Recently, several autoimmune neurological diseases have been defined by the presence of autoantibodies against different antigens of the nervous system. These autoantibodies have been demonstrated to ...be specific and useful biomarkers, and most of them are also pathogenic. These aspects have increased the value of autoantibodies in neurological practice, as they enable to establish more accurate diagnosis and to better understand the underlying mechanisms of the autoimmune neurological diseases when they are compared to those lacking them. Nevertheless, the exact mechanisms leading to the autoimmune response are still obscure. Genetic predisposition is likely to play a role in autoimmunity, HLA being the most reported genetic factor. Herein, we review the current knowledge about associations between HLA and autoimmune neurological diseases with autoantibodies. We report the main alleles and haplotypes, and discuss the clinical and pathogenic implications of these findings.
We summarize the recent discoveries on genetic predisposition to autoimmune encephalitis and paraneoplastic neurological syndromes (PNS), emphasizing clinical and pathophysiological implications.
The ...human leukocyte antigen (HLA) is the most studied genetic factor in autoimmune encephalitis and PNS. The HLA haplotype 8.1, which is widely known to be related to systemic autoimmunity, has been only weakly associated with a few types of autoimmune encephalitis and PNS. However, the strongest and most specific associations have been reported in a subgroup of autoimmune encephalitis that comprises antileucine-rich glioma-inactivated 1 (LGI1) limbic encephalitis, associated with DRB1∗07 : 01 , anticontactin-associated protein-like 2 (CASPR2) limbic encephalitis, associated with DRB1∗11 : 01 , and anti-IgLON5 disease, associated with DRB1∗10 : 01∼DQA1∗01∼DQB1∗05 . Non-HLA genes have been poorly investigated so far in autoimmune encephalitis, mainly in those lacking HLA associations such as anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, with only a few genome-wide association studies (GWAS) reporting equivocal results principally limited by small sample size.
Genetic predisposition seems to be driven mostly by HLA in a group of autoimmune encephalitis characterized by being nonparaneoplastic and having predominantly IgG4 autoantibodies. The contribution of non-HLA genes, especially in those diseases lacking known or strong HLA associations, will require large cohorts enabling GWAS to be powerful enough to render meaningful results.
Paraneoplastic neurological syndromes (PNSs) are rare complications of systemic cancers that can affect all parts of the central and/or peripheral nervous system. A body of experimental and clinical ...data has demonstrated that the pathogenesis of PNSs is immune-mediated. Nevertheless, the mechanisms leading to immune tolerance breakdown in these conditions remain to be elucidated. Despite their rarity, PNSs offer a unique perspective to understand the complex interplay between cancer immunity, effect of immune checkpoint inhibitors (ICIs), and mechanisms underlying the attack of neurons in antibody-mediated neurological disorders, with potentially relevant therapeutic implications. In particular, it is reported that ICI treatment can unleash PNSs and that the immunopathological features of PNS-related tumors are distinctive, showing prominent tumor-infiltrating lymphocytes and germinal center reactions. Intriguingly, similar pathological substrates have gained further attention as potential biomarkers of ICI-sensitivity and oncological prognosis. Moreover, the genetic analysis of PNS-associated tumors has revealed specific molecular signatures and mutations in genes encoding onconeural proteins, leading to the production of highly immunogenic neoantigens. Other than PNSs, autoimmune encephalitides (AEs) comprise a recently described group of disorders characterized by prominent neuropsychiatric symptoms, diverse antibody spectrum, and less tight association with cancer. Other triggering factors seem to be involved in AEs. Recent data have shed light on the importance of preceding infections (in particular, herpes simplex virus encephalitis) in inducing neurological autoimmune disorders in susceptible individuals (those with a selective deficiency in the innate immune system). In addition, in some AEs (e.g. LGI1-antibody encephalitis) an association with specific host-related factors e.g., human leukocyte antigen (HLA) was clearly demonstrated. We provide herein a comprehensive review of the most recent findings in the field of PNSs and AEs, with particular focus on their triggering factors and immunopathogenesis.
Background
The epidemiology of paraneoplastic neurological syndromes (PNS) remains to be defined. We present here the first population-based incidence study and report the clinical spectrum and ...antibody profile of PNS in a large area in Northeastern Italy.
Methods
We performed a 9-year (2009–2017) population-based epidemiological study of PNS in the provinces of Udine, Pordenone and Gorizia, in the Friuli-Venezia Giulia region (983,190 people as of January 1, 2017). PNS diagnosis and subgroups were defined by the 2004 diagnostic criteria. Age- and sex-adjusted incidence rates were calculated.
Results
We identified 89 patients with a diagnosis of definite PNS. Median age was 68 years (range 26–90), 52% were female. The incidence of PNS was 0.89/100,000 person-years. PNS incidence rates increased over time from 0.62/100,000 person-years (2009–2011), 0.81/100,000 person-years (2012–2014) to 1.22/100,000 person-years (2015–2017). The prevalence of PNS was 4.37 per 100,000. Most common PNS were limbic encephalitis (31%), cerebellar degeneration (28%) and encephalomyelitis (20%). Among antibody (Ab)-positive cases, most frequent specificities included: Yo (30%), Hu (26%), and Ma2 (22%), while the most frequent associated tumors were lung (17%) and breast cancer (16%), followed by lymphoma (12%). PNS developed in 1 in every 334 cancers in our region. Statistically significant associations were observed between cancer type and Ab-specificity (
P
< 0.001), and between neurological syndrome and Ab-specificity (
P
< 0.001).
Conclusions
This first population-based study found an incidence of PNS that approximates 1/100,000 person-years and a prevalence of 4/100,000. Moreover, the incidence of PNS is increasing over time, probably due to increased awareness and improved detection techniques.
As the use of cancer immunotherapy with immune checkpoint inhibitors (ICIs) is expanding rapidly for the treatment of many tumor types, it is crucial that both neurologists and oncologists become ...familiar with the diagnosis and treatment of neurological immune-related adverse events (n-irAEs). These are rare complications, developing in their severe forms in only 1–3% of the patients, but are highly relevant due to their mortality and morbidity burden. The diagnosis of n-irAEs is—however—challenging, as many alternative diagnoses need to be considered in the complex scenario of a patient with advanced cancer developing neurological problems. A tailored diagnostic approach is advisable according to the presentation, clinical history, and known specificities of n-irAEs. Several patterns characterized by distinct clinical, immunological, and prognostic characteristics are beginning to emerge. For example, myasthenia gravis is more likely to develop after anti-programmed cell death protein 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) treatment, while meningitis appears more frequently after anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) therapy. Also, peripheral neuropathy and Guillain–Barré syndrome seem to be more common in patients with an underlying melanoma. Central nervous system disorders (CNS) are less frequent and are more often associated with lung cancer, and some of them (especially those with limbic encephalitis and positive onconeural antibodies) have a poor prognosis. Herein, we provide an update of the recent advances in the diagnosis and treatment of neurological toxicities related to ICI use, focusing on the exclusion of alternative diagnoses, diagnostic specificities, and treatment of n-irAEs.
Contactin‐associated protein‐like 2 (CASPR2) is a cell adhesion protein of the neurexin family. Proteins of this family have been shown to play a role in the development of the nervous system, in ...synaptic functions, and in neurological diseases. Over recent years, CASPR2 function has gained an increasing interest as demonstrated by the growing number of publications. Here, we gather published data to comprehensively review CASPR2 functions within the nervous system in relation to CASPR2‐related diseases in humans. On the one hand, studies on Cntnap2 (coding for CASPR2) knockout mice revealed its role during development, especially, in setting‐up the inhibitory network. Consistent with this result, mutations in the CNTNAP2 gene coding for CASPR2 in human have been identified in neurodevelopmental disorders such as autism, intellectual disability, and epilepsy. On the other hand, CASPR2 was shown to play a role beyond development, in the localization of voltage‐gated potassium channel (VGKC) complex that is composed of TAG‐1, Kv1.1, and Kv1.2. This complex was found in several subcellular compartments essential for action potential propagation: the node of Ranvier, the axon initial segment, and the synapse. In line with a role of CASPR2 in the mature nervous system, neurological autoimmune diseases have been described in patients without neurodevelopmental disorders but with antibodies directed against CASPR2. These autoimmune diseases were of two types: central with memory disorders and temporal lobe seizures, or peripheral with muscular hyperactivity. Overall, we review the up‐to‐date knowledge on CASPR2 function and pinpoint confused or lacking information that will need further investigation.
Contactin‐associated protein‐like 2 is a cell adhesion protein that plays a role in development and along with TAG‐1, Kv1.1, and 1.2, forms the voltage‐gated potassium channel complex. Alterations of the CNTNAP2 gene coding for CASPR2 were identified in patients with neurodevelopmental disorders while antibodies directed against CASPR2 were found in patients with neurological autoimmune diseases. Here, we review all available data on CASPR2 function within the nervous system in relation to CASPR2‐related diseases in humans.
Paraneoplastic neurological syndromes and autoimmune encephalitides are immune neurological disorders occurring or not in association with a cancer. They are thought to be due to an autoimmune ...reaction against neuronal antigens ectopically expressed by the underlying tumour or by cross-reaction with an unknown infectious agent. In some instances, paraneoplastic neurological syndromes and autoimmune encephalitides are related to an antibody-induced dysfunction of ion channels, a situation that can be labelled as autoimmune channelopathies. Such functional alterations of ion channels are caused by the specific fixation of an autoantibody upon its target, implying that autoimmune channelopathies are usually highly responsive to immuno-modulatory treatments. Over the recent years, numerous autoantibodies corresponding to various neurological syndromes have been discovered and their mechanisms of action partially deciphered. Autoantibodies in neurological autoimmune channelopathies may target either directly ion channels or proteins associated to ion channels and induce channel dysfunction by various mechanisms generally leading to the reduction of synaptic expression of the considered channel. The discovery of those mechanisms of action has provided insights on the regulation of the synaptic expression of the altered channels as well as the putative roles of some of their functional subdomains. Interestingly, patients’ autoantibodies themselves can be used as specific tools in order to study the functions of ion channels. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
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•Cancers can trigger autoimmunity against ion channels.•Autoantibodies against neuronal ion channels can impair their functions.•The functional effects of the antibodies depend on epitope specificity.•Patients’ antibodies can be used as selective tools to study ion channels functions.
Autoimmune synaptic encephalitides are recently described human brain diseases leading to psychiatric and neurological syndromes through inappropriate brain-autoantibody interactions. The most ...frequent synaptic autoimmune encephalitis is associated with autoantibodies against extracellular domains of the glutamatergic N-methyl-d-aspartate receptor, with patients developing psychotic and neurological symptoms in an autoantibody titre-dependent manner. Although N-methyl-d-aspartate receptors are the primary target of these antibodies, the cellular and molecular pathway(s) that rapidly lead to N-methyl-d-aspartate receptor dysfunction remain poorly understood. In this report, we used a unique combination of high-resolution nanoparticle and bulk live imaging approaches to demonstrate that anti-N-methyl-d-aspartate receptor autoantibodies from patients with encephalitis strongly alter, in a time-dependent manner, the surface content and trafficking of GluN2-NMDA receptor subtypes. Autoantibodies laterally displaced surface GluN2A-NMDA receptors out of synapses and completely blocked synaptic plasticity. This loss of extrasynaptic and synaptic N-methyl-d-aspartate receptor is prevented both in vitro and in vivo, by the activation of EPHB2 receptors. Indeed, the anti-N-methyl-d-aspartate receptor autoantibodies weaken the interaction between the extracellular domains of the N-methyl-d-aspartate and Ephrin-B2 receptors. Together, we demonstrate that the anti-N-methyl-d-aspartate receptor autoantibodies from patients with encephalitis alter the dynamic retention of synaptic N-methyl-d-aspartate receptor through extracellular domain-dependent mechanism(s), shedding new light on the pathology of the neurological and psychiatric disorders observed in these patients and opening possible new therapeutic strategies.
Leucine-Rich Glioma Inactivated protein 1 (LGI1) is a secreted neuronal protein highly expressed in the central nervous system and high amount are found in the hippocampus. An alteration of its ...function has been described in few families of patients with autosomal dominant temporal lobe epilepsy (ADLTE) or with autoimmune limbic encephalitis (LE), both characterized by epileptic seizures. Studies have shown that LGI1 plays an essential role during development, but also in neuronal excitability through an action on voltage-gated potassium Kv1.1 channels, and in synaptic transmission by regulating the surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-R). Over the last decade, a growing number of studies investigating LGI1 functions have been published. They aimed to improve the understanding of LGI1 function in the regulation of neuronal networks using different animal and cellular models. LGI1 appears to be a major actor of synaptic regulation by modulating trans-synaptically pre- and post-synaptic proteins. In this review, we will focus on LGI1 binding partners, “A Disintegrin And Metalloprotease (ADAM) 22 and 23”, the complex they form at the synapse, and will discuss the effects of LGI1 on neuronal excitability and synaptic transmission in physiological and pathological conditions. Finally, we will highlight new insights regarding N-terminal Leucine-Rich Repeat (LRR) domain and C-terminal Epitempin repeat (EPTP) domain and their potentially distinct role in LGI1 function.
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