The role of dendritic cells and their interactions in the pathogenesis of antibody-associated autoimmune encephalitis

Fatme Seval Ismail,Sven G Meuth,Nico Melzer

doi:10.1186/s12974-021-02310-z

Abstract

Autoimmune encephalitis (AE) is an inflammatory brain disease which is frequently associated with antibodies (Abs) against cell-surface, synaptic or intracellular neuronal proteins. There is increasing evidence that dendritic cells (DCs) are implicated as key modulators in keeping the balance between immune response and tolerance in the CNS. Migratory features of DCs to and from the brain are linked to initiating and maintaining of neuroinflammation. Genetic polymorphisms together with other triggers such as systemic or cerebral viral infection, or systemic malignancies could contribute to the dysbalance of “regulatory” and “encephalitogenic” DCs with subsequent dysregulated T and B cell reactions in AE. Novel in vivo models with implantation of mature DCs containing neuronal antigens could help to study the pathogenesis and perhaps to understand the origin of AE. Investigations of DCs in human blood, lymphoid tissues, CSF, and brain parenchyma of patients with AE are necessary to deepen our knowledge about the complex interactions between DCs, T and B cells during neuroinflammation in AE. This can support developing new therapy strategies.

Highlights

Autoimmune encephalitis (AE) is an inflammatory brain disease which is frequently associated with antibodies (Abs) against neuronal cell-surface, synaptic or intracellular neuronal proteins [1,2,3]
In case of the anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, the neurons in the tumor express NMDAR similar to the neurons in the brain leading to an autoimmune response
In ovarian teratoma from patients with anti-NMDAR encephalitis, NMDARexpressing neurons and inflammatory infiltrates of T and B lymphocytes were found, whereas in the tumors from patients without anti-NMDAR encephalitis only few or no B lymphocytes and plasma cells were detected [12]. In addition to this concept of classical onco-neuronal immunity where tumors and neurons express the same antigen, the concept of onco-neuronal cross-reactivity was recently shown likely to be relevant for the immunopathogenesis of anti-GABAAR encephalitis

Summary

Background

Autoimmune encephalitis (AE) is an inflammatory brain disease which is frequently associated with antibodies (Abs) against neuronal cell-surface, synaptic or intracellular neuronal proteins [1,2,3]. The passive cerebroventricular transfer of Abs from the cerebrospinal fluid (CSF) of affected patients resulted in NMDAR internalization and impairment of long-term synaptic plasticity with gradual resolving of the alterations after cessation of the antibody infusion [14, 15] In addition to these direct effects on neuronal function, depending on the Ig-subtype, antibodies may induce antibody-dependent cellular and complement-dependent cytotoxicity thereby destroying the target cells [16]. Unlike CNS-resident DCs, peripheral monocyte-derived DCs are not present under physiological conditions in the brain, but can differentiate from infiltrating monocytes and accumulate in the CNS during neuroinflammation [30] Both DC subsets expanded in the meninges and CNS parenchyma during disease progression in EAE [30].

Clinical symptoms

Genetic polymorphisms