Paraneoplastic and non-paraneoplastic autoimmunity to neurons in the central nervous system

Abstract

Autoimmune central nervous system (CNS) inflammation occurs both in a paraneoplastic and non-paraneoplastic context. In a widening spectrum of clinical disorders, the underlying adaptive (auto) immune response targets neurons with a divergent role for cellular and humoral disease mechanisms: (1) in encephalitis associated with antibodies to intracellular neuronal antigens, neuronal antigen-specific CD8(+) T cells seemingly account for irreversible progressive neuronal cell death and neurological decline with poor response to immunotherapy. However, a pathogenic effect of humoral immune mechanisms is also debated. (2) In encephalitis associated with antibodies to synaptic and extrasynaptic neuronal cell surface antigens, potentially reversible antibody-mediated disturbance of synaptic transmission and neuronal excitability occurs in the absence of excessive neuronal damage and accounts for a good response to immunotherapy. However, a pathogenic effect of cellular immune mechanisms is also debated. We provide an overview of entities, clinical hallmarks, imaging features, characteristic laboratory, electrophysiological, cerebrospinal fluid and neuropathological findings, cellular and molecular disease mechanisms as well as therapeutic options in these two broad categories of inflammatory CNS disorders.

Fig. 1

Putative immunopathogenesis of paraneoplastic and non-paraneoplastic auto-immunity to neurons in the CNS (modified and extended from Melzer et al. [70]). To set up an adaptive humoral and cellular immune response directed towards intracellular (left, yellow circles) or surface membrane (right, bright blue circles) neuronal antigen both professional antigen-presenting cells (APC, green) and naive antigen-specific B cells (BC, orange) need to encounter and engulf soluble or cell-bound neuronal or neuronal-like antigens within secondary lymphatic organs. Subsequently, APCs may process and present this antigen in the context of MHC II molecules to naive antigen-specific CD4⁺ T cells (CD4 TC, blue). MHC II-dependent recognition by these CD4⁺ T cells is then required for full activation of B cells to become antibody-secreting plasma cells (PC, red). In addition, CD4⁺ T cells may license APCs to present neuronal antigen peptides in the context of MHC I molecules also to naive CD8⁺ T cells (CD8 TC, blue) to acquire cytotoxic effector function. Antibody-secreting plasma cells and cytotoxic CD8⁺ T cells may invade the CNS to exert humoral and cellular neuron-directed autoimmunity