Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders

Punga, Anna Rostedt; Maddison, Paul; Heckmann, Jeannine M; Guptill, Jeffrey T.; Evoli, Amelia

doi:10.1016/s1474-4422(21)00297-0

Cited by 110 publications

(105 citation statements)

References 113 publications

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“…A greater understanding of the regulation of acetylcholinesterase in the NMJ is of relevance to research into how muscular dystrophy, muscular sclerosis and the erratic muscular movements of Parkinson'a disease occur (Jacobson et al, 2001;Aldunate et al, 2004). Changes in the basement membrane have also been observed in these and related medical conditions (Jayadev and Sherwood, 2017;Pozzi et al, 2017;Xu et al, 2018;Johnson, 2019;Punga et al, 2022). Perlecan is a functional component of basement membranes and its application in the repair of basal structures in the blood brain barrier following ischemic stroke continue to improve the recovery of this important structure (Bix, 2013;Bix et al, 2013).…”

Section: Conclusion and Future Researchmentioning

confidence: 99%

Perlecan, A Multi-Functional, Cell-Instructive, Matrix-Stabilizing Proteoglycan With Roles in Tissue Development Has Relevance to Connective Tissue Repair and Regeneration

Hayes

Farrugia

Biose

et al. 2022

Front. Cell Dev. Biol.

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This review highlights the multifunctional properties of perlecan (HSPG2) and its potential roles in repair biology. Perlecan is ubiquitous, occurring in vascular, cartilaginous, adipose, lymphoreticular, bone and bone marrow stroma and in neural tissues. Perlecan has roles in angiogenesis, tissue development and extracellular matrix stabilization in mature weight bearing and tensional tissues. Perlecan contributes to mechanosensory properties in cartilage through pericellular interactions with fibrillin-1, type IV, V, VI and XI collagen and elastin. Perlecan domain I - FGF, PDGF, VEGF and BMP interactions promote embryonic cellular proliferation, differentiation, and tissue development. Perlecan domain II, an LDLR-like domain interacts with lipids, Wnt and Hedgehog morphogens. Perlecan domain III binds FGF-7 and 18 and has roles in the secretion of perlecan. Perlecan domain IV, an immunoglobulin repeat domain, has cell attachment and matrix stabilizing properties. Perlecan domain V promotes tissue repair through interactions with VEGF, VEGF-R2 and α2β1 integrin. Perlecan domain-V LG1-LG2 and LG3 fragments antagonize these interactions. Perlecan domain V promotes reconstitution of the blood brain barrier damaged by ischemic stroke and is neurogenic and neuroprotective. Perlecan-VEGF-VEGFR2, perlecan-FGF-2 and perlecan-PDGF interactions promote angiogenesis and wound healing. Perlecan domain I, III and V interactions with platelet factor-4 and megakaryocyte and platelet inhibitory receptor promote adhesion of cells to implants and scaffolds in vascular repair. Perlecan localizes acetylcholinesterase in the neuromuscular junction and is of functional significance in neuromuscular control. Perlecan mutation leads to Schwartz-Jampel Syndrome, functional impairment of the biomechanical properties of the intervertebral disc, variable levels of chondroplasia and myotonia. A greater understanding of the functional working of the neuromuscular junction may be insightful in therapeutic approaches in the treatment of neuromuscular disorders. Tissue engineering of salivary glands has been undertaken using bioactive peptides (TWSKV) derived from perlecan domain IV. Perlecan TWSKV peptide induces differentiation of salivary gland cells into self-assembling acini-like structures that express salivary gland biomarkers and secrete α-amylase. Perlecan also promotes chondroprogenitor stem cell maturation and development of pluripotent migratory stem cell lineages, which participate in diarthrodial joint formation, and early cartilage development. Recent studies have also shown that perlecan is prominently expressed during repair of adult human articular cartilage. Perlecan also has roles in endochondral ossification and bone development. Perlecan domain I hydrogels been used in tissue engineering to establish heparin binding growth factor gradients that promote cell migration and cartilage repair. Perlecan domain I collagen I fibril scaffolds have also been used as an FGF-2 delivery system for tissue repair. With the availability of recombinant perlecan domains, the development of other tissue repair strategies should emerge in the near future. Perlecan co-localization with vascular elastin in the intima, acts as a blood shear-flow endothelial sensor that regulates blood volume and pressure and has a similar role to perlecan in canalicular fluid, regulating bone development and remodeling. This complements perlecan’s roles in growth plate cartilage and in endochondral ossification to form the appendicular and axial skeleton. Perlecan is thus a ubiquitous, multifunctional, and pleomorphic molecule of considerable biological importance. A greater understanding of its diverse biological roles and functional repertoires during tissue development, growth and disease will yield valuable insights into how this impressive proteoglycan could be utilized successfully in repair biology.

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Section: Conclusion and Future Researchmentioning

confidence: 99%

Perlecan, A Multi-Functional, Cell-Instructive, Matrix-Stabilizing Proteoglycan With Roles in Tissue Development Has Relevance to Connective Tissue Repair and Regeneration

Hayes

Farrugia

Biose

et al. 2022

Front. Cell Dev. Biol.

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“…The pathophysiology of MG has been well-studied and is characterised by predominantly antibody and/or complement-mediated disruption of the neuromuscular junction. Antibodies to the acetylcholine receptor (AChR) are most common, whilst those to muscle specific kinase (MuSK) and low-density lipoprotein (LRP4) occur with lower frequency [3] . In addition, a small proportion of patients with typical MG remain seronegative despite repeated testing, suggesting the presence of other currently unrecognised antibodies.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 vaccination and new-onset myasthenia gravis: A report of 7 cases and review of the literature

Ramdas¹,

Hum²,

Price³

et al. 2022

Neuromuscular Disorders

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“…The cardinal symptoms in MG are fatigable skeletal muscle weakness, with fluctuations in symptoms from day to day or even from hour to hour. Based on affected muscle groups ocular MG (OMG) is localized to the extraocular muscles, and generalized MG (GMG) has a general muscle involvement, including bulbar, axial or limb muscles, or even the diaphragm [ 1 ]. MG is to date one of the best characterized autoimmune and neurological diseases, although important aspects, such as pathogenesis and biomarkers able to predict the disease course and response to treatment are ongoing areas of research.…”

Section: Introductionmentioning

confidence: 99%

“…MG diagnosis is made on the combination of clinical presentation, and either positive Ab serology or abnormal electrophysiological testing, consisting of either repetitive nerve stimulation (RNS) or single fiber electromyography (SFEMG) [ 1 ]. Different MG subgroups have been proposed based on the age of onset [early onset MG (EOMG; onset ≤ 50 years of age); late onset MG (LOMG; onset > 50 years of age)], antibody profile [acetylcholine receptor antibody seropositive (AChR+), muscle specific tyrosine kinase antibody seropositive (MuSK+)], weakness distribution (OMG vs. GMG) and thymic abnormalities [ 1 , 2 ]. Different subgroups reflect important implications in both prognosis and therapeutic management [ 1 , 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…Different MG subgroups have been proposed based on the age of onset [early onset MG (EOMG; onset ≤ 50 years of age); late onset MG (LOMG; onset > 50 years of age)], antibody profile [acetylcholine receptor antibody seropositive (AChR+), muscle specific tyrosine kinase antibody seropositive (MuSK+)], weakness distribution (OMG vs. GMG) and thymic abnormalities [ 1 , 2 ]. Different subgroups reflect important implications in both prognosis and therapeutic management [ 1 , 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

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Towards Personalized Medicine in Myasthenia Gravis: Role of Circulating microRNAs miR-30e-5p, miR-150-5p and miR-21-5p

Beretta

Huang

Punga

2022

Cells

Self Cite

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Myasthenia gravis (MG) is an autoimmune neuromuscular disease characterized by fatigable skeletal muscle weakness with a fluctuating unpredictable course. One main concern in MG is the lack of objective biomarkers to guide individualized treatment decisions. Specific circulating serum microRNAs (miRNAs) miR-30e-5p, miR-150-5p and miR-21-5p levels have been shown to correlate with clinical course in specific MG patient subgroups. The aim of our study was to better characterize these miRNAs, regardless of the MG subgroup, at an early stage from diagnosis and determine their sensitivity and specificity for MG diagnosis, as well as their predictive power for disease relapse. Serum levels of these miRNAs in 27 newly diagnosed MG patients were compared with 245 healthy individuals and 20 patients with non-MG neuroimmune diseases. Levels of miR-30e-5p and miR-150-5p significantly differed between MG patients and healthy controls; however, no difference was seen compared with patients affected by other neuroimmune diseases. High levels of miR-30e-5p predicted MG relapse (p = 0.049) with a hazard ratio of 2.81. In summary, miR-150-5p is highly sensitive but has low specificity for MG, while miR-30e-5p has the greatest potential as a predictive biomarker for the disease course in MG, regardless of subgroup.

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Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders

Cited by 110 publications

References 113 publications

Perlecan, A Multi-Functional, Cell-Instructive, Matrix-Stabilizing Proteoglycan With Roles in Tissue Development Has Relevance to Connective Tissue Repair and Regeneration

Perlecan, A Multi-Functional, Cell-Instructive, Matrix-Stabilizing Proteoglycan With Roles in Tissue Development Has Relevance to Connective Tissue Repair and Regeneration

SARS-CoV-2 vaccination and new-onset myasthenia gravis: A report of 7 cases and review of the literature

Towards Personalized Medicine in Myasthenia Gravis: Role of Circulating microRNAs miR-30e-5p, miR-150-5p and miR-21-5p

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