Abstract ............................................................................................................................93
Introduction ......................................................................................................................94
Materials and Methods .....................................................................................................98
Results ............................................................................................................................102
Discussion ........................................................................................................................106
References ........................................................................................................................110
Figure Legends.................................................................................................................115


Chapter 4 - Central B cell Tolerance to Erythrocyte Antigens is Incomplete

........127
Abstract ............................................................................................................................128
Introduction ......................................................................................................................130
Materials and Methods .....................................................................................................134
Results .............................................................................................................................139
Discussion ........................................................................................................................147
References ........................................................................................................................151
Figure Legends.................................................................................................................155

Chapter 5 - Discussion ..................................................................................................169
Summary ..........................................................................................................................170
Discussion ........................................................................................................................175

Microbial Infection can Enhance Alloimmunization to RBC Antigens .....................175
The use of BCR Transgenics to Understand B cell Tolerance to Erythrocyte
Antigens......................................................................................................................178

Limitations to Current BCR Transgenic Mouse Models............................................182
Understanding B cell Tolerance to Erythrocyte Antigens in the Absence of BCR
Transgenics ................................................................................................................183
Future Directions .............................................................................................................186

Short term future directions .......................................................................................186

Long term future directions .......................................................................................193
General conclusions .........................................................................................................197
References ........................................................................................................................199
Figure Legends.................................................................................................................207



List of Figures

Chapter 2

Figure 2.1 ...................................................................................................................82

Figure 2.2 ...................................................................................................................85

Supplemental Figure 2.1 ............................................................................................86

Supplemental Figure 2.2 ............................................................................................87

Figure 2.3 ...................................................................................................................88

Figure 2.4 ...................................................................................................................89

Figure 2.5 ...................................................................................................................90

Figure 2.6 ...................................................................................................................91

Chapter 3

Figure 3.1 ...................................................................................................................117

Figure 3.2 ...................................................................................................................119

Figure 3.3 ...................................................................................................................122

Figure 3.4 ...................................................................................................................123

Figure 3.5 ...................................................................................................................125



Chapter 4

Figure 4.1 ...................................................................................................................158

Figure 4.2 ...................................................................................................................159

Figure 4.3 ...................................................................................................................160

Figure 4.4 ...................................................................................................................161

Figure 4.5 ...................................................................................................................163

Figure 4.6 ...................................................................................................................164

Figure 4.7 ...................................................................................................................165

Figure 4.8 ...................................................................................................................167

Figure 4.4 ...................................................................................................................168

Chapter 5

Figure 5.1 ...................................................................................................................194

List of Tables

Figure 2.1 ...................................................................................................................208





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