Limbic encephalitis with antibodies to LGI1 is associated with an active intrathecal B cell response

Abstract

Background: Leucine-rich glioma inactivated 1 (LGI1) is a component of the voltage-gated potassium channel complex (VGKC). Antibodies against LGI1 are associated with limbic encephalitis and related central nervous system (CNS) disorders. In most patients, anti-LGI1 antibodies are found in the serum, while their occurrence in the cerebrospinal fluid (CSF) is much less common. Oligoclonal IgG (oligoclonal bands, OCB), a prominent indicator for intrathecal B cell activation, are rarely found in patients with LGI1 encephalitis. Overall, the immune pathology resulting in LGI1 autoimmunity is unclear. However, partially due to the absence of OCB, peripheral immune processes are believed to be the principal disease drivers. Objective: To investigate whether an active intrathecal B cell immune response is present in patients with LGI1 antibodies. Methods: We applied PCR amplification and next generation deep immune repertoire sequencing (DIRS) of B cell receptor immunoglobulin (Ig) heavy chain variable regions (VH) from CSF and peripheral blood B cells of 2 patients with LGI1 encephalitis. Extensive bioinformatics clustering of related IgM-VH or IgG-VH transcripts was employed to determine 1) whether active B cell immune mechanisms operate in LGI1 encephalitis, and 2) whether intrathecal B cell repertoires, if present, are related to peripheral B cells. Results: We identified numerous clusters of related Ig-VH transcripts in the CSF of both patients; within these clusters we found a range of somatic hypermutations (SHM) along the IGHV germline segmentderived portion suggesting that local antigen-driven activation of clonally related B cells was involved in shaping the intrathecal immune repertoire. Furthermore, we identified a large number of closely related Ig-VH clusters that were common to both, CSF and periphery. Interestingly, in each patient we identified a small number of dominating Ig-VH clusters that may represent the most active clonally related B cell populations. Conclusion: Our data suggest that in LGI1 encephalitis B cell affinity maturation occurs inside the CNS compartment. The target antigen(s) of the clonally related B cells described here remain unknown; ongoing work will determine whether intrathecally activated B cells and/or B cells that apparently target identical antigens in the periphery and CNS compartments are involved in LGI1 autoimmunity.