Movement Disorders With Neuronal Antibodies

Syndromic Approach, Genetic Parallels and Pathophysiology

Bettina Balint; Angela Vincent; Hans-Michael Meinck; Sarosh R. Irani; Kailash P. Bhatia

Disclosures

Brain. 2018;141(1):13-36. 

In This Article

Pathophysiological Considerations and the Emerging Overlap with Genetic and Degenerative Movement Disorders

Pathophysiological Considerations and Genetic Parallels

Neuronal autoantibodies are neither perfectly specific biomarkers (Box 1) nor necessarily pathogenic, and the exact pathomechanisms leading to specific movement disorder presentations are largely unknown. However, they may be categorized into three groups based on the location of their antigen and its accessibility in vivo, and their presumed pathogenic relevance (Figure 2) (Lancaster and Dalmau, 2012). Evidence for pathogenic relevance comes from observations such as tight correlations between serum or CSF antibody titres and the disease course, pathological studies, and from in vitro or in vivo experiments. Likewise, phenotypic overlaps with pharmacological modulation or genetic disruption of the antigen can support autoantibody pathogenicity. In the following section, we will discuss the pathogenic role of some of the most relevant neuronal autoantibodies with a focus on parallels between genetic and autoimmune conditions, and the existing evidence for antibody-pathogenicity (Table 3).

Figure 2.

The three groups of neuronal antibodies and their pathogenic roles, examples, treatment responses and tumour associations. AMPAR = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CASPR2 = contactin associated protein like 2; D2R = dopamine 2 receptor; DPPX = dipeptidyl peptidase like protein 6; GABAAR and GABABR = gamma aminobutyric acid type A and type B receptors; GlyR = glycine receptor; LGI1 = leucine rich glioma inactivated protein 1; NMDAR = N-methyl-d-aspartate receptor.

Neuronal Surface Antibodies

Antibodies against neuronal surface proteins might exert various effects upon binding, including complement activation and inflammatory cytotoxicity, antigenic modulation leading to receptor loss by internalization, or receptor blockade (Jain and Balice-Gordon, 2016). NMDAR antibodies are neuronal surface antibodies with in vitro and in vivo data supporting pathogenicity. NMDAR is an ionotropic glutamate receptor widely expressed in the brain and pivotal for long-term synaptic plasticity (Standaert et al., 1994). In vitro and in vivo experiments have shown that NMDAR antibodies target the NR1 subunit of the receptor, causing receptor internalization by cross-linking and thereby a reduction of surface NMDAR density (Moscato et al., 2014; Planaguma et al., 2015). Upon removal of the antibodies, the receptor internalization is reversible, and residual deficits may be the result of glutamate excitotoxicity (Manto et al., 2010). The distinct movement disorder associated with NMDAR antibodies, chorea and dyskinesias persisting in states of reduced consciousness, is also seen with 'dissociative' anaesthetics. Interestingly, these are NMDAR antagonists like ketamine or phencyclidine (Stamelou et al., 2012). Furthermore, a genetic phenocopy of NMDAR-antibody encephalitis with mixed hyperkinetic movement disorders (chorea, dystonia, stereotypies, dystonia, oculogyric crises), seizures, and sleep cycle dysregulation is seen with mutations of GRIN1, the gene encoding the NR1 subunit of the NMDAR (Lemke et al., 2016).

SPSD have also a genetic analogue in hereditary hyperekplexia, with which they share the clinical hallmark features of stiffness, spasms and exaggerated startle. Indeed, this clinical parallel inspired the discovery of GlyR antibodies and antibodies against the glycine transporter 2 (encoded by SLC6A5) (Hutchinson et al., 2008; Balint et al., 2015). GlyR antibodies specifically target the α1 glycine receptor subunit expressed on brainstem and spinal cord neurons, and both activate complement and cause receptor internalization via lysosomal pathways in vitro (Carvajal-Gonzalez et al., 2014). The latter effect would be compatible with the clinical signs of decreased glycinergic neurotransmission and a loss of brainstem and spinal inhibition.

In contrast, the presumed pathophysiological mechanisms of DPPX antibodies, which also associate with SPSD, relate to increased CNS hyperexcitability mediated by downregulation of DPPX and Kv4.2 in neuronal membranes as shown in vitro (Piepgras et al., 2015). The antigen is widely expressed in the CNS and on the myenteric plexus, which matches the typically multifocal, combined presentations and chronic diarrhoea as hallmark features in DPPX-antibody-related disease.

Existing evidence for the pathogenic relevance of other neuronal surface antibodies and comparison with their respective genetic counterparts is summarized in Table 3.

Antibodies Against Intracellular Synaptic Antigens

GAD antibodies also target a protein of inhibitory synapses, but their role in disease pathophysiology is more controversial. The antigenic target, glutamic acid decarboxylase-65 (GAD65), is the cytoplasmic, rate-limiting enzyme in the synthesis of GABA, a major inhibitory neurotransmitter in the CNS. GAD antibodies are the most frequent antibody in SPSD and cerebellar ataxia, but they also associate with temporal lobe epilepsy, limbic encephalitis, and type 1 diabetes (Gresa-Arribas et al., 2015). Although a difference between epitopes associated with type 1 diabetes and SPSD/cerebellar ataxia was suggested, epitope mapping did not consistently reveal relevant differences between the antibodies pertinent to such different neurological phenotypes (Manto et al., 2011; Fouka et al., 2015; Gresa-Arribas et al., 2015). The GAD antibody titres usually do not correlate with the clinical course, and the response to immunotherapy is highly variable. These observations have questioned their pathogenicity. Some studies have identified co-occurring, potentially pathogenic neuronal surface antibodies in patients with GAD antibodies, but it is questionable if this is sufficient to explain the varied neurological manifestations (Chang et al., 2013; Petit-Pedrol et al., 2014; Gresa-Arribas et al., 2015). Pathological findings from patients with SPSD or encephalitis with GAD antibodies substantiate a T-cell involvement, and suggest that GAD-antibody-related disease represents an intermediate between neuronal surface antibodies and those directed against cytoplasmic/nuclear antigens (Witherick et al., 2011; Bien et al., 2012). Whereas in vitro experiments yielded contradictory evidence regarding the possible internalization of GAD-antibodies (Hampe et al., 2013; Gresa-Arribas et al., 2015), transfer experiments in rodents were able reproduce some evidence of pathogenicity (Geis et al., 2011).

Similar transfer experiments of purified IgG have shed a new light on amphiphysin antibodies. The antigen has a pivotal role for clathrin-mediated endocytosis, a mechanism to compensate for the fast exocytosis of neurotransmitters by recycling synaptic vesicles, which is particularly important in GABAergic interneurons. Amphiphysin-IgG reduced presynaptic GABAergic inhibition, leading to stiffness and spasms in rodents (Sommer et al., 2005; Geis et al., 2010). Neurons internalized the antibodies and reduced the presynaptic vesicle pool (Werner et al., 2016). Further studies will have to elucidate if the transient presentation of the 'surface-moonlighting' synaptic antigens during endocytosis suffices to generate pathology (Irani, 2016).

Antibodies Against Intracellular Cytoplasmic/Nuclear Antigens

Autoantibodies against intracellular antigens are not considered pathogenic, as their target is inaccessible in vivo. Existing evidence suggests that autoreactive T cells are mediating the disease process, characterized by lymphocytic infiltration and damage of neuronal structures (Lancaster and Dalmau, 2012). This group of antibodies includes those against nuclear or nucleolar antigens, like Hu or Ma, which have a diffuse expression in the CNS and various associated syndromes.

A subgroup of these antibodies, however, target cytoplasmic antigens and specifically associate with cerebellar ataxia with Purkinje cell degeneration. Indeed, these conditions have genetic counterparts involving a functional network of calcium homeostasis and signalling in Purkinje cells, and therefore demonstrate molecular parallels between genetic conditions and autoantibodies considered as non-pathogenic (Table 3 and Figure 3). Although IgG uptake by Purkinje cells has been reported (Hill et al., 2009; Greenlee et al., 2010), further experiments substantiating a possible pathophysiological role of these antibodies are lacking.

Figure 3.

Proteins of the calcium homeostasis and signalling network in Purkinje cells: parallels of genetic cerebellar ataxias and antibody-related autoimmunity. Upon parallel fibre stimulation, glutamate is released and binds to mGlur1, a G-protein-coupled surface receptor highly expressed at the perisynaptic site of Purkinje cells and involved in mediation of slow excitatory potentials and long-term depression. Its intracellular domain in turn interacts with Homer-3, which is a scaffolding protein relevant for mGlur1 clustering, and which crosslinks mGluR1 with ITPR1 in the smooth endoplasmic reticulum. Upon glutamate binding, mGluR1 activates of phospholipase C, an enzyme that cleaves phosphatidylinositol 4,5-bisphosphate in the plasma membrane to produce diacylglycerol and inositol trisphosphate (IP3). IP3 binds to ITPR1 and thereby induces calcium release from the endoplasmatic reticulum, which in turn activates protein kinase C γ (PKCγ) that desensitizes mGluR1 by phosphorylation and induces internalization of AMPA receptors (AMPAR). GluRδ2 is a key binding partner for mGluR1 and PKCγ, relevant for synaptic mGluR1 signalling and also involved in AMPAR trafficking. Similarly, activation of climbing fibres opens voltage gated calcium channels (VGCC) which mediate calcium influx and contribute to the signalling cascade, which results in reduction of AMPAR sensitivity at the synapse. Proteins that are targets of antibodies associated with cerebellar ataxia are in single-lined boxes, proteins that are also affected by mutations in genetic ataxias (Table 3) are highlighted in double-lined boxes, and existing evidence with regards to their pathogenic role is discussed in Table 3. AMPAR = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CARP VIII = carbonic anhydrase VIII; ER = endoplasmic reticulum; GluRd2 = glutamate receptor delta 2; PKCg = protein kinase C gamma.

Similarly, antibodies against transglutaminase 6 (TG6), which is inter alia expressed in the cytoplasm of Purkinje cells, have a genetic counterpart in SCA35 (Wang et al., 2010). TG6 antibodies have been described in patients with gluten sensitivity, but their sensitivity, specificity and diagnostic utility as well as their pathophysiological role remain very controversial (Hadjivassiliou et al., 2008; Boscolo et al., 2010; Lindfors et al., 2011; Hadjivassiliou et al., 2013; McKeon et al., 2014; Stenberg et al., 2014).

The Role of Neuronal Antibodies in Neurodegeneration: Player, Bystander or Biomarker?

The recent discovery of neuronal surface antibodies against IgLON5 in defining a novel tauopathy has more closely apposed the boundaries between neurodegeneration and neuroimmunology (Sabater et al., 2014).

The IgLON5-antibody-linked tauopathy is characterized by prominent sleep movement disorders, first and foremost by a non-REM sleep parasomnia with simple or finalistic movements, resembling daytime activities such as eating, drinking or manipulating objects. Other sleep abnormalities included RBD, and periodic limb movements of sleep.

Breathing difficulties like sleep apnoea or stridor, leading to respiratory insufficiency and often severe enough to require a tracheostomy, appear to be another hallmark feature of this disease. Bulbar symptoms, namely dysarthria, dysphagia and vocal cord paresis, are common findings. Patients may be disabled by a progressive and disabling gait instability with postural reflex loss, which together with a vertical supranuclear gaze palsy give rise to a PSP-like presentation (Gaig et al., 2017; Hoglinger et al., 2017). The range of abnormal eye movements extends however to horizontal gaze paresis, saccadic intrusions, and nystagmus (Sabater et al., 2014; Gelpi et al., 2016). On the other hand, ocular or appendicular cerebellar signs, nocturnal stridor and dysautonomia including orthostatic hypotension, can resemble multiple system atrophy. Possible signs of dysautonomia comprise also urinary symptoms, episodic intense transpiration, cardiac arrhythmias and central hypoventilation. The phenotypic spectrum is indeed broad, and includes also a Huntington's disease lookalike with chorea, myoclonus and cognitive decline.

Disease onset ranged between 48–77 years, and disease duration spanned from 2 months to 12 years. The causes of death were respiratory failure or sudden death during sleep or wakefulness. Notably, brain pathology showed an absence of inflammatory infiltrates but widespread accumulation of hyperphosphorylated three and four repeat tau aggregates in neurons, and neuronal loss predominantly in the hypothalamus and the brainstem tegmentum (Sabater et al., 2014; Gelpi et al., 2016). There was a cranio-caudal gradient of severity until the upper cervical cord. These findings suggest neurodegeneration as the primary disease mechanism, which would fit with the observed absence of a significant response to immunotherapy. However, all genotyped patients had HLA-DQB1*0501 and HLA-DRB1*1001 alleles, suggesting a genetic susceptibility for autoimmunity (Sabater et al., 2014, 2016).

How can these seemingly contradictory and puzzling findings be reconciled? Little is known about the physiological function of IgLON5, a cell adhesion molecule on the neuronal surface. It belongs to the immunoglobulin superfamily and functions in neuronal path-finding and synaptic formation during brain development (Sanz et al., 2015). The IgLON5 antibodies target the extracellular domain of the protein and are predominantly of the IgG4 subtype, which is assigned anti-inflammatory properties. To a lesser extent, patient sera contained co-existent IgG1 antibodies, which caused internalization of IgLON5 in neuronal cultures (Sabater et al., 2016). This effect was not seen with IgG4-subtype antibodies. Thus, the role of the IgLON5 antibodies is still unclear. Perhaps antibody-mediated downregulation of IgLON5 could disrupt its interaction with the internal cytoskeletal network and induce tau accumulation and hyperphoshphorylation, leading to neurodegeneration, which at the time of manifestation may no longer be amenable to immunotherapy (Gelpi et al., 2016). On the other hand, the tau accumulation may indirectly lead to neuronal autoimmunity in susceptible individuals, and have broader implications as a paradigm for the role of inflammation in neurodegeneration.

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