Scherer Hans Ulrich
Department of Rheumatology, Leiden University Medical Center, P.O. Box 9600, NL - 2300RC Leiden, the Netherlands.
Semin Arthritis Rheum. 2024 Feb;64S:152315. doi: 10.1016/j.semarthrit.2023.152315. Epub 2023 Nov 22.
The generation and persistence of autoreactive B and plasma cells is crucial to the pathogenesis of many human autoimmune diseases. Secreted autoantibodies frequently serve as biomarkers in clinical practice and, in some cases, function as pathogenic effector molecules. Nonetheless, the primary break of B cell tolerance against autoantigens, the triggers that maintain autoreactive B cell memory, and the phenotype that autoreactive B cells adopt during the disease course are poorly understood.
To study phenotype and functional characteristics of human autoreactive B cells in the course of human disease using rheumatoid arthritis and the B cell response against posttranslationally modified antigens as prototype.
Combinatorial, antigen-specific identification and multiparameter phenotyping of autoreactive B cells by conventional and spectral flow cytometry in cohorts with well-defined clinical phenotypes, including patients in the phase preceding disease and in those reaching long-term, drugfree remission.
Autoreactive B cells against post-translationally modified proteins operate as remarkably activated effector memory cells in patients with established disease and maintain this state throughout the disease course. The activation generates cytokine-secreting germinal center emigrants that resist conventional therapy, and migratory plasmablasts expressing homing markers that can direct the cells to sites of inflammation. In the pre-clinical at-risk phase, the degree of activation is lower, and migratory plasmablasts are less frequent. The cells are cross-reactive to different posttranslational modifications and express B cell receptors that are extensively glycosylated in the variable domain.
Immune phenotyping of disease-specific, autoreactive B cells reveals heterogeneous features of human autoimmunity that reflect disease stage and course and that are only revealed upon antigen-specific cellular analysis. In rheumatoid arthritis, the picture of germinal center-derived B cell autoreactivity against post-translationally modified antigens emerges that displays extensive cross-reactivity and a likely dependence on T cell help. Such features may be different for other human autoimmune diseases with different disease kinetics, which each may require different strategies for (autoreactive) B cell targeting.
自身反应性B细胞和浆细胞的产生及持续存在对许多人类自身免疫性疾病的发病机制至关重要。分泌的自身抗体在临床实践中常作为生物标志物，在某些情况下还作为致病效应分子发挥作用。然而，B细胞对自身抗原耐受性的初次打破、维持自身反应性B细胞记忆的触发因素以及疾病过程中自身反应性B细胞所采用的表型仍知之甚少。
以类风湿关节炎以及针对翻译后修饰抗原的B细胞反应为原型，研究人类疾病过程中人类自身反应性B细胞的表型和功能特征。
通过传统流式细胞术和光谱流式细胞术，对具有明确临床表型的队列中的自身反应性B细胞进行组合式、抗原特异性鉴定和多参数表型分析，这些队列包括疾病前期患者和实现长期无药缓解的患者。
针对翻译后修饰蛋白的自身反应性B细胞在已确诊疾病的患者中作为显著活化的效应记忆细胞发挥作用，并在整个疾病过程中维持这种状态。这种活化产生分泌细胞因子的生发中心迁出细胞，这些细胞对传统疗法有抗性，以及表达归巢标志物的迁移性浆母细胞，这些标志物可将细胞导向炎症部位。在临床前风险期，活化程度较低，迁移性浆母细胞较少见。这些细胞对不同的翻译后修饰具有交叉反应性，并表达在可变区广泛糖基化的B细胞受体。
疾病特异性自身反应性B细胞的免疫表型分析揭示了人类自身免疫的异质性特征，这些特征反映了疾病阶段和病程，并且只有通过抗原特异性细胞分析才能揭示。在类风湿关节炎中，出现了生发中心来源的B细胞针对翻译后修饰抗原的自身反应性情况，表现出广泛的交叉反应性以及可能对T细胞辅助的依赖性。对于具有不同疾病动力学的其他人类自身免疫性疾病，这些特征可能不同，每种疾病可能需要针对（自身反应性）B细胞的不同靶向策略。
