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Pathogenesis of myasthenia gravis

Pathogenesis of myasthenia gravis
Literature review current through: Jan 2024.
This topic last updated: May 09, 2022.

INTRODUCTION — Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by fluctuating motor weakness involving ocular, bulbar, limb, and/or respiratory muscles. The weakness is due to an antibody-mediated, immunologic attack directed at proteins in the postsynaptic membrane of the neuromuscular junction (acetylcholine receptors or receptor-associated proteins). MG is the most common disorder of neuromuscular transmission.

The pathogenesis of MG will be reviewed here. Other aspects of this disorder are discussed separately.

(See "Clinical manifestations of myasthenia gravis".)

(See "Diagnosis of myasthenia gravis".)

(See "Differential diagnosis of myasthenia gravis".)

(See "Overview of the treatment of myasthenia gravis".)

(See "Chronic immunotherapy for myasthenia gravis".)

The evaluation and diagnosis of rare myasthenic syndromes that occur in infants are discussed elsewhere. (See "Neuromuscular junction disorders in newborns and infants", section on 'Neonatal myasthenia gravis' and "Neuromuscular junction disorders in newborns and infants", section on 'Congenital myasthenic syndromes'.)

ACETYLCHOLINE RECEPTOR ANTIBODIES — Eighty to 90 percent of patients with myasthenia gravis have autoantibodies against the acetylcholine receptor (AChR) detectable in serum, and these antibodies are believed to play a central role in disease pathomechanism.

Pathologic mechanisms of AChR antibodies — Myasthenia gravis is a condition that fulfills all the major criteria for a disorder mediated by autoantibodies against the AChR [1-3]:

The autoantibodies are present in 80 to 90 percent of affected patients.

The autoantibodies react with a specific antigen, AChR.

The condition can be passively transferred by the autoantibodies to an animal model, producing a similar clinical condition.

Repeated injection of the human antigen in other species produces a model disease.

Reduction in autoantibody levels is associated with clinical improvement.

At a cellular level, AChR antibodies cause dysfunction at the neuromuscular junction by blocking ACh binding to the AChR, cross-linking and internalizing AChRs, and activating complement-mediated AChR destruction. There are several observations indicating that the AChR antibody is directly responsible for the clinical symptoms. As an example, a decrease in the number of active AChRs has been demonstrated to occur as a consequence of AChR antibody binding [4]. This may be due to autoantibody binding alone early in the disorder, but destruction of receptors eventually occurs via a complement-mediated process [5].

However, the linkage between AChR antibodies and myasthenia gravis is not absolute. The plasma concentration of AChR antibodies does not correlate well with the severity of the disease, although, in individual patients, changing autoantibody levels can be used to monitor treatment efficacy.

Acetylcholine receptor antibody subtypes — The AChR antibodies in myasthenia gravis are primarily immunoglobulin G1 (IgG1) and G3 (IgG3). In addition to blocking ACh binding to the AChR and cross-linking and internalizing the AChRs, these antibodies act through complement activation.

Individual patients have a mix of immunologically different antibodies to the AChR. In addition, there is little similarity between patients with regard to AChR antibody subtypes. This is partly due to the heterogeneity of the receptor.

The receptor of skeletal muscle consists of five different subunits, which associate to form a transmembrane ion channel [6]. Individual variation can occur among patients and among muscles in the same patient. In addition, antibodies to the same receptor in a patient with myasthenia gravis can vary in their light-chain and subclass types [7,8]. This heterogeneity has important implications for treatment. It means that the B lymphocytes producing the AChR antibodies are also heterogeneous.

MUSCLE-SPECIFIC KINASE ANTIBODIES — Some patients with myasthenia gravis who are seronegative for acetylcholine receptor (AChR) antibodies have antibodies directed against another target on the surface of the muscle membrane, muscle-specific receptor tyrosine kinase (MuSK) [9,10].

Prevalence — MuSK autoantibodies have been found in 40 to 70 percent among patients with AChR-seronegative myasthenia gravis from Europe and Japan [9,11-13]. The prevalence may be lower among other populations; a study from Taiwan found MuSK autoantibodies in only 4 percent of patients with AChR-seronegative myasthenia gravis [14].

Patients with both MuSK and AChR antibodies are uncommon [15], although the frequency may be as high as 10 percent in some regions in Asia [9,11,13].

Pathologic mechanisms of MuSK antibodies — MuSK antibody-positive myasthenia may have a different cause and pathologic mechanism than AChR antibody-positive disease [11]. In contrast with AChR antibody-positive myasthenia gravis, in which complement-fixing immunoglobulin G1 (IgG1) and G3 (IgG3) subclasses predominate [16], MuSK antibodies are mainly IgG4 [11], the IgG subtype that does not activate complement. However, there is evidence that IgG1 subclass antibodies are also present at a low concentration and are capable of activating complement when bound to MuSK [17]. This may account for some of the pathology associated with MuSK antibodies.

The MuSK protein is a transmembrane component of the postsynaptic neuromuscular junction. During neuromuscular junction formation, the MuSK complex mediates the clustering of AChRs that is induced by a nerve-derived proteoglycan called agrin, which binds to lipoprotein-related protein 4 (LRP4), leading to the activation of MuSK [18]. Activated MuSK interacts with the cytoplasmic adaptor protein Dok7 and initiates intracellular signaling systems that recruit AChR binding proteins including rapsyn to promote clustering of AChRs [18-20]. In addition, the collagen Q tail of acetylcholinesterase binds to perlecan and MuSK, thereby anchoring acetylcholinesterase to the neuromuscular junction (figure 1) [21,22]. MuSK is also expressed in the mature neuromuscular junction and is likely important for its maintenance. Thus, it is biologically plausible that MuSK autoantibodies could produce myasthenia.

However, the role of anti-MuSK antibodies in the pathogenesis of myasthenia gravis is not fully understood. The following reports illustrate the range of findings:

Autoantibodies to the extracellular domain of MuSK strongly inhibit MuSK function in cultured myotubes [9].

In animal models, active immunization with various purified extracellular MuSK domains is associated with the development of MuSK autoantibodies, myasthenic weakness, electromyographic evidence of a postsynaptic neuromuscular junction disorder, reduced AChR clustering, and other morphologic disruptions of the neuromuscular junction [23,24].

Passive transfer of IgG from patients with MuSK antibody-positive and AChR antibody-negative myasthenia gravis into mice reduced the density of the postsynaptic AChR and disrupted the neuromuscular junction [25].

In one patient with AChR antibody-negative myasthenia and a high titer of MuSK autoantibodies, no evidence supporting MuSK antibodies as the cause of myasthenic symptoms was found despite comprehensive immunohistochemistry, electron microscopy, and electrophysiologic methods [26]. Nevertheless, the amplitudes of miniature endplate potentials were reduced compared with normal values on in vitro electrophysiologic study of muscle biopsy from this patient.

A report that examined muscle biopsies from 10 patients who had MuSK antibodies with AChR antibody-negative myasthenia gravis found that MuSK antibodies were not associated with loss of AChR at the endplate, complement deposition, or morphologic damage on muscle biopsy [27].

A third study demonstrated reduced amplitude of miniature endplate potentials using in vitro electrophysiologic study of a muscle biopsy specimen from a patient with MuSK myasthenia [28]. Histologic examination revealed some areas of partially denervated endplates and other areas with some degenerating postsynaptic folds.

Human IgG purified from patients with MuSK antibody-positive myasthenia interferes with the binding of the collagen Q subunit of acetylcholinesterase to MuSK receptors [29]. Other experimental studies have shown that AChR clustering is perturbed in the absence of collagen Q [30], suggesting that a similar mechanism is important in the pathogenesis of MuSK antibody-related myasthenia gravis [29].

There are important differences between MuSK and AChR antibody-positive myasthenia gravis in clinical features, including symptom complex and response to pharmacologic treatment with acetylcholinesterase inhibitors, glucocorticoids, and azathioprine [31]. These are discussed in detail elsewhere. (See "Diagnosis of myasthenia gravis", section on 'Classification by antibody status'.)

SERONEGATIVE MYASTHENIA — The term "seronegative myasthenia gravis," also called "antibody-negative myasthenia gravis," originally referred to patients with myasthenia gravis who had negative standard assays for acetylcholine receptor (AChR) antibodies. As testing for muscle-specific receptor tyrosine kinase (MuSK) antibodies became more prevalent, a subset of patients with myasthenia gravis who had no detectable antibodies directed to AChR or MuSK was observed [32]. This group of patients is increasingly referred to as having seronegative myasthenia gravis, although some have used the term "double seronegative" to mean the absence of both AChR and MuSK antibodies. Seronegative myasthenia gravis is an autoimmune disorder with most of the same features as seropositive myasthenia gravis [33,34]. The electrophysiologic findings are identical.

Standard assays for AChR antibodies may fail to detect some patients with AChR antibody-related myasthenia gravis due to suboptimal sensitivity. However, when tested by a specialized cell-based immunofluorescence assay, up to one-half of patients with seronegative myasthenia gravis by standard assays have clustered AChR antibodies (also called low-affinity AChR antibodies) [17,35,36]. These clustered AChR antibodies bind to high densities of AChRs as found at the neuromuscular junction. They can activate complement and passively transfer disease to mice. However, the assay for clustered AChR antibodies is not widely available, and the role of these antibodies in the pathogenesis of myasthenia gravis requires further confirmation.

Antibodies to other self-antigens have been detected in various reports of patients with seronegative myasthenia gravis (ie, those who lack both AChR and MuSK antibodies), although their pathogenicity is not established:

Antibodies to lipoprotein-related protein 4 (LRP4), the agrin-binding receptor of the MuSK complex (figure 1), have been found in up to 50 percent of patients with seronegative myasthenia gravis [37-39]. In the two largest studies, autoantibodies to LRP4 were detected in 2 and 9 percent of such patients [37,39]. These antibodies are primarily of the immunoglobulin G1 (IgG1) subclass capable of activating complement [37]. In addition, they inhibit the binding of LRP4 with neural agrin and disrupt agrin-induced AChR clustering in vitro [37,39]. Transfer of immunoglobulin from patients with LRP4 antibodies induces myasthenia gravis symptoms in mice, suggesting antibodies to LRP4 may be pathogenic in some cases of seronegative myasthenia gravis [40]. However, additional research is needed to confirm this hypothesis.

Cortactin is a protein that mediates clustering of AChR at the neuromuscular junction [41]. In a retrospective report, cortactin antibodies were found in 24 percent of 38 patients with seronegative myasthenia gravis, 10 percent of 201 patients with AChR antibody-associated myasthenia gravis, and none of 11 patients with MuSK antibody-associated myasthenia gravis [42].

Other studies have identified antibodies to various intracellular muscle proteins, including the ryanodine receptor, titin, myosin, alpha actin, actin, rapsyn, and gravin, in both seropositive and seronegative myasthenia gravis [43-45]. However, it remains problematic how antibodies against these proteins can produce their effects in intact muscle cells. (See 'The thymus and the origin of autoimmunity' below.)

OTHER DISEASE MECHANISMS

Role of T cells — T lymphocytes are also important in myasthenia gravis. They are not found in pathologic specimens, suggesting that they do not act as effector cells. They can, however, bind to the acetylcholine receptor (AChR), and their main role is thought to be stimulation of B cell antibody production [46]. As with AChR antibodies, T cell binding is heterogeneous, a factor that must be addressed by immunotherapy.

Anti–T cell receptor antibodies may play a role in immunoregulation in myasthenia. This was illustrated by a study of 40 patients that compared their specific anti-T cell receptor (anti-v-beta 5.1) circulating immunoglobulin G (IgG) antibody levels with those of healthy and other disease controls [47]. While there was an overall increase in the mean antibody titer in those with myasthenia versus controls, there was an inverse correlation between the severity of myasthenia and the antibody titer. Among those with mild versus moderate or severe disease, elevated titers of anti-v-beta 5.1 antibody were present in 92 and 11 percent of patients, respectively. This finding has suggested the possibility that measures that could increase antibodies to potentially pathogenic T cell receptors might have a role in therapy of myasthenia.

The thymus and the origin of autoimmunity — The majority of patients with AChR antibody-positive myasthenia gravis have thymic abnormalities: hyperplasia in 60 to 70 percent and thymoma in 10 to 12 percent [1]. Furthermore, the disease often improves or disappears after thymectomy [2]. As a result, the thymus has been evaluated as a possible source of antigen to drive this autoimmune disease.

The thymus contains a small number of "myoid" cells. These cells are distinguished by striations and the presence of AChR on their surface and are the only known cells to express intact AChR outside of muscle. In addition, thymic epithelial cells produce unfolded AChR subunits that are hypothesized to prime helper T cells. These "autoimmunized" T cells then attack the AChR on myoid cells and create infiltrating germinal centers in the hyperplastic thymus where deposition of complement is found associated with the myoid cells. The autoimmunization completes as the antibodies in the germinal centers diversify to recognize intact muscle AChR [48,49]. Thus, all of the elements necessary to produce and promote autoimmunity reside in microenvironments in the hyperplastic thymus [50].

Antigen presentation by thymic cells via major histocompatibility complex (MHC) class II molecules may be abnormal in patients with myasthenia. In particular, overexpression of cathepsin V, one of the enzymes responsible for cleaving the invariant chain that occupies the antigen-presenting cleft of the MHC class II molecule, has been noted in the thymic tissue of patients with myasthenia and thymoma [51]. Increased production of this enzyme is present in the frankly neoplastic thymic tissue as well as in the area of the inflamed gland (thymitis). Expression of mRNA and cathepsin V protein are not increased in the thymic tissue of patients with thymomas who do not have myasthenia. Other than the important role of the cathepsins in antigen-processing cells, a link between enzyme overexpression and autoantibody production is unclear. (See "Antigen-presenting cells", section on 'Antigen processing' and "Antigen-presenting cells", section on 'Loading of MHC II molecules'.)

Although the factors that initiate and maintain the immune response in myasthenia gravis are unknown, there is some evidence that Epstein-Barr virus (EBV) may play a role. One study found active EBV infection in the thymus of all 17 patients with myasthenia gravis and in none of six control patients [52].

The role of thymoma — The role of thymoma in autoimmunity is not as clear [48]. It is unknown why some patients with thymoma develop myasthenia while others do not:

The subtype of thymoma may be important; the development of myasthenia was significantly associated with mixed thymomas but not with thymomas of the cortical type [53]. (See "Clinical presentation and management of thymoma and thymic carcinoma" and "Pathology of mediastinal tumors".)

In addition to AChR antibodies, some individuals with thymoma have muscle autoantibodies directed against titin or the ryanodine receptor as well as other intracellular muscle proteins [54-56]. Among patients with myasthenia gravis, the presence of anti-titin antibodies is predictive of a thymic epithelial tumor (sensitivity 69 to 80 percent and specificity 90 to 100 percent) [54,57].

Patients who have late-onset myasthenia without thymoma may also have titin or ryanodine receptor antibodies. There is some suggestion that these antibodies may be associated with worse prognosis [56,58]. (See "Diagnosis of myasthenia gravis", section on 'Other antibody testing'.)

Genetic factors — It seems likely that genetic factors also contribute to the pathogenesis of myasthenia gravis. Certain human leukocyte antigen (HLA) types have been associated with myasthenia, including HLA-B8, DRw3, and DQw2 [59]. MuSK antibody-positive myasthenia is associated with haplotypes DR14 and DQ5 [60]. In addition, patients with myasthenia frequently have other immune-mediated diseases, such as systemic lupus erythematosus, rheumatoid arthritis, Graves' disease, and thyroiditis, and a family history of autoimmune disorders.

Other factors — Finally, because AChR antibody levels do not clearly correlate with myasthenia gravis severity, investigators have continued to search for additional factors (eg, other muscle antibodies, secondary cytokines, chemokines) that might positively correlate with the disease [61].

As examples, the chemokines CXCL13 and CCL21 are overexpressed in hyperplastic thymus from individuals with myasthenia gravis and may play a pathologic role in the recruitment of lymphocytes to the thymus [61,62]. As another example, one study exposed cultured human muscle cells to sera from patients with myasthenia gravis of varying severity and observed a direct cytotoxic effect of the sera [63]. This cytotoxic effect was not complement dependent, and ryanodine and titin antibodies were not consistently detected in all sera, suggesting the effect may not be autoantibody mediated. However, the cytotoxic effect correlated with disease severity, making this an interesting phenomenon for further investigation [63].

SUMMARY

Acetylcholine receptor autoantibodies – Myasthenia gravis is an autoimmune disorder characterized by weakness and fatigability of skeletal muscles due to autoantibody-mediated dysfunction at the neuromuscular junction.

Eighty to 90 percent of patients with myasthenia gravis have autoantibodies against the acetylcholine receptor (AChR) detectable in serum, and these antibodies are believed to play a central role in disease pathomechanism via AChR blockade, internalization, and complement-mediated destruction. (See 'Pathologic mechanisms of AChR antibodies' above.)

Muscle-specific kinase antibodies – Some patients with myasthenia gravis who are seronegative for AChR antibodies have antibodies directed against another target on the surface of the muscle membrane, muscle-specific receptor tyrosine kinase (MuSK). The MuSK protein is a transmembrane component of the postsynaptic neuromuscular junction. (See 'Muscle-specific kinase antibodies' above.)

Antibodies in patients with seronegative myasthenia gravis – Seronegative myasthenia gravis, also called antibody-negative myasthenia gravis, refers to the 6 to 12 percent of patients with myasthenia gravis who have negative standard assays for both AChR antibodies and MuSK antibodies. (See 'Seronegative myasthenia' above.)

Standard assays for AChR antibodies may fail to detect some patients with AChR antibody-related myasthenia gravis due to suboptimal sensitivity. Up to one-half of patients with seronegative myasthenia gravis by standard assays may be found to have clustered AChR antibodies by immunofluorescence assays.

Antibodies to other self-antigens may also be found in patients with seronegative myasthenia gravis including lipoprotein-related protein 4 (LRP4), the agrin-binding receptor of the MuSK complex and cortactin, a protein that mediates clustering of AChR at the neuromuscular junction.

Other mechanisms – Other immune mechanisms play a role in the pathogenesis of myasthenia gravis. T lymphocytes can bind to the AChR, to stimulate B cell antibody production. Thymic hyperplasia or thymoma are also possible sources of antigen to drive myasthenia gravis. The disease often improves or disappears after thymectomy.(See 'Other disease mechanisms' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Walter Allan, MD, who contributed to earlier versions of this topic review.

  1. Gilhus NE. Myasthenia Gravis. N Engl J Med 2016; 375:2570.
  2. Yi JS, Guptill JT, Stathopoulos P, et al. B cells in the pathophysiology of myasthenia gravis. Muscle Nerve 2018; 57:172.
  3. Punga AR, Maddison P, Heckmann JM, et al. Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders. Lancet Neurol 2022; 21:176.
  4. Drachman DB, Adams RN, Josifek LF, Self SG. Functional activities of autoantibodies to acetylcholine receptors and the clinical severity of myasthenia gravis. N Engl J Med 1982; 307:769.
  5. Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future. J Clin Invest 2006; 116:2843.
  6. Karlin A, Akabas MH. Toward a structural basis for the function of nicotinic acetylcholine receptors and their cousins. Neuron 1995; 15:1231.
  7. Huijbers MG, Lipka AF, Plomp JJ, et al. Pathogenic immune mechanisms at the neuromuscular synapse: the role of specific antibody-binding epitopes in myasthenia gravis. J Intern Med 2014; 275:12.
  8. Binks S, Vincent A, Palace J. Myasthenia gravis: a clinical-immunological update. J Neurol 2016; 263:826.
  9. Hoch W, McConville J, Helms S, et al. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 2001; 7:365.
  10. Vincent A, McConville J, Farrugia ME, et al. Antibodies in myasthenia gravis and related disorders. Ann N Y Acad Sci 2003; 998:324.
  11. McConville J, Farrugia ME, Beeson D, et al. Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. Ann Neurol 2004; 55:580.
  12. Liyanage Y, Hoch W, Beeson D, Vincent A. The agrin/muscle-specific kinase pathway: new targets for autoimmune and genetic disorders at the neuromuscular junction. Muscle Nerve 2002; 25:4.
  13. Ohta K, Shigemoto K, Kubo S, et al. MuSK antibodies in AChR Ab-seropositive MG vs AChR Ab-seronegative MG. Neurology 2004; 62:2132.
  14. Yeh JH, Chen WH, Chiu HC, Vincent A. Low frequency of MuSK antibody in generalized seronegative myasthenia gravis among Chinese. Neurology 2004; 62:2131.
  15. Gilhus NE, Tzartos S, Evoli A, et al. Myasthenia gravis. Nat Rev Dis Primers 2019; 5:30.
  16. Rødgaard A, Nielsen FC, Djurup R, et al. Acetylcholine receptor antibody in myasthenia gravis: predominance of IgG subclasses 1 and 3. Clin Exp Immunol 1987; 67:82.
  17. Leite MI, Jacob S, Viegas S, et al. IgG1 antibodies to acetylcholine receptors in 'seronegative' myasthenia gravis. Brain 2008; 131:1940.
  18. Ghazanfari N, Fernandez KJ, Murata Y, et al. Muscle specific kinase: organiser of synaptic membrane domains. Int J Biochem Cell Biol 2011; 43:295.
  19. Bergamin E, Hallock PT, Burden SJ, Hubbard SR. The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization. Mol Cell 2010; 39:100.
  20. Okada K, Inoue A, Okada M, et al. The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science 2006; 312:1802.
  21. Cartaud A, Strochlic L, Guerra M, et al. MuSK is required for anchoring acetylcholinesterase at the neuromuscular junction. J Cell Biol 2004; 165:505.
  22. Peng HB, Xie H, Rossi SG, Rotundo RL. Acetylcholinesterase clustering at the neuromuscular junction involves perlecan and dystroglycan. J Cell Biol 1999; 145:911.
  23. Shigemoto K, Kubo S, Maruyama N, et al. Induction of myasthenia by immunization against muscle-specific kinase. J Clin Invest 2006; 116:1016.
  24. Richman DP, Nishi K, Morell SW, et al. Acute severe animal model of anti-muscle-specific kinase myasthenia: combined postsynaptic and presynaptic changes. Arch Neurol 2012; 69:453.
  25. Cole RN, Reddel SW, Gervásio OL, Phillips WD. Anti-MuSK patient antibodies disrupt the mouse neuromuscular junction. Ann Neurol 2008; 63:782.
  26. Selcen D, Fukuda T, Shen XM, Engel AG. Are MuSK antibodies the primary cause of myasthenic symptoms? Neurology 2004; 62:1945.
  27. Shiraishi H, Motomura M, Yoshimura T, et al. Acetylcholine receptors loss and postsynaptic damage in MuSK antibody-positive myasthenia gravis. Ann Neurol 2005; 57:289.
  28. Niks EH, Kuks JB, Wokke JH, et al. Pre- and postsynaptic neuromuscular junction abnormalities in musk myasthenia. Muscle Nerve 2010; 42:283.
  29. Kawakami Y, Ito M, Hirayama M, et al. Anti-MuSK autoantibodies block binding of collagen Q to MuSK. Neurology 2011; 77:1819.
  30. Sigoillot SM, Bourgeois F, Lambergeon M, et al. ColQ controls postsynaptic differentiation at the neuromuscular junction. J Neurosci 2010; 30:13.
  31. Sanders DB, El-Salem K, Massey JM, et al. Clinical aspects of MuSK antibody positive seronegative MG. Neurology 2003; 60:1978.
  32. Chan KH, Lachance DH, Harper CM, Lennon VA. Frequency of seronegativity in adult-acquired generalized myasthenia gravis. Muscle Nerve 2007; 36:651.
  33. Sanders DB, Andrews PI, Howard Jr JF, Massey JM. Seronegative myasthenia gravis. Neurology 1997; 48:S40.
  34. Deymeer F, Gungor-Tuncer O, Yilmaz V, et al. Clinical comparison of anti-MuSK- vs anti-AChR-positive and seronegative myasthenia gravis. Neurology 2007; 68:609.
  35. Jacob S, Viegas S, Leite MI, et al. Presence and pathogenic relevance of antibodies to clustered acetylcholine receptor in ocular and generalized myasthenia gravis. Arch Neurol 2012; 69:994.
  36. Rodríguez Cruz PM, Al-Hajjar M, Huda S, et al. Clinical Features and Diagnostic Usefulness of Antibodies to Clustered Acetylcholine Receptors in the Diagnosis of Seronegative Myasthenia Gravis. JAMA Neurol 2015; 72:642.
  37. Higuchi O, Hamuro J, Motomura M, Yamanashi Y. Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis. Ann Neurol 2011; 69:418.
  38. Pevzner A, Schoser B, Peters K, et al. Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis. J Neurol 2012; 259:427.
  39. Zhang B, Tzartos JS, Belimezi M, et al. Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch Neurol 2012; 69:445.
  40. Yu Z, Zhang M, Jing H, et al. Characterization of LRP4/Agrin Antibodies From a Patient With Myasthenia Gravis. Neurology 2021; 97:e975.
  41. Madhavan R, Gong ZL, Ma JJ, et al. The function of cortactin in the clustering of acetylcholine receptors at the vertebrate neuromuscular junction. PLoS One 2009; 4:e8478.
  42. Cortés-Vicente E, Gallardo E, Martínez MÁ, et al. Clinical Characteristics of Patients With Double-Seronegative Myasthenia Gravis and Antibodies to Cortactin. JAMA Neurol 2016; 73:1099.
  43. Ohta M, Ohta K, Itoh N, et al. Anti-skeletal muscle antibodies in the sera from myasthenic patients with thymoma: identification of anti-myosin, actomyosin, actin, and alpha-actinin antibodies by a solid-phase radioimmunoassay and a western blotting analysis. Clin Chim Acta 1990; 187:255.
  44. Nauert JB, Klauck TM, Langeberg LK, Scott JD. Gravin, an autoantigen recognized by serum from myasthenia gravis patients, is a kinase scaffold protein. Curr Biol 1997; 7:52.
  45. Agius MA, Zhu S, Kirvan CA, et al. Rapsyn antibodies in myasthenia gravis. Ann N Y Acad Sci 1998; 841:516.
  46. Yi Q, Pirskanen R, Lefvert AK. Human muscle acetylcholine receptor reactive T and B lymphocytes in the peripheral blood of patients with myasthenia gravis. J Neuroimmunol 1993; 42:215.
  47. Jambou F, Zhang W, Menestrier M, et al. Circulating regulatory anti-T cell receptor antibodies in patients with myasthenia gravis. J Clin Invest 2003; 112:265.
  48. Willcox N, Leite MI, Kadota Y, et al. Autoimmunizing mechanisms in thymoma and thymus. Ann N Y Acad Sci 2008; 1132:163.
  49. Leite MI, Jones M, Ströbel P, et al. Myasthenia gravis thymus: complement vulnerability of epithelial and myoid cells, complement attack on them, and correlations with autoantibody status. Am J Pathol 2007; 171:893.
  50. Hohlfeld R, Wekerle H. Reflections on the "intrathymic pathogenesis" of myasthenia gravis. J Neuroimmunol 2008; 201-202:21.
  51. Tolosa E, Li W, Yasuda Y, et al. Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis. J Clin Invest 2003; 112:517.
  52. Cavalcante P, Serafini B, Rosicarelli B, et al. Epstein-Barr virus persistence and reactivation in myasthenia gravis thymus. Ann Neurol 2010; 67:726.
  53. Wilisch A, Gutsche S, Hoffacker V, et al. Association of acetylcholine receptor alpha-subunit gene expression in mixed thymoma with myasthenia gravis. Neurology 1999; 52:1460.
  54. Voltz RD, Albrich WC, Nägele A, et al. Paraneoplastic myasthenia gravis: detection of anti-MGT30 (titin) antibodies predicts thymic epithelial tumor. Neurology 1997; 49:1454.
  55. Gautel M, Lakey A, Barlow DP, et al. Titin antibodies in myasthenia gravis: identification of a major immunogenic region of titin. Neurology 1993; 43:1581.
  56. Romi F, Gilhus NE, Varhaug JE, et al. Disease severity and outcome in thymoma myasthenia gravis: a long-term observation study. Eur J Neurol 2003; 10:701.
  57. Yamamoto AM, Gajdos P, Eymard B, et al. Anti-titin antibodies in myasthenia gravis: tight association with thymoma and heterogeneity of nonthymoma patients. Arch Neurol 2001; 58:885.
  58. Romi F, Gilhus NE, Varhaug JE, et al. Thymectomy and antimuscle antibodies in nonthymomatous myasthenia gravis. Ann N Y Acad Sci 2003; 998:481.
  59. Carlsson B, Wallin J, Pirskanen R, et al. Different HLA DR-DQ associations in subgroups of idiopathic myasthenia gravis. Immunogenetics 1990; 31:285.
  60. Niks EH, Kuks JB, Roep BO, et al. Strong association of MuSK antibody-positive myasthenia gravis and HLA-DR14-DQ5. Neurology 2006; 66:1772.
  61. Meraouna A, Cizeron-Clairac G, Panse RL, et al. The chemokine CXCL13 is a key molecule in autoimmune myasthenia gravis. Blood 2006; 108:432.
  62. Berrih-Aknin S, Ruhlmann N, Bismuth J, et al. CCL21 overexpressed on lymphatic vessels drives thymic hyperplasia in myasthenia. Ann Neurol 2009; 66:521.
  63. Luckman SP, Skeie GO, Helgeland G, Gilhus NE. Morphological effects of myasthenia gravis patient sera on human muscle cells. Muscle Nerve 2006; 33:93.
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