Page 916 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPtER 65 Myasthenia Gravis 885

KEY CONCEPtS including the α subunit. Additional factors found uniquely in
Pathogenic Roles of the Thymus in hyperplastic MG thymus include increased expression of che-
mokines that attract immigrant CD4 T and B cells (CXCL13,
Myasthenia Gravis (MG) CCL21); the presence of nAChR-reactive B and CD4 T cells;
• Pathological cytokines that can facilitate B-cell activation, differentiation, and
• 65–75% of patients with MG have follicular hyperplasia with germinal survival (IL1β, IL6, APRIL, BAFF); anti-AChR antibody–secreting
+
+
centers plasma cells; and possibly decreased CD4 CD25 T regulatory
• 10% have thymoma cell function. 21-24
• Clinical As yet, it is not known whether or how such perturbations
• Improvement following thymectomy of the thymus lead to a breach in self-tolerance and the induction
• Immunological
• Acetylcholine receptor (AChR) subunits expressed on myoid cells of anti-AChR antibodies, although there is mounting evidence
and thymic epithelial cells that an antecedent inflammatory reaction in the thymic medulla
• AChR-reactive T and B cells localized in the thymus may serve as the initiating trigger. An understanding of this
• Increased thymic AChRα expression enduring mystery likely holds the key to unlocking the immu-
• Anti-AChR antibody secreted by thymic B-lineage cells nopathogenesis of this disease. The reader is referred to other
• Decreased thymic T regulatory cell (Treg) function works for an in-depth discussion of this topic. 22,24,26
• Interleukin (IL)1-β, IL-6, CXCL13, CCL21, and B cell–activating factor
(BAFF) overexpressed in thymus
ETIOLOGICAL FACTORS
Genetic Factors
Thymic Pathology As in most autoimmune diseases, the MHC represents an
Interest in a primary role for the thymus in the pathogenesis of important genetic susceptibility locus for the development of
MG has been fueled by pathological, clinical, and immunological MG. Studies indicate that the extended human leukocyte antigen
lines of evidence, although the nature of its involvement remains (HLA)-A1-B8-DR3 haplotype is associated with EOMG and
to be elucidated. 21-24 The thymus is pathologically abnormal in hyperplastic thymus in Caucasian individuals. This haplotype
80–90% of patients with MG. The majority of patients (65–75%) has been associated with the development of other autoimmune
have thymic follicular hyperplasia with germinal center formation. disorders. An association with HLA-B7-DR2, although weaker,
The architecture of the hyperplastic thymi is generally preserved, has also been described in patients with onset of MG occurring
with well-demarcated cortical and medullary regions. However, after the age of 40 years and associated with atrophic thymic
the medulla is crowded by numerous germinal centers that display histology. However, the strongest association, focused on a
the architectural features and cellular constituents of germinal Norwegian population of patients with late-onset MG, was
centers in the secondary follicles of peripheral lymph nodes from recently shown to be the DRB1*15:01 allele. A recent study found
normal individuals. Although these germinal centers in patients a strong association between the HLA-DQ5 allele and patients
are generally thought to occupy an intraparenchymal position, with anti-MuSK antibody–positive MG. Interestingly, the MuSK-
some observers feel that they may actually lie extraparenchymally positive T-cell repertoire appears to be skewed to the usage of
in the perivascular space. this HLA MHC class II allele. In murine studies, the MHC class
b
k
Thymomas are seen in approximately 10% of patients with II molecules I-A and I-E have been associated with susceptibility
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MG who tend to be older than those with hyperplastic thymi. 21-24 to EAMG. In EAMG, the permissive MHC class II molecules
The thymomas are characterized by a loss of cortico-medullary are capable of binding AChR peptides that are recognized by
demarcation and consist largely of neoplastic epithelial cells antigen-specific CD4 T cells.
admixed with thymocytes. The affected epithelial cells belong Studies have also addressed the potential genetic contributions
to the cortical epithelial compartment, and the thymocytes have of other immune system–related genes in the pathogenesis of
the immunophenotypic properties of normal immature cortical MG. An association has been reported for a particular IL-1β
thymocytes. allele and MG and increased serum levels of this cytokine have
Further evidence for a pathogenic role of the thymus comes been reported. This was most pronounced in patients who lacked
from the results of empiric trials of thymectomy. Despite the disease-susceptible HLA genes. Several groups have reported an
25
absence of controlled clinical trials until recently, there was association between MG and the presence of particular TNF-α
general agreement in the past that removal of the thymus, polymorphisms. The expression of a high-transcription TNF-α
particularly in young patients with follicular hyperplasia, leads allotype, TNF-α-308 allele 2, correlated with EOMG. In this
to clinical improvement. The underlying basis of this improvement regard, patients with MG demonstrate increased serum levels
remains unknown. of TNF-α and their peripheral blood mononuclear cells display
increased expression of TNF-α messenger RNA (mRNA).
Intrathymic Factors Possibly Contributing to Local Polymorphisms in the IL-10 promoter region have been reported
to be associated with distinct patterns of thymic histology. No
Anti-AChR Antibody Response correlations have been made between IL-4 alleles and MG.
The MG thymus, particularly hyperplastic thymus, is characterized Allotypic markers on IgG and FcγRIIA receptors have been
by several unique features that strongly suggest its primary role associated with the coexistence of MG and thymoma. A single
in the immunopathogenesis of MG. 21-24 The thymus contains nucleotide polymorphism in the gene encoding the intracellular
important constituents necessary for and indicative of an immune tyrosine phosphatase PTPN22, which has been associated with
response directed against nAChRs. There is considerable evidence the risk of developing other autoimmune diseases, has also been
that resident cells in the thymus, including myoid cells and identified in both a subgroup of patients with anti-titin antibody–
medullary epithelial cells, express various subunits of AChR positive nonthymomatous MG and patients with thymomatous