Ultrahigh frequencies of peripherally matured LGI1-and CASPR2reactive B cells characterize the cerebrospinal fluid in autoimmune encephalitis

• 成果类型: Article
• 署名作者: Theorell, Jakob; Harrison, Ruby; Williams, Robyn; Raybould, Matthew I. J.; Zhao, Meng; Fox, Hannah; Fower, Andrew; Miller, Georgina; Wu, Zoe; Browne, Eleanor; Mgbachi, Victor; Sun, Bo; Mopuri, Rohini; Li, Ying; Waters, Patrick; Deane, Charlotte M.; Handel, Adam; Makuch, Mateusz; Irani, Sarosh R.
• 署名单位: University of Oxford; Karolinska Institutet; Karolinska Institutet; Karolinska University Hospital; University of Oxford; University of Oxford; Mayo Clinic; Mayo Clinic; Mayo Clinic
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14231
• DOI: 10.1073/pnas.2311049121
• 发表日期: 2024-02-06
• 关键词: clonality inference; autoantibodies; antibodies; immunotherapy

摘要

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 germline- encoded BCRs versus the founder intrathecal clone revealed marked gains in both affinity and mutational distances (P = 0.004 and P < 0.0001, respectively). Taken together, in patients with LGI1 and CASPR2 antibody encephalitis, our results identify CSF as a compartment with a remarkably high frequency of clonally expanded autoantigen- reactive ASCs whose BCR maturity appears dominantly acquired outside the CNS.