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- ), 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.
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