Neuroimmunology: an expanding frontier in autoimmunity

Abstract

Anti-neuronal autoimmune encephalitis (AIE) comprises a recently characterized group of immune-mediated disorders that result in limbic, multifocal, or diffuse encephalitis due to direct interaction of autoantibodies with neuronal surface or synaptic proteins. The pathological effects of the autoantibodies vary according to the target antigen but when they are removed, neuronal dysfunction is commonly reversed. Ongoing research on AIE constantly increases the number of novel autoantibodies and expands the spectrum of neurological syndromes that are important in the differential diagnosis of psychiatric illness, dementia, or viral encephalitis. This review summarizes recent advances in AIE, focusing on pathogenetic mechanisms and novel associations with other CNS disorders such as neurodegeneration, relapsing symptoms post-herpes simplex virus encephalitis, and demyelinating diseases. In addition, an algorithmic approach to detect and characterize neuronal cell surface autoantibodies is proposed.

Keywords: anti-NMDAR encephalitis; anti-neuronal antibodies; autoimmune encephalitis; limbic encephalitis; tissue-based assay.

Figure 1

Diagnosis of neuronal cell surface autoantibodies and overlapping syndromes. Algorithmic approach for the diagnosis of neuronal cell surface autoantibodies (A) most of the currently known autoantibodies show an intensive neuropil staining in the hippocampus. The autoantibodies are subsequently characterized on HEK293 cells transfected with the antigen of interest (red: commercial antibody against the transfected antigen, green: patient’s serum with autoantibodies to the transfected antigen, blue: nuclear staining with DAPI). If all currently available cell-based assays remain negative (red: commercial antibody against the transfected antigen, green: patient’s serum without autoantibodies to the transfected antigen; blue: nuclear staining with DAPI) the sample may be stained on live hippocampal neurons. Glycin receptor- and D2R-antibodies may not be detectable by immunohistochemistry and should be tested directly with cell-based assays. Overlapping syndrome of anti-NMDAR encephalitis and neuromyelitis optica. (B) Identification of NMDAR-antibodies, aquaporin-4 (AQP-4), or both autoantibodies on tissue-based assay (TBA) showing the hippocampus (A), the dentate gyrus of hippocampus [(B), enlarged from (A)], and cerebellar cortex (C). Examples of patients with autoantibodies targeting only the NMDAR (neuropil staining in hippocampus, dot-like staining in granular layer of cerebellar cortex), only the AQP-4 (mild neuropil staining in hippocampus, staining of glia limitans perivascularis, and reticular staining of granular layer of cerebellar cortex), and both, NMDAR and AQP-4 (strong neuropil staining in hippocampus, staining of glia limitans perivascularis, reticular staining of granular layer of cerebellar cortex). Magnification: (A): ×20, (B,C): ×100.