Cell surface antibody–associated neurodegeneration

Cell surface autoantibodies have become important biomarkers of acquired autoimmune CNS disorders, and typically define potentially severe but treatable acquired autoimmune encephalitis syndromes. However, the discovery of anti-IgLON5 antibodies has forced a reappraisal of the accepted paradigms regarding cell surface antibodies and their associated clinical manifestations.¹ Although anti-IgLON5 antibody is a cell surface antibody, the clinical syndrome is not an encephalitis (there is no lymphocytic inflammatory infiltration), disease onset is more chronic rather than acute, and the neurologic sequelae are not reversible with immunotherapy in most patients, with progressive neurodegeneration and high mortality. This is therefore a novel autoimmune CNS syndrome, inhabiting the borderland between autoimmunity and neurodegeneration: cell surface antibody–associated neurodegeneration. The article by Gaig et al.² in this issue of Neurology® extends our knowledge of the clinical features of this rare but important form of autoimmune neurodegeneration. The study describes 22 patients who were positive for anti-IgLON5 autoantibodies, as tested by the Neuroimmunology Laboratory in Barcelona, comprising the largest cohort with this condition. The main findings were that the clinical syndrome can present with sleep, brainstem, gait, cognitive, or movement disorders, but during the disease course all patients develop manifestations of disordered sleep and ventilation. The course was chronic and progressive in most patients, and 59% died during follow-up. It should be noted that it is possible that the initial description of this condition has resulted in recruitment bias, and the spectrum of symptoms and signs is different from what is described by Gaig et al.

Neuropathologic findings in this condition primarily demonstrate neuronal accumulation of hyperphosphorylated tau, preferentially involving the hypothalamus and tegmental nuclei of the brainstem, with associated severe neuronal loss, gliosis, and a lack of inflammatory infiltrate.³ Another notable feature of anti-IgLON5 disease is the strong correlation with HLA-DRB1*10:01 and HLA-DQB1*05:01.² Proposed criteria for anti-IgLON5-related tauopathy can be separated into definite (typical neuropathology plus CSF/serum IgLON5 antibody), probable (typical neuropathology plus HLA genotype), and possible diagnostic categories (neuropathology findings only).³

The autoantibody syndromes to date have been broadly separated into intracellular antigen-autoantibody syndromes (such as anti-Hu antibody), which define an encephalitis that is often nonresponsive to immunotherapy with a progressive course, and the cell surface autoantibody syndromes, which define an immunotherapy-responsive, clinically reversible autoimmune encephalitis (such as anti–NMDA receptor [NMDAR] encephalitis). The description of anti-IgLON5 antibody now requires a modified paradigm of cell surface antibody–associated neurodegeneration that lacks immune responsiveness, better termed anti-IgLON5-related tauopathy.³

Anti-IgLON5 disease prompts comparison to a classic autoimmune encephalitis syndrome (anti-NMDAR encephalitis)⁴ (table). The similarities are that anti-IgLON5 disease fulfils the cell surface paradigm of IgG binding to the cell surface of live neurons or nonpermeabilized HEK cells transfected with the relevant antigen in cell-based assays,^1,4,5 and the IgG binds to an extracellular domain of IgLON5.⁵ However, anti-IgLON5 disease differs in that the majority of patients have disease onset in middle age or later with a subacute or chronic disease course often lasting years, and a frequently delayed diagnosis, due to the gradually progressive nature of this condition, compared to the more acute presentation of anti-NMDAR encephalitis. The lack of detectable abnormalities on ancillary investigations including CSF examination, EEG, and MRI in most patients with IgLON5 antibodies^1,2 also differs from anti-NMDAR encephalitis. Unlike in anti-NMDAR encephalitis, the overwhelming majority of patients with IgLON5 antibodies have been unresponsive to immunotherapy,² although a patient treated early in the symptom course has done well after short follow-up.⁶ Such case reports raise the possibility that there is a more inflammatory and treatable early phase of disease,⁶ which is replaced by irreversible neuronal loss that is unresponsive to immunotherapy in the chronic phase.³

Autoantibodies in anti-NMDAR encephalitis are in the IgG1–3 subclasses,⁷ but IgLON5 antibodies are usually in the IgG4 subclass, with a lesser IgG1 contribution^1,5; other IgG4-mediated neuroimmunologic conditions include anti-MuSK myasthenia gravis, LGI1 antibody–mediated autoimmune encephalitis, and some chronic inflammatory demyelinating polyneuropathies.⁸ IgG1 and 3 antibodies activate complement, with antigen crosslinking and receptor internalization, but the pathomechanism of IgG4 antibodies is less clear. IgG4 antibodies may directly interfere with antigen function by mechanical blocking of ligand receptor interactions, resulting in prevention of cell adhesion and connectivity.⁸

Anti-IgLON5 IgG binding may initiate cellular neurodegeneration, which is not modifiable using conventional immunosuppression or modulation in most patients. The authors note that it is conceivable that the antibody is an epiphenomenon secondary to the degeneration, which is certainly possible, although the in vitro pathogenic effects of IgG, the strong HLA association, and microglia activation evident on neuropathology suggest there is a definite immune component of this disease.

Autoantibody biomarkers have allowed the clinician to see previously unrecognized phenotypes. It is possible there will be other autoantibodies associated with neurodegenerative syndromes, and these cell surface antibody–associated neurodegeneration syndromes may provide insights into the broader field of neurodegeneration. It is interesting to speculate whether in these cases, early interruption of IgG binding to neurons may arrest the cascade of neurodegeneration.

• © 2017 American Academy of Neurology