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Hemolysis inhibits humoral B-cell responses and modulates alloimmunization risk in patients with sickle cell disease.

溶血抑制镰状细胞病患者的体液b细胞反应并调节同种免疫风险。

  • 影响因子:7.27
  • DOI:10.1182/blood.2020008511
  • 作者列表:"Pal M","Bao W","Wang R","Liu Y","An X","Mitchell WB","Lobo CA","Minniti C","Shi PA","Manwani D","Yazdanbakhsh K","Zhong H
  • 发表时间:2021-01-14
Abstract

:Red blood cell alloimmunization remains a barrier for safe and effective transfusions in sickle cell disease (SCD), but the associated risk factors remain largely unknown. Intravascular hemolysis, a hallmark of SCD, results in the release of heme with potent immunomodulatory activity, although its effect on SCD humoral response, specifically alloimmunization, remains unclear. Here, we found that cell-free heme suppresses human B-cell plasmablast and plasma cell differentiation by inhibiting the DOCK8/STAT3 signaling pathway, which is critical for B-cell activation, as well as by upregulating heme oxygenase 1 (HO-1) through its enzymatic byproducts, carbon monoxide and biliverdin. Whereas nonalloimmunized SCD B cells were inhibited by exogenous heme, B cells from the alloimmunized group were nonresponsive to heme inhibition and readily differentiated into plasma cells. Consistent with a differential B-cell response to hemolysis, we found elevated B-cell basal levels of DOCK8 and higher HO-1-mediated inhibition of activated B cells in nonalloimmunized compared with alloimmunized SCD patients. To overcome the alloimmunized B-cell heme insensitivity, we screened several heme-binding molecules and identified quinine as a potent inhibitor of B-cell activity, reversing the resistance to heme suppression in alloimmunized patients. B-cell inhibition by quinine occurred only in the presence of heme and through HO-1 induction. Altogether, these data suggest that hemolysis can dampen the humoral B-cell response and that B-cell heme responsiveness maybe a determinant of alloimmunization risk in SCD. By restoring B-cell heme sensitivity, quinine may have therapeutic potential to prevent and inhibit alloimmunization in SCD patients.

摘要

: 红细胞同种免疫仍是镰状细胞病 (SCD) 安全有效输血的障碍,但相关风险因素仍在很大程度上未知。血管内溶血 (SCD的标志) 导致释放具有强效免疫调节活性的血红素,尽管其对SCD体液应答,特别是同种免疫的影响仍不清楚。在这里,我们发现无细胞血红素通过抑制对b细胞活化至关重要的DOCK8/STAT3信号通路,以及通过其酶促副产物一氧化碳和胆绿素上调血红素加氧酶1 (HO-1) 来抑制人b细胞浆细胞和浆细胞分化.而非同种异体免疫的SCD b细胞被外源性血红素抑制,来自同种异体免疫组的b细胞对血红素抑制无反应,并且容易分化成浆细胞。与对溶血的差异b细胞应答一致,我们发现与非同种异体免疫SCD患者相比,非同种异体免疫的患者中DOCK8的b细胞基础水平升高,HO-1介导的活化b细胞抑制更高。为了克服同种异体免疫的b细胞血红素不敏感,我们筛选了几种血红素结合分子,并确定奎宁是b细胞活性的有效抑制剂,逆转同种异体免疫患者对血红素抑制的抗性。奎宁的b细胞抑制仅在血红素存在下和通过HO-1诱导发生。总之,这些数据表明溶血可以抑制体液b细胞应答,并且b细胞血红素反应性可能是SCD中同种免疫风险的决定因素。通过恢复b细胞血红素敏感性,奎宁可能具有预防和抑制SCD患者同种免疫的治疗潜力。

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