Autoimmunity to Ryanodine Receptor and Titin in Myasthenia Gravis is Associated with GM Allotypes

Abstract

Myasthenia gravis (MG) is mediated by autoantibodies against the acetylcholine receptor at the muscle endplate. Some MG patients have in addition antibodies (Ab) to the skeletal muscle proteins ryanodine receptor (RyR) and titin. We have examined GM and KM allotypes, RyR and titin Ab in 44 MG patients (37 thymoma patients and 7 non-thymoma, late-onset patients) and 292 non-MG controls to see if GM/KM allotypes associate with differences in autoantibody production. All patients had titin Ab, and 15 thymoma patients had also RyR Ab. The phenotype GM 1, 2, 3 23 5, 21 was significantly increased in the patients with titin Ab compared with the non-MG controls (chi2 = 4.93, p < 0.05). Thymoma patients with RyR Ab had a higher frequency of the GM 3 23 5 phenotype compared with RyR Ab negative patients and controls (chi2 = 7.1, p < 0.05). KM allotypes did not differ between RyR Ab positive or titin Ab positive patients and controls. GM phenotypes may thus be associated with an autoimmune response against the muscle proteins titin and RyR in MG patients.

The significance of titin antibodies in myasthenia gravis

“…In all subgroups of MG patients (MGT, MGH and MGN), the frequency of titin antibodies is highest in MGT (76 %), increasing up to 95 % of MG patients with epithelial predominant-thymoma. The levels of titin antibodies in our MGT were 80 %, similar to that found in other studies [6,13,16]. Nearly 34 % of MGN [4,20].…”

“…The myoid cells of thymus contain both titin mRNA and titin itself. Titin epitopes and mRNA containing the MIR and N2-line regions of titin are expressed in neoplastic epithelial cells in thymoma [13]. In medullary and mixed thymoma, and especially in normal thymus, immunoreactivity to titin antibodies is rare.…”

“…Titin antibodies produced by a thymoma-derived B cell clone had the same specificity as those found in the serum of the same patient, suggesting that the antibody response was a specific antigen-driven immune response [19]. It has been proposed that aberrant positive selection of titin-reactive T cells within thymoma may be the initiating event for the anti-titin reactivity [13].…”

Skeletal muscle titin: physiology and pathophysiology

“…There are no strong HLA associations in thymoma MG patients, but genetic factors are known to be important [61,62]. Associations with Ig heavy-chain genetic markers including GM pheno-and allotypes as well as with a FckRIIA subtype and certain tumor necrosis factor (TNF)-h T1 and TNF-i 2 alleles have been shown for titin-antibody-positive MG patients with thymoma [63][64][65][66]. This suggests that only thymoma patients with a certain immunogenetic makeup will develop MG and titin antibodies.…”

Immunoglobulin gene polymorphisms are susceptibility factors in clinical and autoantibody subgroups of the idiopathic inflammatory myopathies

“…For the IIM, GM and KM associations have been described in both Mesoamerican and Korean populations (10, 11). While the physiologic mechanisms underlying these associations remain uncertain, several studies have identified higher serum titers of specific subclasses of IgG antibodies (i.e., IgG1, IgG2, IgG3) directed against antigenic epitopes of infectious disease agents or self proteins in persons with specific GM and KM markers (12–18). In an effort to understand if these immune response genes may be important in the pathogenesis of myositis, we have performed a comprehensive examination of GM and KM markers in a large population of European American (EA) (n=514) and African American (AA) (n= 123) adult and juvenile IIM patients representing the major clinicopathologic and autoantibody subgroups.…”