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EBOOKS Auto-Immunity Attacks the Body

FOR THE Autoimmune Disease


HUMAN DISEASES AND
HEALTH
Mary E. Miller
CONDITIONS COLLECTION
LIBRARY A. Malcolm Campbell, Editor
The human body is protected in critical ways as our immune
Create your own system provides protection from a broad spectrum of infections
Customized Content and injuries. Unfortunately, in some individuals, their immune
Bundle the more system targets components of their own bodies, causing au-
books you buy, toimmune disease. Many different types of autoimmune dis-
the higher your eases exist, each presenting unique symptoms depending on
discount! the body system that is damaged. It is not clear what triggers

Auto-
the progression from normal immune reactivity to autoimmune
disease, though both environmental and genetic factors are
THE CONTENT
thought to contribute.
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Immunity
This book focuses on three distinct examples of autoim-
Dietetics Practice
Psychology mune disease or reactivity: multiple sclerosis, which involves an
Health, Wellness, autoimmune response against structures that support neurons,
and Exercise rheumatoid arthritis, resulting from autoimmune-dependent
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damage to joints, and organ or graft rejection, which occurs
when the immune system recognizes tissues from another indi-
vidual as foreign. In each case, we consider current and future is-
Attacks the
Body
sues related to disease progression, diagnosis, and treatments.
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Mary E. Miller
Auto-Immunity Attacks
the Body
Auto-Immunity Attacks
the Body
Autoimmune Disease

Mary E. Miller
Auto-Immunity Attacks the Body: Autoimmune Disease
Copyright Momentum Press, LLC, 2017.

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Abstract
The human body is protected in critical ways as our immune system
responds to a broad spectrum of infections and injuries. Unfortunately,
in some individuals, their immune system targets components of their
own bodies, causing autoimmune disease. Many different types of au-
toimmune diseases exist, each presenting unique symptoms depending
on the body system that is damaged. It is not clear what triggers the pro-
gression from normal immune reactivity to autoimmune disease, though
both environmental and genetic factors are thought to contribute. This
book focuses on three distinct examples of autoimmune disease or reac-
tivity: multiple sclerosis, which involves an autoimmune response against
structures that support neurons, rheumatoid arthritis, resulting from
autoimmune-dependent damage to joints, and organ or graft rejection,
which occurs when the immune system recognizes tissues from another
individual as foreign. In each case, we consider current and future issues
related to disease progression, diagnosis, and treatments.

Keywords
Autoimmune disease, MHC, B cell, T cell, tolerance, organ transplant,
multiple sclerosis, rheumatoid arthritis
Contents
List of Figures.........................................................................................ix
Acknowledgment.....................................................................................xi
Introduction.........................................................................................xiii
Chapter 1 Symptoms and Diagnosis................................................. 1
Chapter 2 Causes and Contributing Factors.................................... 15
Chapter 3 Treatment and Therapy.................................................. 23
Chapter 4 Future Prospects............................................................. 27
Conclusion......................................................................................... 29
Bibliography....................................................................................... 31
Glossary.............................................................................................. 35
About the Author................................................................................ 39
Index....................................................................................................41
Figures

Figure 1 Interactions between B cells, T cells, and antigens........... xix


Figure 1.1 Transmission electron micrograph of
a myelinated axon..............................................................3
Figure 1.2 Diagrams representing disease progression over time
in different categories of MS patients ................................5
Figure 1.3 Structure of a healthy knee joint.........................................9
Acknowledgment

I would like to thank Malcolm Campbell for the opportunity to make


contributions to this book series. His forward approach to science and
scientific pedagogy is inspiring. I thank my husband David and daughter
Mallory for their patience and support of these efforts. I am fortunate to
work at Rhodes College, which has supported my professional and intel-
lectual development. I take pride that I have worked with outstanding
students, and thank them for inspiring my passion for science education.
My outstanding mentors, colleagues, and collaborators have made it
possible to carry out rigorous research and forward high-impact educa-
tional practices. Specifically, I thank Mitch Smith, Dan Engel, Jeff Becker,
Fred Cross, and Pam Hanson, whose advice and influence have shaped
my professional success. The editorial staff at Momentum Press have been
supportive and kind, and I appreciate their work in the production of
this book. I hope that some aspect of this work is helpful for individuals
working to better understand or manage these devastating diseases.
Introduction

The human immune system provides a remarkably robust and broad


spectrum of protection against infection and injury. Without this com-
plex response to the presence of foreign materials in our bodies, we would
quickly succumb to disease and no longer enjoy protection through vac-
cinations to diseases such as polio or chicken pox. Unfortunately, in some
individuals, their immune systems target components of their own b odies.
When a persons immune system damages or destroys his or her own cells,
then autoimmune disease or autoimmunityoccurs. More than 80 auto-
immune diseases have been identified where benign immunity progresses
to pathogenic autoimmunity that harms the human body. Autoimmune
diseases can harm specific organs or can be systemic, meaning that dam-
age has occurred throughout the body. For example, when the immune
system targets insulin-producing organs in the body, type I diabetes oc-
curs, which results in a loss of blood sugar regulation. A more systemic
response occurs in the case of lupus, because the DNA that is normally
released into the body when cells naturally die becomes mis-targeted
by the immune system, causing skin rash, fever, and other more serious
symptoms. This book focuses on three distinct examples of autoimmune
disease or reactivity: multiple sclerosis, which involves an autoimmune
response against structures that support neurons, rheumatoid arthritis,
resulting from autoimmune dependent damage to joints, and organ or
graft rejection, which occurs when the immune system recognizes tissues
from another individual as foreign. It is not clear what triggers the pro-
gression from normal immune reactivity to autoimmune disease, though
in most cases both genetic and environmental factors are thought to be
contributing factors. Women are more susceptible than men to develop
autoimmune diseases, suggesting some hormonal contributions to disease
onset. Most autoimmune diseases are not transmitted from one person to
another, but mother-to-child placental transfer is possible. Collectively,
autoimmune diseases carry an annual health care cost of over 100 billion
xiv INTRODUCTION

dollars in the United States, excluding the cost of organ transplant rejec-
tion due to related immunity mechanisms.

The Healthy Immune System: The Innate


andAdaptive Immune Responses
The human immune system protects the body from the introduction of
foreign materials, including infectious microorganisms, or pathogens, to
the body. The immune system is remarkably complex and able to provide
protection from a variety of threats. Some aspects of the immune system
are defensive in a nonspecific way, meaning that they provide barriers
and more generalized mechanisms for removing foreign material from
the body. These systems are usually described as part of the innate im-
mune system, and would be associated with the first line of defenses
that our body presents to pathogens or other foreign materials. Parts of
the innate immune system provide physical barriers like skin or mucus.
Other parts of the innate immune system involve specialized cells that
are able to recognize, target, and destroy these foreign materials. Cells are
the fundamental living units in our bodiesand individual cells have the
ability to grow, multiply, communicate, and at times secrete molecules
into the body. Groups of individual cells can work together to function
collectively and in a coordinated way, giving rise to higher-order tissues
and organs. Cells that function individually as part of the innate immune
system have specialized functions such as phagocytosis. Phagocytosis oc-
curs when a cell surrounds and encases or engulfs target material. Once
inside a phagocytic cell, the material, frequently a pathogen, is degraded
and destroyed. Examples of phagocytic cells of the innate immune system
include neutrophils, which circulate in our blood, and macrophages,
which are larger than neutrophils and found throughout the body, includ-
ing within organs. Other specialized cells capable of phagocytosis include
dendritic cells, which are characterized by their tendency to move to
places in the body that contact the environment, and eosinophils, which
target larger pathogens or parasites such as worms by secreting materials
to destroy them before engulfing those degraded materials. When acti-
vated, macrophages and neutrophils secrete molecules called cytokines
that stimulate blood flow, giving cells of the immune system increased
INTRODUCTION
xv

access to the site of infection or injury, and producing the redness, swell-
ing, and increased temperature that you might normally associate with
inflammation. The inflammation response can be localized or systemic,
depending on the severity of infection or damage to cells and tissues of
the body. Different types of immune responses can be triggered by in-
flammation, and inflammation can be triggered by immune responses,
leading to the self-sustaining cycle of inflammation followed by immune
response followed by more inflammation, and so on. This cycle can stim-
ulate healing, but it can become chronic and thus pathological.
A second major type of immune response that exists in vertebrates, in-
cluding humans, is the adaptive immune response. A major distinction
between the cellular responses of the innate and adaptive immune systems
is the ability to differentiate material normally found in the healthy body
(seen as self ) from material not normally found in the healthy body (seen
as nonself and therefore potentially pathogenic). In the case of the innate
immune response, the material recognized as foreign is usually common
to many pathogens so that the immune system has evolved the ability to
recognize these in a somewhat nonspecific way. For example, some viruses
use the molecule RNA instead of DNA to carry their genetic material.
Double-stranded viral RNA is not normally found in human cells, so
the innate immune system has evolved the ability to recognize the pres-
ence of these viral RNAs and target them for destruction. By targeting all
double-stranded RNA, the innate immune system blocks viral replication
and illnesses. It doesnt matter what type of virus it is as long as it carries
double-stranded RNA. By targeting this common viral molecule, the in-
nate immune system is providing protection from viruses, but in a non-
specific way; one that does not show selectivity toward one type of RNA
virus versus another type. In contrast, structures recognized as foreign
by cells in the adaptive immune response frequently are unique to the
specific pathogen. The adaptive response is generally slower than the in-
nate response the first time that foreign material is detected, but in subse-
quent exposures, the adaptive response is very rapid. A rapid response by
the adaptive immunity is considered a type of immune system memory,
and provides increased protection from specific pathogens after initial
exposures. Immunological memory produces a faster, more prolonged,
and intense response to foreign materials in the body. When considering
xvi INTRODUCTION

autoimmune diseases, it is most likely a breakdown of both innate and


adaptive immune responses, leading to increased inflammation and dam-
age in the body because of inappropriate immune response.
The adaptive immune response is associated with the specialized cell
types found in the blood called white blood cells, specifically lympho-
cytes. White blood cells are distinct from red blood cells since white
blood cells play a critical role in immune response, and do not trans-
port oxygen through the body. Of lymphocytes, the most well-known are
called B cells and T cells. All lymphocytes are originally formed from a
type of stem cell called hematopoietic stem cells located in bone mar-
row, the soft region internal to the bone that supports cellular growth and
replenishment. Hematopoietic stem cells have the ability to divide and
differentiate into several different cell types, including lymphocytes. Stem
cells stay in the bone marrow and turn into B cells, or in the case of T cell
development cells migrate to the thymus. Other hematopoietic stem cells
stay in the blood system and turn into several types of lymphocytes, such
as natural killer cells of the innate immune system. B and T cells are each
capable of interacting with foreign materials in the body, and stimulating
a response that will help clear those materials. Any material that triggers
a response from a B cell or a T cell is called an antigen, and antigens are
usually larger molecules such as foreign proteins. Proteins are composed
of amino acid chains, and each amino acid has chemical and structural
properties that determine the proteins overall shape and thus its func-
tion. The structure of a protein dictates how it interacts with other pro-
teins, and what it can do. For example, a protein with one shape might
work deep within a cell and be involved in turning on and off genes.
Other proteins, encoded by different genes, will have their own chemical
and physical properties and may take up residence at the surface of a cell
and bind (physically interact) with components of the immune system.
The ability of cells to interact with each other via proteins expressed on
their surfaces creates an opportunity for cellular communication. In other
words, surface proteins allow one cell in the body to recognize another.
Proteins on the surface of each cell, often called receptors, physically
interact, change shape, and initiate signals inside the cell, allowing a cell
to recognize another cell. In this way, a cell can sense when it has come in
contact with other cells, or, more specifically, proteins that are present on
INTRODUCTION
xvii

the surface of other cells. When a protein receptor on an immune system


cell binds to an antigen, the immune cell triggers an immune response.
In this way, particular antigens from viruses or bacteria can be identified,
targeted, and destroyed by our immune system. Immunity allows our
cells to recognize in the body harmful material at the molecular level and
mount a destructive response toward that material.
The part of the B cell or T cell that is able to physically interact with an
antigen is called an antigen receptor. The structure of antigen receptors is
different in B cells versus T cells, but in both cases, this initial recognition
of antigen by antigen receptor is a critical event in stimulating an immune
response. In B cells and T cells, antigen receptors are embedded in the
cell membrane (the outermost layer of the cell, composed of lipids and
proteins that encases the cell and provides a structural matrix and a barrier
from the environment), and are displayed on the outside of the cell.
Collectively, a persons population of B and T cells can interact with a vast
variety of antigens, but any given B cell or T cell produces one specific
antigen receptor that binds to one specific antigen. In the case of B cells,
when an individual B cell physically binds to its antigen, the B cell rapidly
produces more receptor-like molecules that are secreted from the B cell
into the fluids of the body. These secreted versions of the receptors are
called antibodies (Ab) or immunoglobulins (Ig), and also bind to the
antigen. B cells allow the immune system to recognize antigens that are
floating free in the fluids of the body because B cells produce circulating
antibodies that bind to antigen and target them for immune response.
T cells do not secrete the antigen receptor, and therefore do not make
antibodies. The structure of T-cell antigen receptors is very different from
B-cell antigen receptors. T-cell receptors only bind to antigens that have
been processed by other human cells and are displayed on the surface
of those cells by a set of proteins called the major histocompatibility
complex (MHC), also called human leukocyte antigen (HLA). Most
cells in our body, with the exception of red blood cells, carry one type
of MHC. There are many different MHC alleles, giving great variation
within a population of individuals to have different versions of MHC.
In every person, MHC complexes of different types exist and carry out
distinct functions in the immune system. In the case of some types of T
cells, the class II MHC (MHC II) marks a cell as an antigen presenting
xviii INTRODUCTION

cell. For example, a host cell such as a macrophage might engulf an


invading pathogenic bacteria in order to kill the invading cell. Protein
components of the bacteria are bound by the MHC, and moved to the
surface of the macrophage so that the captured bacterial protein antigen is
presented on the outside of the macrophage. This processing of bacterial
proteins and antigen presentation can occur in additional cell types than
macrophages alone. When the antigen is held on the surface of a cell by the
MHC, a T-cell receptor on the surface of the T cell can recognize and bind
to the antigen/MHC complex on the surface of an antigen presenting cell
such as the macrophage. This proteinprotein interaction will activate the
T cell and stimulate an immune response. The type of response depends
on the type of T cell (and cognate MHC type) that is involved. In the
case of helper T cells, MHC class II (also referred to as CD4+ cells) would
present antigen, while in the case of cytotoxic T cells, MHC class I (also
referred to as CD8+ cells) would present antigen. MHCI is present on all
nucleated cells, while MHCII is also present on more specialized antigen
presenting cells. So while B cells can target free floating antigens, T cells
target antigen bound by MHC present on the surface of cells.
Maturation of both B and T cells occurs as these cell types interact
with potential antigen, grow and divide in the bone marrow and thy-
mus, respectively. In the case of B cells, maturation and activation oc-
curs when the B-cell receptor binds to antigen and the cell is exposed to
cytokines normally produced by helper T cells in the environment. Once
activated, the B cells can divide further and produce plasma cells, capable
of sustained production and secretion of antibody. Most daughter cells
are clonal, meaning that they can bind to the exact same antigen as the
original cell, and they are specific, meaning that they can bind only to
that one antigen. In the case of T cells, maturation and activation occur
with antigen/MHC binding in the presence of certain cytokines. For ex-
ample, MHCI-dependent antigen interactions generally give rise to cyto-
toxic and memory T cells. Helper T cells facilitate B-cell activation, and
cytotoxic T cells facilitate the targeting of infected cells for destruction.
Some activated T and B cells become memory cells, meaning that they
remain in the lymph and blood system for many years so that a second ex-
posure to the same antigen will result in a more immediate, stronger, and
longer-lasting immune response once these memory cells are activated.
INTRODUCTION
xix

Thus, B and T cells have the ability to recognize specific antigen and cre-
ate this immunological memory of antigen exposure, which are the two
essential components of the adaptive immune system (Figure 1).
Autoimmunity occurs when the innate or adaptive immunity incor-
rectly targets a normal part of the body, so that healthy cells are dam-
aged or destroyed by the immune system, resulting in inflammation. It
is important to understand that immune responses occur at low levels
at all times in our bodies. It is a natural part of how the immune system

Figure 1. Interactions between B cells, T cells, and antigens.


In the left panel, a B cell encounters its triggering antigen and gives
rise to many plasma cells that secrete antibody proteins. Each plasma
cell descended from one B cell secretes millions of identical antibody
molecules into the bloodstream. In the right panel, T-cell activation is
triggered when it encounters antigen, coupled to an MHC molecule, on
the surface of an infected cell or a presenting cell. T cells contribute to
immune defenses in two major ways: some regulate immune responses
by other lymphocytes; others directly attack infected or cancerous cells.
Image files obtained from https://upload.wikimedia.org/wikipedia
/commons/f/f7/B_cell_activation.png and https://upload.wikimedia.org
/wikipedia/commons/2/29/T_cell_activation.png with template drawing
and caption text modified from The Immune System [Public domain],
via Wikimedia Commons.
xx INTRODUCTION

distinguishes foreign material that needs to be targeted for destruction


from normal parts of the human body; in other words, distinguishing
between nonself and self. In addition, there is a low level of mistaken au-
toimmune response that is normally harmless and is ignored or removed
from the body through a process called tolerance. Tolerance is when an
immune response against a specific antigen in the human body is sup-
pressed. One mechanism of tolerance deletes or kills those B cells and
T cells that are autoreactive or strongly interact with self-antigens. As
B and T cells mature in the bone marrow and thymus, respectively, they
are allowed to bind to host antigens. If strong interactions occur to a host
antigen, the B or T cell is either inactivated or undergoes a type of pro-
grammed cell death called apoptosis. Autoreactive immune cells should
never be released into the body where they might cause damage. Those
B and T cells that survive maturation and become activated do not bind
to self-antigens, but bind to other foreign antigens and trigger appropri-
ate immune responses. Despite this initial quality control of developing
B and T cells, occasionally autoreactive immune cells are released into
the body in healthy individuals. Another mechanism of tolerance occurs
when circulating autoreactive immune cells are kept inactive, or anergic.
Anergic autoreactive B and T cells can bind to the self-antigen, but they
are unable to mount an immune response and therefore cannot cause
damage to the body. In addition to these regulatory events that allow
tolerance by inhibiting B and T cells of the immune system, additional
cells circulate through our bodies and turn off a healthy immune response
once it has completed its job. These cells are hypothesized to turn off the
immune response from autoreactive T and B cells. Finally, some areas of
the body are naturally inhibited for a strong immune response, such as
the eyes. It is not clear what aspects of tolerance fail in any one specific
autoimmune disease, but the activation of autoreactive immune cells is
thought to be a common feature.
The purpose of this book is to explain autoimmune diseases by ex-
amining in great detail two representative autoimmune diseases: multi-
ple sclerosis and rheumatoid arthritis. We also include in our discussion
the phenomenon of organ transplant rejection, which involves recog-
nition of nonself and immune response damage in the recipient host
body. Chapter1 describes the current understanding of symptoms and
INTRODUCTION
xxi

diagnostic methods for identifying autoimmune conditions, which vary


widely based on the cells or tissues targeted for destruction. Chapter 2
focuses on the potential causes of symptoms associated with these au-
toimmune diseases. Note that no one trigger or cause has been clearly
described that provides a unifying theory of disease onset for all auto-
immune reactions. Chapter 3 addresses treatments and therapies, which
frequently employ modifiers of immune response. No cure exists for mul-
tiple sclerosis or rheumatoid arthritis, and organ donation requires careful
monitoring of immune response. Chapter 4 looks to future work in the
challenging area of autoimmune diseases.
CHAPTER 1

Symptoms and Diagnosis

Symptoms and Diagnosis of Multiple Sclerosis


Multiple Sclerosis (MS) is described as an autoimmune disease of the
nervous system. In MS, autoimmunity causes nerve damage leading
to many symptoms, usually involving muscle weakness or vision loss.
Estimates suggest that there were approximately 2.3 million cases of MS
worldwide in 2013, increasing from 2.1 million in 2008. In the United
States, there are about 400,000 cases, with about 200 new cases diagnosed
each week with a cost of treating one MS pateint ranging from $8,500 to
$54,000 per year. These estimates are difficult to make, however, because
physicians are not required to report MS and there are no national
studies attempting to track the disease. There are approximately 107,000
MS patients in the United Kingdom but again, there is no mandated
reporting in the UK. Lack of mandatory reporting makes accurate
tracking of potential environmental or genetic components of the disease
more difficult. Available data suggest that MS is more common in women
than in men, and among Caucasians and individuals of Northern or
Central European descent with higher incidence in Europe, the United
States, Canada, and those of British descent in New Zealand and parts of
Australia. It is less common in Asia, the tropics, and among Hispanics,
Asians, and individuals of African descent. MS is rarely observed in some
ethnic groups such as Inuits, Maoris, and Aborigines. It is not clear why
some geographical locations and populations show increased or decreased
likelihood of developing MS.
It is clear that MS results in a decrease in the function of cells impor-
tant for functioning of the nervous system. The nervous system allows
2 AUTO-IMMUNITY ATTACKS THE BODY

the human body to conduct higher-order thinking, and interact with its
environment through sensory input and motion. The nervous system in-
cludes the central nervous system (CNS; brain and spinal cord) and the
peripheral nervous system which consists of those cells outside of the
CNS that interface with the body to produce the complex and coor-
dinated response to our environment. The underlying cause of MS is
thought to be autoimmune-mediated destruction of structures that sur-
round and support neurons. Neurons are the primary cells that trans-
mit signals in the nervous system. More specifically, the myelin sheath
normally surrounding neurons is damaged in MS patients. The myelin
sheath is a structure that physically supports, repairs, and provides po-
tential nutrients to the neurons. The neurons that are normally protected
by the myelin sheath are damaged or dysfunctional in MS patients. One
function of the myelin sheath that is critical for neuron function is to help
propagate electric signals quickly so that neurons can communicate with
other neurons and target cells. An electrical signal, a charge differential
across the cellular membrane, of the neuron is propagated and travels
down the length of the neuron to be transmitted to the next neuron, or
converted to a chemical signal that is conveyed to the next neuron. Neu-
rons can be very long, and the potential for electrical signal weakening
along the length of the neuron is reduced by the presence of the myelin
sheath. The myelin sheath is found on both peripheral and CNS systems,
and is composed of approximately 70 to 80 percent fats or lipids. Also
present are proteins and supporting cells such as Schwann cells that help
produce myelin components (Figure 1.1).
Disease progression in MS can be difficult to anticipate, though
symptoms of impaired vision and muscle weakness are common. Many
patients show only mild symptoms of the disease while others lose the
ability to walk, talk, and write. The variability of disease intensity con-
founds diagnosis and treatment; no single treatment has been found
to be effective for all MS patients. Disease variability is experienced by
each patient, with the intensity of symptoms changing each day. For
an individual with MS, disease progression can vary over time. To aid
in diagnosis and treatment of the disease, MS is categorized based on
changing symptomatic patterns in the patient. In primary progressive
MS (PPMS), disease symptoms occur and continue to worsen over time.
Symptoms and Diagnosis 3

Figure 1.1 Transmission electron micrograph of a myelinated


axon. The myelin layer (concentric layers) surrounds the axon of
a neuron, showing cytoplasmic organelles inside. A Schwann cell is
located above the myelin layer. (Modified from image generated
and deposited into the public domain by the Electron Microscopy
Facility at Trinity College.) https://commons.wikimedia.org/wiki/
File:Myelinated_neuron.jpg.

In progressive relapsing MS (PRMS), the initial onset of disease shows


an initial relapse (reappearance or worsening of symptoms), followed by
continued worsening of symptoms over time. In relapsing-remitting
MS (RRMS), the patient experiences clearly defined periods of new or
continuing symptoms (relapse or exacerbations), followed by periods
of no or little disease symptoms (remission). RRMS can develop into
secondary progressive MS (SPMS) where remission no longer returns
the patient to a symptom-free condition, and the baseline symptoms dur-
ing remission worsen over time. One major distinction is that patients
4 AUTO-IMMUNITY ATTACKS THE BODY

with PPMS, PRMS, and SPMS would not experience full remission of
symptoms, though some remission might occur on occasion. In PPMS,
symptoms may stabilize for periods of time or acute symptoms might
occur followed by some remission, though a steady and gradual increase
in symptoms is observed over time. In RRMS, periods of relapse and re-
mission are more easily recognized by the patient and at times, symptoms
can improve during stages of remission. Approximately 85 percent of MS
patients initially show relapsing with full remitting symptoms; so RRMS
is the most expected course of disease progression. In approximately 80
percent of the cases, individuals with RRMS progress to SPMS/PPMS
after at least 10 years of RRMS. Of the remaining 15 percent of MS cases,
approximately 10 percent are initially diagnosed as PPMS (Figure 1.2).
The most common symptoms of MS are loss of sensory input and
motor control. These symptoms result in fatigue, vision problems, and
difficulty in muscle function that can produce uncoordinated movement.
As the disease progresses, movement can become impaired, making
standing or walking difficult, and in some cases lead to paralysis. Other
symptoms commonly associated with MS include bladder problems and
paresthesia, or feelings of pain, prickling, or numbness that can increase
in intensity and then dissipate. Patients can experience spasticity or mus-
cle stiffness, and general pain. Muscle weakness may also occur because
muscles are left unused over time. Visual symptoms include blurry vi-
sion, difficulties in discerning green and red colors, and in some cases
blindness in one or both eyes. Dizziness and vertigo occur, as well as
possible hearing loss. Patients often report tremors, bladder problems,
sexual problems, and speech problems. Symptoms may include cogni-
tive and emotional changes such as difficulty concentrating, remembering
things, mood swings, or irritability. Depression is a common occurrence
in MS patients. In addition to symptoms that arise due to direct damage
to neurons, there are also secondary symptoms that can be attributed to
complications of the loss of neuronal function. For example, a patient can
develop bed sores from a lack of movement, or urinary tract infections
from bladder dysfunction. MS symptoms are very unpredictable and will
vary for each individual in intensity, occurrence, and re-occurrence. In
fact, many people with MS do not experience severe disability. It is esti-
mated that two-thirds of MS patients maintain mobility with the aid of
Symptoms and Diagnosis 5

Figure 1.2 Diagrams representing disease progression over time


in different categories of MS patients. Patterns shown are examples
of one possible disease progression in each category. Image obtained
from Wikimedia [Public domain] https://commons.wikimedia.org/wiki/
File:Ms_progression_types.svg submitted by GetThePapersGetThePapers
at English Wikipedia [Public domain], via Wikimedia Commons.

canes, crutches, or wheelchair. On average, an individual with MS would


have a life expectancy of approximately 7 years less than an individual
without MS.
MS symptoms usually present in patients between the ages of 40 and
50 years for PPMS, and 20 and 40 years for RRMS, though MS can
begin in small children or older adults. PPMS and RRMS are distin-
guished by patterns of disease progression where disease onset occurs later
for PPMS patients and periods of remission are few or absent. PPMS and
6 AUTO-IMMUNITY ATTACKS THE BODY

RRMS can also be distinguished by the inflammation that occurs during


the autoimmune response. PPMS involves fewer inflammatory cells and
fewer areas of damage, or lesions, in the brain. PPMS damage appears to
localize more commonly in areas of the spinal cord than in the brain, and
for this reason shows more frequent symptoms associated with difficulties
in mobility. In both PPMS and RRMS, patients symptoms are described
as active or not active; active patients experience new symptoms. RRMS
patients can also be described as worsening or not worsening, which re-
flects the increase in disability due to symptoms as the disease progresses.
In a case of worsening RRMS, the patient experiences an incomplete
recovery from the relapse. Increases in disability must be present after
6 months for symptoms to be considered worsening because recovery
after relapse can take time. Every RRMS patient has a unique experi-
ence with variations in the length and intensity of relapse, time between
relapses, and levels of disease worsening.
Diagnosis of MS is difficult because of the potential for symptom
recovery and variety of intensity and nature of symptoms. Difficulty in
diagnosis can lead to years of symptoms that come and go with no identi-
fied cause. Formal diagnosis requires evidence of at least two areas of dam-
age in the CNS in the same or different regions. The regions of the central
nervous system that might be damaged include the brain, spinal cord, or
optic nerves. Two events of damage would need to occur at least 1 month
apart; and some guidelines suggest that symptoms must persist for more
than 1 year. Other possible causes of symptoms would need to be ruled
out before a diagnosis of MS would be appropriate. Other conditions that
might cause similar symptoms due to demyelination of neurons include
viral infection, vitamin B12 deficiency, collagen-vascular diseases, expo-
sure to toxins, and GuillainBarre syndrome. In the case of optic nerve
damage, the physician would also rule out neuromyelitis optica (NMO),
which is described as a separate disease from MS due to the presence
of antibodies unique in NMO patients that recognize a specific protein
called aquaporin 4. Distinguishing between NMO and MS is important,
since treatments differ for the two diseases.
In 2010, an international panel on the diagnosis of Multiple Scle-
rosis provided guidelines called the Revised McDonald Criteria. These
Symptoms and Diagnosis 7

guidelines incorporated the use of advanced imaging techniques such as


magnetic resonance imaging (MRI) to facilitate the diagnosis process.
MRI captures a detailed series of images that can display cross-sections
through the brain and spinal cord. Briefly, MRI uses a very strong mag-
net to align the polarity (a type of directionality) of the hydrogens (pro-
tons) present in our body (largely found in water). A radio wave is passed
through the person, making the protons change direction. Once the radio
wave is removed, the protons move back to their original orientations,
releasing energy. This released energy is sensed by the machine to generate
an image based on how quickly the energy is released from the protons.
The result is a series of high-resolution images showing the relative size
and position of tissues and organs in the human body. In the case of MS,
demyelination of nerves is visible in MRI scans of the brain and spinal
cord. Identification of these lesions by MRI is a powerful aspect to the
diagnosis of MS, but approximately 5 percent of individuals who have
been diagnosed with MS show no lesions. The Revised McDonald Cri-
teria do not require the presence of lesions for an MS diagnosis. MRI
can also detect inflammation. Detection is possible because inflammation
opens the bloodbrain barrier and allows the chemical gadolinium into
the brain. After injection of gadolinium into the patient, MRI detection
of gadolinium in the brain indicates that inflammation is present. Active
inflammation in the brain would be consistent with a diagnosis of MS.
CNS function is determined by tests that measure evoked electronic
potentials in the brain. In this test, electric wires are placed on the p
atients
head near regions of the brain to be stimulated. Sensory inputs are pro-
vided by the device and the brain response is measured. Expected patterns
of electronic potentials, or conductance, slow or change as neurons be-
come demyelinated. This measurement can detect loss of neural function
before a patient experiences noticeable symptoms, which can provide evi-
dence of a second damage before a second symptomatic event occurs. For
example, evoked potentials can be used to test for optic nerve function,
and detect early problems in an individual who is not aware of any visual
symptoms. The test is noninvasive and painless and allows very sensi-
tive detection of damaged areas. Earlier diagnosis allows p atients to take
advantage of disease-modifying treatments earlier in disease progression.
8 AUTO-IMMUNITY ATTACKS THE BODY

Another test frequently employed in the analysis of MS is the detection of


potential biomarkers consistent with immune response or myelin break-
down in the cerebrospinal fluid (CSF). The CSF is a colorless liquid
that surrounds the brain and spinal cord. It cushions these organs and
provides access to nutrients and removes waste products. The presence
of antibodies, proteins called oligoclonal bands, or products of myelin
breakdown in the CSF would be consistent with a diagnosis of MS, but
are not sufficient for a diagnosis of MS.
In 2013, the international advisory committee on clinical trials of MS
made suggestions for describing disease progression, which in addition to
MS symptoms presented in the patient include biomarker and imaging
detection of damaged neurons in the brain, spinal cord, and optic nerve.
Specifically, MRI or optical coherence tomography (OCT) imaging
techniques can be used to detect neuron demyelination characteristic of
MS before patterns of disease relapse or remissions are evident. OCT is a
noninvasive imaging tool for viewing the back of the eye and the retinal
nerve. These advanced imaging techniques allow physicians to consider
active disease states by identifying demyelinated or dysfunctioning neu-
rons, independent of symptom relapse in the patient. More information
would be needed to apply MRI or OCT results to the concept of pro-
gressive MS, since there is no standardized description of MRI or OCT
disease progression.
Identification of the first clinical manifestations of MS may be de-
scribed as clinically isolated syndrome (CIS). CIS is insufficient for a
diagnosis of MS, but when MS-like damage to the brain, spinal cord, or
optic nerve is observed by MRI or OCT scans along with CIS, there is
an increased likelihood that the disease will progress to MS. The ability
to identify CIS makes drug intervention possible at very early stages of
the disease. Specific FDA-approved treatment regimens exist that may
delay MS onset, or ameliorate MS progression in CIS patients. There is
also the possibility that MRI scans would identify patterns of demyelin-
ation consistent with MS with no associated MS symptoms, when the
MRI scan was performed for other clinical reasons. In this case, termed
radiologically isolated syndrome, no diagnosis of MS would be made
but awareness would be increased of MS as a possibility and carefully
monitored in the future.
Symptoms and Diagnosis 9

Symptoms and Diagnosis of Rheumatoid Arthritis


Rheumatoid arthritis (RA) is a chronic (long lasting) autoimmune disease
that causes pain, stiffness, swelling, and motion problems of joints in
the human body. A joint is the place where two or more bones come to-
gether. Many joints allow for movement between the bones, and absorb
the impact caused by movement. Ends of bones are covered in cartilage,
and the entire joint is surrounded by a capsule that supports and protects
the joint (Figure 1.3). The capsule is lined by a type of tissue called the
synovium which produces the synovial fluid. Normally, the synovium
and synovial fluid lubricate and support the cartilage and bones that are
inside of the capsule.
In RA, the autoimmune response causes the synovium to undergo
inflammation. Small joints in the hands and feet are most often in-
volved first, with wrists, elbows, knees, and ankles affected later in disease

Figure 1.3 Structure of a healthy knee joint. In a healthy joint,


the ends of bones are encased in smooth cartilage. Together, they
are protected by a joint capsule lined with a synovial membrane
that produces synovial fluid. Various ligaments, tendons, and other
connective tissues position and support the joint. Image obtained from
https://upload.wikimedia.org/wikipedia/commons/9/9a/Health_joint
.png with the original source http://www.niams.nih.gov/health_info/
Osteoarthritis/default.asp.
10 AUTO-IMMUNITY ATTACKS THE BODY

progression. Usually, the joint symptoms are symmetrical, meaning that


if one joint like the knee is affected, then the other knee will also be af-
fected. RA symptoms may come and go, and an increase in symptom
severity or inflammation, called a flare, can last from days to months. The
inflammation associated with RA can also affect organ function, such as
the heart or lung, and for this reason RA is described as being systemic, or
affecting multiple areas around the body. RA is the most common form
of autoimmune-triggered arthritis, with more than 1.3 million patients in
the United States, 75 percent of whom are women. RA usually develops
between the ages of 40 and 60 years, though a person can develop RA at
any age, and it is present in all ethnic groups. The cost of RA was esti-
mated at approximately $39 billion in the 2005 US Medical Expenditure
Panel Survey. RA can be one of the most disabling types of arthritis, but
with careful treatment can be well managed by patients.
The initial symptoms of RA can be a subtle achiness or stiffness in
the joints as is the case with many diseases at their early stages. Symp-
toms worsen in the morning, and often joint stiffness in the morning is
the first sign of RA. The affected joint will experience inflammation that
causes warmth, redness, and swelling. Muscles and ligaments that sur-
round that joint will experience weakness. Other symptoms include loss
of energy, low fevers, loss of appetite, dry eyes, and lumps below the skin
near the elbows and hands. The development of dry eyes and mouth can
result from Sjogrens syndrome which is a complication of autoimmune
diseases including RA and lupus. Osteoarthritis can be confused with
rheumatoid arthritis, though osteoarthritis results from damage to joints
through use; and not from inflammatory responses. Osteoarthritis does
not cause prolonged morning stiffness like RA. Given the complexity of
other diseases with overlapping symptoms, consultation with a specialist,
such as a rheumatologist, is important.
Disease progression of RA can take different courses. Most often,
RA is progressive meaning that it will continuously worsen over time.
However, there are other patterns of disease progression. Monocyclic
RA progression is when the patient experiences an episode of inflam-
mation with symptoms that last between 2 and 5 years, and then the
symptoms go away and never return. Frequently, monocyclic RA is the
Symptoms and Diagnosis 11

course of disease progression if very early diagnosis is done and im-


mediate treatment is applied. In the case of polycyclic RA progression,
symptoms reoccur and flares occur in unpredictable patterns. In this
case, it is possible for patients to experience long periods of time without
symptoms.
Forty percent of individuals with RA will die from cardiovascular
disease, specifically ischemic heart disease. It is unclear if RA creates
higher risk for cardiovascular disease, or if cardiovascular disease creates
higher risk for RA. Infections, such as tuberculosis, are the next most
common cause of death in 25 percent of all RA patients. It is possible
that RA compromises the immune system, making individuals more sus-
ceptible to tuberculosis infection or less able to fight infection once it
has occurred. It is not clear if a tuberculosis infection contributes to RA
susceptibility.
RA diagnosis involves a physical exam by a physician to identify
symptoms and areas of tenderness, swelling, warmth, pain, or limited
movement. Blood tests can identify anemia (low numbers of red blood
cells), and the presence of any one of several antibodies, called rheumatoid
factors, in the blood. Rheumatoid factors are antibodies associated with
an autoimmune response, and can also be indicative of other autoimmune
disorders. The presence of antibodies to cyclic citrullinated peptides
indicates the presence of an inflammatory response, and has been found
to correlate strongly with RA diagnosis. Recall that the presence of spe-
cific antibodies indicates that a specific antigen has triggered an immune
response, activated a B cell, and that B cell has produced many antibody-
secreting plasma cells. The detection of antibodies against antigens as-
sociated with inflammation is evidence that inflammation has occurred.
Inflammation can also be indicated by elevated erythrocyte sedimentation
rate. Blood tests can be coupled with imaging techniques such as X-rays,
which might show signs of inflammation or erosions of the bone or joint.
Patients with RA may test positive or negative for any of these tests, so it
is important to understand that no single test exists that is sufficient for a
diagnosis of RA. The physician must consider the collection of symptoms
and test results present for the individual patient when considering a di-
agnosis of RA.
12 AUTO-IMMUNITY ATTACKS THE BODY

Symptoms and Diagnosis of Graft Rejection


Graft Rejection, or transplant rejection, describes an outcome from organ
or tissue transplantation where the transplanted material triggers a dam-
aging immune response in the host to the transplanted organs or tissues.
Organ transplants are a promising therapy for individuals experiencing
organ failure and many other diseases, and can be a life-saving procedure
for these patients. Some of the most commonly transplanted organs and
tissues in the United States include kidneys, bones, tendons, ligaments,
skin, heart valves, blood vessels, and corneas. Transplants occur every day,
and in the United States, approximately 655,000 transplants have been
performed since 1998. The demand for organ donations is substantial,
with about 22 individuals dying each day from organ failure that theoreti-
cally could have been treated with a transplant. Organ transplants involve
a surgical process where tissues or organs are removed from one individual
and implanted in a second individual. The role of self versus nonself in
the immune response will determine the success of the transplant and the
survivability of the patient.
Rejection of organs or tissues is generally categorized by how quickly
rejection occurs. Hyperacute rejection occurs within 24 hours, before
the transplanted tissue can be vascularized, or form new blood vessels.
This type of rejection is thought to occur due to preexisting antibodies in
the host that bind to antigens present on the surface of cells in the new
tissue. The inflammation that results from the immune response prevents
vascularization of the tissue and the tissue dies from lack of oxygen. Acute
rejection occurs about 1 week after the transplantation and likely occurs
to varying degrees in all transplants. This type of graft rejection occurs
due to a mismatch between the host and transplanted tissues of MHC
proteins so that the nonself MHC is recognized as an antigen. This type
of rejection is slightly delayed as compared to acute rejection because of
the time that it takes for the host immune system to make new a ntibodies
to the mismatched donor tissues. Chronic graft rejection can occur
months to years following a transplant. With advanced understanding of
immunosuppressant approaches, chronic graft rejection is currently the
Symptoms and Diagnosis 13

ultimate cause of graft rejection for most patients. While not entirely un-
derstood, it is thought that chronic graft rejection occurs after scarring of
the transplanted tissues from continued less severe acute rejection events.
The accumulation of scarring over time incapacitates the transplanted tis-
sue, leading to rejection.
The symptoms associated with a graft rejection will depend somewhat
on the organ or tissue that was transplanted, but generally there will be
a decrease in the function of the transplanted organ. The patient might
experience pain, swelling, chills, nausea, aches, shortness of breath, and
more rarely fever. Other complications from the transplant surgery and
recovery can be a high risk of infection, and the symptoms of infection
can vary depending on the causative agent.
CHAPTER 2

Causes and Contributing


Factors

Causes and Contributing Factors


of Multiple Sclerosis
MS results from an autoimmune response to components of the central
nervous system such as the brain, the spinal cord, and optic nerve. Spe-
cifically, immune response including inflammation causes damage to the
myelin sheath that surrounds neurons. Neurons function by transmitting
electrical signals along their lengths. These electrical signals are acquired
at the dendritic end of neuron, travel through the central body, and then
through the axon of the neuron to be passed to the next neuron or at
times to a target cell in muscle or other parts of the body. In some cases,
the axons of the neuron can be very long, and in the case of motor neu-
rons which control muscle contraction, can extend from the brain or spi-
nal cord to the muscle. One function of the myelin sheath is to protect
these long fragile structures. Additionally, the myelin sheath maintains
the integrity of electrical signal transmission along the length of the axon.
In MS, inflammation destroys the myelin sheath and the axon. Once
damaged, the myelin forms scare tissues called sclerosis. When sclero-
sis occurs, the supported neuron is unable to function properly so that
nerve impulses from the brain and spinal cord become disrupted. These
disruptions can result in many different symptoms, commonly involving
impaired muscle function or vision.
MS is more commonly found in geographical areas farther from
the equator; and individuals who migrate to areas where MS incidence
is high tend to experience the same elevated risk of developing MS
found in that area, though it may be delayed. These patterns suggest
that environmental factors are important elements in the cause of MS.
16 AUTO-IMMUNITY ATTACKS THE BODY

Individuals with other autoimmune diseases, such as type 1 diabetes,


thyroid disease, or inflammatory bowel syndrome, are more likely
to develop MS than those without these conditions, suggesting a link
between the initiating events of these distinct autoimmune diseases.
Inflammation triggers initial demyelination and damage to neurons, but
does not necessarily have to continue for MS to progress. For this reason,
it is possible that neurological deterioration is occurring independent of
active inflammation. The reversibility of damage is an important aspect
of MS. Hope lies in the idea that myelination of neurons can be repaired,
so that this aspect of the disease may be treatable. Treatments that are
initiated early in disease progression of the relapsing-remitting phase may
modify disease progression before permanent disability occurs.
Specific autoantigens that stimulate an autoimmune response have
been identified among MS patients. Autoantigens are components of a
healthy person that should not trigger an immune response, but in au-
toimmune disease are recognized as antigens. Recall that the presence of
specific antibodies in the body means that activated B cells and the result-
ing plasma cells are producing those antibodies, and that the B cell has
come in contact with a specific antigen. For example, the detection of
antibodies toward the mycobacterium that causes tuberculosis is evidence
that a person has experienced a tuberculosis infection even if they were
not aware of it. The presence of antibodies against antigens found on nor-
mal host tissues (autoantigens) is evidence that an autoimmune reaction
has occurred. Detection of autoantigens using antibodies against normal
body components associated with a specific autoimmune disease can be
an important part of the diagnosis of that disease.
In MS patients, autoantigens have included myelin oligodendrocyte
glycoprotein (MOG), proteolipid protein 1 (PLP1), and myelin basic
protein (MBP). MOG is a protein located on the outside edge of the my-
elin sheath that surrounds axons and may be involved in cell-to-cell com-
munication among those cells that make up the myelin sheath. MOG is
in a physical location that would make it accessible to the B and T cells of
the immune system, and targeting MOG for destruction would disrupt
cellular communication in this tissue. PLP1 encodes a transmembrane
protein that along with MBP comprises the majority of protein in my-
elin, so they are important for myelin sheath structure. Immune system
Causes and Contributing Factors 17

destruction of PLP1 or MBP would disrupt the structure of the myelin


sheath and harm neuronal function. The identification of myelin sheath
components as autoantigens in MS supports the idea that the immune
response targets this structure. However, the trigger that initiates the au-
toimmune response against these specific antigens is not clear.
MS is not considered an inherited disorder; however, there does
appear to be a genetic component of the disease, with some individu-
als more or less susceptible to a trigger of MS given their own genetic
background. For example, a person who has a sibling or parent with MS
has an increased risk of developing MS from 0.1 percent for the general
population to between 2.5 and 5 percent; the risk is greater if more than
one person in the family has MS. When a disease runs in the family, it
suggests a genetic contribution since family members could carry shared
alleles of genes. Everyone inherits his or her genome from their biological
parents. DNA contains the code that drives the synthesis of gene prod-
ucts, including proteins. Alleles that contribute to disease can be inher-
ited; therefore, the probability of developing a disease with a contributing
genetic factor increases when another member of a family has the disease.
The increased risk compared to the general population is a consequence
of increased knowledge that a parent must carry the disease allele. It is
important to note that factors other than inherited alleles might cause
familial disease patterns, such as environmental toxins to which an en-
tire family has been exposed. Research supporting a familial component
shows that if you have an identical twin with MS, you have a 30 percent
increased risk of developing MS. The increase of risk that is seen in iden-
tical twins supports the idea that there is a genetic component to the
disease since identical twins have the same genome. However, if the cause
of MS were solely genetic, then a much higher percentage of identical
twins would both develop MS. More studies are required to distinguish
between environmental and genetic factors in MS. Environmental factors
could be related to geography, ethnicity, or prior infections.
The most common gene associated with MS is HLA-DRB1. This
gene is located on chromosome 6 and encodes a protein that is part of
the MHC complex. The encoded part of the human MHC is recog-
nized by T cells and helps the body distinguish between self and nonself.
There are many MHC proteins on every cell, and each MHC protein
18 AUTO-IMMUNITY ATTACKS THE BODY

can come in many forms so that a persons immune system can detect
a wide variety of foreign proteins. Variations in many MHC alleles are
associated with increased risk of MS, and the most common variant is
HLA-DRB1*15:01, where the *15:01 indicates the specific variant of
HLA-DRB1. It is not clear why this particular variant is more prevalent
in MS patients, but its role in immune response supports the idea that
MS is an autoimmune disease. Another gene commonly mutated in MS
patients is IL-7R. This gene is located on chromosome 5 and encodes the
interleukin 7 and thymic stromal lymphopoietin receptors (IL-7 recep-
tor and TSLP receptor, respectively). Both of these receptors work in
immune cells to stimulate growth and survival of immune cells as they
grow, develop, and experience tolerance in the thymus. In both HLA-
DRB1 and IL-7R, we understand that these two genes are important
for the immune response, but it is not clear how or why particular al-
leles would contribute to MS. HLA-DRB1 is also associated with other
autoimmune diseases such as rheumatoid arthritis, type 1 diabetes, and
psoriatic arthritis.

Causes and Contributing Factors


ofRheumatoidArthritis
Rheumatoid arthritis (RA) is an autoimmune disease of the joints.
The trigger or cause of RA is not known, but the target of the immune
response and subsequent inflammation is the synovium, or the tissue
that lines the joint. Synovium normally makes a fluid that lubricates
joints and helps them move smoothly. Inflammation caused by an auto-
immune response to the joint causes the synovium to thicken, resulting
in swelling and pain around the joints. If allowed to continue, human
molecules associated with the inflammation response damage the car-
tilage and the bone of the joint. With continued damage, cartilage is
lost and the space between joints becomes smaller, or the joints become
unstable, loose, and painful as they lose their mobility. RA ultimately
can lead to joint deformity. Joint damage cannot be repaired or reversed,
so early diagnosis of RA is important to initiate treatment and control
disease progression.
Causes and Contributing Factors 19

While an abnormal immune response appears to play a major role


in the inflammation that causes joint damage in RA, the trigger or cause
of the autoimmune response is not clear. Some autoantigens have been
identified for RA patients, including collagen type II. Collagen type II
is a major component of cartilage that is found at the ends of the bones,
and functions within the capsule to provide a smooth lubricated surface
for bone rotation. Ingestion of some forms of collagen type II has been
used as a treatment for both RA and osteoarthritis, though clinical trials
to support these ideas are lacking. Future work is needed to understand
why these proteins are found as autoantigens in RA patients.
Genetic factors may play a role in increasing the risk of developing
RA because a person has an increased risk if a family member has RA. A
gene that is associated with RA is HLA-DRB1. Individuals with a particu-
lar HLA-DRB1 allele will have a five-fold greater chance of developing
RA. Note that the specific allele of HLA-DRB1 enriched in RA patients
is not identical to the allele enriched in MS patients. The function of
HLA-DRB1 protein in antigen recognition through the MHC is con-
sistent with the autoimmune nature of both RA and MS. Over 50 genes
are associated with RA, and most play some role in the normal immune
system through antigen presentation to immune cells. While the presence
of certain alleles increases the risk of RA, individuals have developed RA
without them.
It is possible that hormones play a role because women are at higher
risk of developing RA, and pregnancy or breastfeeding affects RA flares.
Additionally, environmental factors may play a role, and researchers con-
tinue to look for evidence to support a clear connection between RA and
these factors. Environmental factors might be obesity, stress, physical or
emotional trauma, cigarette smoke, air pollution, or insecticides. To date,
no clear causation has been linked to any of these factors.

Causes and Contributing Factors of Graft Rejection


Just as pathogens can be recognized as foreign and be targeted for destruc-
tion by the immune system, so can human cells or proteins from another
individual. Hosting human cells that are not your own can arise after
20 AUTO-IMMUNITY ATTACKS THE BODY

tissue or organ donations, where the host immune system will reject the
newly grafted tissue because the immune cell receptors are able to bind
antigens present on the donated cells. Organ or graft rejection occurs
due to inflammation and cell damage via an immune response. Some
important aspects of tissue or graft rejection involve the identity of the
MHC proteins that display antigens on the surface of host cells. Cells
from another individual will have slight variations in displayed proteins,
and the MHC complex itself can be recognized as nonself. In humans,
more than one dozen different MHC proteins exist; and there can be 100
different alleles of these 12 proteins. The exact versions of MHC that you
normally carry would not be recognized by your immune system, because
the immune cells with receptors that bound to your own MHC were
removed as the immune cells matured. Your immune cells that carry re-
ceptors capable of binding to another persons MHC survived and are cir-
culating as part of your normal immune system. Some of these T cells will
recognize the human cells in the donated tissues as foreignmounting
an immune response to these cells. To prevent immune rejection of
the donated tissue, donors and recipients are matched based on MHC
identity for organ transplants.
Individuals who receive an organ transplant receive tissue from an-
other person into their body. Because all individuals carry small differ-
ences in their MHC proteins, the new organ will carry MHC proteins
different from the host and be recognized as foreign. It is very rare for in-
dividuals who are not family members to have matching types of MHC.
These MHC mismatches trigger a vigorous immune response against the
newly transplanted tissues. In the case of hyperacute rejection, antibod-
ies against these new types of MHC or other antigens must be present in
the patients system prior to surgery, because the reaction is so fast that
there would not be time for the immune system to mount a new response
consistent with the first exposure to the antigen. Nonself antigens might
have been introduced into the host by previous blood transfusions or
pregnancy. Some antibodies against the donated tissue can be detected
prior to surgery which is useful to know since medications can be taken
to suppress this type of graft rejection. In the case of acute graft rejection,
the body responds to the new antigens and initiates an immune response,
Causes and Contributing Factors 21

including antibody production. A first-time response takes 7 to 10 days


to begin in earnest. Immunosuppressant therapies are used to keep tissue
rejection in check with the hope that tolerance and/or anergy will allow
the patient to maintain the health of the new organ without long-term
use of immunosuppressant drugs. Long-term use of immunosuppressant
treatments places the patient at risk for opportunistic infection because
these drugs suppress normal immune response to all foreign materials,
not just the new organ. Chronic rejection is thought to result from scar-
ring that occurs around the transplanted organ after multiple prolonged
acute attacks occur over time.
CHAPTER 3

Treatment and Therapy

Treatment and Therapy for Multiple Sclerosis


Currently there is no cure for MS, though several new drugs intended to
modify disease progression or to treat the symptoms of the disease have
been approved by the US Food and Drug Administration (FDA). In all
cases, current treatments are preventative, not restorative. The best out-
come would be to treat MS early with disease-modifying regimens so that
permanent neural damage can be avoided. Once neuron death occurs,
it cannot be repaired. FDA-approved treatments include three different
forms of beta interferon (Avonex, Betaseron, and Rebif ). Beta interferon
is a type of cytokine, a signaling molecule that balances the pro- and
anti-inflammatory signals in the brain and may inhibit the development
of some types of T cells. Treatment with beta interferon reduces the dura-
tion of relapses, and slows the progression of physical disability, though
it has exacerbated symptoms in some patients who had to discontinue
using it. The FDA has also approved a man-made form of a protein that
helps MBP function in the myelin called Copaxone (or copolymer I).
Copolymer I may reduce the relapses for a patient by up to one-third. The
same drug is also approved to treat patients diagnosed with CSI, but have
not yet progressed to a diagnosis of MS. For relapsing forms of MS, the
FDA has approved the MS drug Teriflunomid that inhibits the activation
of some B and T cells, and dimethyl fumarate which alters cytokine pro-
duction in lymphocytes and microglial neural support cells. Natalizumab
is an antibody treatment that impedes inflammatory cells from enter-
ing the brain, reducing inflammation in the brain associated with MS.
The immunosuppressant mitoxantrone (trade name Novantrone) is also
FDA-approved to treat MS as it progresses to more advanced or chronic
forms. Fingolimod exhibits some concerning side effects in clinical trials
24 AUTO-IMMUNITY ATTACKS THE BODY

and is not recommended for initial treatment, but with careful moni-
toring, could be used as a secondary treatment regimen. Specific symp-
toms can also be helped through drug treatment. For example, difficulties
in walking can be improved with dalfampridine (trade name Ampyra).
Spasticity from chronic muscle stiffness or spasms can be treated with
muscle relaxants such as baclofen, tizanidine, diazepam, clonazepam, and
dantrolene. Fatigue may be treated with amantadine (trade name Sym-
metrel) or pemoline (trade name Cylert). In all cases, the effectiveness
varies among patients.
Physical therapy can have a positive impact on disease symptoms pre-
serving functionality of muscles. In combination with physical aids such
as canes, braces, and walkers, physical therapy can help patients maintain
mobility. Too much activity and overheating appear to increase fatigue
symptoms; so patients are advised to avoid both. Optic symptoms usually
improve over time without drug intervention, though steroid treatments
are sometimes effective. Depression can be treated with anti-depressants.
In all cases of treatment, side effects exist and the possible benefits and
side effects should be carefully discussed with physicians. Treatment ap-
proaches are influenced by the frequency and intensity of the relapses
experienced by the patient whose more active and worsening symptoms
would call for more aggressive treatments. If evidence of disease is present,
but no symptoms are felt by the patient, then treatment regimens might
be altered. Treatments for RRMS described here are effective in increas-
ing the time of remission or lessening symptoms in a relapse. PPMS and
SPMS are much more difficult to treat especially when no active inflam-
mation is present but symptoms continue; research continues for these
forms of MS. In the end, MS is a complex disease with large variability
in symptoms. There is no single treatment regimen that will be successful
for all patients.

Treatment and Therapy for Rheumatoid Arthritis


No cure exists currently for RA, but early treatment can reduce symp-
toms. Current treatments give most patients good relief from symptoms
by controlling swelling, pain, and joint damage due to inflammation
associated with RA. When RA inflammation is stopped, the disease is
Treatment and Therapy 25

described as in remission. Some treatments relieve specific symptoms,


such as over-the-counter and prescription nonsteroidal anti-inflammatory
drugs for pain. To get flares of inflammation under control, cortico-
steroids might be used for a short time, coupled with other long-term
drugs designed to modify disease progression, or disease-modifying
antirheumatic drugs. Disease-modifying drugs would delay disease
progression, but not treat the underlying cause of the disease. Drugs avail-
able to modify disease progression in RA include methotrexate (sold as
Rhematrex, Trexall, Otrexup, Rasuvo), leflunomide (trade name Arava),
hydroxychloroquine (trade name Plaquenil), and sulfasalazine (trade

name Azulfidine). Methotrexate also can be used to treat some cancers
because it inhibits DNA replication through disruption of folate metabo-
lism. The mechanism explaining how methotrexate works in RA is more
complex and likely to involve multiple targets in the immune system.
Hydrochloroquine is an antimalarial medicine that is also an effective
disease-modifying drug for RA because of its ability to inhibit class II
MHC molecules from binding and presenting potential antigen proteins
on the surface of antigen presenting cells. Sulfasalazine inhibits NF-K, a
protein complex critical for B-cell function. In more serious cases, drugs
that nonspecifically inhibit the immune response can reduce inflamma-
tion and additional tissue damage. FDA-approved drugs include abata-
cept (trade name Orencia), golimuma (trade name Simponi), infliximab
(trade name Remicade), rituximab (trade names Rituxan and MabThera),
tocilizumab (trade name Actemra), and tofacitinib. Many times, mix-
tures of these drugs are used for optimal treatment response. Additional
disease-modifying drugs exist for RA that reduce the symptoms associ-
ated, but none offer a cure to the disease. In advanced stages of the dis-
ease, it is possible to surgically remove damaged joints and replace them
with metal or plastic parts. Surgical approaches can involve full joint re-
placement, joint fusions, or tendon repairs. This approach is available
only for some joints damaged by RA.
Low-impact exercise will improve muscle strength around joints and
can help alleviate symptoms. While rest is important during peak joint
inflammation, remaining active at other times can improve joint flex-
ibility and maintain function. A treatment regimen is unique to each
patient as is the role of activity in disease progression. Consultation with
26 AUTO-IMMUNITY ATTACKS THE BODY

a physical or occupational therapist can be helpful in making these deci-


sions. Joint stiffness can be treated with heat therapy and pain can be
treated with cold packs. Other therapies to help control muscle tension
and reduce stress may alleviate RA pain. Maintaining a good attitude and
support system is important in the ability of a patient to move through a
flare, and continue to monitor and care for their RA.

Treatment and Therapy for Graft Rejection


When considering treatments of graft or transplant rejection, the first
line of defense is to avoid rejection as much as possible. The first step is to
carefully match donor MHC alleles to the recipient. Details vary for each
unique type of organ donation, but usually there are at least six MHC
genes that are checked to see if they are similar between the recipient and
the donor. When considering these six antigens, there is a 1-in-100,000
chance that two unrelated individuals will match all six antigens. The
fewer the differences between the donor and the recipient, the less likely
autoimmune complications will result in rejection. For this reason, family
members are often considered first choices for donors since they are more
likely to carry similar tissue antigens.
After the transplantation surgery, immunosuppressant drugs are used
to avoid immune responses toward the new tissue or organ in the patient.
Suppressants include corticosteroids for acute rejection to block T cell
and other immune cell function. Long-term use of immunosuppressant
treatments puts the patient at risk of infection plus any side effects associ-
ated with the specific drug administered. To avoid complications associ-
ated with long-term use of immunosuppressant drugs, other drugs such
as calcineruin inhibitors can be used. This class of drug targets IL-2 and
inhibits T- and B-cell activation when activated cells multiply, meaning
that this drug can be helpful in reducing acute rejection and improving
long-term survivability. Antiproliferative agents such as Azathioprine also
can treat acute rejection and prevent proliferation of immune cells, spe-
cifically T cells. If rejection occurs, suppressing the host immune system
is the primary course of action. There is no cure for graft rejection and the
only solution is to control the host immune response.
CHAPTER 4

Future Prospects

Further research of generalized immunosuppression therapies may aid in


our understanding of some aspects of autoimmune diseases. Future work is
promising, and varies for each type of autoimmune disease. Research focuses
on goals to identify the trigger or cause of the autoimmune response. In most
cases of autoimmune diseases, once damage occurs (in our examples, to the
neuron or joint), nonsurgical repair is impossible. Repairs to these specific
organ systems are very different, but regenerative approaches to repair cells
damaged by the immune response hold great promise for the future.
For MS, treatments aimed at repairing the myelin sheath already are
being used in limited cases. Making use of existing body systems to create
new sheaths is a promising area of research. One approach along these lines
makes use of human stem cells which are regenerative cells, meaning that
they can produce more stem cells through cellular division while maintain-
ing the potential to grow and differentiate into different types of cells in
the human body. Schwann cells can produce components of the myelin
sheath with specific proteins and specialized gene expression patterns that
allow them to carry out this specialized function. In contrast, a stem cell
retains its ability to change gene expression pattern so that it can differen-
tiate into a variety of different cell types. Stem cells could be a powerful
tool for cell replacement therapies in humans. Scientists want to make use
of stem cells to replace damaged cells, so that symptoms of diseases such
as MS might be reversed. Skepticism exists about how effective stem cells
will be at replacing complex and integrated networks of neurons, but the
myelin sheath is a promising candidate for stem cell replacement therapies.
Another approach involves using stem cells to regenerate the entire im-
mune system of an individual with MS. Using drugs normally designed
to treat cancers, all actively dividing immune cells can be killed, including
those capable of recognizing autoantigens, and replaced with new stem
28 AUTO-IMMUNITY ATTACKS THE BODY

cells from the same patient to regenerate the immune system. Clinical trials
should clarify the effectiveness of these promising therapies in humans.
In the area of graft or transplant rejection, new agents are being tested to
aid in the induction of tolerance, as well as antibody treatment to inactivate
specific cells of the immune system. Researchers want to understand better
the trigger or cause of autoimmune diseases, and how tolerance to immune
response might be harnessed in treatments. The immune tolerance network
(ITN) was formed in 1999 by the National Institute of Allergy and Infec-
tious Diseases, part of the National Institutes of Health, and works to iden-
tify biomarkers related to defects in tolerance that might be used for future
treatments. A biomarker is biological material that can be measured to in-
dicate the presence or absence of a disease. Much like high glucose levels
in urine is a biomarker for diabetes, certain factors might be present in the
body of a patient experiencing an autoimmune response that are absent in
a healthy patient. Identification of a biomarker for any autoimmune disease
would facilitate earlier diagnosis, relating to patterns of disease onset and
progression that could help identify genetic or environmental triggers. This
research may also allow recognition of patterns that exist between differ-
ent autoimmune diseases, so that unifying approaches might be possible in
diagnosis and treatment. Work by the ITN over the past 10 years has led to
some clinical trials addressing treatments for specific autoimmune diseases.
Advances in the field of organ transplants show some promise for avoid-
ing complications of immune response. One approach under investigation
is using stem cells from the patient coupled to artificial structures to mimic
organ function. Since these stem cells have the same DNA as the host, they
will have self MHC proteins and should not produce the difficulties in
immune response seen with tissues donated from other individuals. The
idea of producing artificial kidneys is a particularly exciting one, since over
80 percent of all patients waiting for an organ donation wait for kidney
donations. Another advancement designed to avoid graft rejection is to
transplant both the organ to be replaced and cells of the immune system
from the same donor. In this way, T cells that would initially mount an
immediate reaction to donor MHC molecules would be replaced by T cells
from the donor, mitigating the short-term immune response toward the
donated organ. This procedure is being tested, but is not currently available
outside of clinical trials.
Conclusion
The human immune system provides crucial protection to the human
body from invading pathogens and toxins, but when misdirected, is able
to cause significant autoimmune diseases. A wide variety of autoimmune
diseases have been described, and the specific trigger that transitions a
healthy immune and inflammation response to tissue and organ destruc-
tion is not known. The ability of the immune system to recognize self
and nonself antigens is a critical component to this class of diseases. Au-
toantigens have been identified in many autoimmune diseases, as have
antibodies that bind to proteins normally found in the body. In the case
of MS, some of these autoantigens are components of the myelin sheath
surrounding and protecting neurons. In the case of RA, autoantigens are
degraded components of the joint. In the case of graft rejection, the an-
tigens triggering immune response and subsequent tissue or organ rejec-
tion come from the transplanted cells from another individual. However,
the cell-mediated immune responses of the adaptive immune systems
involved in graph rejection are similar to those involved in autoimmune
diseases. Each of these diseases is differenta disease of the nervous sys-
tem, of joints, and of surgical transplantsbut all are worsened, and
possibly even caused, from an imbalance or dysfunction of the human
immune system.
The role of T cells and MHC recognition plays a critical role in organ
or tissue rejection. The presence of clonal B cells producing antibodies
and T cells triggering anti-self immune responses can result in the need
for organ recipients to remain on immunosuppressant drugs for the rest
of their life, risking other health complications from these treatments. Re-
search continues to help us understand more fully the balance of immune
stimulation and inflammation that allows healing after organ transplant
without the complications of tissue rejection. In the cases of MS and
RA, the nuances change. Instead of an amplification of a normal im-
mune response to foreign materials, these diseases result from a failure of
30 CONCLUSION

B and T cells to recognize self or autoantigens as benign, and thus ignore


them. Autoimmune diseases involve the body attacking and destroying
itself. The cells and tissues that are destroyed are specifically targeted by
multiple components of the adaptive immune system via cell-mediated
inflammation response. Just as all aspects of the immune system work in
a coordinated way to protect the body from pathogens, autoimmune dis-
ease is sensitive to many aspects of the same complex network of cellular
and chemical responses.
When considering what might trigger the initial events that result
in autoantigen recognition, a failure in tolerance during lymphocyte de-
velopment, or failure of anergy in circulating immune cells could be to
blame. Alternative explanations could include any stage of immune re-
sponse where recognition fails, or the system becomes overstimulated.
The role of inflammation in disease progression is significant, introducing
additional molecular events that must be properly suppressed to avoid
disease progression. Once an autoimmune disease becomes activated, the
initial trigger could be absent though disease progression continues. Re-
search to identify the trigger of disease onset is ongoing.
Given the complexity of immune response, disease progression is
often unpredictable. Symptoms can come and go, and diagnosis can take
time to establish disease patterns. Treatments address symptoms that are
associated with the specific disease, but currently do not repair tissues or
cells once they have been damaged or killed. Since the originating trigger
of the autoimmune response is not known, we cannot target those events
to avoid disease. Currently, therapies designed to limit disease progression
and restore cellular function when possible are available and are effective
in lessening symptoms of the disease. Future work to better understand
disease onset and progression continues for diseases that result from au-
toimmune response.
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Glossary
acute rejectiona type of graph rejection that occurs approximately one week
after tissue or organ transplant
adaptive immune responsethe antigen specific immune response of the
human body
allelesalternate versions of genes inherited from parents in the form of DNA
that give rise to variations in function
anergicthe lack of response of the immune system to an antigen
antibodies (Ab)secreted versions of B cell receptors that can bind to free float-
ing antigen in the body. Also called immunoglobulins (Ig).
antigenany substance that can be specifically bound by an antibody, B cell or
a T cell; usually a protein or sugar
antigen presenting cella cell where antigen and MHC proteins are present on
the surface of the cell
antigen receptora type of receptor found on B cells and T cells that can bind
to antigen
apoptosisa type of programmed cell death
autoimmunitywhen the innate or adaptive immunity incorrectly targets a
normal part of the body, so that healthy cells are damaged or destroyed by the
immune system
autoreactiveable to strongly interact with self-antigens
disease-modifying antirheumatic drugsdisease modifying drugs used in the
treatment of rheumatoid arthritis that delay disease progression, but do not treat
the underlying cause of the disease
autoantigenpart of a healthy person that should not trigger an immune re-
sponse, but is recognized as an antigen in autoimmune disease
autoimmune diseasedamage or destruction of the human body due to an im-
mune response against components of their own body
B cellsa type of lymphocyte capable of binding antigen and producing
antibodies
biomarkersa biological material that can be measured to indicate the presence
or absence of a disease
bone marrowthe soft cavity internal to bones that supports cellular growth
and replenishment
calcineruin inhibitorsimmunosuppressant drug used in organ transplants
cartilagematerial that covers and protects the ends of bones
36 GLOSSARY

cell membranethe outer most layer of the cell composed of lipids and pro-
teins that encases the cell and provides a structural matrix and a barrier from the
environment
central nervous system (CNS)the part of the nervous system that consists of
the brain and spinal cord
cerebrospinal fluid (CSF)a colorless liquid that surrounds the brain and spi-
nal cord
chroniclong lasting
chronic graft rejectiona type of graph rejection that occurs months or years
after tissue or organ transplant
class I MHC (MHCI)the molecule that holds antigen on the surface of cells
which can be recognized by T cell receptors present on the surface of cytotoxic
T cells
class II MHC (MHCII)the molecule that holds antigen on the surface of cells
which can be recognized by T cell receptors present on the surface of helper T
cells
clinically isolated syndrome (CIS)the first clinical manifestations of symp-
toms consistent with MS
cytokineschemicals secreted by cells of the immune system
dendritic cellsa type of phagocytic cell found in the innate immune system
that is frequently associated with parts of the body that come in contact with the
environment
eosinophilsa type of phagocytic cell found in the innate immune system that
is associated with the defense against multicellular pathogens such as worms
exacerbationsreappearance or worsening of symptoms; also called relapse
flarean increase in symptom severity or inflammation associate with rheuma-
toid arthritis
graft rejectionoutcome from organ or tissue transplantation where the trans-
planted material triggers a damaging immune response in the host; also called
transplant rejection
hematopoietic stem cellsa type of highly regenerative cell that can give rise to
cells of the immune system.
human leukocyte antigen (HLA)the set of proteins that bind to antigen and
hold antigen on the surface of cells so that antigen can be recognized and bound
by T cells; also called major histocompatibility complex (MHC)
hyperacute rejectiona type of graph rejection that occurs within 24 hours of
tissue or organ transplant
immunoglobulins (Ig)secreted versions of B cell receptors that can bind to
free floating antigen in the body. Also called antibodies (Ab)
inflammationphysiological response to cytokines and immune cells that re-
sults in changes to the body such as redness, swelling, and increased temperatures.
innate immune systemone part of the immune system that responds non-
specifically to foreign materials
GLOSSARY 
37

lupusan autoimmune disease that causes a systemic inflammation response


lymphocytesa type of white blood cell found in the adaptive immune system
macrophagesa type of phagocytic cell found in the innate immune system
major histocompatibility complex (MHC)the set of proteins that bind to
antigen and hold antigen on the surface of cells so that antigen can be recognized
and bound by T cells; also called human leukocyte antigen (HLA)
Monocyclic RAa type of rheumatoid arthritis where episodes of inflammation
lasting two to five years go away and do not return
multiple sclerosisan autoimmune disease that disrupts the function of neurons
myelin sheathstructure composed of lipids and proteins that physically sup-
ports, repairs, and provides potential nutrients to the neurons
neuronsthe primary cell type that transmits signals in the nervous system
neutrophilsa type of phagocytic cell in the innate immune system
optical coherence tomography (OCT)an imaging technique used to detect
demylination of neurons
organ rejectionan immune response that results in the damage to transplanted
tissues or organs; also called a graft rejection
paresthesiafeelings of pain, prickling, or numbness
pathogensmicroorganisms capable of causing disease
peripheral nervous systempart of the nervous system that consists of those
neurons outside of the brain and spinal cord
phagocytosisoccurs when a cell surrounds and encases or engulfs material,
frequently another cell
polycyclic RAa type of rheumatoid arthritis where symptoms constantly reoc-
cur in unpredictable patterns
primary progressive MS (PPMS)a form of multiple sclerosis where disease
symptoms occur and continue to worsen over time
progressiveworsening over time
progressive relapsing (PRMS)a form of multiple sclerosis where disease shows
an initial worsening of symptoms followed by a steady worsening of symptoms
over time
proteinmolecules composed of chains of amino acids with specific chemical
and structural properties that allow it to take on a specific shape and function
radiologically isolated syndromethe detection of demyelination by MRI
scans, with no associated symptoms of MS.
receptorsproteins held on the surface of cells that are able to physically inter-
act, change shape, and send signals to the inside of the cell when they interact
with other molecules
relapsereappearance or worsening of symptoms; also called exacerbations
relapsing-remitting MS (RRMS)a form of multiple sclerosis where disease
shows periods of little or no symptoms followed by periods of relapse
remissionperiods of little or no disease symptoms
38 GLOSSARY

rheumatoid arthritisan immune response that causes inflammation and dam-


age in joints
Schwann cellscells that help produce components of the myelin sheath
sclerosisscar tissue on myelin resulting from damage to the myelin sheath in
MS patients
secondary progressive MS (SPMS)a form of multiple sclerosis where disease
no longer enters remission as the disease progresses, and the baseline symptoms
worsen over time
stem cellunspecialized cells that can give rise to cells that will differentiate into
other cell types
synovial fluidthe fluid produced by the synovium that lubricates and supports
cartilage and bones that are inside the capsule of the joint
synoviumtissue that surrounds the capsule that encases the cartilage covered
ends of bones at the joint
systemic diseasedamage from the disease has occurred throughout the body
T cellsa type of lymphocyte capable of binding antigen when bound by MHC
and presented on the surface of another cell.
tolerancesuppression of the immune response against a specific material, or
antigen, in the human body
transplant rejectionoutcome from organ or tissue transplantation where the
transplanted material triggers a damaging immune response in the host; also
called graph rejection
type I diabetesan autoimmune disease that impairs the ability to control levels
of sugar in the bloodstream
white blood cellsa group of cell types that includes cells in the immune system
About the Author
Mary Elizabeth Miller is associate professor and director of the Biochem-
istry and Molecular Biology Program at Rhodes College, Tennessee. She
holds the J. T. and V. B. Robertson Chair of Biological Sciences and has
been awarded the Rhodes College Clarence Day Award for Outstanding
Research or Creative Activity. She received her PhD in microbiology from
the University of Virginia, Charlottesville, and studied as a postdoctoral
fellow at the Rockefeller University, New York. She teaches introductory
biology, genetics, molecular biology, microbiology, and topical seminars
on cancer. She researches cell division and key regulators of cell division
cycle.
Index

A Flare, 10
Abatacept (Orencia), 25 Food and Drug Administration
Acute rejection, 12 (FDA), 23
Amantadine (Symmetrel), 24
Antibodies, detection of, 16 G
Autoantigens, 16 Golimuma (Simponi), 25
Avonex, 23 Graft rejection
Azathioprine, 26 causes and contributing factors
of,1921
B symptoms and diagnosis of, 1213
Baclofen, 24 treatment and therapy for, 26
Betaseron, 23
Biomarkers, 28 H
HLA-DRB1, 17, 19
C Human immune system, 29
Calcineruin inhibitors, 26 Hydroxychloroquine (Plaquenil), 25
Central nervous system, 2 Hyperacute rejection, 12
Cerebrospinal fluid (CSF), 8
Chronic graft rejection, 1213 I
Clinically isolated syndrome (CIS), 8 Immune tolerance network (ITN), 28
Clonazepam, 24 Immunosuppressant therapies, 21
Collagen type II, 19 Inflammation, 11, 16
Copaxone, 23 Inflammatory bowel syndrome, 16
Copolymer I. See Copaxone Infliximab (Remicade), 25

D L
Dalfampridine (Ampyra), 24 Leflunomide (Arava), 25
Dantrolene, 24
Depression, 4, 24
Diazepam, 24 M
Disease-modifying antirheumatic Magnetic resonance imaging (MRI), 7
drugs, 25 Methotrexate, 25
MHC proteins, 1718
Mitoxantrone (Novantrone), 23
E Monocyclic RA progression, 10
Exacerbations, 3 Multiple sclerosis (MS)
causes and contributing factors
F of,1518
Fatigue, 24 symptoms and diagnosis of, 18
Fingolimod, 2324 treatment and therapy for, 2324
42 INDEX

Myelin basic protein (MBP), 16 Rhematrex. See Methotrexate


Myelin oligodendrocyte Rheumatoid arthritis (RA)
glycoprotein(MOG), 16 causes and contributing factors
Myelin sheath, 2 of,1819
symptoms and diagnosis of, 911
N treatment and therapy for, 2426
National Institute of Allergy and Rituximab (Rituxan and
Infectious Diseases, 28 MabThera),25
Neurons, 2
S
O Schwann cells, 2
Optical coherence tomography Sclerosis, 15
(OCT), 8 Secondary progressive MS
Otrexup. See Methotrexate (SPMS),34
Sjogrens syndrome, 10
Spasticity, 24
P Stem cells, 27
Paresthesia, 4 Sulfasalazine (Azulfidine), 25
Pemoline (Cylert), 24 Synovial fluid, 9
Peripheral nervous system, 2 Synovium, 9, 18
Polycyclic RA progression, 11
Primary progressive MS (PPMS), 2
Progressive relapsing MS T
(PRMS),34 T cells, role of, 29
Proteolipid protein 1 (PLP1), 16 Teriflunomid, 23
Thyroid disease, 16
Tizanidine, 24
R Tocilizumab (Actemra), 25
Radiologically isolated syndrome, 8 Tofacitinib, 25
Rasuvo. See Methotrexate Transplant rejection. See Graft
Rebif, 23 rejection, symptoms and
Relapsing-remitting MS (RRMS),34 diagnosis of
Remission, 3 Trexall. See Methotrexate
Revised McDonald Criteria, 67 Type 1 diabetes, 16
OTHER TITLES IN OUR HUMAN DISEASES
AND CONDITIONS COLLECTION
A. Malcolm Campbell, Editor
Genetic Diseases or Conditions: Cystic Fibrosis, The Salty Kiss by Todd T. Eckdahl
Gradual Loss of Mental Capacity from Alzheimers by Mary E. Miller
Hemophilia: The Royal Disease by Todd T. Eckdahl
Nerve Disease ALS and Gradual Loss of Muscle Function: Amytrophic Lateral Sclerosis
by Mary E. Miller
Sickle Cell Disease: The Evil Spirit of Misshapen Hemoglobin by Todd T. Eckdahl

FORTHCOMING TITLES IN THIS COLLECTION


Brain Degeneration from Huntingtons Disease by Todd T. Eckdahl
Bacterial and Viral Infections by Mary E. Miller
Common Intestinal Infections by Mary E. Miller

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EBOOKS Auto-Immunity Attacks the Body
FOR THE Autoimmune Disease
HUMAN DISEASES AND
HEALTH
Mary E. Miller
CONDITIONS COLLECTION
LIBRARY A. Malcolm Campbell, Editor
The human body is protected in critical ways as our immune
Create your own system provides protection from a broad spectrum of infections
Customized Content and injuries. Unfortunately, in some individuals, their immune
Bundle the more system targets components of their own bodies, causing au-
books you buy, toimmune disease. Many different types of autoimmune dis-
the higher your eases exist, each presenting unique symptoms depending on
discount! the body system that is damaged. It is not clear what triggers

Auto-
the progression from normal immune reactivity to autoimmune
disease, though both environmental and genetic factors are
THE CONTENT
thought to contribute.
Nutrition and

Immunity
This book focuses on three distinct examples of autoim-
Dietetics Practice
Psychology mune disease or reactivity: multiple sclerosis, which involves an
Health, Wellness, autoimmune response against structures that support neurons,
and Exercise rheumatoid arthritis, resulting from autoimmune-dependent
Science
Health Education
damage to joints, and organ or graft rejection, which occurs
when the immune system recognizes tissues from another indi-
vidual as foreign. In each case, we consider current and future is-
Attacks the
Body
sues related to disease progression, diagnosis, and treatments.
THE TERMS
Perpetual access for Mary E. Miller is associate professor and director of the bio-
a one time fee chemistry and molecular biology program at Rhodes College,
No subscriptions or
access fees
Unlimited
Tennessee. She holds the J. T. and V. B. Robertson Chair of
Biological Sciences and has been awarded the Rhodes College Autoimmune
Disease
Clarence Day Award for Outstanding Research or Creative Ac-
concurrent usage
tivity. She received her PhD in microbiology from the University
Downloadable PDFs
Free MARC records of Virginia, Charlottesville, and studied as a postdoctoral fellow
at the Rockefeller University, New York. She teaches introduc-
tory biology, genetics, molecular biology, microbiology, and
For further information, topical seminars on cancer. She researches cell division and key
a free trial, or to order,
regulators of cell division cycle.
contact:
sales@momentumpress.net
Mary E. Miller

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