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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,
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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
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at the Rockefeller University, New York. She teaches introduc-
tory biology, genetics, molecular biology, microbiology, and
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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.
10 9 8 7 6 5 4 3 2 1
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
dollars in the United States, excluding the cost of organ transplant rejec-
tion due to related immunity mechanisms.
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
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
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
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
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
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.
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
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.
Future Prospects
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
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
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
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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