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Review
. 2023 Dec 20;13(1):15.
doi: 10.3390/cells13010015.

Pathophysiological Effects of Autoantibodies in Autoimmune Encephalitides

Matias Ryding  1   2 , Anne With Mikkelsen  3 , Mette Scheller Nissen  4 , Anna Christine Nilsson  1   3 , Morten Blaabjerg  1   2   4   5
Affiliations
Review

Pathophysiological Effects of Autoantibodies in Autoimmune Encephalitides

Matias Ryding et al. Cells. .

Abstract

The heterogeneity of autoantibody targets in autoimmune encephalitides presents a challenge for understanding cellular and humoral pathophysiology, and the development of new treatment strategies. Thus, current treatment aims at autoantibody removal and immunosuppression, and is primarily based on data generated from other autoimmune neurological diseases and expert consensus. There are many subtypes of autoimmune encephalitides, which now entails both diseases with autoantibodies targeting extracellular antigens and classical paraneoplastic syndromes with autoantibodies targeting intracellular antigens. Here, we review the current knowledge of molecular and cellular effects of autoantibodies associated with autoimmune encephalitis, and evaluate the evidence behind the proposed pathophysiological mechanisms of autoantibodies in autoimmune encephalitis.

Keywords: autoimmune encephalitides; molecular mechanisms; neuroinflammation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The effect of NMDAR autoantibodies on surface receptor expression. Autoantibodies cross-link multiple NMDARs causing internalization whereafter the receptors are degraded in lysosomes. The loss of surface NMDAR leads to other changes such as alterations in dopamine receptor surface expression in neurons and GLUT1 surface expression in oligodendrocytes. Activation of EPHB2R blocks autoantibody mediated internalization of NMDAR. NMDAR: N-methyl-D-aspartate receptor, D1R: dopamine 1 receptor, D2R: dopamine 2 receptor, GLUT1: glucose transporter 1, EPHB2R: ephrin B2 receptor. Figure created with BioRender.com (accessed on 13 December 2023).
Figure 2
Figure 2
The effect of LGI1, CASPR2 and AMPAR autoantibodies on surface expression. All three autoantibody targets are part of the same receptor complex (top left). LGI1 autoantibodies (top right) are thought to interfere between LGI1 and ADAM22 or ADAM23, but internalization of LGI1-ADAM22/23 complexes have also been observed. The immediate effect of CASPR2 autoantibodies (bottom left) is still unknown. AMPAR autoantibodies (bottom right) cause internalization of AMPARs, which then undergo lysosomal degradation. LGI1: Leucine rich Glioma-Inactivated 1, CASPR2: Contactin-associated protein-like 2, AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ADAM22/23: Disintegrin and metalloproteinase domain-containing protein 22/23, PSD95: postsynaptic density protein 95. Figure created with BioRender.com (accessed on 13 December 2023).
Figure 3
Figure 3
The effect of GABAAR and GABABR autoantibodies on surface expression. GABAAR autoantibodies (left) either directly inhibits or reduce surface expression of GABAARs. GABABR autoantibodies (right) either directly inhibits or cause internalization of GABAARs. Figure created with BioRender.com (accessed on 13 December 2023).
Figure 4
Figure 4
The effect of DPPX, IgLON5, and GlyR autoantibodies on surface expression. DPPX autoantibodies (top) cause a reduction in DPPX surface expression. IgLON5 autoantibodies (middle) internalize IgLON5 which disrupts synapses. GlyR autoantibodies (bottom) directly inhibits GlyR and/or cause internalization of GlyR and subsequent lysosomal degradation. Figure created with BioRender.com (accessed on 13 December 2023).
See this image and copyright information in PMC

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