Antibody Seropositive Myasthenia Gravis Research Articles

Circulating miRNAs as Potential Biomarkers in Myasthenia Gravis: Tools for Personalized Medicine.

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies which attack receptors at the neuromuscular junction. One of the main difficulties in predicting the clinical course of MG is the heterogeneity of the disease, where disease progression differs greatly depending on the subgroup that the patient is classified into. MG subgroups are classified according to: age of onset [early-onset MG (EOMG; onset ≤ 50 years) versus late-onset MG (LOMG; onset > 50 years]; the presence of a thymoma (thymoma-associated MG); antibody subtype [acetylcholine receptor antibody seropositive (AChR+) and muscle-specific tyrosine kinase antibody seropositive (MuSK+)]; as well as clinical subtypes (ocular versus generalized MG). The diagnostic tests for MG, such as antibody titers, neurophysiological tests, and objective clinical fatigue score, do not necessarily reflect disease progression. Hence, there is a great need for reliable objective biomarkers in MG to follow the disease course as well as the individualized response to therapy toward personalized medicine. In this regard, circulating microRNAs (miRNAs) have emerged as promising potential biomarkers due to their accessibility in body fluids and unique profiles in different diseases, including autoimmune disorders. Several studies on circulating miRNAs in MG subtypes have revealed specific miRNA profiles in patients’ sera. In generalized AChR+ EOMG, miR-150-5p and miR-21-5p are the most elevated miRNAs, with lower levels observed upon treatment with immunosuppression and thymectomy. In AChR+ generalized LOMG, the miR-150-5p, miR-21-5p, and miR-30e-5p levels are elevated and decrease in accordance with the clinical response after immunosuppression. In ocular MG, higher levels of miR-30e-5p discriminate patients who will later generalize from those remaining ocular. In contrast, in MuSK+ MG, the levels of the let-7 miRNA family members are elevated. Studies of circulating miRNA profiles in Lrp4 or agrin antibody-seropositive MG are still lacking. This review summarizes the present knowledge of circulating miRNAs in different subgroups of MG.

O-33 Cognitive dysfunction in mice with MuSK + myasthenia gravis

Background Reports on cognitive dysfunction in muscle specific tyrosine kinase (MuSK) antibody seropositive myasthenia gravis (MG) patients, led us to study cognitive dysfunction in the MuSK + passive transfer MG (PTMG) model of mice. Methods Twelve 7-week-old female wild-type C57BL/6 J mice were passively immunized for 14 days with IgG from different MuSK + MG patients and 12 control mice were included into the study. Mice were evaluated with clinical, neurophysiological and behavioral tests [Barnes maze (BM) and novel object recognition (NOR)]. In the end of the study, the mice were euthanized, and muscles were immunostained to evaluate the postsynaptic membrane. Results Two-thirds of the immunized mice developed some myasthenic weakness (grade 0.5–2.0) and did not gain weight during the study. Four immunized mice revealed decrement on RNS on the day 15. In behaviour studies MuSK + PTMG mice spent less time exploring the novel object in the NOR test (MuSK + PTMG 36.4% ± 14.0 vs controls 52.4% ± 13.0, p = 0.02). On the contrary, the Barnes maze test could not demonstrate difference in spatial memory between the groups. Postsynapses of MuSK + PTMG mice were significantly more fragmented and lost their pretzel-shape in comparison to control mice (omohyoid muscle in MuSK + PTMG mice 3.3 ± 1.7 vs control mice 2.7 ± 1.4, p Conclusions We found that unrelated to muscle weakness and regardless of rodents’ innate preference of novelty, recognition memory was affected among MuSK + PTMG mice that provides support for the cognitive dysfunction among MuSK + MG patients.

Evaluation of coexisting polymyositis in feline myasthenia gravis: A case series

Acquired myasthenia gravis (MG) is relatively uncommon in cats. In humans, MG may be associated with other immune-mediated disorders, in particular polymyositis (PM). In this study, we described in-depth electrodiagnostic findings and pathological changes in muscles of cats diagnosed with MG, and assessed the presence of concurrent PM. Six cats with confirmed acetylcholine receptor antibody seropositive MG, and two suspected cases with clinical signs and electrophysiological changes consistent with MG, were reviewed. All animals presented with severe typical signs of generalized weakness and/or fatigability, resembling late-onset MG in humans, in addition to regurgitation. Five cats presented a cranial mediastinal mass, with 3 confirmed as thymoma. Repetitive nerve stimulation revealed a decrement of the compound muscle action potential in all tested cases, starting from low frequencies of stimulation. Serum creatine kinase activity was increased in 6/8 cats. Muscle biopsies performed in 5 cats revealed varying degrees of mixed mononuclear cell infiltrates, positive for the leukocyte markers CD3/CD4/CD8 and CD11b. Further MHC-1/C5b-9 positive sarcolemmal deposits were identified in all tested cases, with or without thymoma. This study documents an association of MG and PM in cats, and provides further support for feline MG as a relevant animal model of human MG.

Isolation and functional characterization of anti-acetylcholine receptor subunit-specific autoantibodies from myasthenic patients: Receptor loss in cell culture

The muscle nicotinic acetylcholine receptor (nAChR) is the major autoantigen in the autoimmune disease myasthenia gravis (MG), in which autoantibodies bind to, and cause loss of, nAChRs. Antibody-mediated nAChR loss is caused by the action of complement and by the acceleration of nAChR internalization caused by antibody-induced cross-linking of nAChR molecules (antigenic modulation). To obtain an insight into the role of the various anti-nAChR antibody specificities in MG, we have studied nAChR antigenic modulation caused by isolated anti-subunit autoantibodies. Autoantibodies against the nAChR α or β subunits were isolated from four MG sera by affinity chromatography on columns carrying immobilized recombinant extracellular domains of human nAChR expressed in the yeast Pichia pastoris. The isolated anti- α and anti- β autoantibodies, as well as untreated MG sera, induced nAChR antigenic modulation in TE671 cells. Partially antibody-depleted sera exhibited reduced modulating activity, whereas a serum completely depleted of anti-nAChR antibodies exhibited no nAChR modulation. Interestingly, the anti- α autoantibodies were, on average, ∼ 4.3 times more effective than the anti- β autoantibodies. The present work supports the notion that anti-nAChR autoantibodies may be the sole nAChR-reducing factor in anti-nAChR antibody-seropositive MG, and that anti- α-subunit autoantibodies are the dominant pathogenic autoantibody specificity.

Increasing incidence of late-onset anti–AChR antibody–seropositive myasthenia gravis

The incidence of myasthenia gravis (MG) from 1970 through 1999 was studied in an area with 2.3 million inhabitants. The mean annual incidence rate of early-onset MG was constant at 3.5 x 10(-6). In late-onset MG, the rate increased from 4.7 to 20.8 x 10(-6). The two onset types of MG may thus be distinct disorders. The author hypothesized that late-onset nonthymoma anti-acetylcholine receptor antibody-seropositive MG may be provoked by environmental factors.