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  Vol. 62 No. 3, March 2005 TABLE OF CONTENTS
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Striational Antibodies in Myasthenia Gravis

Reactivity and Possible Clinical Significance

Fredrik Romi, MD; Geir Olve Skeie, MD; Nils Erik Gilhus, MD; Johan Arild Aarli, MD

Arch Neurol. 2005;62:442-446.

ABSTRACT

Myasthenia gravis is an autoimmune disease caused, in most cases, by antibodies attaching to the acetylcholine receptor. Some myasthenia gravis patients have antibodies that bind in a cross-striational pattern to skeletal and heart muscle tissue sections (striational antibodies). These antibodies react with epitopes on the muscle proteins titin and ryanodine receptor, are found mainly in sera of patients with thymoma and late-onset myasthenia gravis, and may correlate with myasthenia gravis severity. Their presence may predict an unsatisfactory outcome after thymectomy. The detection of titin and ryanodine receptor antibodies provides more specific clinical information than the immunofluorescent demonstration of striational antibodies.



INTRODUCTION
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 •Do striational antibodies have...
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Myasthenia gravis (MG) is caused by antibodies that react mainly with the acetylcholine receptor (AChR) on the postsynaptic site of the neuromuscular junction.1 In 1960, Strauss et al2 used indirect immunofluorescence technique to demonstrate that sera from some patients with MG contained antibodies that gave a cross-striational staining when incubated with sections of striated muscle. These antibodies were named striational antibodies (Figure 1). In 1981, Aarli et al3 demonstrated antibodies attaching to a citric acid extractable striational muscle antigen. Citric acid antigen and striational antibodies correspond to each other and are found mainly in serum samples of MG patients with thymoma.2-3



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Figure 1. Immunofluorescence microscopy image (original magnification x 400) of longitudinally cut human skeletal muscle fibers incubated with serum from a patient with myasthenia gravis shows fluorescein isothiocyanate–labeled striational antibodies bound to the muscle cross striations.


Titin is a major muscle antigen in MG and at least partly responsible for the striational binding pattern.4 Some MG serum samples also contain IgG antibodies that react with another muscle antigen, the ryanodine receptor (RyR), that is found in sarcoplasmic reticulum.5 This study reviews current data on the striational antibodies and their significance in MG.


TITIN
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Titin is a giant protein (3000 kDa) and is the third most abundant protein in the skeletal and cardiac sarcomere (Figure 2A). The molecule is about 1 µm long, extending from the Z disk to the M line.7 Ninety percent of the titin mass is contained in a repetitive structure comprising 244 to 297 copies of 2 different 100-residue repeats; the 112 to 165 immunoglobulin superfamily domains, and 132 fibronectin-like domains. The rest of the titin mass consists of unique sequences with specialized functions.7-8 Titin molecules are arranged in a way that allow augmentation of mechanical stability and tension in the sarcomere.8 The titin-based tension is calcium responsive because titin is a calcium-dependent molecular spring that adapts to the physiological state of the cell.7



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Figure 2. A, The structure of titin. The locations of the main immunogenic region and I-band epitopes are indicated. B, The locations of the main immunogenic region and I-band epitopes are shown in immunofluorescence staining on a stretched skeletal muscle fiber (reprinted with permission from J Neuroimmunol6).


The main immunogenic region of titin is called myasthenia gravis titin-30 (MGT-30) and is situated near the A/I-band junction (Figure 2A).9 Another immunogenic region is located between the N1 and N2 lines. This consists of homologous immunoglobulin domains.6 These are differentially expressed; 15 modules are expressed in cardiac muscle, while there may be up to 68 such modules in skeletal muscle.6 Antibodies to the I-band epitope are present only in sera containing MGT-30 antibodies. When I-band epitope antibodies are present, a double-band immunofluorescence technique staining is obtained (Figure 2B). Patients who have antibodies attaching to I-band epitopes also have antibodies attaching to the main immunogenic region.6 The presence of antibodies attaching to the I-band epitopes may indicate titin epitope spreading.10


THE RyR
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The RyR is a calcium release channel located in the sarcoplasmic reticulum. The name refers to the alkaloid ryanodine that binds selectively to the RyR. There are 2 forms of RyR, skeletal (RyR1) and cardiac (RyR2). The RyR antibodies from MG patients react with both. The RyR is a protein containing 5035 amino acids with a molecular weight of 565 kDa. It is composed of 4 homologous subunits that can build a tetramer with a central channel (Figure 3). 11 The RyR is expressed mainly in striated muscle tissue, but it is also found in epithelium and neurons. The longitudinally spreading depolarization along the sarcolemma continues transversally through the T tubules to the terminal cisternae of the sarcoplasmic reticulum, inducing a conformational change in the RyR leading to calcium release which opens the RyR, allowing calcium flow into the sarcoplasm.11-12 The RyR epitopes are located on the handle domains of the RyR cytoplasmic assembly, near its junction with the transmembrane assembly.13 The main immunogenic region is the peptide chain 2 and RyR type 1 fusion protein located close to the N terminus, and for some sera a more centrally located region called peptide chain 25.14 Both regions are located near each other in the 3-dimensional conformation of the RyR. The antibody response to the central region may represent epitope spreading. The RyR antibodies cause allosteric inhibition of RyR function in vitro, inhibiting Ca2+ release from sarcoplasmic reticulum.14-15



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Figure 3. Drawing of the ryanodine receptor showing the localization of the 2 epitopes, pc2 (main immunogenic region) and pc25, which are recognized by antibodies in the serum samples of patients with myasthenia gravis.



OTHER STRIATIONAL ANTIGENS AND ANTIBODIES
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Antibodies to human myosin were described in 1969.16 Cultured, dissociated, thymic lymphocytes from patients with MG secrete monoclonal striational antibodies that bind to skeletal muscle myosin, {alpha}-actinin, and actin.17 Patients with MG and thymoma have higher titers of anti-myosin and anti-actomyosin antibodies than patients with MG but without thymoma.17-18

Antibodies against rapsyn (a 43-kDa postsynaptic protein essential for anchoring and clustering AChR) have been identified in MG but are also found in serum samples from patients with lupus and chronic procainamide associated myopathy.19


STRIATIONAL ANTIBODIES IN SUBGROUPS OF MG
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Myasthenia gravis can be classified into several subtypes based on the immunological profile.20 Nearly all patients with MG and thymoma and half of the late-onset MG subgroup (onset of MG at ≥50 years of age) demonstrate an antibody profile with a broad striational antibody response.4-5,10, 15, 21 In contrast, AChR antibody–positive patients with early-onset MG (onset of MG at <50 years of age) and AChR antibody–positive MG with purely ocular symptoms have a selective high antibody response against AChR.21 Striational autoantibodies are rarely found in AChR antibody–negative MG.21


STRIATIONAL ANTIBODIES AND THE DIAGNOSIS OF THYMOMA
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Striational autoantibodies and computed tomographic scan of the anterior mediastinum show a similar sensitivity for thymoma MG.21 In our studies, computed tomographic scan failed to predict a thymoma in 27% of the cases.21 The positive predictive value for thymoma is significantly higher for RyR antibodies. The presence of titin/RyR antibodies in a young patient with MG strongly suggests the presence of a thymoma (testing for titin antibodies, but not RyR antibodies, is commercially available). The absence of these antibodies strongly excludes thymoma (Table).5, 10, 15, 21-24


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Table. Titin, RyR Antibodies, and CT Scan of the Anterior Mediastinum in Relation to the Occurrence of Thymoma in Our Myasthenia Gravis Population



STRIATIONAL ANTIBODIES AND THE SEVERITY OF MG
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The AChR antibody serum concentration does not correlate with MG severity, mainly because of individual variations in AChR epitope specificity.25

Myasthenia gravis tends to be more severe in patients with thymoma than in the early-onset MG subgroup.26 The presence of striational autoantibodies is associated with a more severe disease in all MG subgroups, and citric acid antigen, titin, and RyR antibodies occur significantly more often among patients with severe MG than among patients with less severe disease.10, 12, 26-27 These antibodies can therefore be used as prognostic determinants in MG patients.26


STRIATIONAL ANTIBODIES AND THYMECTOMY IN MG
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Patients with early-onset MG may benefit from thymectomy. The AChR antibody concentration does not predict the outcome of thymectomy.28-29 Titin and RyR antibodies are not found in early-onset MG. Patients with late-onset MG benefit far less from thymectomy.29-30 An improvement appears less likely in cases with titin and/or RyR antibodies.29 Myasthenia gravis severity and outcome over time seem to be equal in thymoma and nonthymoma MG,29-32 but the presence of RyR antibodies in thymoma MG and titin/RyR antibodies in nonthymoma MG indicates a less favorable prognosis.29 The RyR antibodies are often found in patients with an invasive or malignant thymoma.27


STRIATIONAL ANTIBODIES AND HLA LINKAGE IN MG
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The correlation between MG and specific HLA antigens has long been recognized.33 Patients with MG and titin antibodies often express the HLA-DR7 haplotype, while those with thymus hyperplasia and no titin antibodies express HLA-DR3.34 Extended haplotypes including tumor necrosis factor {alpha} or {beta} polymorphisms confirm the linkage to specific major histocompatibility complex haplotypes.10 This supports that patients with and without striational antibodies belong to pathogenetically different subsets of MG.


DO STRIATIONAL ANTIBODIES HAVE A ROLE IN THE PATHOGENESIS OF MG?
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The complement concentration in the serum of MG patients varies with disease severity, increasing during remission and decreasing during exacerbation.35 This can be explained by activated complement components attacking the AChR at the end plate.36 However, titin and RyR antibodies also activate complement in vitro through the IgG 1–mediated pathway.37 Complement activation caused by striational antibodies is therefore a potential mechanism for additional immune damage. The presence of titin antibodies in patients with MG correlates with their electromyographic evidence of myopathy.38 This does not prove any pathogenic role for titin and RyR antibodies in MG.

The initial steps in the triggering of humoral immunity in MG presumably take place inside the thymus.39 Fifty percent of patients with cortical-type thymoma have MG, and the presence of muscle-like epitopes within thymomas has been demonstrated.40 MG-associated thymomas are enriched in AChR-like epitopes41 and AChR-specific T-cells.42 Titin and RyR epitopes have also been identified on neoplastic thymoma cells.10, 43 In MG associated thymoma, there is an overexpression of thymic musclelike epitopes and costimulatory molecules indicating that the T-cell autoimmunization is promoted by the pathogenic microenvironment inside the thymoma. Titin and RyR epitopes are coexpressed along with LFA3 and B7 (BB1), which are costimulatory molecules expressed on thymoma antigen–presenting cells in cortical thymoma.42, 44 The steps in the autosensitization that lead to the development of humoral autoimmunity against muscle antigen are incompletely known, but involve both Th1 and Th2 lymphocyte responses.10, 27


AUTHOR INFORMATION
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Correspondence: Fredrik Romi, MD, Department of Neurology, Haukeland University Hospital, N-5021 Bergen, Norway (fredrik.romi{at}haukeland.no).

Accepted for Publication: July 14, 2004.

Author Contributions: Study concept and design: Romi, Skeie, Gilhus, Aarli. Acquisition of data: Romi, Skeie, Gilhus, Aarli. Analysis and interpretation of data: Romi, Skeie, Gilhus, Aarli. Drafting of the manuscript: Romi, Skeie, Gilhus, Aarli. Critical revision of the manuscript for important intellectual content: Romi, Skeie, Gilhus, Aarli. Statistical analysis: Romi, Skeie, Gilhus, Aarli.

Funding/Support: This study was supported by EU grant QRLT-2000-01918.

Author Affiliations: Department of Neurology, Haukeland University Hospital, Bergen, Norway.


REFERENCES
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17. Ohta M, Ohta K, Itoh N, Kurobe M, Hayashi K, Nishitani H. 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 Western blotting analysis. Clin Chim Acta. 1990;187:255-264. FULL TEXT | ISI | PUBMED
18. Mohan S, Barohn RJ, Jackson CE, Krolick KA. Evaluation of myosin-reactive antibodies from a panel of myasthenia gravis patients. Clin Immunol Immunopathol. 1994;70:266-273. FULL TEXT | ISI | PUBMED
19. Agius MA, Zhu S, Kirvan CA, et al. Rapsyn antibodies in myasthenia gravis. Ann N Y Acad Sci. 1998;841:516-521. FULL TEXT | ISI | PUBMED
20. Agius M, Richman D, Fairclough R, Aarli JA, Gilhus NE, Romi F. Three forms of immune myasthenia. Ann N Y Acad Sci. 2003;998:453-456. FULL TEXT | ISI | PUBMED
21. Romi F, Skeie GO, Aarli JA, Gilhus NE. Muscle autoantibodies in subgroups of myasthenia gravis patients. J Neurol. 2000;247:369-375. FULL TEXT | ISI | PUBMED
22. Romi F. Muscle Autoantibodies in Myasthenia Gravis: Clinical, Immunological, and Therapeutic Implications. University of Bergen, Norway, 2001.
23. Buckley C, Newsom-Davis J, Willcox N, Vincent A. Do titin and cytokine antibodies in MG patients predict thymoma or thymoma recurrence? Neurology. 2001;57:1579-1582. FREE FULL TEXT
24. 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;58:885-890. FREE FULL TEXT
25. Oosterhuis HJ, Limburg PC, Hummel-Tappel E, The TH. Anti-acetylcholine receptor antibodies in myasthenia gravis, part 2: clinical and serological follow-up of individual patients. J Neurol Sci. 1983;58:371-385. FULL TEXT | ISI | PUBMED
26. Romi F, Skeie GO, Aarli JA, Gilhus NE. The severity of myasthenia gravis correlates with the serum concentration of titin and ryanodine receptor antibodies. Arch Neurol. 2000;57:1596-1600. FREE FULL TEXT
27. Skeie GO, Lunde PK, Sejersted OM, Mygland A, Aarli JA, Gilhus NE. Autoimmunity against the ryanodine receptor in myasthenia gravis. Acta Physiol Scand. 2001;171:379-384. FULL TEXT | ISI | PUBMED
28. Venuta F, Rendina EA, De Giacomo T, et al. Thymectomy for myasthenia gravis: a 27-year experience. Eur J Cardiothorac Surg. 1999;15:621-625.
29. Romi F, Gilhus NE, Varhaug JE, Myking A, Skeie GO, Aarli JA. Thymectomy and antimuscle antibodies in nonthymomatous myasthenia gravis. Ann N Y Acad Sci. 2003;998:481-490. FULL TEXT | ISI | PUBMED
30. Richman DP, Agius MA. Treatment of autoimmune myasthenia gravis. Neurology. 2003;61:1652-1661. FREE FULL TEXT
31. de Perrot M, Liu J, Bril V, McRae K, Bezjak A, Keshavjee SH. Prognostic significance of thymomas in patients with myasthenia gravis. Ann Thorac Surg. 2002;74:1658-1662. FREE FULL TEXT
32. Evoli A, Minisci C, Di Schino C, et al. Thymoma in patients with MG: characteristics and long-term outcome. Neurology. 2002;59:1844-1850. FREE FULL TEXT
33. Feltkamp TE, van den Berg-Loonen PM, Nijenhuis LE, et al. Myasthenia gravis, autoantibodies, and HL-A antigens. BMJ. 1974;1:131-133.
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35. Plescia OJ, Segovia JM, Strampp A. An assessment of changes in the complement level of myasthenic sera. Ann N Y Acad Sci. 1966;135:580-587. ISI | PUBMED
36. Engel AG, Arahata K. The membrane attack complex of complement at the endplate in myasthenia gravis. Ann N Y Acad Sci. 1987;505:326-332. PUBMED
37. Romi F, Skeie GO, Vedeler C, Aarli JA, Zorzato F, Gilhus NE. Complement activation by titin and ryanodine receptor autoantibodies in myasthenia gravis: a study of IgG subclasses and clinical correlations. J Neuroimmunol. 2000;111:169-176. FULL TEXT | ISI | PUBMED
38. Somnier FE, Skeie GO, Aarli JA, Trojaborg W. EMG evidence of myopathy and the occurrence of titin autoantibodies in patients with myasthenia gravis. Eur J Neurol. 1999;6:555-563. FULL TEXT | ISI | PUBMED
39. Vincent A, Willcox N. The role of T-cells in the initiation of autoantibody responses in thymoma patients. Pathol Res Pract. 1999;195:535-540. ISI | PUBMED
40. Gilhus NE, Aarli JA, Christensson B, Matre R. Rabbit antiserum to citric acid extract of human skeletal muscle staining thymomas from myasthenia gravis patients. J Neuroimmunol. 1984;7:55-64. FULL TEXT | ISI | PUBMED
41. Marx A, Osborn M, Tzartos S, et al. A striational muscle antigen and myasthenia gravis-associated thymomas share an acetylcholine-receptor epitope. Dev Immunol. 1992;2:77-84. PUBMED
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