scholarly journals Hemolysis Inhibits Humoral B Cell Responses and Modulates Alloimmunization Risk in Patients with Sickle Cell Disease

Blood ◽  
2020 ◽  
Author(s):  
Mouli Pal ◽  
Weili Bao ◽  
Rikang Wang ◽  
Yunfeng Liu ◽  
Xiuli An ◽  
...  
Keyword(s):  
B Cells ◽  
Sickle Cell Disease ◽  
B Cell ◽  
Sickle Cell ◽  
Cell Response ◽  
Cell Activity ◽  
Immunomodulatory Activity ◽  
Heme Oxygenase 1 ◽  
Cell Disease ◽  
B Cell Response

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/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 non-alloimmunized SCD B cells were inhibited by exogenous heme, B cells from the alloimmunized group were non-responsive 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 non-alloimmunized compared to 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 only occurred 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. Quinine by restoring B cell heme sensitivity may have therapeutic potential to prevent and inhibit alloimmunization in SCD patients.

scholarly journals Role of heme oxygenase 1 in cardiac ferroptosis in sickle cell disease

2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Archita Venugopal Menon ◽  
Hanting Tsai ◽  
Seungjeong Yang ◽  
Jonghan Kim
Keyword(s):  
Sickle Cell Disease ◽  
Heme Oxygenase ◽  
Sickle Cell ◽  
Heme Oxygenase 1 ◽  
Cell Disease

scholarly journals Impairment of neutrophil oxidative burst in children with sickle cell disease is associated with heme oxygenase-1

Haematologica ◽  
2015 ◽  
Vol 100 (12) ◽  
pp. 1508-1516 ◽  
Author(s):  
C. Evans ◽  
K. Orf ◽  
E. Horvath ◽  
M. Levin ◽  
J. De La Fuente ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Heme Oxygenase ◽  
Sickle Cell ◽  
Oxidative Burst ◽  
Heme Oxygenase 1 ◽  
Cell Disease ◽  
Neutrophil Oxidative Burst

Cytoprotective Mechanisms of the Lung in Sickle Cell Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1538-1538
Author(s):  
Samit Ghosh ◽  
Fang Tan ◽  
Mario Monsunjac ◽  
Solomon F Ofori-Acquah
Keyword(s):  
Sickle Cell Disease ◽  
Lung Disease ◽  
Sickle Cell ◽  
Chronic Lung Disease ◽  
Mrna Level ◽  
Normal Lung ◽  
Mononuclear Leukocytes ◽  
Heme Oxygenase 1 ◽  
Cell Disease ◽  
Cytoprotective Enzymes

Abstract Abstract 1538 Poster Board I-561 Circulating plasma hemoglobin contributes to major vasculopathies including pulmonary hypertension in patients who have sickle cell disease (SCD). There is an emerging concept that such vasculopathies are relatively mild because of activation of several cytoprotective pathways in SCD. The biochemical profile of plasma and the transcriptome of peripheral blood cells in patients who have SCD offer indirect support for this concept. Indeed, heme oxygenase-1 (HO-1), an acute phase enzyme that degrades heme into intermediates and byproducts with vasculoprotective properties is markedly elevated in mononuclear leukocytes of patients who have SCD. Nonetheless, the scope of the cytoprotective mechanisms of the lung and other organs impacted directly by sickle vasculopathies remain poorly appreciated. We previously identified an array of cytoprotective enzymes in lung endothelial cells chronically exposed to non-toxic concentrations of hemin in vitro. In this study, we examined the expression of NAD(P)H oxidase and candidate cytoprotective enzymes in two models of transgenic mice with SCD, and examined HO-1 expression in sickle chronic lung disease. Although NAD(P)H oxidase catalyzes reactive oxygen species generation by heme and is responsible for increased adhesion of leukocytes to the endothelium in SCD mice, there was no elevation of any of its subunits (gp91Phox and p22Phox, p47Phox, p67Phox and p40 Phox) in sickle mice lungs compared to hemizygote control mice lungs. Quantitative RT-PCR analysis revealed unexpectedly no difference in HO-1 mRNA level in sickle and non-sickle control lungs. On the contrary, analysis of the same tissues showed significantly higher NAD(P)H quinone oxidoreductase-1 (NQO1) mRNA level in both Berkeley and Townes knock-in sickle mice compared to controls (p<0.001). Enhanced expression of NQO1 but not HO-1 in sickle mice lungs was confirmed at the protein level by western blot analysis and by immunohistochemistry. Finally, we studied cases of sickle chronic lung disease (n=17) and discovered that NQO1 is expressed in the pulmonary endothelium at significantly higher levels than in normal lung tissues (p<0.002). In agreement with the data in mice, we found no difference in HO-1 staining in sickle human lung and normal lung tissues. Our findings indicate that despite its established role in acute elimination of excess heme, HO-1 is not elevated in sickle lungs. This study highlights the importance of dissecting the cytoprotective phenotype of individual organs impacted by SCD towards a rationale approach to developing efficacious antioxidant therapy for this disorder. Disclosures No relevant conflicts of interest to declare.

Protective Effect of Fetal Hemoglobin On Inflammation-Induced Expression of Hypoxia-Inducible Factor-1α (HIF-1α) in Sickle Mice: Microvascular Implications

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3250-3250
Author(s):  
Dhananjay K. Kaul ◽  
Mary E. Fabry ◽  
Sandra M Suzuka ◽  
Janki Shah
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Hypoxia Inducible Factor ◽  
Heme Oxygenase 1 ◽  
No Production ◽  
Cell Disease ◽  
Activation Markers ◽  
No Bioavailability

Abstract Abstract 3250 Chronic inflammation is a salient feature of human sickle cell disease (SCD) and transgenic-knockout sickle (BERK) mouse model. Although tissue ischemia is the primary instigator of hypoxia-inducible factor (HIF) activation, a number of inflammatory factors/pathways and oxidative stress can potentially induce expression of HIF-1α. Increased oxidative stress and inflammation are implicated in the activation of HIF-1α under normoxic conditions. HIF can trigger transcription of genes for vasoactive molecules such as vascular endothelial growth factor (VEGF), heme oxygenase-1 (HO-1) and endothelin, which are implicated in the pathophysiology of SCD. We hypothesize that, in SCD, inflammation coupled with nitric oxide (NO) depletion will induce expression of HIF-1α. To this end, we have examined the expression of HIF-1α in normoxic BERK mice expressing exclusively human α- and βS- globins, and evaluated the effect of HbF in BERK mice (i.e., <1.0%, 20% and 40% HbF). We have previously shown that HbF exerts anti-sickling and anti-inflammatory effects (Kaul et al. J Clin Invest, 2004; Dasgupta et al. Am J Physiol, 2010). Here, we show that HIF-1α is expressed in BERK mice under normoxic conditions (i.e., normal hemoglobin oxygen saturation levels). In BERK mice expressing HbF, HIF-1α expression decreased concomitantly with increasing HbF, commensurately with increased NO bioavailability, and showed a strong inverse correlation with plasma NO metabolites (NOx) levels. Reduced HIF-1α expression in BERK mice expressing HbF was associated with decreased HO-1 and VEGF expression, and reduced serum endothelin-1 (ET-1) levels, which are among the target vasoactive molecules of HIF-1α. Furthermore, the commensurate decrease in HIF-1α expression with increase in HbF levels in BERK mice was accompanied by a distinct decrease in soluble (s) forms of endothelial activation markers such as sP-selectin and vascular cell adhesion molecule-1 (sVCAM-1). Notably, arteriolar dilation, enhanced volumetric blood flow and low blood pressure in normoxic BERK mice all showed a trend toward normalization with the introduction of HbF. Also, arginine treatment reduced HIF-1α expression as well as ET-1 levels in normoxic BERK mice, supporting a role of decreased NO bioavailability in HIF-1α activation. The present in vivo studies show that reduced inflammation and increased NO production in normoxic BERK mice (expressing HbF or treated with arginine) are distinctly associated with suppression of HIF-1α activation and inhibition of vasodilators, resulting in improved microvascular and hemodynamic parameters in the BERK model of sickle cell disease. The unique feature of inflammation in SCD is that it can be ameliorated by increased HbF, thereby coupling HbS polymerization/sickling to NO depletion, HIF-1α expression and inflammation in this disease. Disclosures: No relevant conflicts of interest to declare.

Induction Of Ferroportin, Erg-1, p21 and IKBα In Sickle Cell Disease May Contribute To HIV-1 Inhibition

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2250-2250
Author(s):  
Sergei A Nekhai ◽  
Namita Kumari ◽  
Denitra Breuer ◽  
Charlee Mclean ◽  
Tatiana Ammosova ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Enzymatic Activity ◽  
Sickle Cell ◽  
Iron Chelators ◽  
Heme Oxygenase 1 ◽  
Cell Disease ◽  
Regulatory Pathways ◽  
Cyclin T1 ◽  
Cellular Iron ◽  
Hiv 1

Abstract Background Hypoxia and low iron induce hypoxia-induced factor 1(HIF-1) by stabilizing its alpha subunit and deregulate HIV-1 which transcription and several other steps of life cycle depend on cellular iron [1]. HIV-1 transcription is inhibited at low oxygen levels and reduced cellular iron through deregulation of CDK9/cyclin T1 and CDK2/cyclin E. Sickle cell disease has low odds of ratio for HIV-1 infection [2]. Sickle cell disease (SCD) leads to hemolytic anemia which results in local ischemia and release of heme. Induction of heme oxygenase-1 (HO-1) by hemin was shown to inhibit HIV-1 [1], although the mechanism of the inhibition was not clarified. Iron depletion by iron chelators or through the expression of ferroportin, an iron export protein, inhibits CDK2 and CDK9 activities and blocks HIV-1 transcription [1]. Because neither CDK2 nor CDK9 require iron for the enzymatic activity, we analyzed the expression of hypoxia and iron –dependent factors that may deregulate HIV-1 infection in SCD. Results Expression profiling followed by real-time PCR analysis showed induction of HO-1, p21, Erg-1, IKBα, HIF-1 and ferroportin mRNA and decrease of hepcidin mRNA in PBMCs from SCD patients. HIV-1 replication was reduced in SCD PBMCs comparing to normal controls, and also in THP1 cells treated with hemin. Subsequent treatment with hepcidin restored HIV-1 replication in SCD PBMC and in hemin-treated THP-1 cells, suggesting that ferroportin played a key role in the HIV-1 inhibition in these settings. Stable ferroportin knock down in THP-1 cells led to the inability of hemin to inhibit HIV-1, suggesting that ferroportin played a key role in the heme-meidated HIV-1 inhibition. Stable HIF-1a knockdown in promonocytic THP1 cells increased HIV replication suggesting that HIF1α is a restriction factor for HIV-1. Iron chelators induced the expression of IKBα, an inhibitor of NF-kB and also induced the expression of HIF-1 and p21. Iron chelators also inhibited enzymatic activity of CDK2 and shifted CDK9/cyclin T1 from the large to the small complex making it unavailable for HIV-1 Tat recruitment. Hemin treatment induced expression of HO-1, ferroportin, IkBα, HIF1α and p21 thus mimicking the effect of iron chelators. Conclusions Hemolytic conditions of sickle cell disease upregulate hypoxia and iron regulatory pathways leading to refraction of HIV-1. Targeting cellular iron, ferroportin and HO-1 may lead to novel anti-HIV-1 therapeutics. Acknowledgments This project was supported by NIH Research Grants 1SC1GM082325, 2G12RR003048, and P30HL107253. References 1. Nekhai S, Kumari N, Dhawan S: Role of cellular iron and oxygen in the regulation of HIV-1 infection. Future Virol 2013, 8(3):301-311. 2. Nouraie M, Nekhai S, Gordeuk VR: Sickle cell disease is associated with decreased HIV but higher HBV and HCV comorbidities in U.S. hospital discharge records: a cross-sectional study. Sex Transm Infect 2012, 88(7):528-533. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease

Blood ◽  
2004 ◽  
Vol 104 (1) ◽  
pp. 270-280 ◽  
Author(s):  
Maria L. Jison ◽  
Peter J. Munson ◽  
Jennifer J. Barb ◽  
Anthony F. Suffredini ◽  
Shefali Talwar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Expression Profiles ◽  
Ischemia Reperfusion ◽  
Transcriptional Analysis ◽  
Heme Oxygenase 1 ◽  
Specific Gene ◽  
Cell Disease

Abstract In sickle cell disease, deoxygenation of intra-erythrocytic hemoglobin S leads to hemoglobin polymerization, erythrocyte rigidity, hemolysis, and microvascular occlusion. Ischemia-reperfusion injury, plasma hemoglobin-mediated nitric oxide consumption, and free radical generation activate systemic inflammatory responses. To characterize the role of circulating leukocytes in sickle cell pathogenesis we performed global transcriptional analysis of blood mononuclear cells from 27 patients in steady-state sickle cell disease (10 patients treated and 17 patients untreated with hydroxyurea) compared with 13 control subjects. We used gender-specific gene expression to validate human microarray experiments. Patients with sickle cell disease demonstrated differential gene expression of 112 genes involved in heme metabolism, cell-cycle regulation, antioxidant and stress responses, inflammation, and angiogenesis. Inducible heme oxygenase-1 and downstream proteins biliverdin reductase and p21, a cyclin-dependent kinase, were up-regulated, potentially contributing to phenotypic heterogeneity and absence of atherosclerosis in patients with sickle cell disease despite endothelial dysfunction and vascular inflammation. Hydroxyurea therapy did not significantly affect leukocyte gene expression, suggesting that such therapy has limited direct anti-inflammatory activity beyond leukoreduction. Global transcriptional analysis of circulating leukocytes highlights the intense oxidant and inflammatory nature of steady-state sickle cell disease and provides insight into the broad compensatory responses to vascular injury.

scholarly journals Early and prominent alterations in hemodynamics, signaling, and gene expression following renal ischemia in sickle cell disease

2010 ◽  
Vol 298 (4) ◽  
pp. F892-F899 ◽  
Author(s):  
Julio P. Juncos ◽  
Joseph P. Grande ◽  
Anthony J. Croatt ◽  
Robert P. Hebbel ◽  
Gregory M. Vercellotti ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Renal Hemodynamics ◽  
Acute Ischemia ◽  
Heme Oxygenase 1 ◽  
Wild Type ◽  
Cell Disease ◽  
Oxide Synthase

Acute ischemic insults to the kidney are recognized complications of human sickle cell disease (SCD). The present study analyzed in a transgenic SCD murine model the early renal response to acute ischemia. Renal hemodynamics were profoundly impaired following ischemia in sickle mice compared with wild-type mice: glomerular filtration rate, along with renal plasma flow and blood flow rates, were markedly reduced, while renal vascular resistances were increased more than threefold in sickle mice following ischemia. In addition to these changes in renal hemodynamics, there were profound disturbances in renal signaling processes: phosphorylation of members of the MAPK and Akt signaling proteins occurred in the kidney in wild-type mice after ischemia, whereas such phosphorylation did not occur in the kidney in sickle mice after ischemia. ATP content in the postischemic kidney in sickle mice was less than half that observed in wild-type mice. Examination of the expression of candidate genes uncovered changes that may predispose to increased sensitivity of the kidney in sickle mice to ischemia: increased expression of inducible nitric oxide synthase and decreased expression of endothelial nitric oxide synthase, and increased expression of TNF-α. Inducibility of anti-inflammatory, cytoprotective genes, such as heme oxygenase-1 and IL-10, was not impaired in sickle mice after ischemia. We conclude that the kidney in SCD is remarkably vulnerable to acute ischemic insults. We speculate that such sensitivity of the kidney to ischemia in SCD may underlie the occurrence of acute kidney injury in patients with SCD and may set the stage for the emergence of chronic kidney disease in SCD.

scholarly journals B-Cell Response during Protozoan Parasite Infections

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
María C. Amezcua Vesely ◽  
Daniela A. Bermejo ◽  
Carolina L. Montes ◽  
Eva V. Acosta-Rodríguez ◽  
Adriana Gruppi
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Response ◽  
Plasma Cells ◽  
Protozoan Parasite ◽  
Parasite Infections ◽  
Protozoan Infections ◽  
Induced Apoptosis ◽  
Cellular Immune ◽  
B Cell Response

In this review, we discuss how protozoan parasites alter immature and mature B cell compartment. B1 and marginal zone (MZ) B cells, considered innate like B cells, are activated during protozoan parasite infections, and they generate short lived plasma cells providing a prompt antibody source. In addition, protozoan infections induce massive B cell response with polyclonal activation that leads to hypergammaglobulnemia with serum antibodies specific for the parasites and self and/or non related antigens. To protect themselves, the parasites have evolved unique ways to evade B cell immune responses inducing apoptosis of MZ and conventional mature B cells. As a consequence of the parasite induced-apoptosis, the early IgM response and an already establish humoral immunity are affected during the protozoan parasite infection. Moreover, some trypanosomatides trigger bone marrow immature B cell apoptosis, influencing the generation of new mature B cells. Simultaneously with their ability to release antibodies, B cells produce cytokines/quemokines that influence the characteristic of cellular immune response and consequently the progression of parasite infections.

scholarly journals Biomaterials direct functional B cell response in a material specific manner

2021 ◽  
Author(s):  
Erika M. Moore ◽  
David R. Maestas ◽  
Chris C. Cherry ◽  
Jordan A. Garcia ◽  
Hannah Y. Comeau ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Response ◽  
Tissue Injury ◽  
Breast Implants ◽  
Cell Immune Response ◽  
Biomaterial Scaffold ◽  
Scaffold Materials ◽  
Antigen Presenting ◽  
B Cell Response

AbstractB cells are an adaptive immune target of biomaterials development in vaccine research but despite their role in wound healing have not been studied in tissue engineering and regenerative medicine. We evaluated the B cell response to biomaterial scaffold materials implanted in a muscle wound; a biological extracellular matrix (ECM) and synthetic polyester polycaprolactone. In the local muscle tissue, small numbers of B cells are recruited in response to tissue injury and biomaterial implantation. ECM materials induced plasmablasts in lymph nodes and antigen presentation in the spleen while the synthetic PCL implants delayed B cell migration and induced an antigen presenting phenotype. In muMt− mice lacking B cells, the fibrotic response to the synthetic biomaterials decreased. Immunofluorescence confirmed antigen presenting B cells in fibrotic tissue surrounding silicone breast implants. In sum, the adaptive B cell immune response to biomaterial depends on composition and induces local, regional and systemic immunological changes.

scholarly journals SARS-CoV-2 spike-specific memory B cells express higher levels of T-bet and FcRL5 after non-severe COVID-19 as compared to severe disease

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261656
Author(s):  
Raphael A. Reyes ◽  
Kathleen Clarke ◽  
S. Jake Gonzales ◽  
Angelene M. Cantwell ◽  
Rolando Garza ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Symptom Onset ◽  
Cell Response ◽  
Severe Disease ◽  
Memory B Cells ◽  
Memory B Cell ◽  
Specific Memory ◽  
Specific Igg ◽  
B Cell Response

SARS-CoV-2 infection elicits a robust B cell response, resulting in the generation of long-lived plasma cells and memory B cells. Here, we aimed to determine the effect of COVID-19 severity on the memory B cell response and characterize changes in the memory B cell compartment between recovery and five months post-symptom onset. Using high-parameter spectral flow cytometry, we analyzed the phenotype of memory B cells with reactivity against the SARS-CoV-2 spike protein or the spike receptor binding domain (RBD) in recovered individuals who had been hospitalized with non-severe (n = 8) or severe (n = 5) COVID-19. One month after symptom onset, a substantial proportion of spike-specific IgG+ B cells showed an activated phenotype. In individuals who experienced non-severe disease, spike-specific IgG+ B cells showed increased expression of markers associated with durable B cell memory, including T-bet and FcRL5, as compared to individuals who experienced severe disease. While the frequency of T-bet+ spike-specific IgG+ B cells differed between the two groups, these cells predominantly showed an activated switched memory B cell phenotype in both groups. Five months post-symptom onset, the majority of spike-specific memory B cells had a resting phenotype and the percentage of spike-specific T-bet+ IgG+ memory B cells decreased to baseline levels. Collectively, our results highlight subtle differences in the B cells response after non-severe and severe COVID-19 and suggest that the memory B cell response elicited during non-severe COVID-19 may be of higher quality than the response after severe disease.

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