Rigorous experimental and animal studies have shown that conditions, such as autoimmune limbic encephalitis and stiff person syndrome, are mediated and influenced by antibodies [
This systematic review intended to examine syndromes linked to neuronal antibodies. This study involved conducting an extensive, systematic search of the literature to locate articles and studies that examined neuronal antibodies and associated syndromes. Additionally, the search focused on identifying studies providing information regarding the mechanism underlying the development of these conditions. The systematic literature search was conducted in 2018, and the primary goal was to identify and analyze peer-reviewed articles related to the study topic. The Embase, PubMed, and CINAHL databases were searched to identify relevant data sources. In each database, the initial search was performed using precise keywords and terms related to the purpose and objectives of the current review, including neuronal antibodies, associated and neurological syndromes, neuroimmunology, diseases, and pathophysiology. In total, 122 studies were identified in the search. After the successful elimination of duplicates from the initial list, 85 records were chosen and subjected to screening to determine their suitability and relevance to the current study. At the end of the screening process, 20 articles met the inclusion criteria. These peer-reviewed studies were used as the basis for the current investigation. For the studies included for investigating autoantibodies associated with neurological disorders see Table
Studies Investigating Autoantibodies Associated with Neurological Disorders.
Citation | Study Purpose | Design | Findings |
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Lai et al. 2010 [ | To examine the relationship between LGI1 and limbic encephalitis. | Case series | This study identified potassium channels as critical elements in the association between LGI1 and limbic encephalitis. |
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Lancaster et al. 2011 [ | To investigate Caspr2 and the development of encephalitis and NMT. | Systematic review | Caspr2 is a critical autoantigen involved in encephalitis and NMT. |
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Balint et al. 2015 [ | To examine the genetic and neurological bases of dystonia syndromes. | Systematic review | Dystonia syndromes occur due to a combination of factors that can compromise neurological system function. |
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Armangue et al. 2014a [ | To explore the links among brain autoimmunity, Herpes simplex virus, and encephalitis. | Systematic review | Herpes simplex virus can trigger brain autoimmunity and contribute to the development of encephalitis. |
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Arino et al. 2014 [ | To study the effect of cerebellar ataxia and GAD antibodies on the development of neurological disorders. | Systematic review | The study revealed that the immunologic profile of cerebellar ataxia and GAD antibodies contributes to the development of neurological diseases. |
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Lancaster 2016 [ | To explore the development, diagnosis, and treatment of autoimmune encephalitis. | Systematic review | Autoimmune encephalitis leads to deficits in cognition and memory. The autoantibody testing showed the involvement of different types of autoimmune responses in the development of this condition. |
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Berger, Hottenrott, Rauer, Stich 2017 [ | To investigate the prevalence of onconeural antibodies predicting paraneoplastic etiology. | Retrospective cohort study | All patients were negative for antibodies targeting intracellular onconeural antigens, including PNMA1, PNMA2, Zic4, CRMP5, and SOX1. |
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Liu et al. 2017 [ | To explore the clinical course of NMDAR encephalitis. | Systematic review | NMDAR encephalitis is a potentially lethal autoimmune disorder characterized by neurologic and psychiatric symptoms. Anti-NMDAR antibodies play a critical pathogenic role in the development of this condition. |
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Kim et al. 2014 [ | To examine pediatric autoimmune encephalitis cases based on anti-neuronal antibody tests. | Randomized controlled trial | In total, 23 cases were included in this study. Eight patients tested positive for the anti-NMDAR antibody, and an additional patient tested positive for the anti-CASPR2 antibody. |
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Murinson and Guarnaccia 2008 [ | To examine the distinguishing clinical features of amphiphysin Ab-associated stiff person syndrome. | Longitudinal study | In a sample population of 621 patients, 116 patients had GAD antibodies, while another 11 patients had amphiphysin antibodies. |
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Panzer and Dalmau [ | To explore immune-mediated movement disorders with an emphasis on treatment, novel antigens, and clinical–immunological associations. | Systematic review | This study showed that movement disorders are usually immune-mediated. Recognition of clinical–immunological associations in these disorders helps with their diagnosis and successful treatment. |
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Grant and Graus 2009 [ | To examine the development, progression, and treatment of paraneoplastic movement disorders. | Systematic review | This study showed that paraneoplastic movement disorders are rare conditions caused by nonmetastatic autoimmune complications and are associated with different serum antibodies, such as those targeting mGluR1, Ta, Tr, PCA-2, ANNA-3, and VGCCA. |
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Psimaras, Carpentier, and Rossi 2010 [ | To examine a wide range of paraneoplastic patients and characterize alterations in CSF. | Longitudinal study | The researchers found abnormal CSF in 93 percent of the patients. Additionally, an elevated number of cells were reported in 47 percent of the patients before the third month. |
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Rakocevic G, Floeter MK 2012 [ | To examine the clinical spectrum, neurophysiological mechanisms, and treatment options for stiff person syndrome. | Systematic review | This study showed that stiff person syndrome is often idiopathic and related to antibodies against GAD and other proteins that impair GABA synthesis. |
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Jung, Jeong, Kim, Kim, and Jeon 2014 [ | To explore cases of stiff person syndrome with favorable outcomes. | Case study | This study reported that stiff person syndrome is a rare disorder often characterized by spasms and fluctuating muscular rigidity. This condition is often associated with antibodies against GAD. |
Studies Investigating Autoantibodies Associated with Psychiatric Disorders.
Citation | Study Purpose | Design | Findings |
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Jiwon and Levy, 2012 [ | To review the recent literature related to neuromyelitis optica. | Systematic review | This study showed that neuromyelitis optica is a recurrent inflammatory disease that targets the spinal cord and optic nerves. |
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Marignier et al. 2010 [ | To study and discuss the prevalence, development, diagnosis, and management of Devic’s neuromyelitis optica (DNMO). | Systematic review | This study showed that AQP4 antibodies are vital, specific biomarkers linked to the development of DNMO. |
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Höftberger, Rosenfeld, and Dalmau 2015 [ | To provide an update on paraneoplastic neurologic syndromes and examine their relationship with tumors and different types of immune responses. | Meta-analysis | Paraneoplastic neurologic syndromes represent a diverse group of disorders caused by changes in the immune response. Early recognition of these conditions substantially assists in their treatment. |
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Honnorat et al. 2009 [ | To examine the association between paraneoplastic neurological disorders and anti-CV2/CRMP5 and anti-Hu antibodies. | Longitudinal study | This study reported numerous cases of uveo-retinal symptoms, chorea, cerebellar ataxia, and LEMS among patients positive for anti-CV2/CRMP5 antibodies. |
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Irani et al. 2010 [ | To examine the clinical spectrum of antibody-mediated CNS disorders while focusing on limbic encephalitis, Morvan syndrome and acquired NMT. | Systematic review | This study linked LGI1 and CASPR2 to neurological conditions, such as limbic encephalitis, Morvan syndrome, and acquired NMT. |
Antibodies/Autoantibody Targets and Associated Diseases.
Antibody/Autoantibody Targets | Association/Disease | Reference |
---|---|---|
SOX1 | PND | [ |
Ma2/Ta | PND | [ |
PCA-2 | PND | [ |
CV2 | PND | [ |
PNMa1 | PND | [ |
NMDA | Encephalopathic autoimmune disorder | 53 |
GABA | Encephalopathic autoimmune disorder | 54 |
LGI1 | Encephalopathic autoimmune disorder | [ |
Anti-GAD antibodies | Stiff person syndrome | [ |
Anti-TG2, TG3, and TG6 antibodies | CD, Opsoclonus-myoclonus, LEMS, MG, and NMT | [ |
CACNA1C and CACNB2 | Psychotic disorders, MDD, ASD, ADHD, and OCD | [ |
PRISMA flow diagram.
Neuroimmunology is a relevant and rapidly evolving field. The witnessed changes in this particular area are primarily attributed to the discovery of new syndromes and antibodies. Neurological syndromes are prominent and prevalent in the neuroimmunology literature [
The studies reviewed in this paper examined different neurological syndromes that have been linked to neuronal antibodies. One of the conditions featured in these studies is autoimmune limbic encephalitis. Limbic encephalitis is a condition that encompasses a broad spectrum of complications that usually manifest as epileptic seizures, neuropsychiatric symptoms, and memory deficit [
Anti-NMDA receptor (NMDAR) encephalitis is another major neurological syndrome linked to neuronal antibodies. NMDAR encephalitis is regarded as an inflammatory encephalopathic autoimmune disorder associated with specific autoantibodies targeting NMDA glutamate receptors [
Recent research has shown that cerebellar degeneration is a major target of autoimmunity in the central nervous system (CNS) [
Neuropathy is a condition characterized by damaged nerves. The signs of neuropathy include numbness and weakness in the hands and feet. Research has revealed serum antibodies against neural antigens in samples obtained from patients with neuropathy [
Other researchers have focused on autoantibodies related to the emergence and progression of retinopathy. Retinal degeneration manifests as a sudden or gradual loss of vision and abnormal electroretinography (ERG) potentially caused by the targeting of retinal proteins by autoantibodies [
Stiff person syndrome is another rare neurological disease investigated in the selected articles. This condition has both nonparaneoplastic and paraneoplastic origins and manifests in patients as severe progressive muscle stiffness in the lower extremities and spine [
Some researchers have reported that autoantibodies may also be involved in the development of dermatomyositis. For instance, anti-Mi-2 antibodies and anti-SRP antibodies have been found in patients recently diagnosed with dermatomyositis [
Another group of conditions that has been studied is paraneoplastic neurological disorders (PNDs) [
Celiac disease (CD) is another condition that has been linked to neural antibodies. This autoimmune disorder is often triggered by the ingestion of gluten [
Opsoclonus-myoclonus, Lambert-Eaton myasthenic syndrome (LEMS), myasthenia gravis (MG), and neuromyotonia (NMT) are also associated with neural antibodies. Opsoclonus-myoclonus occurs due to damage to the cerebellum and is linked to the expression of TG2, TG3, and TG6 [
Accumulating research suggests that autoantibodies and receptors found on the surface of neurons can affect the development of psychiatric conditions [
Recent genomic investigations and analyses have suggested that autoantibodies and receptors, such as calcium voltage-gated channel subunit alpha 1C (CACNA1C) and calcium voltage-gated channel auxiliary subunit beta 2 (CACNB2), are among the primary risk factors for psychotic disorders, major depressive disorder (MDD), autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD) [
The autoantibodies linked to psychiatric disorders can affect neurodegeneration and neuroinflammation processes [
The current review reveals a spectrum of antibodies linked to the development and progression of neurological diseases [
Existing research further shows that autoantibody screening has evolved to become a vital tool in the diagnosis and subsequent management of neurological diseases. This method is both fast and reliable and involves the use of indirect immunofluorescence and multiparametric indirect immunofluorescence test (IIFT) systems that entail recombinant cell substrates and mosaics of tissue sections to ensure accurate results [
Various therapeutic approaches have applied knowledge regarding autoantibody-related disorders to improve patient well-being. However, the success of some interventions has been limited due to the complex nature of these diseases. A broad spectrum of therapies focus on the significance of T-cell transmitted autoimmunity when managing deleterious diseases, such as CD. Some drugs used in the management of autoimmune disorders, such as interferon-
The field of immune-mediated CNS diseases has attracted the attention of researchers in recent years. This particular field is not only exciting but also challenging as it requires intense research investigating these immunotherapy-responsive conditions. This study aimed to examine how neural antibodies contribute to the development and progression of different clinical conditions. This review shows that immunotherapy responses in patients with neurological diseases indicate the involvement of antibodies in the development and progression of these diseases. Knowledge of these processes has been used as the basis for developing interventions and drugs that could lead to optimal health outcomes. Autoantibodies are important and could be of great use in the future. Further antibody testing and studies should be performed to validate the connection between conditions and antibodies and determine how these connections can be used for diagnostic purposes.
Antibody
Attention-deficit/hyperactivity disorder
Acute motor axonal neuropathy
Type 2 anti-neuronal nuclear antibody
Type 3 anti-neuronal nuclear antibody
Anti-ganglioside member 1
Anti-histidyl-tRNA synthetase
Anti-neuronal nuclear antibody type 1
Anti-nuclear matrix protein 2
Anti-isoleucyl-tRNA synthetase
Anti-threonyl-tRNA synthetase
Anti-alanyl-tRNA synthetase
Anti-type 2 anti-neuronal antibody
Autism spectrum disorder
Aquaporin-4
Calcium voltage-gated channel subunit alpha 1C
Calcium voltage-gated channel auxiliary subunit beta 2
Chronic ataxic neuropathy
Cancer-associated retinopathy
Contactin-associated protein-like 2
Complement component 4B
Celiac disease
Central nervous system
Collapsin response mediator protein 5
Cerebrospinal fluid
Delta/notch-like epidermal growth factor-related receptor
Devic’s neuromyelitis optica
Electroretinography
Glutamic acid decarboxylase
Human leukocyte antigen
Indirect immunofluorescence test
Lambert-Eaton myasthenic syndrome
Leucine-rich glioma-inactivated 1
Protein in the nucleoli of neuron nuclei
Myelin-associated glycoprotein
Melanoma-associated retinopathy
Major depressive disorder
Myasthenia gravis
Metabotropic glutamate receptor 1
N-Methyl-D-aspartate
N-Methyl-D-aspartate receptor
Neuromyotonia
Obsessive-compulsive disorder
Purkinje cell cytoplasmic antibody type 1
Purkinje cell cytoplasmic antibody type 2
Paraneoplastic neurological disorders
Paraneoplastic antigen MA1
Paraneoplastic antigen MA2
SRY-Box 1
Sensory ataxic neuropathy
Tissue transglutaminase type 2
Tissue transglutaminase type 3
Tissue transglutaminase type 6
Voltage-gated potassium channel complex
Zic family member 4.
The author declares that there are no conflicts of interest.