Soluble antigen arrays disarm antigen-specific B cells to promote lasting immune tolerance in experimental autoimmune encephalomyelitis.
Soluble antigen arrays disarm antigen-specific B cells to promote lasting immune tolerance in experimental autoimmune encephalomyelitis.
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DOI：
10.1016/j.jaut.2018.06.006
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发表时间：
2018-09
影响因子：
12.8
通讯作者：
Berkland C
中科院分区：
文献类型：
--
作者：
Hartwell BL;Pickens CJ;Leon M;Northrup L;Christopher MA;Griffin JD;Martinez-Becerra F;Berkland C
逃避中枢免疫耐受的自身反应性淋巴细胞可能通过称为无反应性的内源性外周耐受机制沉默。能够诱导无反应性的抗原特异性疗法可以使患有自身免疫性疾病的患者恢复健康表型，同时避免与整体免疫抑制相关的有害副作用。诱导B细胞无反应性可能是一种特别有效的干预措施，因为B细胞可以通过多种机制导致自身免疫性疾病，并提供通过B细胞受体（BCR）直接抗原特异性靶向的潜力。我们以前的研究结果表明，自身反应性B细胞可能被多价"可溶性抗原阵列"（SAgAs）沉默，SAgAs是显示多个自身抗原拷贝的聚合物缀合物，具有或不具有阻断细胞内细胞粘附分子-1（ICAM-1）的二级肽。在这里，通过全面的细胞和体内分析，确定了SAgAs的关键治疗分子特性，并将其与免疫机制联系起来。我们确定了与能够释放缀合抗原的可水解SAgAs相比，展示多价"点击"缀合抗原的不可水解"cSAgAs"更有效地抑制实验性自身免疫性脑脊髓炎（EAE）。cSAgAs通过诱导B细胞和称为自身免疫相关B细胞（ABC）的B细胞亚群中的无反应性应答，恢复疾病特异性抗原呈递细胞（APC）中的健康表型，所述自身免疫相关B细胞（ABC）在自身免疫性疾病中充当有效APC。伴随着细胞因子反应偏向Th2/调节表型，这产生了自身抗原耐受的环境。通过确定关键的治疗分子特性和驱动SAgA功效的免疫机制，这项工作指导了能够诱导无能的抗原特异性免疫疗法的设计。
Autoreactive lymphocytes that escape central immune tolerance may be silenced via an endogenous peripheral tolerance mechanism known as anergy. Antigen-specific therapies capable of inducing anergy may restore patients with autoimmune diseases to a healthy phenotype while avoiding deleterious side effects associated with global immunosuppression. Inducing anergy in B cells may be a particularly potent intervention, as B cells can contribute to autoimmune diseases through multiple mechanisms and offer the potential for direct antigen-specific targeting through the B cell receptor (BCR). Our previous results suggested autoreactive B cells may be silenced by multivalent ‘soluble antigen arrays’ (SAgAs), which are polymer conjugates displaying multiple copies of autoantigen with or without a secondary peptide that blocks intracellular cell-adhesion molecule-1 (ICAM-1). Here, key therapeutic molecular properties of SAgAs were identified and linked to the immunological mechanism through comprehensive cellular and in vivo analyses. We determined non-hydrolyzable ‘cSAgAs’ displaying multivalent ‘click’-conjugated antigen more potently suppressed experimental autoimmune encephalomyelitis (EAE) compared to hydrolyzable SAgAs capable of releasing conjugated antigen. cSAgAs restored a healthy phenotype in disease-specific antigen presenting cells (APCs) by inducing an anergic response in B cells and a subset of B cells called autoimmune-associated B cells (ABCs) that act as potent APCs in autoimmune disease. Accompanied by a cytokine response skewed towards a Th2/regulatory phenotype, this generated an environment of autoantigenic tolerance. By identifying key therapeutic molecular properties and an immunological mechanism that drives SAgA efficacy, this work guides the design of antigen-specific immunotherapies capable of inducing anergy.
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