Humoral signatures of Caspr2-antibody spectrum disorder track with clinical phenotypes and outcomes.

IF 12.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Med Pub Date : 2024-10-03 DOI:10.1016/j.medj.2024.09.004

Paula Terroba-Navajas, Marianna Spatola, Omar Chuquisana, Bastien Joubert, Juna M de Vries, Andre Dik, Laura Marmolejo, Friederike Jönsson, Gordan Lauc, Stjepana Kovac, Harald Prüss, Heinz Wiendl, Maarten J Titulaer, Jérôme Honnorat, Jan D Lünemann

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引用次数: 0

Abstract

Background: Immunoglobulin (Ig) G4 auto-antibodies (Abs) against contactin-associated protein-like 2 (Caspr2), a transmembrane cell adhesion protein expressed in the central and peripheral nervous system, are found in patients with a broad spectrum of neurological symptoms. While the adoptive transfer of Caspr2-specific IgG induces brain pathology in susceptible rodents, the mechanisms by which Caspr2-Abs mediate neuronal dysfunction and translate into clinical syndromes are incompletely understood.

Methods: We use a systems-level approach combined with high-dimensional characterization of Ab-associated immune features to deeply profile humoral biosignatures in patients with Caspr2-Ab-associated neurological syndromes.

Findings: We identify two signatures strongly associated with two major clinical phenotypes, limbic encephalitis (LE) and predominant peripheral nerve hyperexcitability without LE (non-LE). Caspr2-IgG Fc-driven pro-inflammatory features, characterized by increased binding affinities for activating Fcγ receptors (FcγRs) and C1q, along with a higher prevalence of IgG1-class Abs, in addition to IgG4, are strongly associated with LE. Both the occurrence of Caspr2-specific IgG1 and higher serum levels of interleukin (IL)-6 and IL-15, along with increased concentrations of biomarkers reflecting neuronal damage and glial cell activation, are associated with poorer clinical outcomes at 1-year follow-up.

Conclusions: The presence of IgG1 isotypes and Fc-mediated effector functions control the pathogenicity of Caspr2-specific Abs to induce LE. Biologics targeting FcR function might potentially restrain Caspr2-Ab-induced pathology and improve clinical outcomes.

Funding: This study was funded by a German-French joint research program supported by the German Research Foundation (DFG) and the Agence Nationale de la Recherche (ANR) and by the Interdisciplinary Centre for Clinical Research (IZKF) Münster.

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Caspr2-抗体谱系障碍的体液特征与临床表型和结果的关系。

背景：针对接触素相关蛋白样 2（Caspr2）的免疫球蛋白（Ig）G4 自身抗体（Abs）是一种在中枢和外周神经系统中表达的跨膜细胞粘附蛋白。虽然Caspr2特异性IgG可诱导易感啮齿类动物出现脑部病变，但人们对Caspr2-Abs介导神经元功能障碍并转化为临床综合征的机制尚不完全清楚：方法：我们采用系统级方法，结合 Ab 相关免疫特征的高维表征，深入剖析 Caspr2-Ab 相关神经综合征患者的体液生物特征：我们发现了与两种主要临床表型（边缘性脑炎（LE）和无LE（非LE）的主要周围神经兴奋性减退）密切相关的两个特征。Caspr2-IgG Fc驱动的促炎特征与LE密切相关，其特点是与活化Fcγ受体（FcγRs）和C1q的结合亲和力增加，同时除IgG4外，IgG1类抗体的流行率也较高。Caspr2特异性IgG1的出现和较高的血清白细胞介素（IL）-6和IL-15水平，以及反映神经元损伤和胶质细胞活化的生物标记物浓度的增加，都与随访1年后较差的临床结果有关：结论：IgG1异型和Fc介导的效应器功能控制着Caspr2特异性Abs诱导LE的致病性。针对FcR功能的生物制剂可能会抑制Caspr2-Ab诱导的病理变化并改善临床预后：本研究由德国研究基金会（DFG）和法国国家研究署（ANR）支持的德法联合研究计划以及明斯特跨学科临床研究中心（IZKF）资助。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

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