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

被引：17

作者：

Theorell, Jakob ^{[1
,2
,3
]}

Harrison, Ruby ^{[1
]}

Williams, Robyn ^{[1
,4
]}

Raybould, Matthew I. J. ^{[5
]}

Zhao, Meng ^{[1
]}

Fox, Hannah ^{[1
]}

Fower, Andrew ^{[1
]}

Miller, Georgina ^{[1
]}

Wu, Zoe ^{[1
]}

Browne, Eleanor ^{[1
]}

Mgbachi, Victor ^{[1
]}

Sun, Bo ^{[1
]}

Mopuri, Rohini ^{[6
]}

Li, Ying ^{[6
]}

Waters, Patrick ^{[1
]}

Deane, Charlotte M. ^{[5
]}

Handel, Adam ^{[1
,4
]}

Makuch, Mateusz ^{[1
]}

Irani, Sarosh R. ^{[1
,4
,7
,8
]}

机构：

[1] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford Autoimmune Neurol Grp, Oxford OX3 9DU, England

[2] Karolinska Inst, Dept Med Huddinge, S-17177 Stockholm, Sweden

[3] Karolinska Univ Hosp, Dept Neurol, S-17176 Stockholm, Sweden

[4] Oxford Univ Hosp, John Radcliffe Hosp, Dept Neurol, Oxford OX3 9DU, England

[5] Univ Oxford, Dept Stat, Oxford Prot Informat Grp, Oxford OX1 3LB, England

[6] Mayo Clin, Dept Quantitat Hlth Sci, Jacksonville, FL 32224 USA

[7] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA

[8] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2024年 / 121卷 / 07期

关键词：

autoantibody; encephalitis; cerebrospinal fluid; plasmablast; autoantigen; CLONALITY INFERENCE; AUTOANTIBODIES; ANTIBODIES; IMMUNOTHERAPY;

D O I：

10.1073/pnas.2311049121

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

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.

引用

页数：9

共 1 条

[1] Autoimmune Encephalitis with Antibodies: Anti-NMDAR, Anti-AMPAR, Anti-GQ1b, Anti-DPPX, Anti-CASPR2, Anti-LGI1, Anti-RI, Anti-Yo, Anti-Hu, Anti-CV2 and Anti-GABAAR, in the Course of Psychoses, Neoplastic Diseases, and Paraneoplastic Syndromes
Braczkowski, Michal
Soszynski, Dariusz
Sierakowska, Alicja
Braczkowski, Ryszard
Kufel, Klaudia
Labuz-Roszak, Beata
DIAGNOSTICS, 2023, 13 (15)

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