Cytokine storm in a mouse model of IgG-mediated hemolytic transfusion reactions

Hod, Eldad A.; Cadwell, Chantel M.; Liepkalns, Justine S.; Zimring, James C.; Sokol, Set A.; Schirmer, David; Jhang, Jeffrey S.; Spitalnik, Steven L.

doi:10.1182/blood-2008-01-132092

Cited by 38 publications

(44 citation statements)

References 25 publications

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“…Similarly, the ability of anti-GPA to induce Ag modulation demonstrates that Ag modulation is not limited to anti-Fy3. The unique biphasic clearance pattern induced by anti-GPA is consistent with previous studies (35). Given the potential involvement of complement in anti-GPA-mediated clearance (40), complement receptors may initially trap RBCs following Abmediated complement deposition and then release some RBCs following subsequent complement degradation, as suggested by previous studies examining the consequences of complement deposition on RBCs (36,41).…”

Section: Discussionsupporting

confidence: 85%

“…Although nonimmunized recipients failed to clear double Ag + cells, anti-Fy3-immunized and anti-GPA-immunized recipients each effectively cleared double positive cells (Fig. 9A), consistent with previous results and those of this study (35). Examination of bound Ab and detectable Ag demonstrated that Ab could be detected only on double Ag + cells following transfer into immunized recipients and that double positive RBCs experienced modulation of HOD Ag, but not GPA Ag, following transfer into anti-Fy3-immunized recipients (Fig.…”

Section: Decrease In Detectable Ag Extends Intra-but Not Intermoleculsupporting

confidence: 92%

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Antigen Modulation Confers Protection to Red Blood Cells from Antibody through Fcγ Receptor Ligation

Stowell

Liepkalns

Hendrickson

et al. 2013

The Journal of Immunology

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Autoantibodies and alloantibodies can damage self-tissue or transplanted tissues through either fixation of complement or ligation of FcγRs. Several pathways have been described that imbue self-tissues with resistance to damage from complement fixation, as a protective measure against damage from these Abs. However, it has been unclear whether parallel pathways exist to provide protection from FcγR ligation by bound Abs. In this article, we describe a novel pathway by which cell surface Ag is specifically decreased as a result of Ab binding (Ag modulation) to the extent of conferring protection to recognized cells from Fcγ-dependent clearance. Moreover, the Ag modulation in this system requires FcγR ligation. Together, these findings provide unique evidence of self-protective pathways for FcγR-mediated Ab damage.

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Section: Discussionsupporting

confidence: 85%

Section: Decrease In Detectable Ag Extends Intra-but Not Intermoleculsupporting

confidence: 92%

Antigen Modulation Confers Protection to Red Blood Cells from Antibody through Fcγ Receptor Ligation

Stowell

Liepkalns

Hendrickson

et al. 2013

The Journal of Immunology

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“…In malaria, as in diseases with release of Hb from RBCs, there is uncontrolled inflammatory imbalance and intense oxidative stress (2,(38)(39)(40). In this paper, we report that patients with severe P. vivax infection, similar to individuals and mice with falciparum malaria (22, 33, 41), displayed reduced plasma levels of PGE 2 and TGF-b than those with mild infections, with this reduction being inversely proportional to the bilirubin, total heme, and SOD-1 levels.…”

Section: Discussionmentioning

confidence: 99%

Heme Impairs Prostaglandin E2 and TGF-β Production by Human Mononuclear Cells via Cu/Zn Superoxide Dismutase: Insight into the Pathogenesis of Severe Malaria

Andrade

Araújo-Santos

Luz

et al. 2010

The Journal of Immunology

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In many hemolytic disorders, such as malaria, the release of free heme has been involved in the triggering of oxidative stress and tissue damage. Patients presenting with severe forms of malaria commonly have impaired regulatory responses. Although intriguing, there is scarce data about the involvement of heme on the regulation of immune responses. In this study, we investigated the relation of free heme and the suppression of anti-inflammatory mediators such as PGE2 and TGF-β in human vivax malaria. Patients with severe disease presented higher hemolysis and higher plasma concentrations of Cu/Zn superoxide dismutase (SOD-1) and lower concentrations of PGE2 and TGF-β than those with mild disease. In addition, there was a positive correlation between SOD-1 concentrations and plasma levels of TNF-α. During antimalaria treatment, the concentrations of plasma SOD-1 reduced whereas PGE2 and TGF-β increased in the individuals severely ill. Using an in vitro model with human mononuclear cells, we demonstrated that the heme effect on the impairment of the production of PGE2 and TGF-β partially involves heme binding to CD14 and depends on the production of SOD-1. Aside from furthering the current knowledge about the pathogenesis of vivax malaria, the present results may represent a general mechanism for hemolytic diseases and could be useful for future studies of therapeutic approaches.

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“…However, the mechanisms mediating the severe complications of HTRs in SCD patients are unknown, and no specific therapy is available. Because inflammatory cytokines and chemokines are important in the pathogenesis of acute and delayed HTRs and in SCD crises (10,(12)(13)(14), they may be involved in the serious and specific clinical manifestations of HTRs found in SCD patients.…”

Section: Introductionmentioning

confidence: 99%

“…IgG-mediated HTRs involve complement activation, phagocytosis, cytokine production, and various cellular responses (8)(9)(10)(11). In SCD, HTRs can precipitate acute VOC or hyperhemolysis syndrome, resulting in significant morbidity (5-7).…”

Section: Introductionmentioning

confidence: 99%

CXCL1 and its receptor, CXCR2, mediate murine sickle cell vaso-occlusion during hemolytic transfusion reactions

et al. 2011

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Hemolytic transfusion reactions (HTR) can produce acute vaso‐occlusive crisis (VOC), a major cause of morbidity and mortality in sickle cell disease (SCD) patients; however, the mechanisms remain unknown. We established a model of alloimmune IgG‐mediated HTR using a well‐characterized humanized murine model of SCD. In this model, HTR induced acute VOC, resulting in shortened survival of the SCD mice (by 3 h, P<0.05, log‐rank test). Acute VOC was associated with elevated circulating inflammatory chemokine levels, including the neutrophil chemoattractant CXCL1, which was strikingly elevated (139 ± 35 vs 43 ± 10 pg/ml, P<0.05). Recombinant CXCL1 administration corresponding to the HTR‐elicited endogenous CXCL1 levels induced acute VOC in non‐transfused SCD mice, characterized by leukocyte recruitment in venules (2571 ± 193 vs 1464 ± 194 adherent leukocytes per mm2, P<0.01), marked interactions with circulating red blood cells, reduced venular flow rates (430 ± 34 vs 310 ± 36 nL/s, P<0.05), and shortened survival (by 4 h, P<0.001, log‐rank test). In contrast, blocking its receptor, CXCR2, prevented HTR‐elicited acute VOC and prolonged the survival of SCD mice (by 6 h, P<0.01, log‐rank test). Thus, CXCL1 is a key inflammatory mediator of acute VOC in SCD mice and targeted inhibition of CXCL1 and/or CXCR2 may provide new approaches for treating acute VOC in SCD patients.

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Cytokine storm in a mouse model of IgG-mediated hemolytic transfusion reactions

Cited by 38 publications

References 25 publications

Antigen Modulation Confers Protection to Red Blood Cells from Antibody through Fcγ Receptor Ligation

Antigen Modulation Confers Protection to Red Blood Cells from Antibody through Fcγ Receptor Ligation

Heme Impairs Prostaglandin E2 and TGF-β Production by Human Mononuclear Cells via Cu/Zn Superoxide Dismutase: Insight into the Pathogenesis of Severe Malaria

CXCL1 and its receptor, CXCR2, mediate murine sickle cell vaso-occlusion during hemolytic transfusion reactions

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