Autoimmune antibodies to collagen XIII in myasthenia gravis patients

Tu, Hongmin; Pirskanen-Matell, R.; Heikkinen, Anne; Oikarainen, Tuomo; Risteli, Juha; Pihlajaniemi, Taina

doi:10.1002/mus.25969

Cited by 13 publications

(8 citation statements)

References 30 publications

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“…ColQ antibodies have so far been detected in about 3% of MG patients, including among SNMG, although again they do not appear to be MG specific and no evidence of pathogenicity has been found yet (65). Finally, antibodies against collagen XIII, a transmembrane collagen, have been detected in the serum of about 7% of MG patients with AChR antibodies and 16% of SNMG, but their presence did not correlate with symptom severity (66). Furthermore, they too are not specific for MG, since they are also found in patients with Grave's ophthalmopathy (67).…”

Section: Extracellular Antigensmentioning

confidence: 95%

Myasthenia Gravis: Autoantibody Specificities and Their Role in MG Management

Lazaridis

Tzartos

2020

Front. Neurol.

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Myasthenia gravis (MG) is the most common autoimmune disorder affecting the neuromuscular junction, characterized by skeletal muscle weakness and fatigability. It is caused by autoantibodies targeting proteins of the neuromuscular junction; ~85% of MG patients have autoantibodies against the muscle acetylcholine receptor (AChR-MG), whereas about 5% of MG patients have autoantibodies against the muscle specific kinase (MuSK-MG). In the remaining about 10% of patients no autoantibodies can be found with the classical diagnostics for AChR and MuSK antibodies (seronegative MG, SN-MG). Since serological tests are relatively easy and non-invasive for disease diagnosis, the improvement of methods for the detection of known autoantibodies or the discovery of novel autoantibody specificities to diminish SN-MG and to facilitate differential diagnosis of similar diseases, is crucial. Radioimmunoprecipitation assays (RIPA) are the staple for MG antibody detection, but over the past years, using cell-based assays (CBAs) or improved highly sensitive RIPAs, it has been possible to detect autoantibodies in previously SN-MG patients. This led to the identification of more patients with antibodies to the classical antigens AChR and MuSK and to the third MG autoantigen, the low-density lipoprotein receptor-related protein 4 (LRP4), while antibodies against other extracellular or intracellular targets, such as agrin, Kv1.4 potassium channels, collagen Q, titin, the ryanodine receptor and cortactin have been found in some MG patients. Since the autoantigen targeted determines in part the clinical manifestations, prognosis and response to treatment, serological tests are not only indispensable for initial diagnosis, but also for monitoring treatment efficacy. Importantly, knowing the autoantibody profile of MG patients could allow for more efficient personalized therapeutic approaches. Significant progress has been made over the past years toward the development of antigen-specific therapies, targeting only the specific immune cells or autoantibodies involved in the autoimmune response. In this review, we will present the progress made toward the development of novel sensitive autoantibody detection assays, the identification of new MG autoantigens, and the implications for improved antigen-specific therapeutics. These advancements increase our understanding of MG pathology and improve patient quality of life by providing faster, more accurate diagnosis and better disease management.

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Section: Extracellular Antigensmentioning

confidence: 95%

Myasthenia Gravis: Autoantibody Specificities and Their Role in MG Management

Lazaridis

Tzartos

2020

Front. Neurol.

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“…Recently, anti‐collagen XIII antibodies were identified in MG patients, although their possible involvement in the disease's emergence remains enigmatic (Tu et al, ). Genetically, collagen XIII is linked to NMJ disease in that loss‐of‐function mutations in COL13A1 have been proven to cause CMS19.…”

Section: Introductionmentioning

confidence: 99%

Collagen XIII and Other ECM Components in the Assembly and Disease of the Neuromuscular Junction

Heikkinen

Härönen

Norman

et al. 2019

The Anatomical Record

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Alongside playing structural roles, the extracellular matrix (ECM) acts as an interaction platform for cellular homeostasis, organ development, and maintenance. The necessity of the ECM is highlighted by the diverse, sometimes very serious diseases that stem from defects in its components. The neuromuscular junction (NMJ) is a large peripheral motor synapse differing from its central counterparts through the ECM included at the synaptic cleft. Such synaptic basal lamina (BL) is specialized to support NMJ establishment, differentiation, maturation, stabilization, and function and diverges in molecular composition from the extrasynaptic ECM. Mutations, toxins, and autoantibodies may compromise NMJ integrity and function, thereby leading to congenital myasthenic syndromes (CMSs), poisoning, and autoimmune diseases, respectively, and all these conditions may involve synaptic ECM molecules. With neurotransmission degraded or blocked, muscle function is impaired or even prevented. At worst, this can be fatal. The article reviews the synaptic BL composition required for assembly and function of the NMJ molecular machinery through the lens of studies primarily with mouse models but also with human patients. In‐depth focus is given to collagen XIII, a postsynaptic‐membrane‐spanning but also shed ECM protein that in recent years has been revealed to be a significant component for the NMJ. Its deficiency in humans causes CMS, and autoantibodies against it have been recognized in autoimmune myasthenia gravis. Mouse models have exposed numerous details that appear to recapitulate human NMJ phenotypes relatively faithfully and thereby can be readily used to generate information necessary for understanding and ultimately treating human diseases. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc.

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“…Collagen XIII antibodies have been detected in 7.1% of AChR antibody positive MG patient and 15.8% SNMG sera screened (126). No discernible differences were seen among patients with and without collagen XIII antibodies in terms of symptom manifestation.…”

Section: Antibodies Against Other Antigensmentioning

confidence: 87%

Autoantibody Specificities in Myasthenia Gravis; Implications for Improved Diagnostics and Therapeutics

2020

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Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness and fatiguability of skeletal muscles. It is an antibody-mediated disease, caused by autoantibodies targeting neuromuscular junction proteins. In the majority of patients (∼85%) antibodies against the muscle acetylcholine receptor (AChR) are detected, while in 6% antibodies against the muscle-specific kinase (MuSK) are detected. In ∼10% of MG patients no autoantibodies can be found with the classical diagnostics for AChR and MuSK antibodies (seronegative MG, SN-MG), making the improvement of methods for the detection of known autoantibodies or the discovery of novel antigenic targets imperative. Over the past years, using cell-based assays or improved highly sensitive immunoprecipitation assays, it has been possible to detect autoantibodies in previously SN-MG patients, including the identification of the low-density lipoprotein receptor-related protein 4 (LRP4) as a third MG autoantigen, as well as AChR and MuSK antibodies undetectable by conventional methods. Furthermore, antibodies against other extracellular or intracellular targets, such as titin, the ryanodine receptor, agrin, collagen Q, K v 1.4 potassium channels and cortactin have been found in some MG patients, which can be useful biomarkers. In addition to the improvement of diagnosis, the identification of the patients' autoantibody specificity is important for their stratification into respective subgroups, which can differ in terms of clinical manifestations, prognosis and most importantly their response to therapies. The knowledge of the autoantibody profile of MG patients would allow for a therapeutic strategy tailored to their MG subgroup. This is becoming especially relevant as there is increasing progress toward the development of antigen-specific therapies, targeting only the specific autoantibodies or immune cells involved in the autoimmune response, such as antigen-specific immunoadsorption, which have shown promising results. We will herein review the advances made by us and others toward development of more sensitive detection methods and the identification of new antibody targets in MG, and discuss their significance in MG diagnosis and therapy. Overall, the development of novel autoantibody assays is aiding in the more accurate diagnosis and classification of MG patients, supporting the development of advanced therapeutics and ultimately the improvement of disease management and patient quality of life.

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Autoimmune antibodies to collagen XIII in myasthenia gravis patients

Abstract: High-resolution 3D imaging with 7T MRI demonstrated feasibility for imaging nerve fascicular structures. Muscle Nerve 57: 506-510, 2018.

Cited by 13 publications

References 30 publications

Myasthenia Gravis: Autoantibody Specificities and Their Role in MG Management

Myasthenia Gravis: Autoantibody Specificities and Their Role in MG Management

Collagen XIII and Other ECM Components in the Assembly and Disease of the Neuromuscular Junction

Autoantibody Specificities in Myasthenia Gravis; Implications for Improved Diagnostics and Therapeutics

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