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Myasthenia: A Brief Biology
This is a sample chapter from You, Me and Myasthenia Gravis, a complete guide
to Myasthenia Gravis for patients and physicians. The book is now in its third edition and covers vital topics such as:
* The Immune System and MG
* The Symptoms of MG
* How Is MG Diagnosed?
* How Is Myasthenia Gravis Treated?
* The Autoimmune forms of Myasthenia
* The Congenital Myasthenias
* Myasthenia in Children
* Issues of Daily Life
* Psychological Issues and MG
* Patient's Experiences
* and more
To find out more about the book, visit: http://YouMeAndMG.com
To order your copy of the book, visit: http://YouMeAndMG.com/order
You, Me and Myasthenia Gravis
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1
Myasthenia
A Brief Biology
Myasthenia gravis (MG) is a chronic neuromuscular1 disease
which affects the strength and stamina of voluntary muscles2. The
symptoms of MG result from an immune system attack on structures
in the neuromuscular junction (NMJ), the junction between a nerve
fiber and the muscle it supplies.
A second very rare type of myasthenia, the congenital myasthenic
syndrome3 (CMS), is caused by a genetic mutation4 which can be
passed from parent to child. The symptoms of the congenital
myasthenias result from changes in function at the NMJ. These
changes vary depending on the genetic mutation.
This book seeks to explain how myasthenia, both
autoimmune/acquired, and congenital, affects the body. It explains
MG treatments and how they work, and it shares the experiences of
both physicians and patients. We know more about myasthenia now
than ever before. But to understand this knowledge we need to learn
about nerves, muscles and the immune system. In this chapter we'll
examine how nerves and muscles work together to produce
movement, and how the neuromuscular junction (where the problem
is in MG) works. We'll see how the immune system tells the
difference between self and non-self, how it protects us from attack by
1 Neuromuscular: Involving both the nerves and muscles.
2 Voluntary muscles: Muscles which we exercise conscious control over,
such as the muscles of the legs and jaw.
3 Syndrome: A group of signs and symptoms that occur together and are
typical of a particular disease or disorder.
4 Genetic mutation: An error in one of the genes encoding one or more
proteins.
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outside invaders, and finally how errors made by the immune system
produce autoimmune diseases like MG. This knowledge will enable
us to understand the information in later chapters, give us greater
insight into what is happening in the body, and enable us to be better
members of our own health care team.
Translating Intention Into Action
When we reach out to pick up a glass of water we never think of
the intricate chemical and electrical dance the idea of movement sets
off. The intention to pick up the glass forms in the brain, but the
command to pick up the glass races from the brain and down the
spinal cord in the form of an electrical pulse called an action
potential.
The action potential speeds from the spinal cord to the end of the
motor nerves5 where it is transformed into a chemical signal, crosses
the synapse6, and on the other side, is transformed back into an action
potential, which initiates muscle movement. The glass is then picked
up.
The motor nerve terminal, containing ACh vesicles and
voltage-gated calcium channels, the synapse and muscle endplate.
(Drawing courtesy M. Nicolle MD)
5 Motor nerves: Nerves which carry signals to muscle, and are involved in
movement.
6 Synapse: a tiny gap that physically separates neurons.
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Motor nerves end in bulb-like structures called axon (or nerve)
terminals. Nerve terminals make contact with muscle fibers at a
region called the endplate. The nerve terminal contains vesicles7,
which store and release the neurotransmitter 8 acetylcholine (ACh).
Cells are enclosed in a thin wrapper called a membrane. There is
an electrical gradient across this membrane. The outside of the
membrane has a more positive charge than the inside. When an action
potential arrives at the nerve ending it causes an instant reversal of
this polarity, which opens calcium channels on the nerve terminal.
Calcium ions flowing into the nerve terminal causes acetylcholine
(ACh) vesicles to open and release ACh into the NMJ.
The Production of Acetylcholine
Acetylcholine (ACh) is produced by the binding of choline to
acetate. Cofactor A, carrying acetate, sticks to the enzyme choline
acetyltransferase. The acetate and choline molecules then stick
together, producing ACh. After the reaction is complete, the cofactor
A molecule is released. The ACh is then packaged and stored in
vesicles at the nerve terminal, ready to be released when an action
potential arrives.
Endplate Potentials
When an action potential arrives at the nerve terminal, it triggers
the release of ACh from 100 - 300 vesicles. Each vesicle contains one
quantum (10,000 molecules) of ACh. This release of ACh produces
an endplate potential (EPP) and starts the process of muscle
movement by depolarizing the membrane around it and producing an
action potential in the muscle fiber.
MEPPs
The arrival of an action potential triggers results in muscle
movement, but vesicles also leak ACh at a rate of about one per
second. This slow leak of ACh cause what are called miniature
endplate potentials (MEPPs). MEPPs don't cause enough
depolarization of the muscle membrane to trigger movement. There's
no clear understanding of the significance of this release of small
quantities of ACh and the resulting MEPPs, but we know they play a
7 Vesicle: A small bubble filled with chemical.
8 Neurotransmitter: Any chemical that results in the movement of a nerve
signal across a synapse.
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role in the health of the muscle. They may help maintain muscle tone,
as youngsters with less than a normal release of MEPPs have less
muscle tone than normal.
The Neuromuscular Junction
Because this system works on electrical principals and the charge
(action potential) is passed along by the release of ACh, it's important
that the “live wires” (so to speak) are not in contact. The nerve
terminal and the muscle membrane do not touch. There is a small gap
between them, called a synapse or synaptic cleft. The nerve terminal,
the synapse and the muscle membrane are collectively referred to as
the neuromuscular junction (NMJ).
Agrin, MuSK and Rapsyn
The synaptic cleft contains a substance called the basal lamina
which separates the nerve and muscle cell membranes. The basal
lamina also plays a vital role in rebuilding the synapse after an injury.
Basal lamina contains a protein called agrin. When agrin is added to a
lab culture containing muscle cells AChRs gather and grow in the
muscle membrane.
Motor nerves secrete agrin and deposit it in the basal lamina at the
site of the developing NMJ. Agrin acts at its receptor on the surface of
the muscle, helping assemble and stabilize acetylcholine receptors
(AChRs). In lab mice which have been genetically altered to lack
agrin, AChRs do not gather under the axon terminal and NMJs do not
form.
The key components of the agrin receptor are a receptor called
muscle specific kinase (MuSK) and the protein it activates, rapsyn.
MuSK and rapsyn attract immature AChRs to the area beneath the
nerve terminal, causing them to cluster at the endplate and mature into
fully functional AChRs. The basal lamina, agrin, MuSK and rapsyn
are vital components in the constant regeneration of AChRs. Their
function is affected in seronegative MG and some forms of congenital
myasthenic syndrome, reducing the number of AChRs which form
and mature at the neuromuscular junction.
Acetylcholinesterase
The synaptic cleft also contains the enzyme9 acetylcholinesterase
(AChE). When an action potential arrives and ACh floods the synaptic
9 Enzyme: A protein that causes or speeds up reactions in living matter.
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cleft it immediately comes into contact with AChE.
Acetylcholinesterase begins to break ACh down as soon as the two
come into contact. Some ACh is neutralized before it has a chance to
bind to ACh receptor sites, but enough reaches and binds to ACh
receptor sites to create an endplate potential (EPP). Endplate
potentials must last for precisely the right amount of time, and
generate exactly the right amount of current, for depolarization of the
muscle fiber to occur. Thus, after binding briefly to the receptor, ACh
is dislodged and either floats out of the NMJ or is broken down by
AChE.
Ion Channels
Ion channels are gateways (or pores) through cell membranes.
They allow molecules of potassium, calcium, sodium or chloride to
pass in and out of cells. Each type of ion channel responds to a
specific signal. The signal may be a change in voltage (like an action
potential), a change in temperature, or a chemical stimulus, like a
molecule of ACh.
When the appropriate signal arrives the ion channel opens. Most
ion channels allow only one type of ion; sodium, potassium, calcium
or chloride to pass through. Opposites attract; positively-charged ions
move toward a negative charge and vice versa. A membrane may
contain many thousands of ion channels. The surge of ions across the
membrane generates tiny electrical currents that, in the skeletal
muscle cell, begins the process of muscle contraction.
Ion channels are made up of sub-units assembled in groups of
four, five or six, depending on the function of the channel. There are
six types of voltage-gated calcium channels (VGCC). They are
identified by the letters L, N, R, P, Q and T. The calcium channels on
the axon terminal are P and Q types. P and Q calcium channels are
made up of subunits alpha1, alpha2, beta, gamma, and delta.
The ion channel is essentially a pore through the membrane which
opens and closes in response to the appropriate signal. When the
signal arrives and binds to the one subunit which serves as the
receptor, the entire ion channel opens. Ions of the proper shape or
charge can then flow through. When the signaling period expires, the
tube snaps closed and molecules stop flowing.
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The Acetylcholine Receptor
The
acetylcholine
receptor (AChR) spans
the muscle cell membrane.
The adult AChR is made
up of five subunits; two
alpha units, one beta unit,
one epsilon unit, and one
delta unit. Each subunit is
encoded10 by a separate
gene. The five subunits are
arranged in a tubular shape
around a ligand-gated11 ion
channel, like the staves in
a barrel.
AChR spanning the muscle
membrane, and as seen from above.
(Courtesy M. Nicolle MD)
The two alpha units each have binding sites for ACh. When two
ACh molecules bind to the alpha units the complex changes shape and
the ion channel opens. The channel remains open for about one
millisecond and then snaps closed. The ACh molecules are then
released from the receptors, fall into the synapse and are broken down
by AChE. The AChR then reverts to the closed state.
Acetylcholine is the key that opens the ion channel. When ACh
binds to the receptor site it causes depolarization of the muscle
membrane. If the amount of depolarization is enough an action
potential is generated in the muscle membrane. Sodium channels
open, sodium ions flow into the muscle cell which triggers the release
of calcium ions inside the cell. The release of calcium ions then
causes muscle contraction or movement.
ACh Receptor Types
ACh receptors are constantly being replaced. There are two types
of AChRs. The majority are of the so-called stable type. At least 50%
of these are replaced every 12 - 13 days. The second type of receptors
10 Encode: To specify the genetic code for.
11 Ligand-gated: Permitting or blocking passage through a cell membrane in
response to a chemical stimulus.
You, Me and Myasthenia Gravis
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(called RTOs for rapid turnover) are replaced much more quickly.
Fifty percent of them break down and are replaced on a daily basis.
Although RTOs make up only 20 - 30% of the total number of
receptor sites they account for almost 70% of the overall turnover. Not
all RTOs break down this quickly, six to ten percent stabilize and
become the longer-lived type.
The neuromuscular junction, showing the AChRs in place on
the muscle membrane. (Drawing courtesy M. Nicolle MD)
The production of two types of AChRs makes sense. If all
receptors were of the stable type it would take far longer for the body
to recover from an agent that blocked or interrupted neuromuscular
transmission. If all receptors were RTOs the body would have to
expend far more resources constantly making their replacements. A
two-tiered system thus both conserves and protects neuromuscular
function.
Surprisingly, normal neuromuscular transmission requires that
only 25 - 30% of the total number of AChRs be functional at any one
time. Patients may have a 50 - 60% reduction of AChRs and still show
no clinical signs of inadequate neuromuscular transmission.
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The Immune System and MG
The immune system is a network designed to protect the body
from invasion by bacteria, viruses, molds, parasites or any type of
foreign substance. The organs of the immune system are located
throughout the body. They are called lymphoid organs because they
produce, regulate and, in some cases, deliver lymphocytes; white
blood cells that are the main components of the immune system.
Self and Non-Self
The very foundation of the immune system is its ability to
distinguish self from non-self. Immune cells live in a state known as
self-tolerance, because every cell in a person's body carries a unique
self-marker. These self-markers (called epitopes) protrude from the
surfaces of every cell. Every epitope has a unique shape which
functions like a key. The immune system is constantly checking cells
it meets for epitopes. It recognizes its own epitope as the self-marker.
In a healthy body the immune system does not attack organs or tissues
with the self-marker.
The immune system recognizes non-self tissues by the foreign
shape of its protruding epitopes. The immune system has the ability to
recognize unlimited numbers of different non-self molecules and can
produce antibodies to counteract each of them.
Antigens
The parts of proteins which trigger an immune response are
known as antigens. Antigens are found on viruses, bacteria, molds,
and body cells or tissues, which is why transplanted organs such as a
kidney or heart trigger a rejection response. The rejection response is
the immune system attacking tissues it has identified as non-self.
Human Leukocyte Antigens
Human leukocyte antigens (HLA) are proteins found in most cell
membranes in the body. There are high concentrations of HLAs on the
surface of white blood cells. The immune system also uses HLA
antigens to tell self from non-self. There are many different HLA
proteins. Individuals have only a small, relatively unique set inherited
from their parents. Two unrelated people rarely have the same HLA
make-up.
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We inherit one-half of our HLA antigens from our parents. One
quarter of our antigens matches our mother's antigens, and one-quarter
matches our father's antigens. The remaining 50% of our antigens are
drawn from the genetic pool of previous ancestors. This mix becomes
crucial when a person needs a tissue graft or organ transplant when it
is vital that the patient's antigens match the donor's antigens. An HLA
incompatibility may make an organ from a patient's brother or sister
unsuitable for transplant.
Immune System Cells
Immune cells develop in the bone marrow from stem cells12. Some
stem cells develop into white blood cells known as phagocytes or
macrophages. Phagocytes destroy invaders by engulfing and digesting
them. A small number of phagocytes become specialized
inflammatory cells. Other stem cells develop into white blood cells
called lymphocytes. The two major kinds of lymphocytes are B cells
and T cells. B cells produce substances known as antibodies. When a
B cell meets its triggering antigen it begins to mature into large
numbers of plasma cells. These plasma cells then begin producing
quantities of their specific antibody.
T cells play two roles in the immune system. They first develop in
the bone marrow, along with the B cells, but those destined to become
T cells leave the bone marrow and migrate to the thymus, where they
learn to recognize self and non-self antigens. This is the reason they
are called thymus-dependent lymphocyte or T cells.
Helper T cells activate other immune cells including B cells and
other T cells. Suppressor T cells turn off or suppress immune activity
when the invader has been killed and the clean-up is over. Cytotoxic T
cells help rid the body of cells that have been infected by viruses as
well as cells that have been affected by cancer. Cytotoxic T cells are
also responsible for the rejection of tissue and organ transplants.
The Thymus
The thymus is a gland located just behind the breastbone and in
front of the heart. It teaches the T cells to ignore self antigens and
attack foreign antigens. Some T cells help regulate the immune
system, while others act as defenders against viral infection and
cancerous tissues.
12 Stem cell: The most primitive cell in the bone marrow from which all the
various types of blood cells are derived.
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Antibodies
Antibodies consist of two identical heavy chains and two identical
light chains which fit together to form a Y. The stem of the Y is
identical in all antibodies of the same kind and is called the constant
region. It links the antibody to the rest of the body's defense system.
The sections that form the tips of the Y are called the variable region.
The tips are unique to each type of antibody. They fit onto the
epitopes of only one antigen like a key fits into its lock. When an
antibody finds its matching antigen it binds to it.
Immunoglobulins
B cells make antibodies, also called immunoglobulins. There are
nine types of human immunoglobulin; four kinds of IgG and two
kinds of IgA, plus IgM, IgE and IgD. IgG, the major immunoglobulin
in the blood, is also able to enter tissue where it coats
microorganisms, helping other cells in the immune system dispose of
them more quickly. IgD is found in the membrane of B cells, where it
helps regulate the cell's activation. IgE gives protection against
parasites, but also causes allergic reactions.
The Complement System
The complement system is made up of a series of proteins that
complement the work of antibodies. There are 18 complement
proteins (CPs), each with a different job. Complement Proteins
circulate in the blood in an inactive form, activating only when
needed to fight infection.
The complement system protects the body against infection in
several ways. It produces large numbers of activated CPs that bind to
the surface of bacterial and viral invaders. These CPs attract
macrophages (phagocytes) to the site of complement activation and
switch them on once they have arrived. The macrophages respond to
the presence of CP on the surface of the invading cells by surrounding
and devouring the invader cells. Lastly, a complement cascade is
activated when complement protein encounters and recognizes an
antibody bound to an antigen. These complement proteins assemble a
cylinder that punctures the membrane of the cell and helps kill it.
Autoimmune Disease
Sometimes the immune system's ability to distinguish between
self and non-self breaks down, and the immune system produces
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antibodies and T cells targeted against the body's own cells and organs
Antibodies against the self are called auto-antibodies. Auto-antibodies
contribute to many diseases. Organs and tissues commonly affected
by autoimmune disorders include red blood cells, blood vessels,
connective tissues, endocrine glands, muscles, joints and skin. For
instance, T cells that attack cells in the pancreas contribute to some
forms of diabetes, while over 90% of people with the autoimmune
disease Lupus have antinuclear antibodies. Antinuclear antibodies
attack the nucleus of cells and tissues. Other autoimmune disorders
include rheumatoid arthritis, Graves' disease, chronic thyroiditis
(Hashimoto's disease), multiple sclerosis, pernicious anemia and
myasthenia gravis.
Antibodies and MG
Antibodies to acetylcholine receptor (AChR) are found in
approximately 85% of MG patients. Myasthenia gravis is referred to
as a B cell mediated disease, because B cell auto-antibodies attack the
alpha subunit of the AChR. In most cases antibodies are directed
against the main immunogenic region (MIR)13 on the alpha subunit.
AChR antibodies can cause problems in three ways; they can bind to
the AChR and block access by ACh, without damaging the receptor;
they can bind to AChRs and damage them, so that the AChRs break
down and are absorbed into the muscle; and they can bind
complement and damage the muscle endplate. As the number of
receptors decrease the NMJ becomes less responsive to ACh. There is
reduced transmission of the nerve signal, resulting in muscle
weakness.
The role of the thymus in MG cannot be overlooked. T cells,
activated in the thymus, do not attack the NMJ directly, but play a role
in MG autoimmunity. T cells stimulate AChR-reactive B cells, which
results in their transformation into the plasma cells which produce
AChR antibodies. Abnormalities of the thymus are common in MG
patients.
About 85% of MG patients with generalized weakness have
measurable anti-AChR antibodies, but the remaining 15% do not.
Patients who do not have identifiable antibodies against the AChR
have what is called Seronegative 14 MG.
13 MIR: Relating to or producing an immune response.
14 Seronegative: No identifiable antibodies.
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MuSK Antibody and Rapsyn
During development the motor nerve terminal secretes the protein
agrin, which “wakes up” immature AChRs randomly scattered in the
muscle membrane. MuSK and a protein called rapsyn then work
together to assemble and mature the AChRs. Muscle specific kinase
(MuSK) is an enzyme essential to the formation of AChRs during the
development of the neuromuscular junction. Studies of MG patients in
the seronegative group have revealed that a recently discovered MuSK
antibody is present in 30 - 50% of patients in this group, suggesting a
different mechanism for MG in these patients.
MuSK and rapsyn are vital components in the constant
regeneration of AChRs. Some types of the congenital myasthenic
syndromes are caused by mutations which affect the production or
function of rapsyn.
There's Hope for Tomorrow!
Knowledge of the immune system and the neuromuscular junction
have greatly expanded in the past 15 years. This gives us hope that
MG will soon be a disorder which can be quickly brought under
control by treatments which suppress the inappropriate autoimmune
response while leaving the rest of the immune system intact and
functioning normally.