Page 914 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPtER 65 Myasthenia Gravis 883

Anti-LRP4 antibodies were found in the sera of 3% of patients Complement-Mediated Damage
with anti-MuSK antibodies in one study but otherwise were The critical problem in MG is the anti-AChR antibody–mediated
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limited to double-seronegative (anti-AChR /anti-MUSK ) patients. reduction in the number of nAChRs at the myoneural junction.
Anti-LRP4 antibodies were not present in the sera of a large There are several possible mechanisms by which the anti-AChR
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number of patients with other neurological diseases with the antibodies could lead to impaired neuromuscular transmission.
exception of neuromyelitis optica spectrum disorder, where 12.5% Ultramicroscopic studies show marked destructive changes in
of patients had anti-LRP4 antibodies. If larger studies demonstrate some endplates, particularly at the peaks of the postsynaptic
that anti-LRP4 antibodies are found in patients with MG but folds, where AChR is usually present in the greatest concentration.
without anti-AChR or MuSK antibodies and are rare in other The architecture of the muscle endplate is simplified, with loss
neurological disorders, this test could become important in the of junctional folds and widening of the synaptic cleft that contains
diagnosis of MG. membrane debris. C3, C9, and the membrane attack complex
MG sera also contain antibodies reacting with the ryanodine are deposited at the muscle endplate, suggesting a role for
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receptor. These receptors, which are critically involved in muscle complement in membrane destruction. Indeed, in many patients,
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contraction, are Ca release channels located in the sarcoplasmic anti-AChR antibodies can fix complement in vitro when bound
reticulum of striated muscles. Antibodies to ryanodine receptors to skeletal muscle and can damage cultured rat myotubes with
are found in 50% of patients with MG who have thymoma, a resultant decrease in AChR content.
and patients with high levels have a worse prognosis than do Although antibody-directed, complement-mediated destruc-
antibody-negative patients with MG who have thymoma. In vitro tion is important in the pathophysiology of MG, it is not the
studies have suggested a pathogenic role for these autoantibodies entire story. The rapid clinical improvement in MG following
in MG. certain therapeutic interventions and the lack of destructive
Antirapsyn antibodies have been detected in a small subset changes in many neuromuscular junctions of symptomatic areas
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of patients with MG. Seropositive patients with MG are indis- despite prominent immunoglobulin deposition suggest that a
tinguishable from seronegative patients with regard to clinical more readily reversible process is also likely to be involved in
and laboratory features of disease. The presence of antirapsyn the neuromuscular block.
is not specific for MG, having been detected in the sera of an
occasional patient with MS and a majority of the patients with Acceleration of AChR Degradation
lupus tested. In vitro and in vivo studies have shown that anti-AChR antibodies
Antiagrin antibodies have recently been reported, often in can accelerate the rate of degradation of extrajunctional and
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MG patients with anti-AChR or anti-MuSK antibodies and junctional receptors, respectively. This reaction is complement
occasionally in patients with MG who are “triple seronegative” independent and results from the endocytosis of AChRs via
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(AChR MuSK LRP4 ). Studies of larger numbers of patients shallow depressions, presumably clathrin-coated pits. Other
will be necessary to determine the prevalence of antiagrin antibod- membrane receptors are not affected. Both stable and rapidly
ies in triple seronegative MG patients and their degree of specific- turned-over receptors appear to be affected, thereby explaining
ity for MG. the greater than expected antibody-mediated loss of AChRs
Patients with MG associated with thymoma show distinct observed at neuromuscular junctions. The reaction requires
patterns of antibody production. Almost all patients with cross-linking of adjacent AChRs, as it can be mediated by
thymoma are anti-AChR antibody positive, and most produce F(ab′) 2 fragments, but not Fab fragments, of anti-AChR anti-
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antistriational antibodies. These latter antibodies react with titin, bodies. The effect of antibody on the synthesis of new AChR is
a giant filamentous protein of striated muscle. Titin filaments controversial.
are involved in muscle assembly and contribute to the muscle’s
ability to recoil following stimulation. Such antistriational Receptor Blockade
antibodies are also found in approximately 50% of the sera of The inhibition of ACh binding has been assessed by studying
older patients with MG who have thymic atrophy but not the effects of MG serum on the binding of the neurotoxin
thymoma; however, they are not frequently detected in patients α-bungarotoxin to AChRs. Such blocking antibodies are found
with early-onset disease and thymic hyperplasia. The finding of in a variable number of MG sera. Blockade has been generally
antistriational antibodies in a patient with MG who is less than attributed to steric hindrance of the ligand-binding site, rather
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40 years old strongly suggests the presence of thymoma. There direct binding to the ACh-binding site. The importance of
is no evidence that antistriational antibodies are involved in these antibodies in the pathophysiology of MG remains unclear.
muscle weakness. However, in one study the functional ability of an individual
serum to accelerate degradation and cause blockade of AChRs
Pathogenic Effects of Anti-AChR Antibodies paralleled most closely the clinical status of the patient. The in
vivo significance of such antibodies has also been demonstrated
KEY CONCEPtS by passive transfer of certain rat monoclonal anti-AChR antibodies
into chicks. Complete paralysis was observed within 1 hour of
• Effects of anti–acetylcholine receptor (AChR) antibodies in myasthenia
gravis pathology the transfer, presumably before there was time for complement-
• Reduced number of receptors mediated damage. It has been reasoned that in patients with
• Widening of the synaptic cleft MG, such blocking antibodies could further diminish synaptic
• Distorted geometry of the synaptic membrane function already decreased owing to complement-mediated
• Mechanism of damage damage or accelerated receptor degradation. This could result
• Complement-dependent damage to muscle endplate in acute clinical deterioration or a rapid clinical improvement
• Enhanced rate of AChR degradation
• Block cholinergic binding sites after plasmapheresis, before the repair of damaged membrane
and regeneration of new AChRs.