Page 915 - Clinical Immunology_ Principles and Practice ( PDFDrive )

884 PARt SEVEN Organ-Specific Inflammatory Disease

antibody production requires the integrity of the three-
Role of T Cells dimensional structure of the receptor, as immunization with
An overwhelming body of data indicates that anti-AChR antibody denatured AChR elicits antibody production but not disease, even
production in patients with MG and rodents with experimental in susceptible animals. Anti-AChR antibody levels correlate with
autoimmune myasthenia gravis (EAMG) is dependent on the anti-AChR/AChR complexes and with the AChR content of the
activity of CD4 T cells. Researchers have used freshly isolated muscle, but not with clinical disease severity. No characteristic
CD4 T cells, T-cell lines and T-cell clones stimulated with AChR feature distinguishing disease-producing and nonpathogenic
purified from the electric organs of Torpedo californica (T-AChR), autoantibodies has been defined. Antibodies in rats with and
recombinant human AChR, human AChR concentrated on without disease are predominantly of the same immunoglobulin
immunomagnetic beads, and synthetic AChR peptides. Most of isotope and subclass, express similar clonotypic heterogeneity,
the T cells derived from patients with MG have responded to and show similar avidities. The percentage of antibodies that
the complete AChR or the α subunit, but responses to the δ, ε, recognize the native receptor (as opposed to the foreign eel
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and γ subunits have also been demonstrated. Unlike EAMG, receptor immunogen) is low (0.2–2%) but similar between the
a T cell–immunodominant epitope has not been found in humans. symptomatic and the asymptomatic mice. The percentage of
However, T cells from most patients recognize a limited number antibody directed against the main immunogenic region of AChR
of AChR sequences. In an individual patient, T cells reactive is also similar. The antibodies that develop in asymptomatic
with a particular AChR epitope can show limited T-cell receptor animals can bind and cause a decrease in receptor half-life, as
Vβ (TCR Vβ) usage, but the same TCR Vβ usage has not been well as those that develop in paralyzed animals. In fact, EMG
observed for different patients. A range of major histocompat- abnormalities can be demonstrated in mice that appear disease
ibility complex (MHC) class II molecules can present AChR free. An analogous situation in humans may be the high frequency
epitopes. This is not surprising, given the degenerate binding of single fiber EMG abnormalities in asymptomatic family
capabilities of MHC molecules needed to present an extremely members of patients with MG. Importantly, antibodies from
large and diverse group of peptides to the immune system. T affected animals will cause disease in resistant strains, indicating
cells from normal controls respond to some of the same epitopes that disease differences between strains is not caused by differences
to which MG patients’ T cells respond, albeit in smaller numbers in the AChR receptor itself.
and less vigorously. Although EAMG is mediated by autoantibodies, it is a T
cell–dependent process. Examination of T-cell responses in rats
EXPERIMENTAL AUTOIMMUNE and mice has shown that EAMG requires the action of CD4 T
MYASTHENIA GRAVIS cells. These cells recognize immunodominant T-cell epitopes
located on the α subunit. The T-cell responses to the immuno-
The serendipitous discovery that rabbits injected with purified dominant epitope in rats involve a variety of TCRVβ and Jβ
AChR developed not only anti-AChR antibodies but signs gene segments (Chapter 4). However, in susceptible C57BL/6
of MG provided the evidence for the pivotal role of antibodies mice, there is a predominant use of the TCRVβ6 family in the
in this disease and paved the way for the development of an CD4 T-cell response. CD4 T cells in susceptible and resistant
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experimental model of human MG. EAMG has been studied strains recognize different immunodominant AChR α-chain
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in a number of different animal species. It is generally induced epitopes. 17
by immunizing animals with AChR purified from the electric Early reports suggested that AChR-reactive T-cell clones did
organs of T. californica emulsified in adjuvant. Disease can also not fit neatly into T-helper-1 (Th1) and Th2 subsets. However,
be passively transferred by immunoglobulin from affected animals later studies suggested that interferon-γ production by Th1 cells
or from patients with myasthenia. Animals suffer from fatigue, is essential for the development of disease and that IL-4 may
hypoactivity, weight loss, paralysis, difficulty breathing, and subserve a protective role. 16,18 In addition to interferon-γ, tumor
dysphagia; these signs are reversible with anticholinesterases. necrosis factor (TNF)-α, interleukin (IL)-6, IL-12, IL-18, IL-1,
There is a decremental response to repetitive nerve stimulation IL-5, and IL-10 have been reported to promote the development
on electromyography in EAMG as in MG. Anti-AChR antibodies of EAMG. However, a more recent publication indicated that
are present, and most are directed against the main immunogenic C57BL/6 mice genetically deficient in IL-12/IL-23 and IFN-γ are
region (see Fig. 65.2). They are deposited along with complement susceptible to experimental EAMG, suggesting a pathogenic role
at the muscle endplate. Similar to the pathology in humans, of non-Th1 cells. This result led the authors to suggest that
there is simplification of the muscle endplate and a loss of AChR AChR-specific Th17 cells may also contribute to the pathogenesis
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content of muscles in the experimental disease. A major difference of this experimental autoimmune disease. Subsequently, Th17
between the induced rodent models of EAMG and spontaneous cells were, indeed, shown to be important in the pathogenesis
human MG is the absence of thymic pathology in the former. of EAMG. 20
In murine models, there are disease-resistant and disease- The roles of a number of costimulatory factors have also been
susceptible strains. The MHC determines this susceptibility, in investigated in EAMG. CD28/B7 and CD40/CD40L appear to
part, with specific H-2 alleles being associated with susceptibility be required for the development of the primary immune response
or resistance. However, even in the high-responder strains, only to AChR. An interaction between ICOS and B7RP-1 may play
50–70% of immunized animals manifest disease. This lack of an important role in the secondary response and/or in the
concordance remains to be fully explained. Differences in the maintenance of the immune response to this autoantigen.
level of complement activation and the physiological safety factor
of neuromuscular transmission may partly account for the THE THYMUS IN MYASTHENIA GRAVIS
variability in disease expression.
Most immunized animals demonstrate anti-AChR antibodies, Several lines of evidence have suggested that the thymus is directly
whether or not they develop EAMG. Induction of pathogenic linked to the pathogenesis of MG.