Plasma Cell Differentiation Pathways in Systemic Lupus Erythematosus.
Plasma Cell Differentiation Pathways in Systemic Lupus Erythematosus.
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DOI：
10.3389/fimmu.2018.00427
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发表时间：
2018
影响因子：
7.3
通讯作者：
Diamond B
中科院分区：
文献类型：
--
作者：
Malkiel S;Barlev AN;Atisha-Fregoso Y;Suurmond J;Diamond B
浆细胞（PC）负责产生针对传染源的保护性抗体，但它们也在自身免疫性疾病中产生致病性抗体，例如系统性红斑狼疮（SLE）。传统上，高亲和力 IgG 自身抗体被认为是通过生发中心 (GC) 反应产生的。然而，类别转换和体细胞超突变可能发生在滤泡外 (EF) 位置，并且该途径也与 SLE 有关。 PC 的起源途径可能决定一些特征，例如 PC 的寿命和对治疗的敏感性。尽管 GC 和 EF 反应都与 SLE 相关，但我们假设这些途径之一在每个患者中占主导地位，并且遗传风险因素可能推动这种优势。虽然区分有助于 GC 驱动或 EF B 细胞反应的多态性以开发靶向治疗非常重要，但挑战不仅在于确定分化途径，还在于所涉及的分子机制。在 B 细胞中，这项任务因 B 细胞受体、Toll 样受体 (TLR) 和细胞因子信号分子之间的串扰而变得复杂，这些信号分子导致 GC 和 EF 反应。虽然影响树突状细胞和滤泡辅助性 T 细胞功能的风险变异可能主要影响 GC 反应，但发现干扰素和 TLR 途径中的某些风险变异是否优先影响 EF 反应也很重要。识别 SLE 中自身反应性 PC 分化的途径可能有助于我们了解患者的异质性，从而指导精准治疗。
Plasma cells (PCs) are responsible for the production of protective antibodies against infectious agents but they also produce pathogenic antibodies in autoimmune diseases, such as systemic lupus erythematosus (SLE). Traditionally, high affinity IgG autoantibodies are thought to arise through germinal center (GC) responses. However, class switching and somatic hypermutation can occur in extrafollicular (EF) locations, and this pathway has also been implicated in SLE. The pathway from which PCs originate may determine several characteristics, such as PC lifespan and sensitivity to therapeutics. Although both GC and EF responses have been implicated in SLE, we hypothesize that one of these pathways dominates in each individual patient and genetic risk factors may drive this predominance. While it will be important to distinguish polymorphisms that contribute to a GC-driven or EF B cell response to develop targeted treatments, the challenge will be not only to identify the differentiation pathway but the molecular mechanisms involved. In B cells, this task is complicated by the cross-talk between the B cell receptor, toll-like receptors (TLR), and cytokine signaling molecules, which contribute to both GC and EF responses. While risk variants that affect the function of dendritic cells and T follicular helper cells are likely to primarily influence GC responses, it will be important to discover whether some risk variants in the interferon and TLR pathways preferentially influence EF responses. Identifying the pathways of autoreactive PC differentiation in SLE may help us to understand patient heterogeneity and thereby guide precision therapy.