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Chapter: Medical Immunology: Organ-Specific Autoimmune Diseases

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Autoimmune Diseases of the Neuromuscular Systems

Myasthenia gravis (MG) is a chronic autoimmune disease caused by a disorder of neuro-muscular transmission.

AUTOIMMUNE DISEASES OF THE NEUROMUSCULAR SYSTEMS

A. Myasthenia Gravis

Myasthenia gravis (MG) is a chronic autoimmune disease caused by a disorder of neuro-muscular transmission. Two main pathological findings are characteristic of myasthenia gravis: (1) the production of antinicotinic acetylcholine receptor antibodies, detected in 85–90% of the patients, and (2) a 70–90% reduction in the number of acetylcholine recep-tors in the neuromuscular junctions.

The reduction in the number of acetylcholine receptors is believed to be due to their destruction by the immune system. This could be a consequence of direct cytotoxicity by complement, opsonization, ADCC, activation of phagocytic cells, or T-cell–mediated cy-totoxicity. Cell-mediated immunity has been suggested as playing the major pathogenic role due to the lymphocytic infiltration often seen at the neuromuscular junction level, and because blast transformation can be achieved in vitro by stimulating T lymphocytes iso-lated from myasthenia gravis patients with acetylcholine receptor protein. However, the lymphocytic infiltrates are not detected in a significant number of patients clinically indis-tinguishable from those with infiltrates.

Thymic abnormalities are frequent in myasthenia gravis. Seventy percent of the pa-tients have increased numbers of B-cell germinal centers within the thymus, which some authors have suggested to be the source of autoantibodies. About 10% of the patients de-velop malignant tumors of the thymus (thymomas).

The symptoms of myasthenia gravis are increased muscular fatigue and weakness, especially becoming evident with exercise. Weakness is usually first detected in extraocu-lar muscles, resulting in diplopia or ptosis. The face, tongue, and upper extremities are also frequently involved. Skeletal muscle involvement is usually proximal. The disease is usu-ally marked by spontaneous remission periods. The diagnosis is confirmed by the finding of anti–acetylcholine receptor antibodies.

Treatment is based on the administration of acetylcholinesterase inhibitors, such as neostigmine and pyridostigmine (Mestinon), in combination with atropine. Virtually com-plete or partial relief of symptoms can be achieved with medical treatment in a significant number of patients. Thymectomy is undertaken with improvement in 75% of patients and with remission in the other 25%, although it may be several months after surgery when clin-ical improvement starts to be obvious. Those patients that do not respond to either form of therapy may be treated with glucocorticoids, which can induce clinical improvement in 60–100% of patients, depending on the series. Plasmapheresis and thoracic duct drainage can also be effective by removing circulating antibodies. However, the benefits of this type of therapy are very short-lived, unless the synthesis of autoantibodies is curtailed with glu-cocorticoids or immunosuppressive drugs.

B. Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease that results from the destruction of the myelin sheath in the central nervous system. MS lesions observed at autopsy are charac-terized by areas of myelin loss surrounding small veins in the deep white matter. A perivenous cuff of inflammatory cells is associated to acute lesions but is absent from old lesions where gliosis replaces myelin and the oligodendrocytes that produce and support it.

The inflammatory cells found in MS lesions are a mixture of T and B lymphocytes and macrophages (known as microglial cells in the central nervous system). The T lym-phocytes are mostly CD4+ , express IL-2R, and secrete IL-2 and IFN-γ . A smaller pro-portion of CD4+ lymphocytes produce IL-4 and IL-10, suggesting that TH1 activity pre-dominates over TH 2 activity. A few CD8+ lymphocytes are also present in the lesions. Several lines of evidence support the importance of T lymphocytes in the pathogenesis of MS:

1.           Experimental allergic encephalomyelitis (EAE), the best animal model for MS, is transferred by CD4+ T lymphocytes but not by serum. Injection of T-cell clones specific for the immunodominant epitope of myelin basic protein (MBP) derived from sick animals is the most efficient protocol to transmit the disease to healthy animals.

 

2.           MBP-specific CD4 clones can be established from lymphocytes isolated from the spinal fluid of MS patients. These clones generally recognize an epitope lo-cated at amino acids 87–99, but clones specific for other groups of 12 amino acids in the MBP molecule and to other myelin components, such as proteolipid protein and myelin-associated glycoprotein, are also expanded. Therefore, many different T-cell clones with different TcRs appear to be involved in the autoim-mune response.

 

MS occurs mostly in young adults between the ages of 16 and 40 years with a 3-to-1 female predominance. It is more frequent in northern latitudes. In the United States it is more prevalent north of the Mason-Dixon line. In Europe, Scandinavian countries and Scotland have the highest incidence.

As in many other autoimmune diseases, the role of genetic factors was suggested by the finding that some HLA alleles are overpresented among MS patients, particularly HLA-DR2 and HLA-DQ1, which are found in up to 70% of the patients. These class II MHC molecules are likely to be involved in peptide presentation to CD4+ lymphocytes. It has been demonstrated that normal individuals have myelin-specific T cells in their blood, suggesting that MBP-specific T lymphocytes are not deleted during differentia-tion, probably because myelin antigens are not expressed in the thymus. However, many of the normal individuals with myelin-specific T cells in their blood do not develop MS, even when they are HLA-DR2. Thus, in normal individuals these clones remain in a state of anergy or tolerance.

Very little is known about what activates previously unreactive MBP-specific clones and other autoreactive clones involved in MS. Viral infections have been proposed as the trigger for MS, perhaps as a consequence of molecular mimicry. In fact, many viral anti-gens from corona viruses, Epstein-Barr virus, hepatitis B virus, herpes simplex virus, and others have sequences identical to MBP epitopes. Consequently, the immune response to the virus would activate cross-reactive sets of T cells recognizing peptides derived from myelin basic protein. Another possibility is that a viral superantigen could inadvertently ac-tivate MBP-specific T lymphocytes and cause their expansion.

In any case, autoreactive T lymphocytes, by themselves, are incapable of damaging the myelin sheath. However, autoreactive T lymphocytes secrete interferon-γ, which acti-vates the macrophages found in the lesions. Some of these activated macrophages are seen attached to the myelin sheath, which they actively strip and phagocytose, becoming lipid laden. In addition, once they have engulfed myelin, they present myelin-derived antigens to T cells, contributing to the perpetuation of the immune reaction.

The clinical manifestations of MS are protean and often include visual abnormalities, abnormal reflexes, and sensory and motor abnormalities. This variety of manifestations re-flects the fact that lesions can occur anywhere in the white matter of the brain, cerebellum, pons, or spinal cord at any time. The multiplicity and progression (both in number and ex-tent) of MS lesions is the major clinical diagnostic criterion for this disease.

The course of MS is characterized by relapses and remissions in about 60% of the pa-tients, but each new attack may bring additional deficits when the myelin sheaths are in-completely or imperfectly replaced. Frequently after 5–15 years of evolution these patients enter a phase of relentless chronic progression and become wheelchair bound, bedridden, and totally dependent for all activities of daily living. In the remaining 40% of the cases, MS is chronically progressive from the onset.

Confirmation of a diagnosis of MS is not easy. Magnetic resonance imaging (MRI) is an invaluable diagnostic tool. It demonstrates the breakdown of the blood-brain barrier that is always present at the beginning of a new attack and can also document the spatial dissemination of MS lesions. However, MRI abnormalities alone are not diagnostic, be-cause several other diseases can be associated with similar abnormalities. Spinal fluid elec-trophoresis is another valuable diagnostic test, based on the detection of oligoclonal bands (multiple electrophoretically homogeneous bands) of IgG in the spinal fluid. It is not spe-cific for multiple sclerosis, because this can be observed in other neurological illnesses as-sociated with an intrathecal immune response.

The present treatment of MS is not satisfactory. Glucocorticoids have been used ex-tensively during the past 20 years. Usually high doses are required (to seal the blood-brain barrier), not suitable for long-term administration. In addition, glucocorticoid administra-tion does not affect significantly disease progression.

Recombinant interferon β1b and the closely related interferon β1a are recommended for the treatment of relapsing-remitting MS. These interferons act by downregulating IFN-γ production and class II expression on antigen-presenting cells. Interferon β administra-tion has been shown to slow down the progression of MS.

Copolymer-1 (COP-1, Copaxone), a synthetic basic copolymer of four amino acids designed to resemble MBP epitopes, without the ability to induce T-cell proliferation, has been recently introduced with some success. Administration of this product reduces the fre-quency of relapses of MS, lessens disease activity as measured by MRI, and can induce neurological improvement. Two mechanisms of action have been proposed for Copaxone based on studies carried out in experimental animals:

1.           Cop 1 is a TCR antagonist of the immunodominant 82–100 epitope of MBP, thus turning off the immune response to MBP.

 

2.           Oral Copaxone administration may lead to a tolerant state by downregulating T-cell immune responses to MBP. This effect is supposed to be mediated by IL-10–secreting regulatory T cells.

 

In humans, administration of Copaxone is associated with an elevation of serum IL-10 levels and profound changes in T lymphocyte activity, including suppression of the pro-inflammatory cytokine TNF mRNA, and elevation of the anti-inflammatory cytokines TGF- β and IL-4 mRNA. These results suggest that Copaxone may induce a shift from TH1 to a regulatory T-cell cytokine profile, possibly associated with bystander suppression of the autoreactive immune response.

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