Ultrahigh frequencies of peripherally matured LGI1- and CASPR2-reactive B cells characterize the cerebrospinal fluid in autoimmune encephalitis
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.
| Errataetall: |
CommentIn: Proc Natl Acad Sci U S A. 2024 Feb 27;121(9):e2401337121. - PMID 38354256 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:121 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 121(2024), 7 vom: 13. Feb., Seite e2311049121 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Theorell, Jakob [VerfasserIn] |
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| Links: |
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| Themen: |
Autoantibodies |
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| Anmerkungen: |
Date Completed 08.02.2024 Date Revised 13.03.2024 published: Print-Electronic CommentIn: Proc Natl Acad Sci U S A. 2024 Feb 27;121(9):e2401337121. - PMID 38354256 Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2311049121 |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Ultrahigh frequencies of peripherally matured LGI1- and CASPR2-reactive B cells characterize the cerebrospinal fluid in autoimmune encephalitis |
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| 500 | |a CommentIn: Proc Natl Acad Sci U S A. 2024 Feb 27;121(9):e2401337121. - PMID 38354256 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
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| 700 | 1 | |a Williams, Robyn |e verfasserin |4 aut | |
| 700 | 1 | |a Raybould, Matthew I J |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Meng |e verfasserin |4 aut | |
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| 700 | 1 | |a Sun, Bo |e verfasserin |4 aut | |
| 700 | 1 | |a Mopuri, Rohini |e verfasserin |4 aut | |
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| 700 | 1 | |a Deane, Charlotte M |e verfasserin |4 aut | |
| 700 | 1 | |a Handel, Adam |e verfasserin |4 aut | |
| 700 | 1 | |a Makuch, Mateusz |e verfasserin |4 aut | |
| 700 | 1 | |a Irani, Sarosh R |e verfasserin |4 aut | |
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