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  • Updated 01.18.2024
  • Released 01.18.2024
  • Expires For CME 01.18.2027

Autoantibodies: mechanism and testing



Autoantibodies have long been observed in a variety of diseases affecting various organs, including the central and peripheral nervous systems. Antibody-mediated neurologic disorders have heterogenous presentations and phenotypes, such as encephalopathy (antibodies against N-methyl-D-aspartate [NMDA] receptors and leucine-rich glioma inactivated 1 [LGI1]); demyelination (aquaporin-4 antibodies [AQP4] in neuromyelitis optica spectrum disorder [NMOSD] and myelin oligodendrocyte glycoprotein antibodies [MOG] in MOG-associated disease [MOGAD]); movement disorders, such as chorea (collapsin response mediator protein-5 [CRMP5/CV2]) and parkinsonism (dopamine receptor 2 [DR2]); diencephalic involvement (anti-Ma2); brainstem involvement (immunoglobulin-like cell adhesion molecule 5 [IgLON5], Kelch-like protein 11 [KLH11] and dipeptidyl-peptidase-like protein 6 [DDPX]); myelitis (CRMP5 and glial fibrillary acidic protein [GFAP]); neuromuscular junction, including myasthenia gravis (acetylcholine receptor [AChR] antibodies, muscle specific kinase [MusK], anti-low-density lipoprotein receptor-related protein 4 [LPR4]), and Lambert-Eaton myasthenic syndrome [P/Q type voltage-gated calcium-channel, VGCC]); sensory neuronopathy (anti-Hu); autoimmune sensorimotor and autonomic peripheral neuropathies; and myositides, such as acute necrotizing myopathy with 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMGCR] antibodies. Improved recognition and the exponential discovery of new neuronal and glial autoantibodies have revolutionized the autoimmune neurology field. Most prominently, the overall incidence and prevalence of autoimmune encephalitis has markedly increased over the past several decades and is now considered equivalent to infectious encephalitis (12; 36). As providers interact with growing numbers of patients with autoantibody-associated neurologic disorders, they will be exposed to the novel challenges of autoantibody testing. As such, it is increasingly important to understand the underlying mechanisms of autoantibodies in neurologic disease, their associated clinical syndromes, methods of testing, and common pitfalls. This article aims to address these topics, with special attention on autoantibodies that affect the central nervous system, as well as discuss the indications and new directions for autoantibody testing.

Key points

• Autoantibody-mediated neurologic diseases have heterogenous presentations, showcasing the importance of familiarity with the various clinical phenotypes.

• Autoimmune encephalitis is just as prevalent as infectious encephalitis.

• Correct and prompt diagnosis of autoantibody-mediated neurologic disease is key for the timely treatment of potentially reversible pathologies and identification of any underlying malignancy.

Historical note and terminology

Autoantibody-mediated neurologic syndromes were first described in the 1800s, although the underlying autoimmune pathophysiology was not understood. Paraneoplastic autoimmune encephalitis was described by Oppenheim in 1888, when he reported a 54-year-old woman who presented with neuropsychiatric symptoms and aphasia who was later found to have gastric cancer on autopsy. In 1960, Brierley identified three patients with subacute encephalitis affecting the limbic area, all presenting with memory impairment, depressive symptoms, and behavioral abnormalities; this was coined as “limbic encephalitis” by Corsellis in 1968 (21). Antineuronal nuclear antibody-1 (ANNA-1, also known as anti-Hu) was one of the first antibodies identified. It was initially reported in 1985 in two patients with sensory neuronopathy and small cell lung cancer and was subsequently reported in a case of limbic encephalitis with cerebellar degeneration in the setting of colon adenocarcinoma in 1993 (16; 42; 21). Over the next several decades, more autoantibodies were described in association with encephalitis, among other syndromes, with the most notable being anti-NMDA receptor antibodies, which was described by Dalmau’s group in 2007. They later reported a 100-patient cohort with features of prominent psychiatric symptoms, movement disorders, and seizures, with the presence of ovarian teratomas in a subset of those patients, now commonly known as anti-NMDAR encephalitis (NMDARE) (09; 21).

Autoantibody-mediated demyelinating diseases have a similar timeline; neuromyelitis optica spectrum disorder (NMOSD) was first reported in 1894 by Eugene Devic, who described a syndrome characterized by optic neuritis and myelitis (25). NMOSD was considered a more severe variant of multiple sclerosis for years. In 2004, AQP4 IgG was discovered, followed by the discovery of its antigen a year later, separating NMOSD from multiple sclerosis (24). MOG-associated disease (MOGAD) is unique in that the autoantibody was described prior to the clinical syndrome. Several papers in the 1970s and 1980s hypothesized an immune response to myelin similar to that seen in an experimental autoimmune encephalomyelitis guinea pig animal model. They described an antigenic component of myelin, initially deemed M2 and now known as MOG, thought to be involved with completion and maintenance of the myelin sheath (28). MOG and its immunogenicity have been shrouded with controversy for the better part of nearly 40 years, mainly due to the use of testing methods that allowed antigen denaturation, leading to conflicting results. The emergence of cell-based assays allowed the expression of pathogenic anti-MOG antibodies targeting the native conformation of MOG epitopes. This led to the identification of non–multiple sclerosis demyelinating syndromes, now known as MOG-associated disease or MOGAD (05; 40).

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