Etiology
MG is an organ-specific, antibody-mediated autoimmune disease. Antibodies are present at the neuromuscular junction (NMJ), the site of pathology.[1]
About 80% to 90% of MG patients have detectable antibodies against the nicotinic acetylcholine receptor (AChR) on the postsynaptic muscle membrane at the NMJ.[2][5] Some patients who do not have detectable AChR antibodies by standard binding and modulating assays have been shown to have AChR binding antibodies using a cell-based assay.[38] Removal of antibodies (by plasma exchange, reduction by immunomodulation, inhibition of pathogenic mediators, or reduction by immunosuppression) ameliorates symptoms in patients with MG.[39][40]
Antibodies against other NMJ proteins have been detected in patients with MG:[2][5][9][10][11][27][28][41]
Approximately 3% to 7% of patients have antibodies directed against muscle-specific tyrosine kinase (MuSK).
Antibodies to low-density lipoprotein receptor-related protein (LRP4) have been reported; often these are detected in patients who are negative for both AChR and MuSK antibodies.
Antibodies to agrin have been demonstrated in the serum of patients who have antibodies to AChR (but to date not in patients with MuSK antibodies), and in patients without antibodies to AChR, MuSK, or LRP4.
The clinical importance of antibodies to collagen Q and cortactin is not yet clear.
The etiology for the synthesis of autoimmune antibodies remains unclear, although certain genotypes, particularly linked to the human leukocyte antigen (HLA) complex, may be more susceptible.[42][43] Single nucleotide polymorphisms (SNPs) have been reported in a wide variety of genes in different populations with MG, including several SNPs of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4).[44][45][46]
The thymus may be involved in the etiology of MG. MG is associated with thymic follicular hyperplasia in 70% of patients and with thymoma in 10% of patients.[47] While virtually all patients with MG and thymoma have AChR antibodies, concurrent MG and malignant thymoma has been reported in several AChR seronegative patients.[48][49] Thymic myoid cells express AChR and may trigger autoantibody synthesis. In contrast, in patients with MuSK-MG, thymus gland histology is usually, but not invariably, normal and thymoma is rare.[25]
Numerous studies demonstrate abnormalities in number and function of regulatory T and B cells in patients with MG, which are likely to be involved in the state of autoimmunity and autoimmune disease.[50][51][52][53]
There are no specific risk factors for the development of MG other than genetics (major histocompatibility complex and other genes) and the presence of other autoimmune diseases in the patient and family members.[45][46][54][55] A study of 462 MG patients in Spain found that 16 cases (3.46%), from 8 unrelated families, were familial.[56]
The use of checkpoint inhibitors in cancer therapy has been associated with the development of inflammatory and autoimmune disease, including MG with or without concomitant myositis, and worsening of preexisting MG.[3][57][58][59][60]
Pathophysiology
In MG characterized by acetylcholine receptor (AChR) antibodies, an autoimmune attack against AChRs frequently results in complement-mediated destruction of the postsynaptic membrane.[23] AChR antibodies can increase AChR endocytosis or block acetylcholine binding sites.[61] The reduced number of available binding sites for acetylcholine leads to inconsistent generation of muscle fiber action potentials, which manifests as skeletal muscle weakness.
Muscle-specific tyrosine kinase (MuSK) is an agrin-dependent protein localized to muscle membranes with an essential role in anchoring AChR at the tips of the postsynaptic folds. Antibodies to MuSK in plasma isolated from patients with MuSK-MG strongly inhibited AChR clustering in cultured muscle cells.[62]
Antibodies to LRP4 and agrin modify post-synaptic junction activity in vitro.[11][28] Sensitization of animals with LRP4 results in experimental MG, and antibodies to LRP4 transfer neuromuscular blockade to naïve animals.[63] Induction of experimental autoimmune MG in mice following immunization with agrin has been reported.[64] There is evidence that human LRP4 and probably agrin antibodies lead to inhibition of neuromuscular transmission in mice.[61][65] The status of end plates in MG patients with LRP4 and agrin antibodies is not known.
The role, if any, of antibodies to cytoplasmic components, including titin and other cross-striational antibodies, rapsyn, and ryanodine, is not clearly understood. They may affect severity but do not cause deficits in neuromuscular transmission.
Classification
Myasthenia Gravis Foundation of America clinical classification[4]
Class I: Any eye muscle weakness; possible ptosis; all other muscle strength is normal
Class II: Mild weakness of other muscles; may have eye muscle weakness of any severity
IIa: Predominantly limb or axial muscles or both
IIb: Predominantly oropharyngeal or respiratory muscles or both
Class III: Moderate weakness of other muscles; may have eye muscle weakness of any severity
IIIa: Predominantly limb or axial muscles or both
IIIb: Predominantly oropharyngeal or respiratory muscles or both
Class IV: Severe weakness of other muscles; may have eye muscle weakness of any severity
IVa: Predominantly limb or axial muscles or both
IVb: Predominantly oropharyngeal or respiratory muscles or both; use of feeding tube without intubation
Class V: Intubation needed to maintain airway
Presence of antibodies directed against muscle-specific tyrosine kinase (MuSK)[5][6][7]
Non-MuSK-MG: without MuSK antibodies
MuSK-MG: MuSK antibodies present
These types often have different epidemiologic and clinical features.
Patients with MG may rarely have antibodies to both acetylcholine receptor (AChR) and MuSK.
Presence of antibodies directed against LRP4, agrin, collagen Q, or cortactin
There is not enough information to know whether there are specific clinical phenotypes associated with antibodies to low-density lipoprotein receptor-related protein 4 (LRP4), agrin, collagen Q, or cortactin, or if these antibodies may also be rarely seen in other disorders.[8]
Some patients with antibodies to LRP4 do not seem to have detectable antibodies to either AChR or MuSK.
Some patients with antibodies to agrin also have AChR antibodies; some have no detectable antibodies to AChR, MuSK, or LRP4; and some have antibodies to another neuromuscular junction antigen.
The clinical importance of antibodies to collagen Q is not yet clear. Because collagen Q is a protein that anchors acetylcholinesterase at the neuromuscular junction, antibodies might affect neuromuscular transmission.
One study found that 3% (12/415) of serum samples from patients with MG had antibodies to collagen Q, compared with 2% of controls (1/43). Of the 12 MG patients positive for collagen Q antibodies, 5 were also positive for antibodies to AChR, and 2 were positive for MuSK antibodies. It is not clear if these antibodies affect the response to acetylcholinesterase in these patients.
Studies have reported antibodies reactive with cortactin in MG patients. The clinical importance of these antibodies is not yet established, and the presence of such antibodies is not specific for MG. Cortactin interacts with actin, and may be involved in contraction in muscle cells. However, because it is an intracellular protein, antibodies to cortactin would be unlikely to see their target antigen in intact muscle.
To date, cortactin antibodies have been observed in patients who also have antibodies to AChR but not to MuSK, as well as in patients who are “double seronegative” (i.e., no detectable antibodies to AChR using standard assays or to MuSK).
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