biostudies-literaturePal MNHLBI NIH HHS269-280https://www.ebi.ac.uk/biostudies/studies/S-EPMC7820872biostudies-literatureUnknown137(2)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 werBloodHemolysis inhibits humoral B-cell responses and modulates alloimmunization risk in patients with sickle cell disease.PMC7820872P01 HL149626R01 HL130139Liu YShi PAManwani DMinniti CWang RLobo CAMitchell WBBao WAn XZhong HYazdanbakhsh KPal MfalseHemolysis inhibits humoral B-cell responses and modulates alloimmunization risk in patients with sickle cell disease.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 wer2021-01-01T00:00:00Z2021 Jan2025-04-18T15:12:57.342Z2025-04-07T01:47:01.57ZS-EPMC78208723315274910.1182/blood.2020008511