Neuroimmunology in Clinical Practice - part 1 ppt

Neuroimmunology in Clinical Practice
NICP_A01 03/05/2007 10:31 AM Page i
Neuroimmunology in
Clinical Practice
Edited by Bernadette Kalman and Thomas H. Brannagan III
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© 2008 by Blackwell Publishing Ltd
BLACKWELL PUBLISHING
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The right of Bernadette Kalman and Thomas H. Brannagan III to be identified as the Authors
of the Editorial Material in this Work has been asserted in accordance with the UK Copyright,
Designs, and Patents Act 1988.
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the prior permission of the publisher.
First published 2008 by Blackwell Publishing Ltd
1 2008
Library of Congress Cataloging-in-Publication Data
Neuroimmunology in clinical practice / edited by Bernadette Kalman and Thomas H. Brannagan III.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-1-4051-5840-4 (hardback : alk. paper)
ISBN-10: 1-4051-5840-9 (hardback : alk. paper) 1. Neuroimmunology. 2. Nervous
system—Diseases—Immunological aspects. I. Kalman, Bernadette. II. Brannagan, Thomas H.
[DNLM: 1. Autoimmune Diseases of the Nervous System—physiopathology. 2. Nervous
System—immunology. WL 140 N49152 2008]
RC346.5.N4785 2008

616.8′0479—dc22
2007001113
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NICP_A01 03/05/2007 10:31 AM Page iv
Contents
Preface, vii
Foreword, viii
Contributing authors, ix
Part I: Basic science introduction
to clinical neuroimmunology, 1
Editor: Bernadette Kalman
1 The basics of cellular and molecular
immunology, 3
Amy E. Lovett-Racke, Anne R. Gocke,
and Petra D. Cravens
2 Major components of myelin in the
mammalian central and peripheral
nervous systems, 11
Alexander Gow

Part II: Inflammatory demyelination
in the central nervous system, 27
Editor: Bernadette Kalman
3 Multiple sclerosis, 29
3.1 Epidemiology and genetics
(Bernadette Kalman), 29
3.2 Immunopathogenesis
(Thomas P. Leist), 35
3.3 Courses and diagnosis of MS
(Bernadette Kalman), 38
3.4 Clinical features
(Bernadette Kalman), 42
3.5 The pathology of MS: A quest
for clinical correlation
(William F. Hickey), 50
3.6 Cerebrospinal fluid
(Mark S. Freedman), 54
3.7 Magnetic resonance imaging
characteristics of MS (Jennifer L. Cox
and Robert Zivadinov), 56
3.8 Treatment of MS (Sean Pittock), 63
4 Dévic’s disease, 83
Bernadette Kalman
5 Acute disseminated encephalomyelitis
and related conditions, 88
Robert S. Rust
Part III: Autoimmune diseases
of the peripheral nervous system
and the muscle, 115
Editor: Thomas H. Brannagan III

6 Guillain–Barré syndrome, 117
Eduardo A. De Sousa and Thomas H.
Brannagan III
7 Immune-mediated chronic demyelinating
polyneuropathies, 123
Thomas H. Brannagan III
8 Immune-mediated autonomic
neuropathies, 139
Louis H. Weimer and Mill Etienne
9 Autoimmune myasthenic syndromes:
Myasthenia gravis and Lambert–Eaton
myasthenic syndrome, 153
Andrew Sylvester and Armistead
Williams
10 Polymyositis and dermatomyositis, 169
S. Christine Kovacs
Part IV: Disorders of the central and
peripheral nervous systems related to
known or assumed system-immune
abnormalities, 179
Editor: Bernadette Kalman
11 Neuro-Sjögren’s syndrome, 181
Bernadette Kalman
NICP_A01 03/05/2007 10:31 AM Page v
vi CONTENTS
12 Neuro-Behçet’s syndrome, 185
Bernadette Kalman
13 Steroid-responsive encephalopathy
associated with Hashimoto’s
thyroiditis, 189

Bernadette Kalman
14 Rasmussen’s encephalitis, 191
Bernadette Kalman
15 Susac’s syndrome, 197
Bernadette Kalman
16 Cogan’s syndrome, 200
Bernadette Kalman
17 Neurosarcoidosis, 203
Bernadette Kalman
18 Anti-VGKC syndromes: Isaacs’ syndrome,
Morvan’s syndrome, and autoimmune
limbic encephalitis, 207
Bernadette Kalman
19 Paraneoplastic neurological
autoimmunity, 210
Daniel H. Lachance and
Vanda A. Lennon
20 Vasculitis and connective
tissue diseases, 218
David S. Younger and
Adam P.J. Younger
21 Poststreptococcal movement
disorders, 240
Andrew J. Church and
Gavin Giovannoni
22 Neurological manifestations of
gluten sensitivity, 251
Marios Hadjivassiliou
23 Anti-GAD associated neurological
diseases, 256

Marios Hadjivassiliou
Index, 259
NICP_A01 03/05/2007 10:31 AM Page vi
Neurology, as many other fields in medicine, has
evolved into a framework of rapidly developing sub-
specialties increasingly dependent on technology-
driven advances in clinical and basic sciences.
Neuroimmunology is a particularly dynamic sub-
specialty with daily emergence of new information
in imaging, electrophysiology, clinical trials, molecular
immunology, neurosciences, and genetics, which
necessitates frequent changes in clinical practice.
The authors of this book recognize the difficult task
that neurology residents and other young medical
professionals have to face when preparing for their
exams and practicing modern neuroimmunology.
With the intention to alleviate this task, here we
provide a comprehensive but concise description of
immune-mediated neurological disorders comple-
mented with the most pertinent and up-to-date
scientific data. We hope that not only residents,
fellows, young neurologists, physician assistants,
and nurses, but also scientists working in the area
of neuroimmunology will find this volume useful.
The editors invited coauthor experts who both teach
and study specific aspects of neuroimmunology
at academic medical centers. Non-author experts
including Drs. John O. Susac, Mark Keegan, Christian
G. Bien, Horst Urbach, Alexander G. Khandji, and
Fred D. Lublin generously contributed to several

chapters with their constructive comments and
images of rare disorders.
Preface
NICP_A01 03/05/2007 10:32 AM Page vii
Foreword
Neuroimmunology in Clinical Practice provides a use-
ful and comprehensive review of the field of clinical
neuroimmunology. In addition to presenting timely
updates of such common conditions as multiple
sclerosis, autoimmune neuropathies, myasthenia
gravis, and polymyositis, it highlights less familiar
neuroimmunological entities such as anti-VGKC
syndromes, and gluten-induced neurological dys-
function, which can go unrecognized in common
clinical practice. It provides a scientific background
for understanding the underlying pathophysiology,
and guides the physician through the diagnosis and
management of patients with these conditions. The
book is a welcome and timely addition to our library
of neurological subspecialties.
Norman Latov, M.D., Ph.D.
Professor of Neurology and Neuroscience
Weill Medical College of Cornell University
NICP_A01 03/05/2007 10:32 AM Page viii
Contributing authors
Thomas H. Brannagan, III. M.D.
Associate Professor
Director, Diabetic Neuropathy Research Center,
Peripheral Neuropathy Center
Department of Neurology

Weill Medical College of Cornell University
635 Madison Avenue, Suite 400
New York, NY 10022, USA

Andrew Church, Ph.D.
Fellow
Department of Neuroinflammation
National Institute of Neurology
University College of London
Queen Square
London WC1N 3BG, United Kingdom

Jennifer L. Cox, Ph.D.
Assistant Professor
Department of Neurology
SUNY School of Medicine and Biomedical Sciences
The Jacobs Neurological Institute
100 High Street
Buffalo, NY 14203, USA

Petra D. Cravens, Ph.D.
Postdoctoral Fellow
Department of Neurology
University of Texas Southwestern Medical Center
5323 Harry Hines Blvd
Dallas, TX 75390-9036, USA

Eduardo Adonias De Sousa, M.D.
Assistant Professor
Department of Neurology

Thomas Jefferson University
900 Walnut Street, Suite 200
Philadelphia, PA 19107, USA

Mill Etienne, M.D.
Fellow
Department of Neurology
College of Physicians and Surgeons
Columbia University
710W 168th Street
New York, NY 10032, USA

Mark S. Freedman M.Sc., M.D., FAAN, FRCP(C)
Professor of Medicine (Neurology)
Director, Multiple Sclerosis Research Unit
University of Ottawa
The Ottawa Hospital-General Campus
Box 601, 501 Smyth Road
Ottawa, ON K1H8L6, Canada

Gavin Giovannoni, M.D., Ph.D.
Department of Neuroinflammation
Consultant Neurologist
National Institute of Neurology
University College of London
Queen Square
London WC1N 3BG, United Kingdom

Alexander Gow, Ph.D.
Associate Professor

Center for Molecular Medicine and Genetics
Wayne State University School of Medicine
3216 Scott Hall, 540 E Canfield Ave
Detroit, MI 48201, USA

Anne R. Gocke, B.S.
Student
Department of Neurology
NICP_A01 03/05/2007 10:32 AM Page ix
x CONTRIBUTING AUTHORS
University of Texas Southwestern Medical Center
5323 Harry Hines Blvd
Dallas, TX 75390-9036, USA

Marios Hadjivassiliou, M.D.
Consultant Neurologist
Department of Neurology
The Royal Hallamshire Hospital
Glossop Road
Sheffield S10 2JF, United Kingdom
m.hadjivassiliou@sheffield.ac.uk
William F. Hickey, M.D.
Professor of Pathology and Neuropathology
Senior Associate Dean for Academic Affairs
Department of Pathology
Dartmouth-Hitchcock Medical Center
One Medical Center Drive
Lebanon, NH 03756, USA

Bernadette Kalman, M.D., Ph.D.

Associate Professor of Neurology, Associate
Chief of Staff
VAMC and SUNY Upstate Medical University
800 Irving Avenue, Research (151)
Syracuse, NY 13210, USA

S. Christine Kovacs, M.D.
Assistant Clinical Professor of Medicine
Division of Rheumatology
Lehay Clinic
41 Mall Road
Burlington, MA 01805, USA
Tufts Medical School
Boston, MA

Daniel H. Lachance, M.D.
Assistant Professor of Neurology
Consultant, Neurology and Neuroimmunology
Laboratory
Mayo Clinic College of Medicine
Rochester, MN 55905, USA
200 First St. SW

Thomas P. Leist, M.D., Ph.D.
Associate Professor
Director of the Comprehensive MS Center and the
Division of Neuroimmunology
Department of Neurology
Thomas Jefferson University
900 Walnut Street, Suite 200

Philadelphia, PA 19107, USA

Vanda A. Lennon, M.D., Ph.D.
Director, Neuroimmunology Laboratory,
Professor of Immunology and Neurology
Director, Autoimmune Neurology Fellowship
Program
Mayo Clinic College of Medicine
200 First St. SW
Rochester, MN 55905, USA

Amy Lovett-Racke, Ph.D.
Assistant Professor
Department of Molecular Virology
Immunology and Medical Genetics
Ohio State University College of Medicine
333 W. 10th Avenue
2166D Graves Hall
Columbus, OH 43210, USA

Sean J. Pittock, M.D.
Assistant Professor of Neurology
Co-Director Neuroimmunology Laboratory
Co-Director Autoimmune Neurology Fellowship
Mayo Clinic College of Medicine
200 First St. SW
Rochester, MN 55905-0001, USA

Robert S. Rust Jr., M.D.
Thomas E. Worall, Jr. Professor of Epileptology and

Neurology and Professor of Pediatrics
Department of Neurology and Pediatrics
University of Virginia
P.O. Box 800394
Charlottesville, VA 22908, USA

Andrew Sylvester, M.D.
Attending Neurologist
International Multiple Sclerosis
Management Practice
521 West 57th Street, Suite 400
New York, NY 10019, USA

NICP_A01 03/05/2007 10:32 AM Page x
Contributing authors xi
Louis H. Weimer, M.D.
Associate Clinical Professor
Department of Neurology
College of Physicians and Surgeons
Columbia University
710W 168th street, R55
New York, NY 10032, USA

Armistead Williams, M.D.
Fellow
International Multiple Sclerosis
Management Practice
521 West 57th Street, Suite 400.
New York, NY 10019, USA

Adam P.J. Younger
Research Assistant
Edgemont Science Scholar Program
300 White Oak Lane
Scarsdale, NY 10583, USA
David S. Younger, M.D.
Clinical Associate Professor
Department of Neurology
New York University School of Medicine
St. Vincent’s Catholic Medical Center
Lenox Hill Hospital
550 First Avenue
New York, NY 10016, USA

Robert Zivadinov, M.D., Ph.D.
Associate Professor
Department of Neurology
SUNY School of Medicine and
Biomedical Sciences
The Jacobs Neurological Institute
100 High Street
Buffalo, NY 14203, USA

NICP_A01 03/05/2007 10:32 AM Page xi
The immune system is composed of cells, tissues,
and vessels that collectively protect the body from
pathogens. In some instances, the immune system
can inadvertently cause tissue damage resulting in
immune-mediated diseases, and appears to be at least
partially responsible for the pathology seen in multiple

sclerosis (MS). The immune system provides defenses
against pathogens in nonspecific mechanisms, termed
innate immunity, and pathogen-specific mechanisms,
termed adaptive immunity. Innate immunity is
composed of phagocytic cells that engulf and digest
microorganisms, natural killer cells that nonspecific-
ally kill infected cells, and physical barriers as a means
to eradicate pathogens. Adaptive immunity is com-
posed of cells that specifically recognize components
of pathogens and directly target a particular infected
cell. It is the adaptive immune response that is be-
lieved to be responsible for targeting self-proteins in
autoimmunity, but innate immunity plays a critical
role in the events that initially condition the environ-
ment that ultimately determines the phenotype of
the cells of the adaptive immune response.
B lymphocytes and T lymphocytes are the key
cells that provide adaptive immunity. B cells have
multiple functions, including antibody production,
antigen presentation, and immune modulation via
cytokine expression. The production of antibodies
by B cells is the key feature of humoral immunity,
which is critical to the defense against extracellular
microbes. Cell-mediated immunity is primarily
provided by T cells, which recognize antigens of
intracellular pathogens displayed on the surface
of infected cells. Together, B cells and T cells can
usually eradicate an infection in a pathogen-specific
manner with minimal damage to the host, and
further protect the host from future infections of that

pathogen by establishing immunological memory.
Humoral immunity
B cells express and secrete antibodies that are unique
and specific for proteins. This provides humoral
immunity to the host, which was originally described
as a form of immunity that could be transferred from
immunized to naive hosts via serum. All antibodies,
which are also referred to as immunoglobulins (Ig),
have a common structure composed of two heavy
and two light chains (Edelman et al., 1969). The
heavy chain is composed of four sequence domains,
three of which are highly conserved and referred
to as constant regions (C
H
) (Hilschman and Craig,
1969). The fourth domain, the variable region (V
H
),
has a unique sequence that provides the specificity of
the antibody for its target protein. Two identical
heavy chains are linked by disulfide bonds between
the C
H
1 and C
H
2 domains as shown in Fig. 1.1. In
addition, there are two light chains that are each com-
posed of a single constant region (C
L
) and a single

variable region (V
L
). The light chain is connected
to the heavy chain at C
H
1 and C
L
. The V
H
and V
L
regions form the antigen-binding site. The V regions
of both the heavy and light chains contain three
short, highly diverse sequences called the hypervari-
able or complementary-determining regions (CDR),
1
The basics of cellular and molecular immunology
Amy E. Lovett-Racke, Anne R. Gocke, and Petra D. Cravens
Li
g
h
t
c
h
a
i
n
Heav
y
c

h
a
i
n
Com
p
lementar
y
-
determinin
g
re
g
ions (CDR
)
V
H
C
H
1
C
H
2
C
H
3
F
C
re
g

io
n
V
L
C
L
Anti
g
en
-
bindin
g
site
F
c
rece
p
to
r
com
p
lemen
t
bindin
g
site
Fig. 1.1 Antibodies are composed of two heavy and two
light chains that form an antigen-specific binding site.
NICP_C01 04/05/2007 12:27PM Page 3
4 AMY E. LOVETT-RACKE, ANNE R. GOCKE, AND PETRA D. CRAVENS

which encode the unique binding site for specific
antigens (Wu and Kabat, 1970).
Antibodies are classified into five isotypes based on
the differences in the structure of their heavy chain
C regions, IgA, IgD, IgE, IgG, and IgM. IgM and IgD
serve as the antigen receptors for the activation of
naive B cells. Antigen binding to membrane-bound
IgM and IgD results in the secretion of IgM and
expression of other Ig isotypes. This process, termed
isotype switching, results from a new C
H
chain being
produced by the B cells, while the V regions remain
unchanged and thus the specificity of the antibody is
the same (Kataoka et al., 1980). Both secreted IgM,
which is typically found in a pentameric form, and
IgG can utilize the complement system to mediate
the lysis of IgM- or IgG-coated targets. IgG can also
facilitate the opsonization of microbes by promoting
the phagocytosis of IgG-coated targets by binding to
the F
C
(constant region framework of IgG) receptors
on phagocytes (Leijh et al., 1981). IgA provides
defenses against microbes that enter through mucosal
surfaces such as the gastrointestinal and respiratory
tracts. IgA is produced by mucosal lymphoid tissues,
secreted through the epithelium, binds to pathogens
in the lumen, and prevents the entry of pathogens
into the host (South et al., 1966). IgE is the antibody

isotype that mediates immediate hypersensitivity
reactions, as well as defense against helminthic
parasites. Mast cells and basophils express an IgE
receptor that interacts with antigen-bound IgE, re-
sulting in degranulation of mast cells and basophils,
and the expression of immediate hypersensitivity
reactions (Schleimer et al., 1986). Eosinophils express
IgE receptors and can elicit antibody-dependent cell-
mediated cytotoxicity (ADCC) of IgE-coated hel-
minthes (Gounni et al., 1994). Thus, antibodies protect
the host by providing a very diverse set of antigen-
specific antibodies with multiple isotypes to control
the numerous pathogens that the host encounters.
In addition, antigen-specific memory B cells are
established following the initial infection with a
particular pathogen. Memory B cells produce anti-
bodies rapidly following re-exposure to a pathogen,
protecting the host from a subsequent infection
(Uhr and Finkelstein, 1963).
Monoclonal antibodies have provided a valuable
research tool, as well as a mechanism to develop
antigen-specific therapeutic agents. Since each B
cell produces an antibody with a unique specificity,
immortalized B cells have been generated that can
produce an unlimited amount of an antibody specific
for an antigen of interest. Immortalized B cells are
generated by fusing B cells with a myeloma cell to
form a hybridoma, and then selecting B cell clones
that produce an antibody with the desired specificity.
Because monoclonal antibodies can be generated

for virtually any protein or peptide, and even for
polysaccharides and lipids, they have become a major
tool in studying many molecules. Some of the in vitro
research techniques, which utilize monoclonal anti-
bodies, include ELISA, ELISPOT, western blot, flow
cytometry, and immunohistochemistry. Monoclonal
antibodies have also been utilized in vivo to study
particular molecules, pathways, and the function of
a specific cell population. In vivo, monoclonal anti-
bodies that induce complement or ADCC can be used
to deplete a particular cell population by targeting a
cell-surface molecule specific for that cell population.
In addition, monoclonal antibodies administered
in vivo can be used to physically block a particular
molecule, thus preventing the natural ligand from
binding and initiating a signal. It is these in vivo
research strategies that have extended into the devel-
opment of monoclonal antibodies as therapeutic
agents. A monoclonal antibody specific for the
adhesion molecule, VLA4, expressed on T cells was
developed as a therapeutic agent for multiple sclerosis.
The anti-VLA4 antibody prevented the binding of
VLA4 to VCAM on the vascular epithelium, physic-
ally preventing the entry of T cells into the central
nervous system (CNS) (Yednock et al., 1992; Miller
et al., 2003). Using an alternative strategy, a mono-
clonal antibody specific for CD20, a molecule expressed
specifically by B cells, was developed to treat B
cell malignancies (Maloney et al., 1997). Anti-CD20
binds to B cells and elicits an immune-mediated

destruction of these cells. Thus, monoclonal anti-
bodies have been an invaluable tool in both the
understanding and treatment of diseases.
Cell-mediated immunity
T lymphocytes are the mediators of cell-mediated
immunity. T cells recognize antigens in the con-
text of major histocompatibility complex (MHC)
molecules. The human MHC, often referred to as
human leukocyte antigens (HLA), contains at least
50 genes on chromosome 6. T cells recognize anti-
gens bound to HLA class I molecules called HLA-A,
-B, and -C; and HLA class II molecules called HLA-
DR, -DP, and -DQ. Class I molecules are single-chain
glycoproteins that pair with β
2
-microglobulin. In
contrast, class II molecules are heterodimeric, com-
posed of α and β chains.
NICP_C01 04/05/2007 12:27PM Page 4
The basics of cellular and molecular immunology 5
MHC molecules bind peptides derived from
microbes generated by two distinct processing path-
ways (Morrison et al., 1986). Endogenous cytosolic
proteins from intracellular viruses or tumors are
digested into peptides in proteosomes, transported to
the endoplasmic reticulum where they bind MHC
class I molecules, and presented on the cell surface
(Braciale, 1992). Virtually all nucleated cells express
MHC class I molecules with one notable exception
being neurons ( Joly, Mucke, and Oldstone, 1991).

It is also important to note that cell-surface MHC
molecules always contain a peptide, usually a self-
peptide, which is not recognized by autologous T
cells. Peptides presented by MHC class I molecules
are recognized by T cells that express the CD8
molecule. CD8 binds to nonpolymorphic regions
of the class I molecule and actively participates
in transducing signals necessary for activation in
coordination with the T-cell receptor (Emmrich,
Strittmatter, and Eichmann, 1986).
MHC class II molecules are expressed by a sub-
population of cells called antigen-presenting cells
(APC). The primary APC include dendritic cells,
macrophages, and B cells. Dendritic cells, which are
very efficient at antigen capture and constitutively
express class II molecules, are present in lymphoid
tissues, blood, epithelia of the skin and gastroin-
testinal and respiratory tracts, and most paren-
chymal organs (Steinman and Nussenweig, 1980).
Macrophages, which typically express low levels of
class I molecules, are phagocytic cells and typically
present peptides derived from extracellular pathogens
such as bacteria and parasites. Class II expression
is significantly increased by interferon-γ (IFNγ),
which is often expressed by immune cells in the
presence of infection. B cells, which constitutively
express class II molecules, utilize their antigen
receptor (membrane-bound antibody) to bind and
internalize foreign proteins. Thus, APC internalize
extracellular proteins, which are digested into

peptides in endocytic vesicles and bound to MHC
class II molecules (Cresswell 1995). Peptide–MHC
class II complexes are then transported to the cell
surface for recognition by CD4+ T cells.
Activation requirements for naive T cells are distinct
from those from effector T cells. Naive T cells recogn-
ize antigens presented by dendritic cells in peripheral
lymphoid organs. Activation of naive T cells requires
multiple signals other than peptide/MHC engagement,
including costimulation and cytokine signaling
(Fig. 1.2). Engagement of the peptide/MHC complex
by the T-cell receptor is often referred to as signal one
of T-cell activation. T-cell receptors are composed of
unique α and β chains that form an antigen-specific
binding site. In addition, naive T cells express a
molecule called CD28 that binds B7 molecules on
the APC and provides essential costimulatory signals
necessary for T-cell activation, referred to as signal
two. B7 is constitutively expressed on APC and ini-
tially engages CD28 on T cells, resulting in prolifera-
tion and cytokine expression (Fraser et al., 1991).
Activated T cells then differentiate into antigen-
specific effector T cells or memory T cells. Effector
T cells and memory T cells require signal one, but
usually do not require costimulation for activation
(Lovett-Racke et al., 1998). Thus, recognition of
foreign antigens in peripheral tissues where co-
stimulatory molecules may not be present does not
preclude effector T cells or memory T cells from effect-
ively targeting those cells. Once T cells become act-

ivated, they proliferate or clonally expand primarily
in response to the autocrine growth factor IL-2. After
T cell–APC engagement, activation, and prolifera-
tion, an additional ligand for B7 called CTLA-4
is induced. CLTA-4 interaction with B7 sends an
inhibitory signal to the T cell, resulting in decreased
Produces
IFNγ, IL-2 and
Iymphotoxin
Produces
IL-4, IL-5
and IL-13
IL-4
CD4
CD28 B7
TCR peptide MHC
IFNγ and IL-12
Th2 cell
CD4+ T cell Dendritic
cell
Th1 cell
Fig. 1.2 Naive T cells require two signals from the APC
for differentiation and activation. T cells that encounter
antigen in the presence of IFNγ and IL-12 differentiate
into Th1 cells which express IFNγ, IL-2, and lymphotoxin,
while IL-4 promotes the differentiation of Th2 cells which
express IL-4, IL-5, and IL-13.
NICP_C01 04/05/2007 12:27PM Page 5
6 AMY E. LOVETT-RACKE, ANNE R. GOCKE, AND PETRA D. CRAVENS
activation and return of the T cell to a resting state

(Krummel and Allison, 1995).
The other critical factor in the differentiation of
naive T cells is the cytokine milieu in which the naive
T cells are differentiated. CD4+ T cells are generally
classified into T helper 1 (Th1) and T helper 2 (Th2)
cells based on the cytokines that are expressed by
the CD4+ T cells (Cherwinski et al., 1987) (Fig. 1.2).
The cytokines expressed by CD4+ T cells are actually
determined by the cytokine present in the lymphoid
tissue during the initial activation. IFNγ and IL-12,
often expressed by APC and innate immune cells,
direct the differentiation of Th1 cells, which subse-
quently express IFNγ, IL-2, and lymphotoxin (Hsieh
et al., 1993; Reynolds, Boom, and Abbas, 1987). Re-
cognition of pathogens occurs partially through a
set of evolutionarily conserved proteins, called toll-like
receptors (TLR), expressed by macrophages and other
cells of the innate immune system. TLR recognize
conserved pathogen-associated molecular patters,
generating proinflammatory signals that are critical
to the generation of an antigen-specific response.
TLR signaling directly contributes to the cytokines
generated by the APC and therefore effects the
cytokine milieu in which antigen-specific T cells dif-
ferentiate. For example, TLR signaling that induces
the expression of IFNγ and IL-12 would promote
the development of Th1. Th1 cells express these pro-
inflammatory cytokines, which are often associated
with immune-mediated tissue damage. In contrast,
IL-4 directs the differentiation of Th2 cells which

express IL-4, IL-5, IL-6, IL-10, and IL-13 (Swain et al.,
1990). These anti-inflammatory cytokines expressed
by Th2 cells can downregulate the effects of Th1
cells. More recently, a small, yet distinct population
of CD4+ T cells that express IL-17 has been de-
scribed. The requirement for the differentiation of this
T-cell population is still unclear, but it appears that
IL-23 plays a role in at least promoting the expansion
of these T cells (Harrington et al., 2005; McKenzie,
Kastelein, and Cua, 2006). CD4+ T cells primarily
provide help to other immune cells by the cytokines
that they express. For example, isotype switching of
Ig genes is dependent on IL-4, which is primarily
expressed by Th2 cells. Thus, B cells are very depend-
ent on CD4+ T cells for antibody production.
Naive CD8+ T cells require the same three signals
(T-cell receptor engagement, costimulation, and
cytokine signaling) as CD4+ T cells for differentia-
tion into cytotoxic T lymphocytes (CTL). Since most
nucleated cells express MHC class I molecules, CD8+
T cells can differentiate in both the lymphoid tissue
and any peripheral tissue that express foreign or
tumor antigens. CD4+ T cells often play a critical role
in CD8+ T-cell differentiation by producing cytokines
or activating APC via CD40– CD40L engagement,
which subsequently stimulates CD8+ T cells. CD8+ T
cells mediate their effects by two primary mechanisms.
CD8+ T cells can function as CTL in which cytoplasmic
granules containing perforin and granzymes are
released by the CD8+ T cell upon T-cell receptor

engagement resulting in the killing of the antigen-
presenting cell (Masson and Tschopp, 1987). In
addition, CD8+ T cells can produce cytokines, such
as IFNγ, lymphotoxin, and TNFα, which can activate
phagocytes, increase inflammation, and alter the func-
tion of other immune cells (Ramshaw et al., 1992).
Trafficking of lymphocytes is key to an effective
immune response. Chemokines play a central role
in the recruitment of immune cells to the site of
infection. Chemokines up-regulate expression of
adhesion molecules on the vascular endothelium,
which are necessary for lymphocytes to enter tissues
when directed by chemotactic signals. The CNS entry
of activated lymphocytes, monocytes, and dendritic
cells positive for distinct sets of chemokine receptors
is also controlled by a gradient of corresponding
chemokines between the CNS and the peripheral
circulation. The intervening blood–brain barrier
is composed of cerebrovascular endothelial cells,
pericytes, and astrocytic processes (Carlson et al.,
2006). This multifunctional complex structure is
involved in the regulation of cell trafficking and the
development of CNS autoimmunity (see Chapter 3).
Lymphocyte maturation and immunogenetics
Lymphocytes arise from pluripotent stem cells in
the bone marrow. Early lymphocyte maturation
is dependent on rapid proliferation of lymphocyte
progenitors promoted by IL-7 (Peschon et al., 1994).
The generation of large numbers of immature lym-
phocytes provides a sizable group of cells with a highly

diverse repertoire of antigen receptors necessary to
protect the host from diverse pathogens. The diverse
repertoire of antigen receptors for both B and T cells
is generated by somatic recombination, also termed
genetic rearrangement (Okada and Alt, 1994).
Human B cell receptor genes are located on three
different chromosomes: the heavy chain locus is on
chromosome 14; the κ light chain is on chromosome
2; and the λ light chain is on chromosome 22. Each
locus contains a set of V (variable) genes, J ( joining)
genes, and C (constant) genes. In addition, the heavy
NICP_C01 04/05/2007 12:27PM Page 6
The basics of cellular and molecular immunology 7
gene locus contains D (diversity) genes. The number
of V, D, and J genes varies between loci and species.
For example, the V region of the heavy chain of
human B cells contains approximately 45 genes,
while the Vκ locus contains about 35 genes and the
Vλ locus contains about 30 genes. Although all cells
have these loci, these germline genes are not tran-
scribed into messages that encode antigen receptors.
In B cells, a gene from each V, (D), and J region is
joined by somatic recombination, involving double-
strand DNA breaks within the V, (D), and J regions,
and ligating these segments together such that a
single V, (D), and J gene form a single exon capable of
being transcribed. This V–(D)–J gene codes for the
antigen-binding site of antibodies. The diversity of
B cell antigen receptors is created by the multiple V,
(D), and J genes which can potentially combine, the

additions or deletions of nucleotides that can occur
during ligation of V, (D), and J genes; somatic muta-
tions within recombined V–(D)–J segments that can
occur following B-cell activation; and antigen receptor
editing in which a B cell may select a new light chain
to pair with an existing heavy chain. Immature B
cells that express an antigen receptor then undergo a
process of negative selection in the bone marrow in
which B cells with antigen receptors specific for self-
proteins are deleted or fail to mature (Grandien et al.,
1994). These nonself-reactive B cells then migrate
into the periphery where they are capable of recog-
nizing and responding to foreign proteins.
Maturation of T cells and development of the T-cell
receptor is quite similar to B cells. T-cell precursors
are derived from stem cells in the bone marrow
or fetal liver and migrate to the thymus where these
thymocytes proliferate and undergo somatic recom-
bination. The germline configuration of T-cell re-
ceptor genes is similar to B-cell receptor genes. T-cell
receptors can form from the pairing of an α and β
chain or a γ and δ chain, with αβ T-cell receptors
expressing significantly more diversity and being
expressed by the majority of T cells (Kronenberg et al.,
1986). The α, δ locus is located on chromosome 14,
the β locus is on chromosome 7, and the γ locus is on
chromosome 7. The α and γ loci contain multiple V
and J genes, while the β and δ genes also include a
set of D genes. The recombination of V–(D)–J genes
within thymocytes results in a unique T-cell receptor

gene for each T cell. The diversity of T-cell receptors
results from combinatorial and junctional diver-
sity similar to that observed in B cells, but somatic
mutations and receptor editing have not been observed
in T cells. Thymocytes with a T-cell receptor that
recognize self-MHC are stimulated to survive and
thus positively selected (Pardoll and Carerra, 1992).
Subsequently, thymocytes that have a T-cell receptor
that strongly recognizes self-peptides are programmed
to die and thus negatively selected. Therefore, the
host’s T cells only recognize peptides in the context
of self-MHC and potentially autoreactive T cells are
eliminated in the thymus. Mature T cells exit the
thymus and migrate to lymphoid tissues, where they
await the encounter with antigen-laden APC.
Immune privilege, tolerance, and
autoimmunity
There are several sites in the body, called immuno-
logically privileged sites, in which normal immune
responses are not typically elicited. Immune privilege
was originally described when tissue grafts placed
in some areas of the body failed to elicit an immune
response and consequently were not rejected. Im-
munologically privileged sites include the brain, eye,
testis, and uterus. The brain has several features that
normally protect it from immune-mediated damage
(Steilein, 1993). First, there is limited lymphatic drain-
age from the brain. Second, there is a blood–brain
barrier established by vascular endothelium cells
that form tight junctions, preventing the transport of

most cells and proteins into the brain. Third, there is
limited expression of MHC molecules in the brain,
reducing the possibility that T cells can become
activated in the brain.
Interestingly, antigens sequestered in immunologic-
ally privileged sites may be the target of autoimmune
diseases. For example, experimental autoimmune
encephalomyelitis, a model for multiple sclerosis, is
induced by immunization with myelin proteins and
the disease can be transferred to naive recipients
by transfer of myelin-specific T cells (Martin and
McFarland, 1995). In addition, both healthy indi-
viduals and multiple sclerosis patients have myelin-
specific T cells, but the activation state of these
T cells is different (Lovett-Racke et al., 1998). Thus,
it appears that autoreactive T cells are not com-
pletely eliminated in the thymus during negative
selection. The failure to delete some autoreactive
T cells may be due to low avidity T-cell receptors
on these cells or minimal expression of some self-
peptides in the thymus during T-cell maturation.
The realization that all individuals have T cells
that recognize self-peptides has led to the discovery
that T-cell tolerance is critical to limiting autoim-
mune disease. Central tolerance is the phenomenon
NICP_C01 04/05/2007 12:27PM Page 7
8 AMY E. LOVETT-RACKE, ANNE R. GOCKE, AND PETRA D. CRAVENS
described above in which self-reactive T cells are
deleted in the thymus during maturation. Peripheral
tolerance is obtained through several mechanisms.

Naive CD4+ T cells, which normally require both
T-cell receptor-peptide/MHC engagement and costi-
mulation for activation, can become anergic (unre-
sponsive to antigen) if they engage peptide/MHC in
the absence of costimulation (Gimmi et al., 1993).
Since peripheral antigen-presenting cells express
few, if any, costimulatory molecules in the absence
of infection, autoreactive T cells may commonly
engage self-peptide/MHC complexes in the absence
of costimulation in the periphery, resulting in clonal
anergy. T cells may also become tolerant in the peri-
phery if the T cell expresses CTLA-4, the inhibitory
receptor for B7, at the time of T-cell receptor engage-
ment (Perez et al., 1997). Since CTLA-4 binds B7
with a higher affinity, autoreactive T cells that express
low levels of B7 may preferentially bind CTLA-4 and
become anergic. It has recently been postulated that
regulatory T cells, defined as CD4+CD25+Foxp3+
T cells, induce tolerance by blocking the function
and activation of effector T cells. Mutation in the
human Foxp3 gene results in multisystem auto-
immune disease, suggesting that the regulatory T
cells are critical for self-tolerance (Patel, 2001).
It is speculated that infections may play a critical
role in the loss of self-tolerance and the onset of
autoimmunity. Infections can induce the expression
of costimulatory molecules on cells presenting self-
proteins. Thus, peripheral antigen-presenting cells,
once incapable of activating self-reactive T cells, may
now be capable of eliciting a destructive immune

response against self-tissues. This is supported by the
observation that mice with a transgenic T-cell recep-
tor for myelin basic protein usually remain healthy
in a pathogen-free environment, but frequently
develop spontaneous experimental autoimmune
encephalomyelitis in a conventional environment
(Goverman et al., 1993). Another mechanism by
which infections may trigger autoimmunity is
molecular mimicry (Fujinami and Oldstone, 1985).
Pathogens induce the activation of T cells and B cells
that may have antigen receptors that can cross-react
with self-proteins. As a result, T cells and antibodies
originally expanded by recognition of a foreign
protein may target and destroy self-tissues.
Summary
The immune system is designed to protect the host
from pathogens and tumors. The diversity of the
antibody and T-cell repertoire and the selection
process that occurs during lymphocyte maturation
ensures that the immune system is capable of recog-
nizing and responding to the vast array of potential
microbes with minimal damage to the host. How-
ever, this does not preclude the possibility that some
hosts harbor lymphocytes that may inadvertently
recognize self-proteins under some circumstances.
Our increasing understanding of lymphocyte matura-
tion, selection, activation, and tolerance will provide
insight into the understanding of immune-mediated
diseases and potential therapeutic interventions.
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Introduction

Insulation of large diameter axons by supporting
glia in the nervous system is a feat of evolution that
has appeared independently at least three times
(Waehneldt, 1990): in worms (Annelida), in crusta-
ceans (Crustacea), and in terrestrial and some marine
vertebrates (Gnathostomata). Although each of these
incarnations has yielded insulation with distinct
morphologies, the critical feature in each instance is
a multilayered cellular sheath that confers high-speed
neural transmission, enables large reductions in
energy expenditure, and allows for compaction of
the nervous system. In vertebrates, this insulation
takes the form of the myelin sheath, which is a very
stable lipid-rich membrane that is wrapped around
segments of larger diameter axons in the central
nervous system (CNS) and peripheral nervous system
(PNS) and some dendrites.
In its native state, the myelinated axon is often
descriptively likened to link-sausage in lay terms; the
sausage portions being analogous to myelin sheaths
and the knots in between analogous to short bare
regions of the axon, which are called nodes of Ranvier
(sites of sodium channel clustering for neural trans-
mission). However, myelin sheaths are not simply
blobs of fatty substance along the axon but, rather,
are large specialized flattened membrane domains
that are spirally wrapped around segments of axons,
as illustrated in Fig. 2.1 for a CNS myelin sheath. In
further contrast to the humble sausage, myelin sheaths
are by no means amorphous or uniform membranes

but are highly organized and compartmentalized.
At the ultrastructural level, the vertebrate myelin
sheath has a very distinct organization. A flattened,
cytoplasm-containing membrane process from a
myelinating cell contacts and expands radially and
longitudinally around an axon, loosely enveloping
it in a manner analogous to rolling up a newspaper.
The membrane then compacts to tighten around the
axon and extrude the cytoplasm. During this process,
cytoplasmic membrane surfaces become juxtaposed
and appear to fuse together. In electron micrographs,
these fused surfaces are darkly stained by lead salts
and the spiral line is known as the major dense line.
The extracellular surfaces of the membrane also
become juxtaposed; however, these surfaces do not
fuse but, rather, maintain a discrete distance to form
the minor dense line.
Myelinating oligodendrocytes and
Schwann cells
Myelin sheaths elaborated by oligodendrocytes in
the CNS and Schwann cells in the PNS share similar
organizations and serve the same functions (Arroyo
and Scherer, 2000). Typically, axons are small caliber
in the CNS and myelin sheaths may reach 500 µm
in length with 50–100 lamellae. In the PNS, myelin
sheaths may be over 1000 µm in length and com-
prise 200 or so lamellae. There is a linear relation-
ship between the diameter of an axon and the size of
the myelin sheath. In the CNS and PNS, axons must
exceed minimum diameters to be myelinated, which

are approximately 0.5 µm and 1 µm, respectively.
Several features distinguish CNS and PNS myelin:
a Schwann cell establishes a one-to-one relation-
ship around a segment of a single axon while most
oligodendrocytes synthesize and maintain multiple
myelin sheaths around a number of nearby axons,
perhaps as many as 50; a Schwann cell synthesizes
a collagenous basement membrane around the out-
side of the cell to form a tube, oligodendrocytes do
not; in the event of axonal transection in the PNS,
axons usually regrow through the original basement
membrane tube and are reinvested by Schwann
cells and remyelinated; in the CNS transected axons
generally do not regrow.
Major functions of myelin
A major function of the myelin sheath is to electric-
ally insulate a segment of axon. In this regard, myelin
is analogous to the coating around the outside of
2
Major components of myelin in the mammalian
central and peripheral nervous systems
Alexander Gow
NICP_C02 04/05/2007 12:27PM Page 11
12 ALEXANDER GOW
copper wires in underground cables that supply a
suburb with electricity. Shielding the conductive
fiber (copper wire or axon) dramatically reduces
current dissipation to the environment and isolates
the signal from interfering with signals in other
conductive fibers.

In similar fashion to an underground cable,
electrical signals traveling along an axon (action
potentials) must be boosted at regular distances
to maintain signal strength and integrity. This is
achieved for the underground cable using step-up
transformers at relay stations. In the axon, boosting
the signal is achieved at nodes of Ranvier between
the myelin sheaths. In these regions of an axon,
voltage-sensitive sodium channels are clustered at
high density and open when they detect an approach-
ing action potential. The current that flows into the
axon through these ion channels is greater than
that flowing along the axon; thus, depolarization
at nodes of Ranvier boosts the signal and propag-
ates it toward the nerve terminal. After an action
potential has passed through a region of the axon,
ATPases in the axonal membrane must pump out
the sodium ions that entered through the channels
and repolarize the axon in preparation for the next
action potential.
There are several advantages conferred on neural
communication by myelin that are pivotal to the
success of the insulated nervous system. First, myelin
enables an electrical signal to travel along the axon
Inner
Loop
Tight
Junctions
Axon JP Paranode
Cyt.

Node of
Ranvier
Axoglial
Junction
Compact
Myelin
Axon
Tight
Junctions
Paranode
BC
A
Internode
Paranode
Node of
Ranvier
Node of
Ranvier
JP JPAxon
Paranodal
Tight Junction
Internodal
Tight Junction
Compact
Myelin
Outer
Loop
Paranodal
Loop
Axoglial

Junction
Fig. 2.1 Salient features of a myelin sheath in the CNS. (a) Myelin sheath synthesized by an oligodendrocyte has been “unfurled”
from around an axonal segment to reveal the major features of this rhomboidal-flattened membrane process. The central region of
the myelin sheath, or internodal myelin, contains no cytoplasm to allow for membrane compaction; however, the perimeter of the
sheath maintains a cytoplasmic channel for maintenance of the myelin components and signaling with the cell body. Cytoplasmic
channels, or Schmidt–Lantermann incisures, are also observed in compact regions of large myelin sheaths, especially in the PNS.
Tight junctions are observed throughout the myelin sheath. They form the radial component of compact myelin that is observed in
electron micrographs. At paranodes, tight junctions seal the extracellular space between myelin lamellae, which is analogous to
their function in polarized epithelial cell layers. The axonal membrane is segmented underneath each myelin sheath into at least
three distinct compartments: paranodes, juxtaparanodes (JP), and an internode. Cytoplasmic scaffolds anchor and maintain
boundaries between distinct sets of proteins in each domain. A sodium channel domain is also maintained at nodes of Ranvier
between myelin sheaths. (b) Transverse section through the internodal region of a myelinated axon reveals the spiraling,
multilamellar structure of myelin and the locations of tight junctions. (c) Longitudinal section through the paranodal region of a
myelinated axon reveals the axoglial junction (black dots) that sticks the cytoplasm-filled (Cyt.) paranodal loops of the myelin
sheath to the axon. In electron micrographs, these junctions are referred to as transverse bands.
NICP_C02 04/05/2007 12:27PM Page 12
Major components of myelin in the mammalian CNS and PNS 13
approximately 10 times faster than it would in an
unmyelinated axon of similar size; thus, animals can
respond to their environment very rapidly. Further-
more, axons can be of smaller diameter and still con-
duct signals rapidly which enables miniaturization
of the nervous system or enhancement of its com-
plexity by increasing the number of axons. Second,
myelin dramatically reduces energy consumption.
Membrane depolarization/repolarization is an energy-
intensive process that, in an unmyelinated axon,
occurs along its entire length as the action potential
moves like a wave to the nerve terminal; however,
myelin limits depolarization to nodes of Ranvier as the

action potential jumps from node to node (saltatory
conduction) and only small regions of the axon need
to be repolarized.
Diseases of myelin
In neurodegenerative disease states myelin sheaths
can be direct or indirect targets, which renders
vulnerable the critical communication networks in
the CNS and between the nervous system and the
body. Certain regions of the myelin sheath are more
sensitive to damage than others. The myelin paranode
is particularly sensitive because it compartmentalizes
the axonal membrane to cluster sodium channels
at the node and potassium channels at the juxta-
paranode, by means of the axoglial junction. Action
potentials are slowed or may even fail to reach the
nerve terminal (conduction block) if this compart-
mentalization is compromised. In contrast, inter-
nodal myelin is relatively resilient and can enable
near normal conduction velocity with only a frac-
tion of the normal number of lamellae around each
segment of the axon.
Although genetic diseases of myelin may damage
specific regions of myelin sheaths, diseases involving
the immune system such as multiple sclerosis or
Guillain–Barré syndrome usually damage large regions
of the nervous system containing hundreds or thous-
ands of myelin sheaths and it is unlikely that the
destruction will be localized to specific regions of these
sheaths. Nonetheless, it is instructive to understand
that myelin repair will be ineffective unless myelin

paranodes can reestablish compartmentalization.
In the event that axons are transected during the
disease process, the CNS and PNS respond very differ-
ently. In the PNS, myelin sheaths around degener-
ating axons are cleared by macrophages and the
proximal axon stumps sprout neurites which grow
out to reinnervate their targets. In the CNS, axonal
regrowth is very limited and is potently inhibited by
several components of myelin sheaths that particip-
ate in the Nogo ligand–receptor complex.
To serve as a guide to molecular components of
the myelinated axon, I describe general features of
the major proteins and lipids that comprise myelin
sheaths in the CNS and PNS as well as important
neuronal proteins with which the myelin proteins
interact. In addition, I briefly touch on transcriptional
regulation of myelin genes and provide some discus-
sion aimed at dispelling the notion of the myelin
sheath as an immune-privileged compartment.
Internodal proteins
CD9
Located on the short arm of chromosome 12 in
humans (12p13) and on chromosome 6 in mice
(6 F2), the CD9 gene yields a single transcript
(Boucheix et al., 1991).
CD9 is a polytopic membrane glycoprotein with
four putative transmembrane domains and the amino
and carboxyl termini exposed to the cytoplasm. This
protein was initially recognized as an abundant pro-
tein on the surface of developing B lymphocytes and

platelets but is not required for development of these
cell types. The protein is expressed by differentiated
Schwann cells and its gene is regulated by the pre-
sence of axons in vitro and in vivo in similar fashion to
other myelin genes (Banerjee and Patterson, 1995).
CD9 is also expressed by oligodendrocytes and local-
ized to myelin paranodes in the CNS (Ishibashi et al.,
2004; Nakamura, Iwamoto, and Mekada, 1996).
CD9 has been associated with a number of
functions. It is the receptor for pregnancy-specific
glycoprotein-17 in mice (Waterhouse, Ha, and
Dveksler, 2002). CD9 functions in concert with CD81
and integrin-α
6
β
1
to regulate sperm–egg fusion
(Le Naour et al., 2000; Miyado et al., 2000) and also
appears to interact with this integrin in myelinating
cells. Female knockout mice exhibit reduced fertility
and both males and females exhibit mild paranodal
pathology in the CNS and PNS where axoglial junc-
tions of some paranodes are partially disrupted and
important paranodal components including Caspr
and NF155 are mislocalized (Ishibashi et al., 2004).
Myelin associated glycoprotein, MAG
Located on the long arm of chromosome 19 in
humans (19q13.1) and on chromosome 7 in mice
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14 ALEXANDER GOW

(7 B1), MAG is alternatively spliced at the mutu-
ally exclusive exons 2 and 12, which yield the
protein isoforms S-MAG and L-MAG, respectively
(Schachner and Bartsch, 2000).
MAG is a member of the immunoglobulin super-
family (IgSF) and is one of the earliest proteins to be
inserted into the myelin membrane during develop-
ment. This glycoprotein is localized to the inner loop
in mature myelin where it can interact with surface
lipids or proteins from the axon. One such interact-
ing protein is the Nogo-66 receptor (NgR), which is
present at the axolemma and in neurites. MAG is
one of a number of myelin proteins that are involved
in suppressing axonal outgrowth in the CNS, pos-
sibly through its interaction with the Nogo receptor
on the surface of growth cones (Hunt, Coffin, and
Anderson, 2002).
Deletion of the MAG gene in mice causes a subtle
late-onset phenotype in the CNS characterized by
delayed myelin sheath formation (Bartsch et al.,
1997; Li et al., 1994; Li et al., 1998; Montag et al.,
1994). The PNS is also abnormal in MAG-null mice
with tomaculae forming in some myelin sheaths
shortly after birth and increasing in frequency with
age, which suggests that MAG may regulate axonal
caliber, at least in the PNS (Cai et al., 2002; Yin et al.,
1998).
Myelin basic protein, MBP
Located on the long arm of chromosome 18 in
humans (18q23) and on chromosome 18 in mice

(18 E2-E4), the MBP gene is alternatively spliced
at exons 2, 5, and 6 and gives rise to five major
isoforms (de Ferra et al., 1985; Newman, Kitamura,
and Campagnoni, 1987; Takahashi et al., 1985). In
addition, several promoters are known for MBP; the
canonical promoter used by myelinating oligoden-
drocytes and two upstream promoters that give rise
to multiple Golli-forms of MBP by alternative splicing
(Campagnoni et al., 1993).
MBP is the second most abundant protein in CNS
myelin and comprises approximately 35% of total
protein by weight (Braun, 1984). MBP is an extrinsic
membrane protein which is bound to the cyto-
plasmic surfaces of the myelin membrane and may
serve as an electrostatic adhesive to form the major
dense line of compact myelin (Omlin et al., 1982).
The protein has a high content of positive charged
amino acids and exhibits very little higher-ordered
structure even when purified under non-denaturing
conditions (Gow and Smith, 1989) and binds very
strongly to the headgroups of negatively charged
lipids (Smith, 1992).
The absence of the MBP gene in naturally occur-
ring mutant mice, shiverer and mld, causes severe
disease from an early age which is characterized by
whole-body intention tremors and an inability to
compact CNS myelin to form the major dense line
( Jacobs, 2005). MBP appears to play a similar role in
PNS myelin (Martini et al., 1995a), although this is a
minor role because of its low abundance and the

presence of the MPZ protein (Giese et al., 1992;
Martini et al., 1995a).
The functions of Golli-MBP proteins have also
been characterized in some detail. These proteins
are not only expressed by oligodendrocytes, but also
by neurons and in lymphoid tissue during develop-
ment and autoimmune disease (MacKenzie, Ghabriel,
and Allt, 1984; Pribyl et al., 1993). These proteins
are localized to cell nuclei (Landry et al., 1996)
and negatively regulate Ca
2+
-mediated signal trans-
duction in T-lymphocytes (Feng et al., 2004) and
oligodendrocytes ( Jacobs et al., 2005). Golli-null
mice have a subtle phenotype characterized by re-
gional hypomyelination and delayed myelination
in the CNS.
Myelin-associated oligodendrocyte
basic protein, MOBP
Located on the short arm of chromosome 3 in humans
(3p22.1) and on chromosome 9 in mice (9 F4), the
MOBP gene yields at least five isoforms by altern-
ative splicing, with all isoforms sharing a common
amino terminus (Holz et al., 1996; McCallion et al.,
1999; Yamamoto et al., 1994).
MOBP isoforms are small soluble proteins expressed
at high levels by oligodendrocytes that are incor-
porated into compact myelin. Interestingly, one of
the MOBP isoforms (MOBP155) includes tandem
repeats of a proline-rich domain, suggesting it may

interact with other proteins (Yamamoto et al., 1994).
The gene is not expressed by Schwann cells. Similar
to MBP, MOBP has an unusually high proportion of
positively charged amino acids in its primary struc-
ture and is hypothesized to function at the major
dense line (Yamamoto et al., 1994). Indeed, dele-
tion of the MOBP gene in mice renders the myelin
ultrastructure less stable to organic solvents than
wild-type controls (Yamamoto et al., 1999). In
addition, the organization of tight junctions in the
mutant myelin appears to be partially disrupted.
However, this disruption does not cause a behavioral
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Major components of myelin in the mammalian CNS and PNS 15
phenotype, even though absence of the gene pro-
ducts is not compensated (Yoo et al., 2005).
Myelin oligodendrocyte glycoprotein, MOG
Located on the short arm of chromosome 6 in humans
(6p22.1) and on chromosome 17 in mice (17 C), the
MOG gene gives rise to six alternatively spliced trans-
cripts in humans and to a single transcript in mice
(Ballenthin and Gardinier, 1996; Pham-Dinh et al.,
1995a; Pham-Dinh et al., 1995b).
MOG is a type I transmembrane glycoprotein
and is an IgSF member (Ballenthin and Gardinier,
1996; Kroepfl et al., 1996). The function of MOG is
currently unknown; however, this protein is an anti-
genic component of CNS myelin and has been pos-
tulated as a major autoantigen for multiple sclerosis
(Bernard et al., 1997). A proportion of the MOG

pool in oligodendrocytes is glycosylated with the
L2/HNK-1 epitope, suggesting that this protein may
be involved in antigen presentation or serve as a
co-receptor for T-cell activation (Burger et al., 1993;
Steinman, 1993). Neither the absence of the MOG
gene (Delarasse et al., 2003), nor overexpression of
MOG (unpublished data) in transgenic mice causes a
detectable oligodendrocyte phenotype.
Several lines of evidence provide tantalizing hints
that MOG may be involved in the pathophysiology
of multiple sclerosis. First, the MOG gene is located
in the major histocompatibility complex (MHC) in
humans and mouse and shares homology with three
other genes located in this region: butyrophilin, BT2.1,
and BT3.2/B7-3 (Linsley et al., 1994; Pham-Dinh
et al., 1995b). Second, although a minor component
of myelin, MOG is known to be a very immunogenic
protein in multiple sclerosis patients and in experi-
mental autoimmune encephalomyelitis, EAE (Sun
et al., 1991), and elicits both B- and T-lymphocyte
reactivity. Finally, the localization of this protein at
the plasma membrane of oligodendrocytes and to
the external surfaces of myelin sheaths makes MOG
an accessible target for immune interaction.
Myelin protein zero, MPZ (P
0
)
Located on the long arm of chromosome 1 in humans
(1q22) and on chromosome 1 in mice (1 H3), the
MPZ gene yields a single transcript and protein.

MPZ is the major structural protein in PNS myelin.
It is a type I transmembrane glycoprotein and an
IgSF member. Crystallization of the extracellular
domain of MPZ has revealed the mechanism by which
this protein effects myelin membrane adhesion at
minor dense lines of compact myelin (Shapiro et al.,
1996). Thus, MPZ forms homotetramers in cis at the
extracellular surfaces of the membrane, which pack
together in a continuous array. Furthermore, these
units interact in trans with tetramers on the appos-
ing membrane surface and have been likened to
molecular Velcro. At the major dense line, the tail
of MPZ carries a net positive charge and appears to
stabilize the major dense lines by interacting electro-
statically with the negatively charged headgroups
of myelin lipids (Giese et al., 1992; Martini et al.,
1995a; Martini et al., 1995b), in similar fashion to
MBP. Mutations in MPZ are known to cause Charcot–
Marie–Tooth disease and Dejerine–Sottas syndrome
(Patel and Lupski, 1994) and demonstrate the
importance of this protein at the major and minor
dense lines.
Nogo (reticulon 4, RTN4)
Located on the short arm of chromosome 2 in humans
(2p16.3-16.1) and on chromosome 11 in mice (11
A3.3), the Nogo gene gives rise to at least 12 mRNAs
in humans by alternative splicing of exons 1–5 and
alternative use of up to six tissue-specific promoters
(Hunt, Coffin, and Anderson, 2002). These mRNAs
encode seven distinct proteins, although there are

only three major isoforms (Nogo-A, -B, and -C).
Nogo appears to be an intrinsic membrane protein
with two putative transmembrane domains and the
amino and carboxyl termini exposed to the cytoplasm
(Teng and Tang, 2005) and is the latest member of
the reticulon family (Oertle et al., 2003). Nogo-B
and -C are broadly expressed; however, Nogo-A is
specific to the CNS and includes a large amino-terminal
domain (amino-Nogo) not present in the other iso-
forms. One of the major functions of Nogo in many
regions of the CNS is to suppress neurite outgrowth,
and this inhibitory activity is widely believed to
account for the virtual absence of regeneration fol-
lowing spinal cord injury. A 66-amino acid peptide
located between the transmembrane domains of
Nogo-A appears to be extracellular and confers the
neurite outgrowth inhibition. This Nogo-66 domain
interacts with the Nogo receptor (NgR) on neurons
and causes growth cone collapse (Fournier et al.,
2001; GrandPre et al., 2000). In addition, the
amino-Nogo domain appears to inhibit neurite out-
growth, even though this region of the protein is
probably exposed to the cytoplasm (McKerracher
and Winton, 2002).
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16 ALEXANDER GOW
The NgR is a heteromeric complex expressed by
several classes of neurons and includes at least three
co-receptors: p75NTR, LINGO-1, and TROY (Park
et al., 2005). This protein complex is thought to effect

neurite outgrowth through activation of RhoA and
protein kinase C (Yamashita et al., 2005). Despite
a plethora of evidence in favor of Nogo serving as a
regeneration inhibitor, Nogo-null and NgR-null mice
generated in several laboratories provide equivocal
supporting evidence (Teng and Tang, 2005). Thus,
regeneration in the CNS of experimentally injured
mice may be enhanced or marginally improved, and
these data suggest more complex regulation than,
hitherto, has been appreciated. On the other hand,
dominant-negative suppression of Nogo-66 binding
to neuronal NgR enables neurite sprouting in vivo after
spinal cord injury (Li et al., 2005). In this animal model,
Li and colleagues use the astrocyte-specific Gfap pro-
moter to drive expression of a soluble NgR fragment,
which is secreted into the CNS and blocks Nogo-66
binding to the endogenous receptor on neurons.
Oligodendrocyte-myelin glycoprotein, OMG
Located on the long arm of chromosome 17 in
humans (17q11.2) and on chromosome 16 in mice
(16 B1), the OMG gene gives rise to a single mRNA
in humans and mouse (Mikol et al., 1993).
OMG is a type I membrane glycoprotein attached
to the membrane surface via a glycosyl-phospha-
tidylinositol (GPI) anchor (Mikol et al., 1993) and is a
member of a small family of proteins with a conserved
leucine-rich repeat domain that is required for func-
tion, at least in vitro (Vourc’h and Andres, 2004;
Vourc’h et al., 2003). OMG is a potent inhibitor of
neurite outgrowth in the CNS (Kottis et al., 2002;

Wang et al., 2002). This protein serves as a ligand for
the NgR expressed on neurons and appears to com-
pete with Nogo-66 for binding to the NgR (Hunt, Coffin,
and Anderson, 2002). Like Nogo-66, OMG is expressed
by some neurons and may also interact with the
NgR in cis (Hunt, Coffin, and Anderson, 2002).
In the CNS, OMG is localized at myelin paranodes
but is expressed by NG2-like cells that extend OMG
+
processes to encircle nodes of Ranvier (Huang et al.,
2005). In this location, OMG is ideally located to
inhibit neurite outgrowth. In the PNS, OMG is
expressed by Schwann cells and may be localized
to microvilli that contact nodes of Ranvier. In OMG-
null mice, neurite sprouting at CNS nodes of Ranvier
are observed (Huang et al., 2005), which confirms a
major function of this protein.
Peripheral myelin protein, PMP22
Located on the short arm of chromosome 17 in
humans (17p12-p11.2) and on chromosome 11 in
mice (11 B3), the PMP22 gene expression is regu-
lated from two tissue-specific promoters which give
rise to distinct 5′ untranslated regions. The distal pro-
moter is utilized by Schwann cells while the proximal
promoter is used in non-neural tissues (Bosse et al.,
1994; Suter et al., 1994). However, the coding regions
encoded by both mRNAs are identical.
PMP22 is a polytopic membrane glycoprotein
expressed by myelinating Schwann cells that has
four transmembrane domains, the first of which is

N-glycosylated, and the amino and carboxyl termini
are exposed to the cytoplasm (D’Urso and Muller,
1997). PMP22 is also expressed by growth-arrested
fibroblasts that have been serum starved or contact
inhibited (Manfioletti et al., 1990). Dedifferentiation
and resumed proliferation in either cell type down-
regulates expression of PMP22.
Although the specific function of PMP22 remains
elusive, it is clear that this protein is involved in the
maintenance of myelin thickness and stability as
well as regulating Schwann cell proliferation. Over-
expression, gene deletion, and coding region muta-
tions have been found to cause several subtypes
of Charcot–Marie–Tooth disease, which are motor
and sensory peripheral neuropathies in humans.
Naturally occurring missense mutations have also
been characterized in rodents (Chance et al., 1993;
Matsunami et al., 1992; Patel et al., 1992; Roa et al.,
1993; Suter et al., 1992) and are thought to cause
disease via a toxic gain-of-function mechanism
similar to that proposed for PLP1 mutations in the
CNS (Gow, 2004).
Proteolipid protein, PLP1
Located on the long arm of the X chromosome
in humans (Xq22) and on the X chromosome in
mice (X F1-F2), PLP1 gene products comprise the
major protein component of CNS myelin (Willard
and Riordan, 1985). The PLPP1 gene in most ter-
restrial vertebrate species is alternatively spliced in
exon 3, giving rise to two protein products, PLP1

and DM-20, which differ only by the presence or
absence (respectively) of a 35-amino acid PLP1 specific
peptide in the central cytoplasmic domain of the
proteins (Hudson and Nadon, 1992).
PLP1 and DM-20 together comprise approximately
50% of total myelin protein by weight (Braun, 1984)
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