The clinical features, underlying immunology, and treatment of autoantibody-mediated movement disorders

Abstract

An increasing number of movement disorders are associated with autoantibodies. Many of these autoantibodies target the extracellular domain of neuronal surface proteins and associate with highly specific phenotypes, suggesting they have pathogenic potential. Below, we describe the phenotypes associated with some of these commoner autoantibody-mediated movement disorders, and outline increasingly well-established mechanisms of autoantibody pathogenicity which include antigen downregulation and complement fixation. Despite these advances, and the increasingly robust evidence for improved clinical outcomes with early escalation of immunotherapies, the underlying cellular immunology of these conditions has received little attention. Therefore, here, we outline the likely roles of T cells and B cells in the generation of autoantibodies, and reflect on how these may guide both current immunotherapy regimes and our future understanding of precision medicine in the field. In addition, we summarise potential mechanisms by which these peripherally-driven immune responses may reach the central nervous system. We integrate this with the immunologically-relevant clinical observations of preceding infections, tumours and human leucocyte antigen-associations to provide an overview of the therapeutically-relevant underlying adaptive immunology in the autoantibody-mediated movement disorders. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Keywords: Neuroimmunology; autoantibody; autoimmune encephalitis; immunology; stiff person syndrome.

Figure 1

Autoantibodies directed at intracellular and extracellular domains of neuronal proteins. (A) Autoantibodies against constitutive nuclear or cytoplasmic proteins do not appear to gain access to their targets, whereas those directed against predominantly intracellular synaptic proteins may gain access at the time of vesicle fusion. (B) Pathogenic mechanisms of neuronal surface proteins. Neuronal surface proteins have a direct pathogenic effect on the antigen through various mechanisms: (A) antibody‐dependent cell‐mediated cytotoxicity (ADCC), (B) direct target modulation through agonist/antagonist effects, (C) complement activation, and (D) antigen internalization. * = ions; red circle with horizontal white line denotes a “no entry” sign; C1q, complement component 1q.

Figure 2

Model of B cell activation in neuronal surface autoantibody‐associated movement disorders. Triggers of immunological activation in CNS autoimmunity may lead to exposure of antigen (red star) and its presentation in the germinal centres of the cervical lymph nodes. Interaction between naïve B cells and CD4⁺ T helper cells in germinal centres causes maturation of B cells into antigen‐specific cells that can switch their immunoglobulin chain to express IgG. These cells can subsequently differentiate into antibody‐secreting plasmablasts and become tissue‐resident plasma cells. Circulating memory B cells and plasmablasts can reach the CNS through the internal carotid artery, re‐encounter the antigen, and produce antibodies (intrathecal synthesis). Modified with permissions from Wilson et al.83 IgG (immunoglobulin G), IL‐2 (interleukin 2), IL‐21 (interleukin 21), IgD (Immunoglobulin D), TNF alpha. CD = cluster of differentiation.

Figure 3

Radiological spectrum of faciobrachial dystonic seizures with LGI1‐antibodies and clinical spectrum of glutamic acid decarboxylase (GAD) antibodies. (A) Multimodal radiological involvement of the basal ganglia in patients with LGI1‐antibodies and faciobrachial dystonic seizures using FLAIR and DWI‐weighted MRI (top 2 panels), PET (bottom left panel), and SPECT (bottom right panel) imaging. Arrows indicate abnormal basal ganglia regions. Reproduced with permissions.20, 49, 52 (B) Spectrum of overlapping autoimmune neurological diseases associated with GAD65 antibodies and concommittant CNS‐specific autoimmunity. Autoantibodies highlighted in bold. DPPX, dipeptidyl‐peptidase‐like protein‐6; LGI1, leucine‐rich glioma‐inactivated‐1, FLAIR, Fluid Attenuated Inversion Recovery; DWI, diffusion‐weighted imaging; SPECT, single‐photon emission computed tomography. (C) Circos diagram depicting the relative presence of phenomenological features in patients with NMDAR‐antibody encephalitis (adapted from Varley et al.29)