首页> 外文期刊>Journal of Autoimmunity >Soluble antigen arrays disarm antigen-specific B cells to promote lasting immune tolerance in experimental autoimmune encephalomyelitis
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Soluble antigen arrays disarm antigen-specific B cells to promote lasting immune tolerance in experimental autoimmune encephalomyelitis

机译:可溶性抗原阵列解除抗原特异性B细胞,以促进实验性自身免疫脑髓炎中的持久免疫耐受性

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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 andin vivoanalyses. 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.
机译:自身反应性淋巴细胞可以通过称为Anergy的内源性外周公差机制沉默。能够诱导毒剂的抗原特异性疗法可以将患有自身免疫疾病的患者恢复到健康的表型,同时避免与全球免疫抑制相关的有害副作用。在B细胞中诱导毒性可能是特别有效的干预,因为B细胞可以通过多种机制促进自身免疫疾病,并提供通过B细胞受体(BCR)直接抗原特异性靶向的可能性。我们以前的结果表明自身反应性B细胞可以由多价“可溶性抗原阵列”(SAGAS)沉默,其是在具有或不具有阻断细胞内细胞 - 粘附分子-1(ICAM-1)的次级肽的多种自身抗体拷贝的聚合物缀合物。这里,通过综合细胞和体内诱导蛋白酶和与免疫机制联系在这里,通过综合细胞和蛋白的诱导体内鉴定和与免疫机制相关的关键治疗分子特性。我们确定了不可变化的“CSAGAS”显示多价'咔蛋缀合的抗原更易于抑制的实验性自身免疫脑脊髓炎(EAE)与能够释放共轭抗原的可水解索兰相比。 Csagas通过在B细胞中诱导B细胞和称为自身免疫疾病中有效APC的B细胞的阴影来诱导疾病特异性抗原呈递细胞(APC)的健康表型。伴随着朝向Th2 /调节表型的细胞因子反应,这产生了自身抗体耐受的环境。通过鉴定关键的治疗分子特性和驱动Saga疗效的免疫机制,这项工作指导设计能够诱导盲肠的抗原特异性免疫治疗。

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