Muscles enable us to walk, throw and stand up straight. The majority of muscle imbalances are caused by strains or any sudden exertions. One type of strain is a charley horse, which is caused by a sudden stretching. Muscle fibers tend to tear, and this causes pain and swelling. It usually takes a couple of weeks for it to heal. A completely different type of muscle imbalance is myasthenia gravis (MG), which causes fluctuating muscle weakness. This is most commonly found in muscles controlling the eye movements. Myasthenia gravis is caused by a defect in neuromuscular transmission, where chemical signals are improperly transmitted.(1)
It's typical for a patient with MG to have: droopy eyes, irregular posture after standing for a short time, nasal speech, difficulty chewing and swallowing, and weakness in the arms, hands and fingers. Reflexes are not lost, instead there is localized fatigue of the most repeatedly used muscle groups. MG targets skeletal muscles, where the nicotinic acetylcholine receptors are located. The most affected muscles include: the ocular, bulbar, and facial muscles, as well as the muscles of the limbs, neck, shoulders, hips and trunk.(2) In rare cases, there is weakness of the diaphragm and thoracic chest muscles, which can result in respiratory impairment. MG symptoms tend to be worse with repetitive activity, excessive heat, overexertion and emotional stress.(1) MG symptoms are improved with rest and cooler environmental temperatures. Myasthenia gravis is a non-inherited autoimmune disease characterized by the presence of antibodies in the blood that destroy muscle cell receptors for acetylcholine.(3) This disease is an example of both synaptic and autoimmune disorders. In most patients, it is caused by antibodies specific for the nicotinic acetylcholine receptor (AChR), which is concentrated at the post-synaptic region of the neuromuscular junction.(3) The most common disorder for myasthenia gravis is neuromuscular transmission. As this disease progresses, the number of AChRs are reduced by antibodies, causing a defect in neuromuscular transmission and muscle weakness.(3) The immune system consists of white blood cells, one of which is a lymphocyte. One type of lymphocyte is T cells, which are made from stem cells in the bone marrow and migrate to the thymus. Another type of lymphocyte is a B cell, where it migrates to the blood stream. Both of these lymphocytes work in recognizing foreign microbes and antigens. In an autoimmune response, helper T cells identify self- cells in the body and mark them for destruction. The immune system lacks the ability to distinguish self from foreign invaders. This is what occurs in Myasthenia gravis patients, the T cells that contain "self-marks" can get out into the blood stream and initiate a response against the body.(4) The nicotinic AChR is found on the skeletal muscle cell and is affected by the autoimmune response provoked by myasthenia gravis. The receptor is composed of five subunits: one of b, g, and d, and two a subunits. The subunits are arranged in a transmembrane channel that is lined with leucine side chains to prevent the passage of ions.(5) At the neuromuscular junction, an action potential moves along the motor neuron and carries a depolarization wave to the presynaptic neuron. The presynaptic neuron is then depolarized and it releases ACh. Here ACh binds to the alpha subunit of the receptor, where ions are collected and attracted to charged residues. The binding of ACh causes a conformational change in the channel, which opens it to allow the passage of ions. This occurs when ACh reacts with the residues to form weak bonds, and allow the ions to enter the channel. The negative charges of the ACh receptor attract cations such as, Na+ and Ca2+. The inward flow of positive charges depolarizes the plasma membrane initiating an action potential, which ultimately causes the muscle to contract.(5) Usually ACh concentration is kept low by acetylcholinesterase or the AChR is desensitized when ACh levels are high, resulting in a closed channel. The normal function of the body relies on signal transmission from nerve to muscle. In order to sustain effectiveness, the neuromuscular transmission must withstand various physiological conditions. The ability to accomplish this is referred to as the 'safety factor.'(6) It is determined that the measured excess of released transmitter is the safety factor. When AChRs decreases, this leads to the reduction of the safety factor and transmission is blocked. Therefore, the safety factor plays a significant role with myasthenia gravis and neuromuscular transmission. It was also found that monoclonal antibody, mAb35, results in contractile dysfunction and symptoms of experimental myasthenia gravis (EAMG).(7) This antibody binds the muscle receptor for AChR. Exposure to mAb35 causes increased levels of interferon-gamma-activating cytokine (IFN-g) and Interleukin-15 (IL-15) produced by the muscle. Interferons are proteins that are released to protect uninfected cells from virus-infected cells.(4) Gamma cytokines are secreted by lymphocytes and enhances the activity of B cells and T cells.(4) Rat myocytes responded to IL-4 by producing IL-15, which is an activator in the production of IFN-g.(7) Muscle is not a passive participant in the development of disease symptoms in EAMG and may play a very important active role by producing immunomodulating factors such as muscle-derived cytokines.(7) Those factors can influence the impact of the immune system on the muscle. Antibodies have been shown to decrease the usefulness of ACh receptors through accelerated endocytosis & blockage of the receptor.(8) Anti-AChR antibodies are linked to AChRs, causing endocytosis and degradation of those AChRs. The blockage of ACh binding sites is due to antibodies binding near the ACh binding site, rather than directly on it. The antibody gets in the way of the ACh molecule as it moves towards the receptor. The blockage of ACh binding site does not occur in autoimmune myasthenia gravis, but in recurrent congenital arthrogryposis. In arthrogryposis there is a limitation to the motion of a joint and muscle weakness. In maternal myasthenia gravis, babies born from mothers with MG develop symptoms, such as muscle weakness after placental transfer of anti-AChR antibodies. Arthrogryposis occurs with maternal myasthenia gravis where the antibody binds to the g subunit of the AChR diminishing the effects of the AChR.(8) The difference between a normal and a myasthenic neuromuscular junction depends on the number of ACh receptors. In a myasthenic neuromuscular junction there are decreased numbers of ACh receptors. The decreased number of ACh receptors will result in fewer interactions between ACh and its receptors. This will also lead to a decrease in activation of action potentials, where the power of the muscle's contraction is reduced thus causing weakness.(2) The loss of normal synaptic folds also contributes to the decrease in the number of interactions between ACh and AChRs, thus resulting in muscle weakness.(1) The types of MG include: antibody-negative, drug related, viral/bacterial, transient neonatal and adult-onset. Patients who don't have detectable AChR antibodies are said to be antibody-negative and cause an accelerated degradation of the AChRs.(2) Immunoglobulin has been found to be the cause of accelerated degradation by binding to the muscle cells. Alteration in the immune system due to the effects of drugs such as penicillamine is drug-related MG. When the protein amino acid sequence of a foreign invader is similar to a sequence in the body, the immune system recognizes both as foreign, this is viral/bacterial MG. Transient neonatal MG occurs in infants born to myasthenic mothers. Adult-onset MG is more likely to occur in women over the age of 50, than in men.(1) Treatment for myasthenia gravis includes: cholinesterase inhibitors, thymectomy, corticosteroids, immunosuppressant drugs, and plasma exchange. Cholinesterase inhibitors allow the accumulation of ACh at the neuromuscular junction, prolonging the effect of ACh for muscle contraction. After the removal of the thymus gland, it usually takes 2 to 5 years after the surgery to show improvements. The rationale for a thymectomy is due to the fact that the thymus gland contains T cells, which are part of the immune system. Most MG patients have thymic deficiencies, such as tumors. The defect with the neuromuscular transmission is due to the connection between the thymus gland and the antibodies of the AChR. Severely ill patients usually take corticosteroids, but this causes increased blood pressure and mild weakness in the arms and legs. Immunosuppressant drugs such as azathioprine are effective, but like the corticosteroids, they have severe side effects. After prolonged use, azathioprine causes an increase in blood pressure and a decrease in resistance to infection. Another type of immunosuppressant is cyclosporine, which is taken to limit tissue rejection during and following organ transplant surgery. Lastly, plasma exchange lasts temporarily for patients with worsened MG.(1) A recent source of treatment for MG is mycophenolate mofetil (MM). MM is an immunosuppressant that inhibits the de novo pathway of guanosine nucleotide synthesis required for B and T lymphocyte proliferation.(9) This inhibition of the B cells and T cells also inhibits the production of autoantibodies. Mycophenolate blocks the enzyme inosine-5'-monophosphate dehydrogenase (IMPDH), which is needed by B cells and T cells for an immune response. Cells not associated with the immune system don't require IMPDH and are not affected by its blockage.(10) A patient with myasthenia gravis reported a progressive increase in strength of grip anterior leg muscles after taking mycophenolate.(10) The results of MM treatment on MG are great because it controls its signs and symptoms. Onset is quick, occurring in 3 weeks after the initiation of treatment and with side effects of diarrhea, low white blood cell count (leukopenia), and vomiting.(9) Another recent source for treatment of myasthenia gravis has been found by using tacrolimus (FK-506) on transplant recipients. Tacrolimus is a calcium-calcineurin inhibitor used as an immunosuppressant on patients with MG. It acts through the inhibition of the calcium-calcineurin pathway and exerts its immunosuppressive effect by reducing the proliferation of activated T cells.(11) The use of tacrolimus was reported to have less nephrotoxicity than other treatments. Tacrolimus binds to the FK-506 binding protein, which inhibits calcineurin. Calcineurin is required for the signaling of T lymphocytes. Although Tacrolimus doesn't cure MG, it is used to control it when taken at low doses. Muscle weakness and defects in neuromuscular transmission are symptoms of the autoimmune disorder, myasthenia gravis. It is a non-inherited disease that acquires antibodies that fight against the body by destroying acetylcholine receptors. The number of acetylcholine receptors are reduced due to the degradation of acetylcholine receptors and the loss of normal synaptic folds. This results in less depolarization of the membrane, contributing to less muscle contraction. Transmission from nerve to muscle depends on increased levels of 'safety factor' in order to sustain a prolonged transmission. Muscle cells produce immunomodulating factors such as, IFN-g, which influence the immune system, when bound to the antibody mAb35. There are many types of myasthenia gravis that involve autoimmune responses, such as those that are induced by drugs to those that occur in adulthood. The best manner in which to treat myasthenia gravis is with cholinesterase inhibitors, which prolong the effect of ACh. A second alternative would be a thymectomy, which will rid the body of T cells that may cause the autoimmune deficiency. There is still ongoing research to obtain a rational treatment for the illness that self attacks the immune system and causes muscle weakness.
Copyright © 2002 Vanessa Berumen and Koni Stone
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