Figure 5.

Possible mechanisms contributing to autoimmune encephalitides. In the center of the figure, an axial, T2-weighed magnetic resonance imaging section of a human brain is shown. The hyperintense (whitish “S”-shaped) structures represent inflammed, swollen hippocampi that are frequently affected in so-called autoimmune (limbic) encephalitis. Several forms are mainly B-lymphocyte- (B cell-) mediated with identification of a causative antibody (green). T-lymphocytes (T cell) and activated microglia (M1) may also contribute to neuroinflammation. Edited dsRNA in the 3′UTR of mRNAs may not be perfectly base-paired and thus contains loop structures that are not recognized by melanoma differentiation-associated gene 5 (MDA5), a cytoplasmic, soluble viral RNA receptor that activates a type I interferon mediated immune response (upper left graph). MDA5 consists of a N-terminal caspase recruitment domain (orange) a helicase domain (gray), and a C-terminal domain (blue; after Berke and Modis, 2012). Hypoedited and thus perfectly base-paired double-stranded RNA binds to the helicase and C-terminal domains and induces changes in the conformation and oligomerization of MDA5 that triggers an inflammatory response. An equivalent neuroinflammatory mechanism remains to be investigated in encephalitis patients (indicated by red question mark), but also in patients with neurodegenerative diseases, epilepsy, and other diseases where neuroinflammation is an important co-factor.