Page 938 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 67 Autoimmune Peripheral Neuropathies 905

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Cytokines and chemokines released by the activated T cells or IgM paraproteinemic polyneuropathies, as discussed later.
complement activation may increase capillary permeability and Anti-GQ1b IgG antibodies are also found in postinfectious
facilitate transmigration of additional macrophages or T cells. ophthalmoplegias as well as in GBS with ophthalmoplegia, but
When the demyelination is extensive or chronic, it is followed not in those without ophthalmoplegia or other autoimmune
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by axonal degeneration. The degree and effectiveness of remy- conditions. Of interest, anti-GQ1b antibody binds the paranodal
elination and axonal regeneration dictate the degree of clinical regions of oculomotor nerves III, IV, and VI, suggesting that
recovery. damage to these regions blocks impulse propagation at the nodes
The role for a T cell–mediated process in GBS is mostly derived of Ranvier, resulting in a conduction block that is characteristic
by analogy to the animal model of EAN, which resembles GBS in for GBS. Many patients with antibodies to GQ1b also have
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both its pathology and its clinical course. Animals sensitized to antibodies to GD1a.
whole human nerve or to various myelin proteins, such as P0, P2, The reasons for different clinical syndromes in connection
and the neutral glycolipid galactocerebroside, develop segmental with specific gangliosides remains unclear, but distribution,
demyelination with mononuclear cell infiltrates consisting of accessibility, and density or configuration of gangliosides at
macrophages and T cells. In EAN, T cells are sensitized against different sites may be critical factors. For example, there is more
myelin and can passively transfer the disease to healthy animals. GM1 in ventral roots than in dorsal roots, hence the predomi-
Increased levels of interleukin-2 (IL-2) and soluble IL-2 receptors nantly motor neuropathy seen with anti-GM1 antibodies; there
are noted in serum during the acute phase of GBS, suggesting is also more GQ1b in the ocular motor nerves, which may explain
ongoing T-cell activation. Further, lymphocytes from patients the involvement of eyes in MFS. How these antibodies induce
with GBS exert myelinotoxic activity when applied to cultures disease, however, remains unclear. Current evidence suggests
of myelinated axons. that antibodies against different acidic glycolipids or sulfatides
may be related to different viral or bacterial antecedent factors,
Humoral Factors and Antiganglioside Antibodies as discussed below.
There is much stronger evidence that circulating serum factors
are responsible for GBS. On clinical grounds, this is supported Molecular Mimicry: Relationship Between
by the beneficial effect of plasmapheresis, presumably by removing Campylobacter jejuni and Gangliosides in Acute Motor
putative antibodies. On laboratory grounds, it is supported by Axonal Neuropathy
the variety of autoantibodies detected in patients’ sera. Serum Antecedent infection with C. jejuni has been commonly
from the acute phase of GBS can demyelinate rodent dorsal root associated with AMAN. The strain of C. jejuni associated with
ganglionic extracts in a complement-dependent manner. Fur- AMAN (Penner D: 19 serogroup) is, however, different from
thermore, GBS serum injected into rat sciatic nerves causes those causing common enteritis and is more likely to have the
demyelination and conduction block. Complement-fixing IgM genes for enzymes that synthesize sialic acid in the bacterial wall
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antibodies against a human peripheral nerve myelin glycolipid mimicking ganglioside GM1, GD1a, or GQ1b. These patients
that contains carbohydrate epitopes as well as high-titer antibodies have a higher incidence of anti-GM1 antibodies, which suggests
against various sulfated or acidic glycosphingolipids are present cross-reactivity between epitopes in the lipooligosaccharide in
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in several patients with GBS. 1-7 the bacterial wall and the ganglioside. Further, injection of
Gangliosides are present in all tissues but are especially lipooligosaccharides extracted from C. jejuni into rabbits has
abundant in the nervous system. Their lipid portion lies in the been shown to induce acute neuropathy, with development of
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cell membrane, and their signature sugar residues are exposed anti-GM1 antibodies identical to those found in AMAN. In
at the extracellular surface bearing one or more sialic acid addition, immunization of mice with these lipooligosaccharides
molecules, such as one sialic acid ganglioside (GM1), two (GD1a), generates a monoclonal antibody (mAb) that reacts with GM1
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three (GT1a), or four (GQ1b). Although they do not form a and binds to human peripheral nerve. This GM1 mAb as well as
common “GBS antigen,” different gangliosides are involved in the anti-GM1 IgG extracted from patients with GBS block muscle
different GBS subtypes. They are of pathogenic relevance because action potentials in muscle–spinal cord coculture. Carbohydrate
immunization of rabbits with GM1 and GD1b induces acute mimicry between the bacterial lipooligosaccharide and human
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neuropathy with histological features of AMAN. Their patho- GM1 is therefore an important cause of AMAN. Because C.
genicity was also confirmed by an inadvertent experiment in jejuni is a common cause of a diarrheal illness worldwide, and
humans who had received ganglioside injections for various diarrhea has been an antecedent event in up to 50% of patients
maladies and developed AMAN accompanied by anti-GM1 with GBS, Campylobacter appears to trigger the disease in many
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antibodies. Additionally, antibodies to GQ1b or GD1a cause patients, especially in certain parts of the world. Isolation of
conduction block at the motor nerve terminals in a preparation Campylobacter from stools early in acute GBS varies from 44% to
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of mouse phrenic nerve. Similarly, antibodies to GalNAc-Gd1a 88% of patients, and IgG or IgM Campylobacter-specific antibody
from a patient with AMAN blocked neuromuscular transmission titers are seen in a higher percentage (36%) of patients with GBS
in a mouse spinal cord muscle coculture system. than in controls (10%).
IgG antibodies that react with GM1, GD1a, GalNAc-GD1a, Molecular mimicry may not be limited to C. jejuni because
and GM1b are found in 80% of cases with the motor axonal GM1 and GQ1b epitopes are also found in the bacteria wall of
form of GBS (AMAN and AMSAN), but in the most common Hemophilus influenzae, which is also a triggering factor in GBS.
GBS subtype, AIDP, ganglioside-specific antibodies are uncom- GBS triggered by CMV infection has been also associated with
mon. Among gangliosides, the one that clearly correlates with the presence of IgM anti-GM2 antibodies. Another potential
a specific clinical syndrome is the GQ1b, which is specifically factor for molecular mimicry is M. pneumoniae, which precedes
associated with the MFS variant with IgG anti-GQ1b antibodies GBS in 5% of cases and is known to stimulate antibodies against
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present in >90% of these patients In contrast, anti-GQ1b human carbohydrate antigens, including galactocerebroside, the
antibodies of the IgM class can be found in patients with chronic main glycolipid antigen in peripheral nerves. 1-7