Autoantibodies: mechanism and testing …

Neuroimmunology

Updated 01.18.2024
Released 01.18.2024
Expires For CME 01.18.2027

Autoantibodies: mechanism and testing

Authors: Lama Abdel Wahed MD, Erik Arneson MD

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Editor: Anthony T Reder MD

Autoantibodies: mechanism and testing

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Introduction

Overview

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).

Description

	• Common triggers for autoimmunity include infections, tumors, and iatrogenic causes, such as the use of immune checkpoint inhibitors in patients with cancer.
	• Autoantibodies against cell surface antigens are directly pathogenic and are typically responsive to immunosuppressant therapy.
	• Autoantibodies against intracellular antigens are not pathogenic but serve as biomarkers for cytotoxic T-cell activity, and the majority are associated with occult malignancy.
	• Onconeural autoantibodies against intracellular antigens are less responsive to immunosuppressant therapy given irreversible neuronal loss.

Mechanism of autoantibody activity

Autoimmunity, in general, is due to overactivity of the humoral immune response, causing it to be directed against a healthy organ system. During normal development, the B-cell receptor, a membrane-tethered antigen receptor on B cells, is secreted as an antibody when the B cells mature into plasmablasts and plasma cells, also collectively known as antibody-secreting cells. The B-cell receptor is subject to random recombination, leading to an extensive variety of B-cell receptors against both foreign and self targets (41). These autoreactive B cells are subsequently selected against at several stages in the bone marrow and periphery, mediated by regulatory T cells and various cytokines, in addition to apoptosis or receptor editing (03; 27; 41). Failure of these regulatory checkpoints or inappropriate expansion of B cells selective towards self-antigen can lead to autoantibody-mediated diseases.

Common triggers for loss of immune tolerance include infectious, neoplastic, and iatrogenic triggers, such as the use of novel immune checkpoint inhibitors in patients with cancer. When the trigger is neoplastic, the antitumor immune response occurs against intracellular or cell surface onconeural proteins expressed by malignant cells but also present coincidentally in neural and glial cells, leading to a paraneoplastic neurologic phenomenon. On apoptosis of tumor cells, the innate immune response through the dendritic cells mediates the capture, transport, and presentation of onconeural antigens presented on major histocompatibility complex (MHC) to naive T cells in the lymph nodes. More specifically, MHC I presents intracellular antigens to CD8+ cytotoxic T cells, leading to irreversible neuronal loss; MHC II presents surface antigens to CD4+ helper T cells, which, in turn, activates and expands autoreactive B cells, leading to autoantibody-mediated response (27; 17; 35; 36).

A commonly used example is NMDARE, which is mediated by NMDAR antibody, targeting the extracellular domain of the NR1 subunit of NMDAR. This form of encephalitis is associated with neoplastic triggers, classically ovarian teratomas, but can also be provoked after a recent herpes simplex virus (HSV) encephalitis. This is potentially due to HSV destruction of NMDAR-expressing cells in the brain, subsequent clearance of cell debris, and simultaneous presentation of viral antigens and NMDAR antigen to B cells, leading to an autoimmune response (35).

One of the mechanisms described in autoimmunity and B-cell expansion is molecular mimicry, with Guillain-Barre syndrome as a classic example. Initially, patients are infected with an organism like Campylobacter jejuni, which exhibits pathogenic antigens similar in structure to host antigens, specifically the lipids found in peripheral nerve myelin. Activation of B and T cells ensues, causing a cross-reactive response against both invading and self antigens (03). However, it is unclear yet whether there is a role for molecular mimicry between viral and self antigens leading to autoantibody-mediated encephalitis (35). In a considerable number of patients with autoimmune encephalitis, the neoplastic and infectious workup are negative, and the trigger to the autoimmune response remains unknown (08).

The blood-brain barrier significantly prevents the entry of autoreactive B and T cells. Thus, it was thought that this immune response must start within the CNS rather than in the periphery, a mechanism hypothetically supported by certain types of autoimmune encephalitis, like NMDARE, which seroconvert in CSF before serum (08). However, we now know that although the blood-brain barrier is a significant roadblock to immune molecules, such as antibodies and complement, peripheral cells can cross the intact blood-brain barrier, and the immune system can drain cellular and other soluble components from CSF into the cervical lymph nodes (03; 08; 41). This supports a model of the peripheral immune system as the source of humoral cell expansion with subsequent CNS infiltration. Although the initial antigen presentation occurs in the periphery, autoantibody production does eventually occur on both sides of the blood-brain barrier; in fact, autoantibody titers are almost always higher in the serum than in CSF (07). Brain parenchyma can also support B-cell survival, and the detection of oligoclonal bands unique to the CSF is often a sensitive biomarker for intrathecal IgG synthesis in several autoimmune encephalitides (35). On entering the CNS, immune-mediated damage occurs via several proposed mechanisms based on the cellular location of the targeted antigens by autoantibodies.

Autoantibodies targeting surface antigens. These autoantibodies target neuronal or glial surface antigens, including surface membrane receptors, ion channels, and other extracellular antigens. They are directly pathogenic, and their associated syndromes are generally B cell–mediated processes typically responsive to immunotherapy. They can impair surface receptor function directly by reversible modulation and internalization of receptors (leading to decreased receptor density), such as NMDAR and alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor. Alternatively, they may spare the structure but block the function of synaptic receptors without internalization, such as with gamma-aminobutyric acid-B (GABAB) antibodies. Complement activation is limited in autoimmune encephalitides but is the main mechanism of pathology for AQP4 antibodies in NMOSD, leading to complement-dependent cytotoxicity and astrocytic damage. Disruption of protein-protein interaction is characteristic of antibodies of the IgG4-related class, such as LGI1 antibodies, which block the interaction between LGI1 and its receptor A disintegrin and metalloprotease domain 22 (ADAM22) and ADAM23 (35).

Autoantibodies targeting intracellular antigens. These autoantibodies are not directly pathogenic as intracellular antigens are not accessible to antibody binding. However, there is mounting evidence that these autoantibodies can enter cells and contribute to apoptosis and irreversible neural cell death via a T cell–mediated mechanism, hence, serving as excellent biomarkers, especially in the setting of an occult systemic malignancy (03). Given that the majority of intracellular autoantibodies are associated with malignancy (05; 06), they are also coined “onconeural antibodies.” They are rare in children compared to surface antibodies, which are found in children and adults alike (39). The intracellular mechanism of pathogenicity of these antibodies helps to explain why paraneoplastic syndromes involving intracellular autoantibodies respond poorly to therapy, as most available treatments work by reducing circulating autoantibodies. If the antibodies aren’t directly pathogenic, then reducing their levels likely won’t contribute to clinical improvement (05; 06).

Notably, patients with autoimmune neurologic conditions often have family members with systemic autoimmunity. This suggests that there are genetic influences on autoimmune disease pathogenesis and potentially explains the increased risk of developing autoimmune disease in individuals with preexisting immune-mediated disorders (33). For example, human leukocyte antigen (HLA) mediates antigen presentation to T cells. HLA haplotypes are sets of genes located on chromosome 6, and one set is inherited from each biological parent. They are highly polymorphic, leading to extreme diversity among individuals. Specific HLA subunit haplotypes are associated with intracellular, extracellular, and glial autoantibodies. These mostly belong to the IgG4 subclass, such as anti-LGI1 (90% of patients are positive for HLA-DRB*07:01), anti-IgLON5, anti-contactin-associated protein-like 2 (CASPR2), and anti-KLH11. Proving the presence of a strong HLA association has been less successful in NMDARE and NMOSD as both causative autoantibodies are predominantly of the IgG1 subclass (33; 41; 35; 37).

Clinical applications

	• Typical features of autoantibody-associated neurologic diseases include subacute presentation, rapid progression, prior history of cancer or autoimmunity, and recent use of immune checkpoint inhibitors.
	• Localization of symptoms to a compartment in the nervous system and use of phenotype-based panel testing is important in reaching an accurate and prompt diagnosis.
	• Brain MRI is normal in most patients with NMDA receptor encephalitis.
	• The general rule for testing autoantibodies, especially when they affect the central nervous system, is to send paired CSF serum samples for testing.
	• Anti-AQP4 and anti-MOG are more sensitive and specific when tested in serum.
	• Tissue-based indirect immunofluorescence (TIIF) is the screening method of choice for most autoantibodies and is interpreter-dependent. The confirmatory method for autoantibodies against intracellular antigens is with immunoblot; for cell surface antigens, it is with cell-based assays.

Clinical syndromes associated with neuroglial autoantibodies

Autoantibody-associated neurologic disease presents with a wide variety of clinical syndromes affecting either the central or peripheral nervous systems, and on some occasions, both simultaneously (ie, anti-Hu antibodies), with an equally extensive range of laboratory and imaging findings. Some autoantibodies are highly associated with a specific clinical syndrome, whereas others have overlap with other autoantibodies (08). Clinical interpretation of the history, exam findings, and workup are paramount to guiding diagnostic testing. The onset and tempo of neurologic symptoms is usually subacute, less than 3 months in many cases of encephalitis, although some can present more indolently (ie, certain cases of LGI1 encephalitis, anti-DPPX encephalitis, and anti-IgLON5 disease) (10). Imaging findings vary widely in sensitivity and specificity in autoantibody-mediated neurologic diseases, but when present, they can play a key role in the determination of the predominantly affected compartment, which can narrow the differential substantially (43). Other paraclinical findings include CSF analysis; neurophysiological studies, such as EEG and electromyography with nerve conduction studies (EMG/NCS); autoantibody testing of serum and CSF; and extraneural imaging, such as body computed tomography, positron emitted tomography, and ultrasound in the setting of suspected occult malignancy.

Central nervous system involvement

Meningitis. The main autoantibody associated with meningoencephalitis is GFAP IgG; it can also manifest as myelitis and optic neuritis. The hallmark MRI finding of this entity is periventricular linear radial enhancement on postcontrast T1-weighted sequences (43).

GFAP meningoencephalitis (MRI)

Axial T1 postcontrast MRI showing characteristic radial linear enhancement perpendicular to the lateral ventricles (arrows) in a patient with GFAP meningoencephalitis. (Contributed by Dr. Lama Abdel Wahed.)

Encephalitis. Depending on the compartment affected in the CNS, autoimmune encephalitides have heterogenous presentations. The most common autoimmune encephalitis is NMDARE, which affects the parenchyma diffusely, presenting with subacute progressive behavioral and psychiatric symptoms, anterograde memory loss, autonomic instability, seizures, and involuntary movements, such as orofacial dyskinesias (19; 08). Neuropsychiatric symptoms are variable, including depression, anxiety, insomnia, and psychosis (18; 08). CSF will often show a moderate lymphocytic pleocytosis. EEG can also be helpful if it demonstrates the pathognomonic extreme delta brush (18). MRI findings are variable but most frequently normal in 89% of patients initially and in up to 77% on follow-up imaging; occasionally T2 hyperintensities in the bilateral mesial temporal lobes can be seen (43).

Other autoantibodies leading to autoimmune encephalitides are briefly discussed here based on the CNS compartment they have a predilection to, such as the cortex/subcortex in MOG and GABAA antibodies (in contrast to GABAB antibodies, which are usually associated with autoimmune seizures without major MRI abnormalities); the deep brain and basal ganglia leading to autoimmune chorea in CRMP5/CV2 antibodies and parkinsonism in D2 antibodies; the diencephalon in Ma2 antibodies; the limbic system in LGI1 and anti-Hu antibodies; the brainstem in AQP4 IgG-positive NMOSD, IgLON5, and KLH11 antibodies; and, lastly, the cerebellum in GAD65, Purkinje cell antibody 1 (PCA1, or anti-Yo), and metabotropic glutamate receptor 1 antibodies (mGLUR1) (43).

Hyperintensities in acute disseminated encephalomyelitis and dual positivity for MOG and NMDAR antibodies (MRI)

Axial T2 FLAIR sequence MRI (A) showing bilateral posterior confluent hyperintensities, extending into the corpus callosum, restricted to the white matter, and involving the U-fibers. The hyperintensities are more prominent on ...
Hyperintensities in patient with negative serum studies but isolated positive MOG IgG in the CSF (MRI)

Axial T2 FLAIR sequence MRI (A) showing bithalamic hyperintensities (arrows), the FLAIR hyperintensities are also scattered throughout the supra- (arrowheads) and infratentorial areas (not demonstrated) in a patient with negati...
Hyperintensity in AQP4 IgG-positive neuromyelitis optica spectrum disorder (MRI)

Axial T2 FLAIR sequence MRI (A) showing a right-sided dorsal pontine hyperintensity extending into the right middle cerebellar peduncle and abutting the fourth ventricle (arrow) in a patient with AQP4 IgG-positive neuromyelitis...

Some autoantibodies lead to clearly defined clinical syndromes, such as opsoclonus myoclonus ataxia syndrome with anti-Ri (ANNA2) antibodies as well as stiff person syndrome and its variant progressive encephalomyelitis with rigidity and myoclonus (PERM) with GAD65 and amphiphysin and glycine receptor antibodies (01).

Table 1. Autoantibodies And Their Associated Manifestations in the Central Nervous System

Antigen	Intracellular or Cell Surface	Neurologic Clinical Features	Common Cancer Associations (When Known)
AMPAR	Cell surface	Limbic encephalitis	Small cell lung cancer, thymoma
Amphiphysin*	Intracellular	Limbic encephalitis, stiff person syndrome, cerebellar ataxia, polyradiculopathy	Small cell lung cancer, breast cancer
ANNA-1 (Hu)*	Intracellular	Limbic encephalitis, cerebellar ataxia, sensory neuronopathy, opsoclonus myoclonus ataxia syndrome	Small cell lung cancer, neuroblastoma in children
ANNA-2 (Ri)*	Intracellular	Brainstem syndrome, cerebellar ataxia, peripheral neuropathy, opsoclonus myoclonus ataxia syndrome	Small cell lung cancer, breast cancer
AP3B2*	Intracellular	Sensory and/or cerebellar ataxia	Small cell lung cancer, melanoma, neuroblastoma
AQP4	Cell surface	Demyelination: ADEM, optic neuritis, myelitis, area postrema syndrome	Rare, in elderly
CASPR2*	Cell surface	Limbic encephalitis, cerebellar ataxia, sleep disorders, neuromyotonia, painful neuropathy	Thymoma
CRMP5*	Intracellular	Limbic encephalitis, chorea, cerebellar ataxia, polyradiculopathy, optic neuropathy, sensory neuronopathy	Small cell lung cancer, thymoma
D2	Cell surface	Movement disorders (dystonia, oculogyric crises, parkinsonism, chorea)
DPPX	Cell surface	Encephalopathy, brainstem syndrome	Lymphoma
GABAAR	Cell surface	Seizures, encephalopathy, hyperkinetic movement disorders	Thymoma
GABABR	Cell surface	Limbic encephalitis, autoimmune seizures	Small cell lung cancer
GAD65	Intracellular	Limbic encephalitis, stiff person syndrome, cerebellar ataxia
GFAP	Intracellular	Meningoencephalitis, inflammation can extend to the spine causing myelitis, optic neuritis	Ovarian teratoma
GlyRa1	Cell surface	PERM, stiff person syndrome	Thymoma
GRAF1*	Intracellular	Cerebellar ataxia, brainstem syndrome, peripheral neuropathy	Squamous cell carcinoma of the head and neck
IgLON5	Cell surface	Ataxia, chorea, brainstem syndrome, sleep disorders	Thymoma
ITPR1*	Intracellular	Neuropathy, cerebellar ataxia	Wide variety
KLHL11	Intracellular	Rhombencephalitis, cerebellar ataxia, limbic encephalitis	Seminoma and other testicular germ cell tumors
LGI1*	Cell surface	Limbic encephalitis, faciobrachial dystonic seizures, sleep disorders, neuromyotonia, painful neuropathy	Thymoma
Ma1	Intracellular	Brainstem syndrome, cerebellar degeneration	Lung cancer
Ma2	Intracellular	Limbic encephalitis, brainstem syndromes, diencephalic syndrome, parkinsonism, cerebellar degeneration, sleep disorders	Testicular germ cell tumors, lung cancer
mGluR1	Cell surface	Ataxia	Lymphoma
mGluR5	Cell surface	Limbic encephalitis, seizures, hyperkinetic movement disorders	Hodgkin lymphoma
MOG	Cell surface	Demyelination: ADEM, myelitis, optic neuritis Cortical encephalitis
Neurexin-3alpha	Cell surface	Dyskinesias
Neurochondrin	Intracellular	Cerebellar ataxia, brainstem syndrome
NIF*	Intracellular	Encephalopathy, ataxia, myelopathy, polyradiculoneuropathy	Neuroendocrine‐lineage carcinomas (ie, Merkel cell or small cell type)
NMDAR	Cell surface	Limbic encephalitis, orofacial dyskinesias, dysautonomia	Ovarian teratoma
PCA-1 (Yo)*	Intracellular	Cerebellar ataxia, brainstem syndrome, peripheral neuropathy	Ovarian and breast cancer
PCA-2	Intracellular	Encephalopathy, limbic encephalitis, cerebellar ataxia	Small cell lung cancer
PCA-Tr (DNER)	Cell surface	Cerebellar ataxia	Hodgkin lymphoma
Recoverin	Intracellular	Retinopathy	Small cell lung cancer, melanoma, gynecologic cancers
Septin-5	Extracellular	Cerebellar ataxia, opsoclonus myoclonus
Septin-7	Extracellular	Ataxia, myelopathy, encephalopathy
SKOR	Intracellular	Encephalitis, cerebellar degeneration	Adenocarcinoma
TRIM46	Intracellular	Cerebellar syndrome, encephalomyelitis, parkinsonism	Small cell lung cancer, pancreatic cancer, adenocarcinoma, GI malignancy, neuroendocrine carcinoma
ZIC	Intracellular	Cerebellar degeneration	Small cell lung cancer
* May occur in both the central and peripheral nervous systems
Adapted from: (18; 17; 02; 23; 05; 14; 34; 30; 22; 01)

Peripheral nervous system involvement

Autoantibodies can affect any compartment in the peripheral nervous system, starting with the neuromuscular junction with myasthenia gravis and Lambert-Eaton myasthenic syndrome. Myasthenia gravis is most commonly associated with AChR antibodies, and screening for thymoma is recommended. A small subset of seronegative patients is positive for MusK or LPR4 antibodies (01). Lambert-Eaton myasthenic syndrome is associated with P/Q VGCC. Around 50% of patients have underlying cancer, usually small cell lung cancer (17).

Autoantibodies can lead to inflammatory myopathies, like necrotizing myopathy and dermatomyositis, and inflammatory neuropathies, such as acute demyelinating polyneuropathy (AIDP), chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy, sensory ganglionopathy or neuronopathy, autonomic neuropathies, and channelopathies with hyperexcitability and neuromyotonia, such as Isaac (purely peripheral) and Morvan (combination of peripheral and central) syndromes (45).

Table 2. Autoantibodies And Their Associated Manifestations in the Peripheral Nervous System

Antigen	Intracellular or Extracellular	Neurologic Clinical Features	Common Cancer Associations (When Known)
AChR	Extracellular	Myasthenia gravis	Thymoma
ACHR alpha3 subunit	Extracellular	Autonomic neuropathy, myotonia	Bladder cancer, small cell lung cancer
AGNA-1 (SOX1)*	Intracellular	Lambert-Eaton myasthenic syndrome, ataxia, sensory neuropathy, opsoclonus-myoclonus, limbic encephalitis	Small cell lung cancer
Contactin-1	Extracellular	CIDP	Breast cancer? Wide variety
Ga1NAc-GD1a	Extracellular	AIDP
GD1b	Extracellular	Sensory ataxia
GM1	Extracellular	Multifocal motor neuropathy, AIDP
GQ1b	Extracellular	Miller-Fisher syndrome
HMGCR	Intracellular	Necrotizing myopathy
anti-Jo-1	Intracellular	Myositis
LRP4	Extracellular	Myasthenia gravis	Thymoma
MAG	Extracellular	Demyelinating neuropathy	Monoclonal gammopathy
Mi2	Intracellular	Dermatomyositis
MusK	Extracellular	Myasthenia gravis	Thymoma
Myelin protein 0	Extracellular	CIDP
NF155	Extracellular	CIDP
PMP22	Extracellular	CIDP
VGCC*	Extracellular	Lambert-Eaton myasthenic syndrome, cerebellar degeneration, myoclonus	Small cell lung cancer
* May occur in both the central and peripheral nervous systems
Adapted from: (31; 01)

Testing methods

There are several methods for testing neuroglial autoantibodies with different indications. Select clinical laboratories offer reflexive panel-based autoantibody testing. This is preferrable to individual antibody testing given the comprehensiveness and faster turnaround time compared to the substantial diagnostic delays when autoantibodies are tested individually, especially if there aren’t any pathognomonic clinical features that would justify targeted testing, such as faciobrachial dystonic seizures in LGI1 encephalitis. Several commercially available panels are categorized based on the predominant syndromic phenotype. For example, autoimmune encephalopathy panels can assess more than 20 intra- and extracellular autoantibodies known to contribute to autoimmune encephalitis simultaneously compared to a demyelination panel (ie, ordered in the setting of optic neuritis), which will only assess for AQP4 and MOG antibodies (05).

One of the most important steps the managing clinician needs to be aware of is testing both serum and CSF simultaneously, which is applicable in most cases of immune-mediated neurologic diseases, especially those affecting the central nervous system. A few exceptions include anti-AQP4 and anti-MOG, which are known to be more sensitive and specific when tested in serum (29; 05). New studies are showcasing a subset of MOGAD patients who have isolated MOG IgG CSF positivity, so CSF testing may play a future role in further identifying patients with negative serologies but convincing clinical phenotype (04). LGI1 antibodies are better detected in serum than in CSF through the currently available cell-based assays, but other techniques, such as brain immunohistochemistry, show that LGI1 antibodies are at least as frequent in CSF as in serum (10). Otherwise, as most common antibodies seen in autoimmune encephalitis are more specific when tested in CSF, paired serum CSF testing is generally recommended to optimize sensitivity and specificity and identify false positives, especially in patients with atypical clinical presentations and isolated serum positivity.

Testing for neural autoantibodies is frequently two-tiered: screening followed by confirmation. Tissue-based indirect immunofluorescence (TIIF) is the screening test for most neural autoantibodies, both classified and not yet classified. This is the oldest method for antibody detection, used when anti-Hu was originally identified in the 1960s (44), and continues to enable the discovery of new autoantibodies. However, the confirmatory test differs: immunoblots when the autoantibody is against intracellular antigens and cell-based assays for cell surface antigens (05).

TIIF is an immunohistochemistry testing method that uses various sections of animal brain (eg, cortex, hippocampus, cerebellum) and non-brain tissues (eg, gastrointestinal, kidneys) as a substrate to help identify non-organ-specific antibodies. The tissues can be either fresh-frozen or fixed in formalin; then patient serum or CSF is incubated with these sections. If an autoantibody is present, it will bind to the antigen of choice in its natural conformation and will be detectable using fluorescent commercial anti-human secondary antibodies. The fluorescence is visualized under a microscope, and depending on the complex staining patterns, an autoantibody may be identified. The last step is highly dependent on the interpreter’s expertise and skills (05).

Western blot or line blot are other frequently used assays, usually for confirmation of autoantibodies against intracellular antigens detected on TIIF. The substrate is generated from neural tissue solubilized in detergent leading to denaturation of the proteins. They are subsequently separated through electrophoresis, transferred to a film, and incubated with patient CSF or serum, which allows autoantibodies to bind to antigen. Results are further quantified by a fluorescent anti-human secondary antibody conjugated to an enzyme. Western blot and line blot systems are commercially available for onconeural antibodies. They are a convenient and attractive option given the ease of implementation and are less dependent on expertise in interpretation than TIIF (05; 39). However, their use as a screening tool without correlation with a positive TIIF should be with caution given low clinical sensitivity and poor positive predictive value (05). Unlike other autoantibodies against intracellular antigens, GAD65 antibodies are rarely associated with malignancy and may be detected by a highly sensitive method called radioimmunoprecipitation assays. This method was originally designed to detect low titers to optimize detection of type 1 diabetes mellitus. However, low titer GAD65 antibodies do not strongly correlate with neurologic disease, and radioimmunoprecipitation assay results should be cautiously interpreted. As a point of reference, patients with neurologic presentations with characteristic staining on TIIF have radioimmunoprecipitation assay values over 1000-fold higher than the upper limit of normal (05). Other antibodies using the radioimmunoprecipitation assay method for detection include antibodies against ACh receptors and MuSK in myasthenia gravis as well as P/Q VGCC antibodies in Lambert-Eaton myasthenic syndrome (44).

Detection of autoantibodies targeting cell surface antigens require the target antigen to be expressed in its natural confirmation; hence, methods leading to protein denaturation, such as Western blot or line blot and enzyme-linked immunosorbent assay (ELISA) are inappropriate in this context. Therefore, cell-based assays were developed for both extracellular and glial antibody testing (including GFAP antibody, despite its antigen being intracellular), using different mammalian cell lines (most often, human embryonic kidney [HEK]). These cells are transfected with a plasmid encoding target antigens, which allows for expression of said antigens in their native conformation. These cells are subsequently fixed and incubated with patient CSF or serum, along with a fluorescent anti-human secondary antibody to facilitate visualization and scoring (05; 35; 39). Most cell-based assay kits use fixed cells, though live cell formats are available in limited clinical laboratories and have superior clinical performance, especially for detecting AQP4 IgG and MOG IgG. Antigen expression is often higher with cell-based assays than with TIIF; therefore, cell-based assay sensitivity is higher for LGI1 and CASPR2 antibody detection. However, the use of cell-based assays as a single screening test has not been studied extensively and is still associated with pitfalls, such as false positives, so the recommendation remains to use cell-based assays as a reflexive test following TIIF rather than in isolation (05).

Indications for testing

There are no definitive criteria for ordering autoantibody testing, and testing is largely driven by clinical history. Scoring systems are available to predict the likelihood of antibody positivity and autoimmune encephalitis, such as the Antibody Prevalence in Epilepsy and Encephalopathy score (APE2) in patients presenting with cognitive decline or epilepsy (05). The APE2 score uses patient characteristics that are strongly associated with autoimmune etiologies, such as a viral prodrome, subacute rapid progression (1–6 weeks), inflammatory CSF (pleocytosis and elevated protein), brain MRI findings concerning for encephalitis, and characteristic clinical features, including new-onset refractory seizures, neuropsychiatric changes, autonomic instability, facial dyskinesias, faciobrachial dystonic seizures, and cancer diagnosis within 5 years of symptom onset. An APE2 score equal to or greater than 4 (maximum up to 18) is 99% sensitive and 85% specific for autoimmune encephalopathy or epilepsy (13; 11). Applying these scoring systems may help in avoiding cost-ineffective and low-yield testing.

Clinical interpretation, value, and limitations

Autoantibody testing has clinical value that provides information for diagnosis, prognosis, and long-term clinical monitoring. In general, higher antibody titers are more specific. Given the pathogenicity of extracellular autoantibodies, their positivity is associated with disease activity. Additionally, some studies have shown that higher NMDAR antibody titers are associated with an increased likelihood of having an underlying tumor and worsened outcomes (19; 05).

On the other hand, intracellular autoantibodies are frequently not pathogenic, and their titers do not correlate with disease activity. However, intracellular autoantibody titers are highly associated with the presence of cancer, which makes them a valuable biomarker in the evaluation of paraneoplastic neurologic syndromes (17).

There is also consideration for the use of repeated autoantibody testing in the role of clinical monitoring in a subset of cases. CSF NMDAR antibodies are more sensitive than serum for correlation with clinical relapse, and those with good outcomes have a faster and larger drop in CSF antibody titers than those with poorer outcomes (19). Another example, albeit more controversial, is MOG antibody titers in MOGAD. Although the disease can be relapsing in up to 20% in the pediatric population and in up to 50% to 60% in adults, reliable prognostic factors are still under investigation. The serum MOG IgG titers at disease onset do not have a strong predictive value for recovery or relapse. However, persistent seropositivity of high MOG titers may be associated with an increased risk of relapse, but confirmatory studies are needed (04).

Caution should be taken when interpreting autoantibody results. Although extremely useful when acquired in the right clinical context, tests can be fraught with many pitfalls and limitations. Only a handful of labs perform neuroglial autoantibody testing, and even fewer perform panel testing, leading to high costs on the order of several hundred up to a thousand dollars for each separate panel. Research is lacking in analysis of the cost-benefit ratio. A study looking at the cost-effectiveness of routine serum screening for autoimmune encephalitis in patients presenting with first-time psychosis revealed possible benefit, given available data on effective immunotherapy and improved outcome with early detection (38). Further research is required in this area. In addition to cost, long turnaround time of up to 1 to 2 weeks is another barrier to autoantibody testing. Given the aggressive nature of many neurologic conditions associated with autoantibodies and the importance of early and prompt management, providers often make treatment decisions while results are pending. Deficits in the knowledge of autoantibody testing or anxiety towards missing a potentially severe diagnosis are also limiting factors of accurate evaluation. Lack of familiarity with testing will often cause providers to make a variety of errors when ordering tests for autoantibodies. Common misuses found in a retrospective observational study at a tertiary care center included sending single samples on either serum or CSF “non-paired testing,” ordering multiple antibody panels that may not correlate with the appropriate clinical syndrome, and ordering overlapping or accidentally duplicated panels within a 14-day window. Repeat panel testing more than 14 days apart yielded no new information in the vast majority of patients, at which point the results were likely altered by empiric immunosuppressant therapy (15). These practices influence the predictive value of testing and result in false positives or negatives, leading to frequent misdiagnoses in this field. Examples include clinical insignificance of serum results, such as GFAP and glycine antibodies, voltage-gated potassium channel (VGKC) antibodies without LGI1 or CASPR2 specificity, use of commercial kits (for anti-Yo and anti-Sry-like high mobility group box [SOX1]), and not taking titer cutoffs into consideration, such as the case of low serum titers of MOG antibodies and GAD65 antibodies (especially when positivity is isolated to serum without evidence of intrathecal synthesis) (10).

A phenotypical approach guided by the patient’s clinical syndrome and radiological findings is recommended, sending paired samples from both serum and CSF, and avoiding repeat testing unless suspicion remains high for a specific autoantibody and associated syndromes or there is a major change in the clinical state.

New directions

Our understanding of the role of autoantibodies in neurologic disease is rapidly growing, and new autoantibodies continue to be discovered. More remain unknown, a likelihood supported by many documented cases of probable antibody-negative autoimmune encephalitides per the Graus criteria (18), despite optimization of neural antibody testing, including brain immunohistochemistry, and despite ruling out clinically distinct entities, such as ADEM, Bickerstaff encephalitis, and limbic encephalitis. The underlying pathophysiology is hypothesized to be due to an unknown T cell–mediated process or a yet unidentified autoantibody. Given the lack of clear biomarkers, misdiagnosis is common, and research is challenging given the heterogeneity of this cohort. These call for more careful adherence to diagnostic criteria and selection of correct antibody testing methodology, including paired serum-CSF samples. Length of therapy in these cases is controversial, with recommendations of stopping empiric immunotherapy if the response is suboptimal anywhere after 3 months to 1 year (26; 10). Additional multicenter studies are needed to further identify clinical syndromes, novel autoantibodies, and more effective treatment approaches.

With regards to novel therapies and iatrogenic autoimmunity, immune checkpoint inhibitors are increasingly being used for the treatment of various types of cancer. These treatments are monoclonal antibodies that target programmed death protein 1 (PD-1), its ligand PD-L1, or cytotoxic T lymphocyte–associated protein 4 (CTLA-4), which are receptors expressed on T cells. Inhibition of these receptors upregulates T-cell activity and potentiates the immune system to detect and effectively destroy malignant cells. Unfortunately, this mechanism carries a risk of immune-related adverse reactions (irAEs). Neurologic irAEs appear in 1% to 12% of patients treated with immune checkpoint inhibitors and are mostly reported in the peripheral nervous system, such as myasthenia gravis, muscle disease, and immune-mediated neuropathies. Immune checkpoint inhibitors can also affect the CNS, leading to meningitis, encephalitis, vasculitis, demyelination, and transverse myelitis (20).

Hyperintensities in limbic encephalitis after treatment with PD-1 inhibitor

Axial T2 FLAIR sequence MRI showing bilateral mesiotemporal hyperintensities (arrows) in a patient with a history of type 1 diabetes mellitus limbic encephalitis with underlying active non-small cell lung cancer, treated with d...

Neurologic irAEs usually occur early in the treatment course and within the first 6 months from the last immune checkpoint inhibitors infusion. Treatment is usually initiated with immunosuppressant and immunomodulatory therapies, such as corticosteroids or discontinuation of the immune checkpoint inhibitor infusions. Paraneoplastic neurologic syndromes can also occur, either triggered or exacerbated by immune checkpoint inhibitors. It can be difficult to determine if they are purely a neurologic irAE or if they are driven by the underlying cancer; an example of this phenomena is Lambert-Eaton myasthenic syndrome, which rarely occurs in patients on immune checkpoint inhibitors (20). Autoantibodies are common in patients with neurologic irAEs. A small study investigating the presence of autoantibodies in patients with cancer and immune checkpoint inhibitor use, whether they did or did not develop neurologic irAEs, showed high sensitivity and specificity of neuromuscular antibodies in immune checkpoint inhibitor–induced myositis, myocarditis, and myasthenia gravis. Brain-reactive antibodies were common in both patient groups, with and without neurologic irAE; therefore, their pathogenic significance was less clear and not necessarily associated with neurologic symptoms (32). This serves to highlight the importance of using the clinical context as a guide to direct antibody testing rather than empirically checking for autoantibodies. Further investigations are needed to determine which of these autoantibodies (especially the intracellular onconeural autoantibodies) are more likely to increase the risk of developing a paraneoplastic neurologic syndrome and whether immune checkpoint inhibitor use should be avoided in certain cancers that are highly associated with paraneoplastic phenomena, such as small cell lung cancer.

Conclusion

Autoantibodies are a growing cause of neurologic disease, and autoantibody testing is becoming a frequent part of the neurologic work-up. Familiarity with the mechanism of autoantibody-mediated neurologic diseases, common clinical and radiological syndromes, and the testing methodologies available is essential to avoid common diagnostic pitfalls. This leads to more prompt diagnosis and management in a cost-effective and efficient manner, resulting in better outcomes for patients.

Media

References

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

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Lama Abdel Wahed MD

Dr. Abdel Wahed of University of Iowa Hospitals and Clinics has no relevant financial relationships to disclose.
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Erik Arneson MD

Dr. Arneson of the University of Iowa Carver College of Medicine has no relevant financial relationships to disclose.
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Anthony T Reder MD

Dr. Reder of the University of Chicago received honorariums from Biogen Idec, Genentech, Genzyme, and TG Therapeutics for service on advisory boards and as a consultant as well as stock options from NKMax America for advisory work and an unrestricted lab research grant from BMS.
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Autoantibodies: mechanism and testing

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Clinical Categories

Neuroimmunology

Autoantibodies: mechanism and testing …

Autoantibodies: mechanism and testing

Introduction

Overview

Key points

Historical note and terminology

Description

Mechanism of autoantibody activity

Clinical applications

Clinical syndromes associated with neuroglial autoantibodies

Central nervous system involvement

Table 1. Autoantibodies And Their Associated Manifestations in the Central Nervous System

Peripheral nervous system involvement

Table 2. Autoantibodies And Their Associated Manifestations in the Peripheral Nervous System

Testing methods

Indications for testing

Clinical interpretation, value, and limitations

New directions

Conclusion

Media

References

Contributors

Authors

Editor

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Paraneoplastic syndromes

Anti-IgLON5 disease

Anti-LGI1 encephalitis

Progressive encephalomyelitis with rigidity and myoclonus and glycine receptor antibodies

Giant cell arteritis

Chronic inflammatory demyelinating polyradiculoneuropathy

Autoimmune autonomic neuropathy

HTLV-1 associated myelopathy

Autoantibodies: mechanism and testing

Introduction

Overview

Key points

Historical note and terminology

Description

Mechanism of autoantibody activity

Clinical applications

Clinical syndromes associated with neuroglial autoantibodies

Central nervous system involvement

Table 1. Autoantibodies And Their Associated Manifestations in the Central Nervous System

Peripheral nervous system involvement

Table 2. Autoantibodies And Their Associated Manifestations in the Peripheral Nervous System

Testing methods

Indications for testing

Clinical interpretation, value, and limitations

New directions

Conclusion

Media

References

Contributors

Authors

Editor

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Paraneoplastic syndromes

Anti-IgLON5 disease

Anti-LGI1 encephalitis

Progressive encephalomyelitis with rigidity and myoclonus and glycine receptor antibodies

Giant cell arteritis

Chronic inflammatory demyelinating polyradiculoneuropathy

Autoimmune autonomic neuropathy

HTLV-1 associated myelopathy

This is an article preview.
Start a Free Account
to access the full version.