Galactosylation of serum immunoglobulin G in myasthenia gravis with different autoantibodies.

Myasthenia gravis (MG) is a disease with impaired transmission at the neuromuscular junction, characterised by weakness and fatigability of skeletal muscles. In acquired autoimmune MG, antibodies against acetylcholine receptor (AChRAb) or muscle-specific tyrosine kinase (MuSKAb) are present. There is not much data about immunoglobulin G (IgG) galactosylation in MG, and none based on interactions with lectins. This study aims to examine IgG galactosylation in two types of myasthenia, using affinity immunoelectrophoresis with lectin concanavalin A (Con A). Affinity of Con A-IgG interaction, expressed as retardation coefficient (R), indicated the presence of degalactosylated IgG. The average R values were significantly different between three examined groups, being the lowest in controls (healthy subjects), higher in acetylcholine receptor (AChR) MG, and the highest in muscle-specific tyrosine kinase (MuSK) MG (ANOVA, p < .05). This indicated decreased galactosylation of IgG in both types of MG compared to controls, more pronounced in MuSK MG. IgG galactosylation was also investigated in relation to the disease severity score, determined according to the Myasthenia Gravis Foundation of America (MGFA) criteria, at the time of diagnosis, nadir of the disease and last check-out visit. The average R values for mild disease (stages I-IIIa) were significantly lower than for severe disease (stages IIIb-V), both at the time of diagnosis (p < .05), and at the nadir of the disease (p < .05). Thus, IgG galactosylation was associated with the presence of specific autoantibodies in MG, as well as with disease severity for both types of MG, and may be a predictive marker of MG outcome.

The expanding field of IgG4-mediated neurological autoimmune disorders.

At least 13 different disease entities affecting the central nervous system, peripheral nervous system and connective tissue of the skin or kidneys are associated with immunoglobulin G4 (IgG4) immune reactivity. IgG4 has always been considered a benign, non-inflammatory subclass of IgG, in contrast to the well-known complement-activating pro-inflammatory IgG1 subclass. A comprehensive review of these IgG4 autoimmune disorders reveals striking similarities in epitope binding and human leukocyte antigen (HLA) associations. Mechanical interference of extracellular ligand-receptor interactions by the associated IgG4 antibodies seems to be the common/converging disease mechanism in these disorders.

A retrospective multicenter study on clinical and serological parameters in patients with MuSK myasthenia gravis with and without general immunosuppression.

Introduction: Muscle-specific kinase (MuSK)- myasthenia gravis (MG) is caused by pathogenic autoantibodies against MuSK that correlate with disease severity and are predominantly of the IgG4 subclass. The first-line treatment for MuSK-MG is general immunosuppression with corticosteroids, but the effect of treatment on IgG4 and MuSK IgG4 levels has not been studied. Methods: We analyzed the clinical data and sera from 52 MuSK-MG patients (45 female, 7 male, median age 49 (range 17-79) years) from Italy, the Netherlands, Greece and Belgium, and 43 AChR-MG patients (22 female, 21 male, median age 63 (range 2-82) years) from Italy, receiving different types of immunosuppression, and sera from 46 age- and sex-matched non-disease controls (with no diagnosed diseases, 38 female, 8 male, median age 51.5 (range 20-68) years) from the Netherlands. We analyzed the disease severity (assessed by MGFA or QMG score), and measured concentrations of MuSK IgG4, MuSK IgG, total IgG4 and total IgG in the sera by ELISA, RIA and nephelometry. Results: We observed that MuSK-MG patients showed a robust clinical improvement and reduction of MuSK IgG after therapy, and that MuSK IgG4 concentrations, but not total IgG4 concentrations, correlated with clinical severity. MuSK IgG and MuSK IgG4 concentrations were reduced after immunosuppression in 4/5 individuals with before-after data, but data from non-linked patient samples showed no difference. Total serum IgG4 levels were within the normal range, with IgG4 levels above threshold (1.35g/L) in 1/52 MuSK-MG, 2/43 AChR-MG patients and 1/45 non-disease controls. MuSK-MG patients improved within the first four years after disease onset, but no further clinical improvement or reduction of MuSK IgG4 were observed four years later, and only 14/52 (26.92%) patients in total, of which 13 (93.3%) received general immunosuppression, reached clinical remission. Discussion: We conclude that MuSK-MG patients improve clinically with general immunosuppression but may require further treatment to reach remission. Longitudinal testing of individual patients may be clinically more useful than single measurements of MuSK IgG4. No significant differences in the serum IgG4 concentrations and IgG4/IgG ratio between AChR- and MuSK-MG patients were found during follow-up. Further studies with larger patient and control cohorts are necessary to validate the findings.

Is paravertebral muscles edema a consequence of neurogenic changes in MuSK-positive myasthenia gravis?

Anti-MuSK myasthenia gravis (Anti-MuSK MG) is a chronic autoimmune disease caused by complement-independent dysfunction of the agrin-MuSK-Lrp4 complex, accompanied by the development of the pathological muscle fatigue and sometimes muscle atrophy. Fatty replacement of the tongue, mimic, masticatory and paravertebral muscles, revealed by muscle MRI and proton magnetic resonance spectroscopy (MRS), is considered to be a consequence of the myogenic process in anti-MuSK antibody MG in the patients with a plenty long course of the disease. However, in most experimental studies on animal models with anti-MuSK MG, complex presynaptic and postsynaptic changes are revealed, accompanied by the functional denervation of masticatory and paravertebral muscles predominantly. This study presents the MRI, nerve conduction studies (NCS), repetitive nerve stimulation (RNS) and electromyography (EMG) of neurogenic lesions of the axial muscles (m. Multifidus Th12, L3-L5; m. Erector spinae L4-L5) in two patients K. (51 years old), and P. (44 years old), both of whom were having weakness of the paravertebral muscles for 2-4 months due to anti-MuSK MG. The clinical manifestations, as well as the edematous changes in the paravertebral muscles, regressed after therapy. Thus, these clinical examples may confirm the presence of the neurogenic changes at an early stage of anti-MuSK myasthenia gravis and indicate importance of immediate initiation of therapy to avoid the development of muscle atrophy and fatty infiltration.

Anti-Neuronal IgG4 Autoimmune Diseases and IgG4-Related Diseases May Not Be Part of the Same Spectrum: A Comparative Study.

Background: IgG4 is associated with two emerging groups of rare diseases: 1) IgG4 autoimmune diseases (IgG4-AID) and 2) IgG4-related diseases (IgG4-RLD). Anti-neuronal IgG4-AID include MuSK myasthenia gravis, LGI1- and Caspr2-encephalitis and autoimmune nodo-/paranodopathies (CNTN1/Caspr1 or NF155 antibodies). IgG4-RLD is a multiorgan disease hallmarked by tissue-destructive fibrotic lesions with lymphocyte and IgG4 plasma cell infiltrates and increased serum IgG4 concentrations. It is unclear whether IgG4-AID and IgG4-RLD share relevant clinical and immunopathological features. Methods: We collected and analyzed clinical, serological, and histopathological data in 50 patients with anti-neuronal IgG4-AID and 19 patients with IgG4-RLD. Results: A significantly higher proportion of IgG4-RLD patients had serum IgG4 elevation when compared to IgG4-AID patients (52.63% vs. 16%, p = .004). Moreover, those IgG4-AID patients with elevated IgG4 did not meet the diagnostic criteria of IgG4-RLD, and their autoantibody titers did not correlate with their serum IgG4 concentrations. In addition, patients with IgG4-RLD were negative for anti-neuronal/neuromuscular autoantibodies and among these patients, men showed a significantly higher propensity for IgG4 elevation, when compared to women (p = .005). Last, a kidney biopsy from a patient with autoimmune paranodopathy due to CNTN1/Caspr1-complex IgG4 autoantibodies and concomitant nephrotic syndrome did not show fibrosis or IgG4+ plasma cells, which are diagnostic hallmarks of IgG4-RLD. Conclusion: Our observations suggest that anti-neuronal IgG4-AID and IgG4-RLD are most likely distinct disease entities.

Seropositive Muscle-Specific Tyrosine Kinase Myasthenia Gravis Presenting as a Late-Onset Isolated Sixth Nerve Palsy: A Case Report and a Brief Review of Subtypes of Myasthenia Gravis.

Autoimmune myasthenia gravis (MG) is a well-characterized post-synaptic disorder of neuromuscular transmission. Immunologically, there is complement activation with autoantibodies binding to the acetylcholine receptor (AChR), leading to cross-linking and internalization of the receptor. The diminished functional clustering leads to impaired folding of the post-synaptic membrane. The antibodies generated by the autoimmune process are directed at the various components of the post-synaptic membrane and its scaffolding, including the AChR, muscle-specific tyrosine kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), and the other recently described epitopes including the extracellular membrane proteins agrin and collagen Q (ColQ). MuSK MG is phenotypically different from classic AChR-antibody-mediated MG by a more frequent presentation of bulbar weakness, less responsiveness to symptomatic therapy with acetylcholinesterase inhibitors, the absence of a thymoma, and a better therapeutic response to a cluster of differentiation (CD-20) B-cell therapy such as rituximab. The pleiotropic ocular findings of ocular MG include ptosis, fluctuating and variable involvement of cranial nerves III, IV, and VI, pseudo-internuclear ophthalmoplegia (INO), near-complete or complete ophthalmoplegia, and variable gaze palsies. To our knowledge, we present one of the very few reported cases of MuSK MG presenting as isolated sixth nerve palsy. The localization of a sixth nerve palsy with lateral rectus muscle weakness can be due to disease anywhere along its path from the abducens nucleus, coursing at the skull base through Dorello's canal, through the cavernous sinus, and along its path through the superior orbital fissure and into the orbits. A painless sixth nerve palsy should alert the clinician to MuSK-MG as we outline in this case report.

Tacrolimus inhibits Th1 and Th17 responses in MuSK-antibody positive myasthenia gravis patients.

Muscle specific tyrosine kinase antibody positive myasthenia gravis (MuSK- MG) is characterized by autoantibodies against the MuSK protein of the neuromuscular junction resulting in weakness of bulbar and proximal muscles. We previously demonstrated that patients with MuSK-MG have increased pro-inflammatory Th1 and Th17 responses. Tacrolimus, an immunosuppressant used in AChR-MG and transplantation patients, inhibits T cell responses through interference with IL-2 transcription. The therapeutic efficacy and immunological effect of tacrolimus in MuSK-MG is unclear. In the current study we examined the proliferation, phenotype and cytokine production of CD4+ and CD8+ T cells in peripheral blood mononuclear cells of MuSK-MG following a 3-day in vitro culture with or without tacrolimus. We determined that tacrolimus profoundly suppressed CD4 and CD8 T cell proliferation and significantly suppressed Th1 and Th17 responses, as demonstrated by a reduced frequency of IFN-γ, IL-2, and IL-17 producing CD4 T cells and reduced frequencies of IFN-γ and IL-2 producing CD8 T cells. Tacrolimus also inhibits pathogenic Th17 cells coproducing IL-17 and IFN-γ. In addition, tacrolimus suppressed follicular T helper cell (Tfh) and regulatory T helper cell (Treg) subsets. These findings provide preliminary support for tacrolimus as a potential alternative immunosuppressive therapy for MuSK-MG.