Immunology and Serology Case study

CASE 42 Myasthenia Gravis

The immune response turns against the host.

The specific adaptive immune response can, in rare instances, be mounted against self antigens and cause autoimmune disease. Injury to body tissues can result from antibodies directed against cell-surface or extracellular-matrix molecules, from antibodies bound to circulating molecules that deposit as immune complexes, or from clones of T cells that react with self antigens. A special class of autoimmune disease is caused by autoantibodies against cell­ surface receptors (Fig. 42.1). Graves' disease and myasthenia gravis are two well-studied examples . Graves' disease is caused by autoantibodies against the receptor on thyroid cells for thyroid-stimulating hormone (TSH), secreted by the pituitary gland. In this disease, autoantibody binds to the TSH recep­ tor; like TSH, it stimulates the thyroid gland to produce thyroid hormones. In myasthenia gravis, the opposite effect is observed: antibodies against the acetylcholine receptor at the neuromuscular junction impede the binding of acetylcholine and stimulate internalization of the receptor, thereby block­ ing the t ransmission of nerve impulses by acetylcholine (Fig. 42.2). In addi­ tion, the presence of autoantibodies at the neuromuscular junction initiates complement-mediated lysis ofthe muscle endplate and damages the muscle membrane.

Myasthenia gravis means severe (gravis) muscle (my) weakness (asthenia). This disease was first identified as an autoimmune disease when an immun­ ologist immunized rabbits with purified acetylcholine receptors to obtain antibodies against this receptor. He noticed that the rabbits developed floppy ears, like the droopy eyelids (ptosis) that are the most characteristic symptom of myasthenia gravis in humans. Subsequently, patients with this disease were found to have antibodies against the acetycholine receptor. In addition, pregnant women with myasthenia gravis transfer the disease to their newborn infants. As IgG is the only maternal serum protein that crosses the placenta fro m mother to fetus, neonatal myasthenia gravis is clear evidence that myasthenia gravis is caused by an anti-IgG antibody. More recently, patients with myasthenia gravis have been identified who have autoantibodies against muscle-specific kinase (MUSK) rather than the acetylcholine receptor. MUSK is a tyrosine kinase receptor involved in clustering acetylcholine receptors; therefore, these autoantibodies also inhibit signaling through the neuromuscular junction.

Topics bearing on this case:

Humoral autoimmunity

Transfer of maternal antibodies

Mechanisms for breaking tolerance

This case was prepared by RaifGeha , MD, in collaboration with Janet Chou, MD.

~ Case 42: Myasthenia Gravis

Fig. 42.1 Autoimmune diseases caused by antibody against surface or matrix antigens. These are known as type II autoimmune diseases. Damage by IgE-mediated responses (type I) does not occur in autoimmune disease. In most type II diseases, autoantibodies bind to the cell surface or extracellular matrix and target them for destruction by phagocytes (often with the help of complement) and/ or natural killer cells. A special class of autoimmune diseases is caused by autoantibodies that bind cellular receptors and either stimulate or block their normal function. Immune-complex disease (type III) is discuss ed in Case 37. T cell-mediated disease (type IV) is discussed in Cases 36, 40, and 53.

Normal neuromuscular 'unction

••••••• acetylcholine receptors

no Na+ influx Na+ influx ~ +

muscle relaxed muscle contraction

Myasthenia gravis

w @ acetylcholine

receptors internalized no Na- influx and degraded no muscle contraction

Some common type II autoimmune diseases caused by antibody against surface or matrix antigens

Syndrome Autoantigen Consequence

Autoimmune hemolytic anemia (see Case 41)

Rh blood group antigens, Destruction 01 red blood cells

by complement and I antigen

phagocytes, anemia

Autoimmune thrombocytopenic purpura

Platelet integrin

I Abnormal bleeding

Gpll b: llia I

Goodpasture's syndrome Noncollagenous domain 01 Glomerulonephritis

basement membrane Pulmonary hemorrhagecollagen type IV

Pemphigus vulgaris (see Case 43)

Epidermal cadherin II Blisteri ng 01 skin I

Graves' disease Thyroid-stimulating hormone

II Hyperthyroidism

receptor I Myasthenia gravis Acetylcholine receptor III Progressive weakness I Insulin-resistant diabetes Insulin receptor (antagonist) II I Hyperglycemia, ketoacidosis I Hypoglycemia Insulin receptor (agonist) II Hypoglycemia I

The case of Mr Weld: from floppy ea rs to droopy eyelids.

Mr Weld, a 71-year-old retired engineer, had been in good health and active all his life. He developed double vision (diplopia). Initially, he did not want to seek medical attention because the double vision sometimes improved spontaneously. However, it gradually worsened over the course of 4 months and he finally scheduled an appoint­ ment with his physician.

On examination, the doctor noticed that Mr Weld had ptOSis of both eyeUds so that they covered the upper third of the Irises of his eyes. When the doctor asked Mr Weld to look to the right and then to the left, he noticed limitations in the ocular movements of both eyes, as shown in Fig. 42.3.

The remainder of the neurological examination was normal. No other muscle weak­ ness was fo und during the examination.

Fig. 42.2 Autoantibodies against the ac etylcholine recepto r weaken the recepti on of the signal from nerve ends that cause t he muscle cell to contract. At the neuromuscular junction, acetylcholine is released from stimulated neurons and binds to acetylcholine receptors, triggering muscle contraction . The acetylcholine is destroyed rapidly by the enzyme acetylcholinesterase after release. In myasthenia gravis, autoantibodies against the acetylcholine receptor induce its endocytosis and degradation, and prevent muscles from responding to neuronal impulses .

Case 42 : Myasthenia Gravis ~

A radiological examination of the chest was performed, and it was norm al. There was no evidence In the radiograph of enlargement of the thymus gland. A blood sam ple was taken from Mr Weld, and his serum was tested for antibodies against the acetyl­ choline receptor. The serum contained 6.B un its of antibody against the acetyl cho­ line receptor (normal less than 0.5 units). Mr Weld was told to take pyridostigmine, an in hibitor of cholinesterase. His dou ble vis ion improved steadily but he developed diarrhea from the pyridostigmine, and this limited th e amount he could take.

Three years later, Mr Weld developed a severe respiratory infection. Soon afterward, his ptosis became so severe that he had to lift his eyelids by taping them with adhe­ sive tape. His diplopia recurred an d his speech became indisti nct. He developed dif­ ficulty in chewing and swallowing food. He could only tolerate a diet of soft food and it would take him several hours to finis h a meal.

On examination the neurologist noted that Mr Weld now had weakness of the facial muscles and the tongue, and the abnormality in ocular movements again became apparent. Because of the diarrhea Mr Weld was only able to tolerate one-quarter of the prescribed dose of pyridostigmlne. He also developed difficulty in breathing. His vital capacity (the amount of air he could exhale in one deep breath) was low, at 3.5 liters.

He was admitted to hospital and treated with azathiopri ne. Thereafter he showed steady improvement. His pto sis and diplopia improved re markably and he was able to eat normally. His vital capacity returned to norm al and was measured to be 5.1 liters.

Myasthenia gravis.

The defining characteristic of myasthenia gravis is a fluctuating weakness that worsens with activity and improves with rest. Normally, repetitive nerve stimulation during sustained physical activity results in the release of decreased amounts of acetylcholine with each successive stimulus; however, enough acetylcholine is released to achieve the desired muscle strength in he althy individuals. In contrast, patients with myasthenia gravis have fewer functional acetylcholine receptors as a result of the presence of anti-receptor autoantibodies. During repetitive nerve stimulation, the combination of fewer functional acetylcholine receptors with the physiologic decrease in neurotransmitter release results in muscular weakness.

Mr Weld experienced a common type of myasthenia gravis, called the oculo­ bulbar form because it primarily affects the muscles of the eye. Older patients tend to have more generalized muscle weakness as well, and often have autoantibodies against muscle proteins in addition to anti-acetylcholine receptor antibodies. In very severe cases, difficulty in swallovving can cause the aspiration of food particles into the lung and impaired breathing, which may be fatal. Plasmapheresis (the filtration and removal of plasma from whole blood) can be used to remove the autoantibodies and treat a myasthenic crisis.

Gaze to right Straight ahead Gaze to left Fig . 42.3 Diagram of oc ular movement limitation.

~ Case 42: Myasthenia Gravis

Azathioprine

converSion~H In VIVO N

=i> N I N N

6-mercaptopurine

azathioprine

Fig. 42.4 The structure of azathioprine and its active product, mercaptopu rin e.

In yo unger people. the disease presents most often with weakness in the eye muscles. Chest radiographs of yo unger people with myasthenia gravis fre­ quently reveal enlargement of the thymus gland; however. an association between myasthenia gravis and tumors of the thymus (thymomas) is more common in adults. Early removal of the thymus gland (thymectomy). par­ ticularly in those with thymomas. may lead to symptomatic improvement. Although the definitive mechanisms underlying the association between thy­ momas and myasthenia gravis are not yet identified, it h as been hypothesized that neoplastic epithelial cells in the thymoma express selflike epitopes resem­ bling proteins such as the acetylcholine receptor. In addition, thymomas have been found to have decreased expression of the autoimmune regulator gene (AJRE; see Case 17) and smaller numbers of regulatory T cells, indicating that an abnormal microenvironment within the thymomas results in impaired negative selection. However. as the occurrence of myasthenia gravis does not correlate with decreased expression of AIRE in the thymus, there are still unidentified factors that influence the development of myasthenia gravis in patients with thymomas.

Questions.

mNewborn infants of mothers with myasthe nia gravis exhibit symptom s of myasthenia gravis at birth. How long would the disease be likely to last in these infants?

Ls Pyridostigmine is an idea l drug for the treatd'lent of myasthenia gravis. It inhibits the enzyme cholinesterase, which normally cleaves and inactivates acetylcholine. In this way, pyridostigmine prolongs the biological half- life of acetylcholine. Unfortunately, it also causes diarrhea by increasing the amount of acetylcholine in the intestine. Acetylch oline binds to the muscarinic receptors in the intestine and increases intestinal motility. Becau se he could not tolerate full thera peutic doses of pyridostigmine and was getting worse, Mr Weld was given aza thioprine (Fig. 42.4) and showed marked improvement. What did t he azat hioprine do? What would concern you about prolonged use of this drug?

~ Mr Weld had a severe rela pse in his disease after a respiratory infection. Many autoimmune diseases seem to be triggered by infection, and relapses in autoim mune diseases frequently follow an infection. Can you explain how this might happen?