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  • Updated 10.25.2023
  • Released 12.19.2015
  • Expires For CME 10.25.2026

Autoantibodies: disease markers



Advances over the last couple of decades in the field of autoimmune neurology, specifically relating to autoantibody discovery, are tremendous. The number and incidence of known autoreactive antibodies have increased over time due to the ongoing discovery of these biomarkers (173). The discovery of certain antibodies like AQP4 Ab and MOG Ab has led to the recognition of new neurologic disease entities. In the case of paraneoplastic neurologic syndromes, autoreactive antibodies may be directly pathogenic and cause neurologic clinical symptoms; in other cases, they represent an epiphenomenon with no clearly identified role in the pathogenesis or a post-infectious process (as with anti-NMDAR encephalitis after herpes simplex virus encephalitis) (10). Detection of autoreactive antibodies helps to establish a diagnosis and also helps detect occult malignancies. Testing autoreactive antibodies can be quite expensive. Therefore, to avoid futile tests, it is important to know their sensitivity and specificity for the diagnosis or the possibly associated cancer. The reliability of the techniques used for antibody detection is also reviewed in this article.

Key points

• Autoreactive antibodies against central or peripheral nervous system antigens may be useful for diagnosing several neurologic diseases.

• In paraneoplastic neurologic disorders, their detection can also help identify an associated cancer at a stage before it is clinically overt, potentially leading to early successful therapy.

• Testing autoreactive antibodies might often be quite expensive.

• The sensitivity and specificity and the reliability of the commercially used techniques are important to evaluate to avoid useless tests.

Historical note and terminology

Autoreactive antibodies occur in various neurologic disorders involving the central and peripheral nervous system. These antibodies may be directly responsible for the disease process or represent an epiphenomenon without having a specific pathogenic role. The role of autoreactive autoantibodies is well-established in the pathogenesis of neuromuscular junction disorders such as myasthenia gravis and Lambert-Eaton myasthenic syndrome. Myasthenia gravis was first proposed as an autoimmune disorder by Simpson in 1960 (149). The association of anti-acetylcholine receptor (anti-AChR) antibodies with myasthenia gravis was first reported in the 1970s (06). The presence of antibodies to a defined antigen specific to the disease process, clinical response to immunomodulatory therapy, and transmission of the disease to animals by passive transfer of immunoglobulins provide evidence for antibody-mediated autoimmune mechanisms in this and in other neurologic disorders of the peripheral nervous system.

In the CNS, however, the pathogenic role of autoantibodies is not as well-defined and relies on their temporal relationship with the disease onset and the response to immunological therapies. The CNS disorders associated with autoreactive antibodies can be divided into those with known autoantigens, such as neuromyelitis optica with circulating antibodies to aquaporin-4 (93). Similar to myasthenia gravis, there are some patients in whom the association is tight and others in whom no antibodies are identified despite a typical clinical picture. There are other disorders in which no specific antigen has yet been identified, such as multiple sclerosis (88). Various autoreactive antibodies, including anticardiolipin, antinuclear, and antithyroid antibodies, which are usually associated with specific vasculitic or systemic syndromes, may occur in multiple sclerosis patients. Autoimmune diseases do not seem to occur with higher frequency in patients with multiple sclerosis and their family members (129).

Autoantibodies against central or peripheral nervous system antigens can, eventually, occur in paraneoplastic neurologic disorders. Although a pathogenic role for autoantibodies has been established only for some paraneoplastic neurologic disorders, the presence of autoantibodies can be extremely important in the diagnostic workup. In fact, the clinical symptoms and antibodies associated with paraneoplastic neurologic disorders precede the detection of a tumor by several months in almost 80% of patients, and positron emission tomography might detect a tumor or tumor recurrence in 90% of antibody-positive paraneoplastic neurologic disorder patients (96; 68). These antibodies are sometimes highly specific for a particular cancer and can help identify it at a stage before it is clinically overt, potentially leading to early successful therapy.

This article evaluates the usefulness of autoantibody testing for diagnosing neurologic diseases, reviewing the sensitivity and specificity of autoantibody testing. When sensitivity and specificity are indicated or can be calculated from the data of relevant papers, the number of patients and healthy controls or other neurologic disease patients will also be indicated to show reliability.

Autoantibodies are detected with different immunoassays.

Tissue-based assays. Patients’ antibodies are identified in the brain tissue of rodents or primates. The antigen-antibody complex is stained with anti-human-IgG chemically linked to a fluorophore (indirect immunofluorescence) or conjugated to an enzyme, such as peroxidase, that can catalyze a color-producing reaction (indirect immunohistochemistry).

Immunoblot. Antibodies are identified as specific bands. Patients’ antibodies are separated through gel electrophoresis by size, charge, or other differences in individual proteins. Separated antibodies are then transferred onto a nitrocellulose membrane and are identified by specific antibodies. The antigen-antibody complex is stained with peroxidase-conjugated anti-human-IgG.

Cell-based assays. Patients’ antibodies are identified on suitable cell lines (eg, HEK293 cells) transfected with an eukaryotic expression vector (plasmid) encoding the antigen.

Enzyme-linked immunosorbent assay (ELISA). A recombinant antigen is immobilized on a solid support, and the detection antibody is added, forming a complex with the antigen. The antigen-antibody complex is then stained with peroxidase-conjugated anti-human-IgG. This technique allows the determination of antibody titer.

When an autoantibody test is useful for a disease diagnosis, the most relevant technique for each test will also be indicated. This will provide clinicians with important information on autoantibodies that are really useful in the correct diagnosis.

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