In Silico Prediction Analysis of Idiotope-Driven T-B Cell Collaboration in Multiple Sclerosis.
In Silico Prediction Analysis of Idiotope-Driven T-B Cell Collaboration in Multiple Sclerosis.
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DOI：
10.3389/fimmu.2017.01255
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发表时间：
2017
影响因子：
7.3
通讯作者：
Holmøy T
中科院分区：
文献类型：
--
作者：
Høglund RA;Lossius A;Johansen JN;Homan J;Benth JŠ;Robins H;Bogen B;Bremel RD;Holmøy T
记忆 B 细胞作为抗原呈递细胞被认为在多发性硬化症 (MS) 中很重要，但它们呈递的抗原仍然未知。我们假设 B 细胞可能通过将自身免疫球蛋白可变区的独特位呈递到人类白细胞抗原 (HLA) II 类分子上来激活多发性硬化症患者中枢神经系统中的 CD4+ T 细胞。在这里，我们对 11 名 MS 患者和 6 名患有其他炎症性神经系统疾病 (OIND) 的对照者的 B 细胞免疫球蛋白可变区进行生物信息学预测分析，以评估这种独特位驱动的 T-B 细胞协作的先决条件是否存在。我们的研究结果表明，来自 MS 患者互补决定区 (CDR) 3 的独特位平均对疾病相关的 HLA-DRB1*15:01 分子具有较高的预测亲和力，并且预计会在允许发生此类 HLA 结合的位置由组织蛋白酶 S 和 L 进行内体加工。此外，来自 MS 患者脑脊液 (CSF) B 细胞的互补决定区 3 序列平均包含比来自 OIND 患者脑脊液 (CSF) B 细胞更罕见的 T 细胞暴露基序，这些基序可能会逃避耐受并刺激 CD4+ T 细胞。其中许多特征与多发性硬化症患者的脑脊液 B 细胞优先使用 IGHV4 基因家族有关。这是第一项将患者免疫库的高通量测序与大规模预测分析相结合的研究，并为未来的体外和体内分析提供了关键指标。
Memory B cells acting as antigen-presenting cells are believed to be important in multiple sclerosis (MS), but the antigen they present remains unknown. We hypothesized that B cells may activate CD4+ T cells in the central nervous system of MS patients by presenting idiotopes from their own immunoglobulin variable regions on human leukocyte antigen (HLA) class II molecules. Here, we use bioinformatics prediction analysis of B cell immunoglobulin variable regions from 11 MS patients and 6 controls with other inflammatory neurological disorders (OINDs), to assess whether the prerequisites for such idiotope-driven T–B cell collaboration are present. Our findings indicate that idiotopes from the complementarity determining region (CDR) 3 of MS patients on average have high predicted affinities for disease associated HLA-DRB1*15:01 molecules and are predicted to be endosomally processed by cathepsin S and L in positions that allows such HLA binding to occur. Additionally, complementarity determining region 3 sequences from cerebrospinal fluid (CSF) B cells from MS patients contain on average more rare T cell-exposed motifs that could potentially escape tolerance and stimulate CD4+ T cells than CSF B cells from OIND patients. Many of these features were associated with preferential use of the IGHV4 gene family by CSF B cells from MS patients. This is the first study to combine high-throughput sequencing of patient immune repertoires with large-scale prediction analysis and provides key indicators for future in vitro and in vivo analyses.