Page 913 - Clinical Immunology_ Principles and Practice ( PDFDrive )

882 PARt SEVEN Organ-Specific Inflammatory Disease

Anti-AChR antibodies are detected in 85–90% of MG patients decrease in anti-AChR antibody levels often accompanies
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and are responsible for the impaired neuromuscular transmission. deterioration or improvement, respectively, in clinical activity.
There are several lines of evidence to support this contention. As the quantity of anti-AChR antibodies produced does
Immunoglobulin G (IgG), along with C3 and the terminal attack not fully explain disease severity, studies have also focused
complex (C5–C9), is deposited at AChR-containing areas of the on qualitative differences in these antibodies among different
postsynaptic membrane, and anti-AChR/AChR complexes can patients. These studies, however, have not been able to distin-
be extracted from the muscles of patients with MG. Transfer of guish properties of anti-AChR antibodies that lead to greater
myasthenic serum from mother to fetus, or from human to pathogenicity. Differences in specificity and avidity of binding
mouse, results in symptoms or signs of myasthenia in the recipient. to AChR have not been associated with particular functional
Plasmapheresis, which decreases anti-AChR antibody levels, is effects or disease severity. Anti-AChR antibodies that bind or
associated with clinical improvement. compete for the same region of AChR can have different functional
effects (see anti-AChR blocking antibody discussion). Anti-AChR
Properties of Anti-AChR Antibodies and antibodies show extensive heterogeneity by isoelectric focusing,
but this characteristic also does not correlate with pathogenic
Characterization of B-Cell Epitopes potential.
Anti-AChR antibodies are produced by a small subset of B cells Patients previously classified as seronegative have been found
in affected people. The frequency of IgG-producing AChR-specific to have low-affinity AChR-specific IgG antibodies when their
peripheral blood mononuclear cells is estimated to be 1 in sera were tested with very sensitive assays that rely on tissue
6,7
15 000–70 000. IgG anti-AChR–secreting cells are also found in substrates on which the receptors are aggregated. Antibody
the peripheral blood of healthy volunteers, albeit in much lower binding was facilitated by the high concentrations of AChRs,
numbers. The proportion of immunoglobulin producing AChR- which compensate for the low affinity of the autoantibodies.
specific B cells or plasma cells is greater in the germinal centers Like the anti-AChR antibodies in classic anti-AChR antibody-
of hyperplastic thymuses, but still only 1 in 1000–10 000 antibod- positive MG, these antibodies belong largely to the IgG1 subclass.
ies produced is AChR specific. Anti-AChR antibodies are pre- Like the conventional antibodies, the low-affinity antibodies also
dominantly IgG1 and IgG3, but IgG2 and IgG4 isotypes have bind complement.
also been found. IgA and IgM anti-AChR antibodies are present As noted above, 10–15% of MG patients are persistently
in some patients, but never in the absence of IgG anti-AChR antibody negative. Approximately 50% of these patients have
antibodies. The IgA and IgM anti-AChR antibodies tend to appear been discovered to have serum IgG antibodies specific for muscle-
7,8
in patients whose disease is of longer duration and greater severity specific tyrosine kinase (MuSK). This skeletal muscle receptor
and in association with high IgG anti-AChR titers. tyrosine kinase is activated by agrin and is critical for formation
The pathogenic anti-AChR antibodies in MG are thought to of the neuromuscular junction. Originally, anti-MuSK antibodies
be directed to conformationally dependent structures. Immuniza- were found in patients with marked facial and bulbar weakness,
tion of animals with irreversibly denatured AChR leads to the including tongue weakness and respiratory involvement with
formation of anti-AChR antibodies capable of binding to native relative sparing of upper- and lower-extremity muscles. Oph-
AChR, but the antibodies are not capable of causing disease. thalmoparesis was also seen but was not a first symptom in at
This observation indicates that conformationally dependent least one series of patients. Subsequently, it has become apparent
epitope(s) are important in the induction of disease. Many of that patients with anti-MuSK antibodies can also have a more
the anti-AChR antibodies are directed against the α subunit, traditional clinical phenotype similar to that seen with anti-AChR
particularly to a small region on the extracellular portion referred patients. Patients often respond poorly to anticholinesterase
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to as the main immunogenic region (see Fig. 65.2). Approximately agents and benefit greatly from plasmapheresis but only modestly
60% of the anti-AChR antibodies are directed against this region, from intravenous immunoglobulin (IVIG). They typically lack
which encompasses a set of overlapping epitopes clustered around thymus pathology and, not surprisingly, thymectomy is not
5
amino acids 67–76 of the α subunit. The reason for the pre- typically beneficial. Most anti-MuSK antibodies are of the
dominant role of the α chain in the antibody response in non–complement-fixing IgG4 isotype. Anti-MuSK antibodies
myasthenia is not known. Not all disease-producing antibodies do not cause destruction of the muscle endplate, as might be
in humans or rats appear to be directed to this region. Many expected because of their inability to activate the classical comple-
patients also have antibodies recognizing the γ-containing ment pathway and reduced capacity to bind activating Fcγ
embryonic form of AChR. This observation has spawned specula- receptors on monocytes and macrophages. However, they have
tion about a nonmuscle source of sensitization. been shown to affect AChR clustering on cultured myotubes.
The clinical relevance of these autoantibodies is underscored by
Anti-AChR Antibody Levels and Relationship to the appearance of a myasthenic illness in animals either immu-
nized with MuSK or infused with serum antibodies from patients
Disease Activity with anti-MuSK antibody–associated MG.
The relationship of anti-AChR antibody and disease activity in IgG antibodies specific for lipoprotein-related protein 4 (LRP4)
MG is complicated. In general, serum levels of anti-AChR antibody have also recently been discovered in the sera of patients with
7,9
or anti-AChR/AChR complexes correlate poorly with disease anti-AChR antibody–negative MG. LRP4 is an important
severity. Among patients within one clinical grade, anti-AChR component of the neuromuscular junction, which serves as a
antibody levels can vary by several orders of magnitude. In receptor for agrin and which is required for agrin-induced
addition, approximately 10–15% of patients with clinical MG activation of MuSK and AChR clustering. The prevalence of
have no anti-AChR antibody by standard assays. Anti-AChR reactivity to LRP4 varied from 2–50% of patients who are negative
antibodies are more likely to be present if the disease is generalized for anti-AChR and MuSK antibodies (double seronegative), with
or severe. In addition, in an individual patient an increase or the differences possibly being related to geography or ethnicity.