Ultrahigh frequencies of peripherally matured LGI1- and CASPR2-reactive B cells characterize the cerebrospinal fluid in autoimmune encephalitis

作者：Jakob Theorell, Ruby Harrison, Robyn Williams, Matthew I. J. Raybould, Meng Zhao, Hannah Fox, Andrew Fower, Georgina Miller, Zoe Y. Wu, Eleanor Browne, Victor Mgbachi, Bo Sun, Rohini Mopuri, Ying Li, Patrick Waters, Charlotte M. Deane, Adam E. Handel, Mateusz Makuch, Sarosh R. Irani · 发表于：Proceedings of the National Academy of Sciences · 年份：2024 · DOI：10.1073/pnas.2311049121 · 被引用次数：43 · 研究领域：Autoimmune Neurological Disorders and Treatments、Peripheral Neuropathies and Disorders、Cellular transport and secretion

Intrathecal synthesis of central nervous system (CNS)-reactive autoantibodies is observed across patients with autoimmune encephalitis (AE), who show multiple residual neurobehavioral deficits and relapses despite immunotherapies. We leveraged two common forms of AE, mediated by leucine-rich glioma inactivated-1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies, as human models to comprehensively reconstruct and profile cerebrospinal fluid (CSF) B cell receptor (BCR) characteristics. We hypothesized that the resultant observations would both inform the observed therapeutic gap and determine the contribution of intrathecal maturation to pathogenic B cell lineages. From the CSF of three patients, 381 cognate-paired IgG BCRs were isolated by cell sorting and scRNA-seq, and 166 expressed as monoclonal antibodies (mAbs). Sixty-two percent of mAbs from singleton BCRs reacted with either LGI1 or CASPR2 and, strikingly, this rose to 100% of cells in clonal groups with ≥4 members. These autoantigen-reactivities were more concentrated within antibody-secreting cells (ASCs) versus B cells ( P < 0.0001), and both these cell types were more differentiated than LGI1- and CASPR2-unreactive counterparts. Despite greater differentiation, autoantigen-reactive cells had acquired few mutations intrathecally and showed minimal variation in autoantigen affinities within clonal expansions. Also, limited CSF T cell receptor clonality was observed. In contrast, a comparison of ger...