Paraneoplastic and Other Autoimmune Encephalitides: Antineuronal Antibodies, T Lymphocytes, and Questions of Pathogenesis.

Ida Herdlevær,Justin R. Abbatemarco,Stacey L. Clardy,Noel G. Carlson,Christian A. Vedeler,John E. Greenlee

doi:10.3389/fneur.2021.744653

Abstract

Autoimmune and paraneoplastic encephalitides represent an increasingly recognized cause of devastating human illness as well as an emerging area of neurological injury associated with immune checkpoint inhibitors. Two groups of antibodies have been detected in affected patients. Antibodies in the first group are directed against neuronal cell surface membrane proteins and are exemplified by antibodies directed against the N-methyl-D-aspartate receptor (anti-NMDAR), found in patients with autoimmune encephalitis, and antibodies directed against the leucine-rich glioma-inactivated 1 protein (anti-LGI1), associated with faciobrachial dystonic seizures and limbic encephalitis. Antibodies in this group produce non-lethal neuronal dysfunction, and their associated conditions often respond to treatment. Antibodies in the second group, as exemplified by anti-Yo antibody, found in patients with rapidly progressive cerebellar syndrome, and anti-Hu antibody, associated with encephalomyelitis, react with intracellular neuronal antigens. These antibodies are characteristically found in patients with underlying malignancy, and neurological impairment is the result of neuronal death. Within the last few years, major advances have been made in understanding the pathogenesis of neurological disorders associated with antibodies against neuronal cell surface antigens. In contrast, the events that lead to neuronal death in conditions associated with antibodies directed against intracellular antigens, such as anti-Yo and anti-Hu, remain poorly understood, and the respective roles of antibodies and T lymphocytes in causing neuronal injury have not been defined in an animal model. In this review, we discuss current knowledge of these two groups of antibodies in terms of their discovery, how they arise, the interaction of both types of antibodies with their molecular targets, and the attempts that have been made to reproduce human neuronal injury in tissue culture models and experimental animals. We then discuss the emerging area of autoimmune neuronal injury associated with immune checkpoint inhibitors and the implications of current research for the treatment of affected patients.

Highlights

Autoimmune encephalitides represent a rapidly expanding— and increasingly important—group of disorders characterized by the presence of an immunoglobulin G (IgG) antibody response directed against neuronal proteins
Not all patients with antibodies to intracellular neuronal antigens have evidence of an antigen-specific T cell response: lymphocytic infiltrates have been absent in the brains of some patients with anti-Yo associated paraneoplastic cerebellar degeneration [14, 92]; and some investigators have failed to detect cytotoxic T lymphocytes in serum or CSF of patients with anti-Hu antibodies and paraneoplastic neurological disease [93,94,95]
Recent studies by Yshii et al, documented upregulation of MHC class 1 molecule expression in Purkinje cells in an experimental model of paraneoplastic cerebellar injury following treatment with an immune checkpoint inhibitor [96], and in ongoing studies, we have observed similar neuronal upregulation of MHC class I receptors in slice cultures incubated with anti-Hu antibodies (Carlson et al, unpublished data)

Summary

Introduction

Autoimmune encephalitides represent a rapidly expanding— and increasingly important—group of disorders characterized by the presence of an immunoglobulin G (IgG) antibody response directed against neuronal proteins. Multiple additional autoantibodies have been identified in patients with paraneoplastic neurological disease: almost all of these antibodies are directed against intracellular neuronal antigens.

Results

Conclusion