Old and Novel Humoral Biomarkers of Autoimmune Myasthenia Gravis

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Autoimmune Myasthenia Gravis (MG) is mediated by pathogenic autoantibodies to components of the postsynaptic muscle endplate at the neuromuscular junction. Due to the clinical heterogeneity of the disease, there is a great need for objective biomarkers for diagnostic as well as therapeutic purposes. Humoral biomarkers of MG can be divided into two categories: 1) autoantibodies; and 2) other immune-related molecules including inflammatory proteins, microRNA, HLA genes.
Regarding autoantibodies, the radio immuno assay (RIA) allows for the detection of IgG1 and IgG3 antibodies directed against the nicotinic acetylcholine receptors (AChRAb) in 85% of the patients with generalized MG, but only in 50% of those with the ocular form. Treatment with acetylcholinesterase inhibitors is very helpful, although immunosuppressive therapy is frequently necessary. Thymoma or thymic hyperplasia can occur, implicating surgery. In AChRAb negative generalized MG patients, a very variable percentage has IgG4 antibodies towards muscle specific tyrosine kinase (MuSKAb): typically, bulbar weakness is the first symptom often associated with neck and respiratory involvement.

Acetylcholinesterase inhibitors are less effective and induce frequent side effects; first and second line suppressive treatments are commonly required. More rarely, IgG towards low density lipoprotein receptor-related protein 4 (Lrp4Ab), agrin or cortactin are detected: if there are not associated AChRAb or MuSKAb, often patients present with milder forms of MG. Few patients have been demonstrated positive to AChRAb or to other autoantibodies with the more sensitive cell based assay. Finally, titin and ryanodine receptor antibodies can occur in association with AChRAb MG, indicating the possibility of thymoma or, in the context of late-onset myasthenia gravis, severe disease with a need for long-term immunosuppression and no response to thymectomy.

In regards to immune-related molecules, two recent studies reported increased serum levels of a proliferation-inducing ligand (APRIL), cytokines IL-19, IL-20, IL-28A and IL-35, matrix metalloproteinase 10 (MMP-10), which is a member of the metalloproteinase family, transforming growth factor alpha (TGF-α), a growth factor that has important roles for epithelial proliferation and differentiation, and the extracellular newly identified receptor for advanced glycation end-products binding protein (EN-RAGE, also known as protein S100-A12), a protein that binds to calcium, zinc and copper. These three last proteins are involved in the cell cycle progression and differentiation, and play multiple roles in immunity response. Circulating microRNAs (miRNA) have been reported to be potential biomarkers in some MG patients; in particular, miR-150-5p and miR-21-5p for AChRAb MG and the let7 family for MuSKAb MG. These miRNA are involved in the development of T- and B-cell autoimmune responses. Some HLA associations have been reported, such as DR3-B8-A1 in early onset AChRAb MG and DR14, DR16 and DQ5 in MuSKAb MG.

Characterization of novel humoral biomarkers is a topic of great importance for diagnosis, prognosis and therapy of the various subgroups of MG, although it remains a partially fulfilled clinical need. Other serum biomarkers are currently the subject of active research.

Abstract

Chapter 1. Introduction
1.1. Autoimmune Myasthenia Gravis
1.2. Pathogenesis of MG: Immune System
1.3. Pathogenesis of MG: Thymus
1.4. Humoral Biomarkers for MG

Chapter 2. Acetylcholine Receptor Antibodies

Chapter 3. Muscle-Specific Receptor Tyrosine Kinase Antibodies

Chapter 4. Low-Density Lipoprotein Receptor-Related Protein 4 Antibodies

Chapter 5. Striational Antibodies
5.1. Introduction
5.2. Rapsyn Antibodies
5.3. Titin Antibodies
5.4. Ryanodine Receptor Autoantibodies
5.5 Kv1.4 Autoantibodies
5.6. Conclusion

Chapter 6. Agrin Antibodies

Chapter 7. Collagen Q Antibodies

Chapter 8. Cortactin Antibodies

Chapter 9. Cytokines, Crmp5, Presynaptic Voltage-Gated Calcium Channel Antibodies of the P/Q and N-Type, Glutamic Acid Decarboxylase 65 and Other Autoantibodies

Chapter 10. Biomarkers Related to B Lymphocyte
10.1. Activated B Cells and Plasma Cells
10.2. Regulatory B Cells [300]

Chapter 11. Biomarkers Related to T Lymphocyte
11.1. T Cell Receptor
11.2. T Helper Cells
11.3. Follicular CD4+ Th Cells
11.4. CD4+CD25+ Regulatory T Cells

Chapter 12. Inflammatory Proteins

Chapter 13. Serum Albumin, Uric Acid and Other Antioxidants as Biomarkers in MG

Chapter 14. Epigenetic Markers

Chapter 15. Genetic DNA Markers of MG

Chapter 16. Sex Hormones, Conclusion, References

Keywords: Myasthenia, biomarker, acetylcholine receptor, muscle specific kinase, autoimmune disorder, cell based assay, double seronegative, enzyme-linked immunosorbent assay, low density lipoprotein receptor-related protein 4, radioimmune precipitation assay, agrin, rapsyn, titin, ryanodine receptor, Kv1.4, striational antibody, collagen Q, cortactin, CRMP5, presynaptic voltage-gated calcium channel, glutamic acid decarboxylase 65, regulatory B cell, T cell receptor, T helper cell, follicular CD4+ T helper Cell, B-cell activating factor, cytotoxic T lymphocyte-associated antigen-4, interleukin, resistin, heat shock protein, toll-like receptor, human serum albumin, uric acid, epigenetics, miRNA, DNA, HLA, GWAS.

This book was written for Neurologists, neurosurgeons, psychiatrists, other clinicians and trainees at all levels who treat neurological patients.

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