scholarly journals Altered type 1 interferon responses in alloimmunized and nonalloimmunized patients with sickle cell disease

eJHaem ◽  
2021 ◽  
Author(s):  
Emaan Madany ◽  
June Lee ◽  
Chelsea Halprin ◽  
Jina Seo ◽  
Nicole Baca ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Disease ◽  
Type 1 Interferon ◽  
Interferon Responses

scholarly journals Type I Interferon Gene Signature in Peripheral Blood Mononuclear Cells of Sickle Cell Disease Patients and a Connection to RBC Alloimmunization

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 26-27
Author(s):  
Emaan Madany ◽  
June Young Lee ◽  
Jeanne E. Hendrickson ◽  
David R Gibb
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Whole Blood ◽  
Gene Signature ◽  
Small Sample ◽  
Type I ◽  
Healthy Controls ◽  
Cell Disease ◽  
Interferon Gene

Background RBC alloimmunization is a clinically significant issue in transfusion medicine; patients with sickle cell disease have an increased risk of alloantibody production (30-50% of SS patients) compared to that of other hospitalized patients (3-10%). However, mechanisms underlying the increased frequency of alloimmunization in sickle cell patients are poorly understood. In previous studies, inflammation in the recipient has been shown to promote alloimmunization. Transfusion models, type 1 interferons (IFNα/β) and Interferon Stimulated Genes (ISGs) have been shown to promote alloimmunization in mice. Other studies have shown that patients with inflammatory autoimmune diseases express an IFNα/β signature which may contribute to the increased frequency of alloimmunization in these populations. One recent study reported significantly elevated ISGs in neutrophils as well as evidence that IFNα is upregulated in SS patients compared to controls. Given the chronic inflammatory state in SS patients, we sought to determine the role of PBMCs and whether they also expressed an IFN gene signature that contributes to the increased frequency of alloimmunization. Methods The expression of the ISG, myxovirus resistance protein 1 (MxA), was measured in the blood of SS patients with more patients with SS disease (SS, n=13) and race matched healthy controls (ββ, n=3) by whole blood immunoassay (ELISA). qPCR was performed on 5 previously established ISGs to determine an IFN score, a measure of overall gene expression, from whole blood and IFNβ stimulated PBMCs of SS patients (SS, n=15) and healthy race matched controls (ββ, n=5). A LEGENDplex™ Human Anti-Virus Response Panel assay was used to determine the expression of various type 1 IFNs, cytokines and ISGs in patients with SS disease (SS, n=15) and healthy race matched controls (ββ, n=5). Results SS patients had significantly elevated levels of MxA (mean ± standard error of the mean, SS MxA = 12.27 ng/mL ± 15.68) compared to control patients without SS (ββ MxA = 1.52 ng/mL± 0.26, p< 0.05) (Figure 1 A) . The Legendplex showed a significant increase in IL-6, IL-10 and the ISG, IP-10. (SS IP-10= 147.81 pg/mL ± 49.24) (ββ IP-10 = 68.85 pg/mL ±10.70, p<0.01) (Figure 1 B) Analyzing the 5 ISGs, we saw a trend towards a higher IFN score in patients with SS disease than healthy controls in whole blood; this difference was significant in PBMCs stimulated with IFNB (IFN Score SS = 20.76 ± 17.18 ,ββ = 0.00 ± 3.71 , p<0.01) (Figure 1 C). Discussion SCD is a complex disease with many environmental and genetic factors that play roles in the severity of the disease. Any number of these factors may influence the high rates of alloimmunization found in sickle cell patients. We found increased cytokines, ISGs and IFN scores in SS patients compared to healthy controls. These findings suggest the presence of an IFNα/β gene signature in patients with sickle cell disease. Due to the relatively small sample size, we are unable to determine a correlation between alloantibodies and MxA levels or high IFN scores with this cohort. Further studies will allow us to determine if the increased interferon gene signature plays a role in the increased alloimmunization burden that these patients experience. Disclosures No relevant conflicts of interest to declare.

scholarly journals Increased Expression of Type 1 Interferon Stimulated Genes in Sickle Cell Disease and a Potential Association with RBC Alloimmunization

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 716-716
Author(s):  
Emaan Madany ◽  
Najwa El Kadi ◽  
Sumaarg Pandya ◽  
Jeanne E. Hendrickson ◽  
David R Gibb
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Flow Cytometric Analysis ◽  
Gene Signature ◽  
Cell Disease ◽  
Interferon Stimulated Genes ◽  
Flow Cytometric ◽  
Increased Risk ◽  
Significant Difference

Background RBC transfusion can lead to the production of alloantibodies against RBC antigens and is a clinically significant issue in transfusion medicine. Patients with sickle cell disease have an increased risk for alloimmunization; 30-50% of SS patients have alloantibodies compared to 3-10% of other hospitalized patients. These alloantibodies can cause dangerous hemolytic transfusion reactions and limit the availability of compatible antigen-negative RBC products. This is of particular importance in SS patients, who commonly make alloantibodies against multiple RBC antigens and need regular transfusions to treat their disease. However, mechanisms underlying the increased frequency of alloimmunization in sickle cell patients are poorly understood. In previous studies, inflammation in the recipient has been shown to promote alloimmunization in both mice and humans. In mouse transfusion models, type 1 interferons (IFNα/β) and Interferon Stimulated Genes (ISGs) have been shown to promote alloimmunization. Other studies have shown that patients with inflammatory autoimmune diseases express an IFNα/β signature, which may contribute to the increased frequency of alloimmunization in these populations. Given the chronic inflammatory state in patients with sickle cell disease, we hypothesize that: SS patients may also have an IFN gene signature that may contribute to the increased frequency of alloimmunization. Methods To test this hypothesis, we initially measured the expression of the ISG, myxovirus resistance protein 1 (MxA), in the blood of previously-transfused patients (n=50) with SS disease (SS, n=13) and without SS disease (ββ, n=37) by whole blood immunoassay (ELISA). We then measured expression of another ISG, Siglec-1 (SS n=5, ββ=24), expressed on monocytes by flow cytometric analysis. To determine the degree to which ISG expression correlated with alloimmunization frequency, expression of MxA in non-alloimmunized patients was compared to the expression in patients with 1 or more alloantibodies. Statistical analysis of 2 groups was completed with a Mann-Whitney U test. Significance between 3 groups was determined using a Kruskal-Wallis test with a Dunn's post-test. Results SS patients had significantly elevated levels of MxA (mean ± standard error of the mean, SS MxA = 8.98 ng/mL ± 2.46) compared to control patients without SS (MxA = 1.25 ± 0.54, p<0.0001). (Figure 1 A). SS patients also had significantly elevated levels of Siglec-1 on blood monocytes, measured by flow cytometric mean fluorescence intensity (MFI, SS MFI = 132.72 ± 42.9, ββ MFI = 64.9 ± 6.17, p< 0.05). (Figure 1 B,C). For all 50 patients, including SS and ββ control patients, there was a trend toward elevated MxA expression in alloimmunized patients. Patients with 2 or more alloantibodies had significantly elevated MxA (MxA 8.16 ± 2.61), compared to non-alloimmunized transfused patients (MxA = 2.05 ± 1.65, p < 0.01) or patients with only 1 alloantibody (MxA = 1.18 ±0.48, p<0.01). There was no significant difference in MxA levels between patients with 0 and 1 alloantibody. Of the 13 patients with SS disease, only 2 patients lacked alloantibodies. (SS with 1 alloantibody, n=3, SS with 2 or more alloantibodies, n=8). Therefore, a correlation between MxA levels and alloimmunization in SS patients could not be assessed. Discussion Factors that contribute to RBC alloimmunization in sickle cell disease are poorly understood. In this study, we found that sickle cell patients had an increase in the expression of ISGs compared to other transfused patients. We also found that MxA levels are increased in patients that have 2 or more alloantibodies compared to patients without alloantibodies. These findings suggest the presence of an IFNα/β gene signature in patients with sickle cell disease. Further studies are needed to determine the relationship between interferon-stimulated responses in sickle cell patients and the increased frequency of alloantibody production. Disclosures No relevant conflicts of interest to declare.

Phosphatidylserine externalization in sickle red blood cells: associations with cell age, density, and hemoglobin F

Blood ◽  
2003 ◽  
Vol 102 (1) ◽  
pp. 365-370 ◽  
Author(s):  
Zahida Yasin ◽  
Scott Witting ◽  
Mary B. Palascak ◽  
Clinton H. Joiner ◽  
Donald L. Rucknagel ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Fetal Hemoglobin ◽  
Lower Percentage ◽  
Cell Disease ◽  
Low Level ◽  
Sickle Cells ◽  
Cell Age

Abstract Phosphatidylserine (PS) is normally confined to the cytoplasmic leaflet of the red blood cell (RBC) membrane, but some sickle RBCs expose PS in the outer leaflet (PS+ cells). This study examined the relationships among PS externalization, fetal hemoglobin content, hydration state, and cell age. Sickle RBCs exhibit a wide range of PS externalization. Those with low-level exposure (type 1 PS+) include many young transferrin-receptor-positive (TfR+) cells. This is not specific for sickle cell disease because many nonsickle TfR+ cells are also PS+. RBCs with higher PS exposure (type 2 PS+) appear to be more specific for sickle cell disease. Their formation is most likely sickling dependent because type 2 PS+ dense sickle cells have a lower percentage of fetal hemoglobin (HbF) than PS- cells in the same density fraction (1.7 vs 2.9; n = 8; P < .01). In vivo experiments using biotin-labeled sickle cells showed a sharp decrease in the percentage of circulating, labeled PS+ cells in the first 24 hours after reinfusion. This decrease was confined to type 1 PS+ cells and was thus consistent with the reversal of PS exposure in very young cells. As the labeled cells aged in the circulation, the percentages of type 1 and type 2 PS+ cells increased. These studies indicate that PS externalization in sickle cells may be low level, as observed in many immature cells, or high level, which is associated with dehydration and appears to be more specific for sickle RBCs. (Blood. 2003;102: 365-370)

Type-2 Phosphatidylserine (PS)-Positive Erythrocytes and Their Association with Markers of Hemolysis and Hemostatic Activation in Children with Sickle Cell Disease (SCD)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 943-943
Author(s):  
Yamaja B. Setty ◽  
Suhita Gayennebetal ◽  
Nigel S. Key ◽  
Marie Stuart
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Red Cells ◽  
Red Cell ◽  
Cell Disease ◽  
Activation Markers ◽  
D Dimer

Abstract Introduction: Type-2 phosphatidylserine (PS)-positive red cells are a subpopulation of erythrocytes that are highly positive for PS, contain low levels of fetal hemoglobin, are specific for sickle cell disease (SCD) and have been identified in the dense red cell fraction. Studies have implicated PS-positive red cells in enhancing anemia due to phagocytosis and hemolysis. Shielding of red cell PS by diannexin, a synthetic homodimer of human annexin-V, has been demonstrated to provide protection against hemolysis and prevent activation of prothrombinase. Methods: Using flow cytometry, we measured the levels of type-1 (red cells with low PS positivity) and type-2 PS-positive red cells in 50 children with SCD (31 with HbSS and 19 with HbSC), and assessed their association with various markers of hemolysis and hemostatic activation. Markers of hemolysis evaluated included plasma lactate dehydrogenase (LDH), reticulocyte count, and hemoglobin. Whole blood tissue factor (WBTF), pro-thrombin fragment F1+2, and D-dimer were evaluated as markers of hemostatic activation. Results: We demonstrate that the levels of type-2 PS-positive red cells are significantly increased in HbSS patients (1.37 ± 0.97%, p<0.01) compared to children with HbSC disease (0.32 ± 0.21%) and age- and race-matched controls (0.15 ± 0.15%, n=19). WBTF and D-dimer showed significant associations with both type-1 and -2 red cells with no significant differences in the strength of their association. However, significantly greater correlations were noted between type-2 PS red cells and hemolytic markers compared to those noted with type-1 (Steiger's Z=3.05 to 4.59, p<0.01). In addition our in vitro studies demonstrate increased osmotic fragility of these red cells. Table 1. Association of PS-positive RBCs with markers of hemolysis and hemostatic activation Biomarker Type-1 PS-positive RBCs Type-2 PS-positive RBCs Markers of Hemolysis LDH r = 0.44, p<0.002 r = 0.63, p<0.00001 % Reticulocyte r = 0.43, p=0.002 r = 0.66, p<0.00001 Hemoglobin r =-0.35, p=0.014 r =-0.63, p<0.00001 Markers of Hemostatic Activation WBTF r = 0.41, p=0.008 r = 0.56, p<0.0002 F1+2 r = 0.26, p=0.07 r = 0.31, p<0.03 D-dimer r = 0.46, p<0.001 r = 0.56, p<0.0005 Conclusions: Type-2 PS-positive red cells are elevated in SCD and the number of these cells correlates significantly with both markers of hemolysis and hemostasis. These findings provide a patho-physiologic link between the intravascular hemolytic milieu of SCD and the hemostatic perturbations previously noted in this disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals COVID-19 Outcomes in Individuals with Sickle Cell Disease and Sickle Cell Trait Compared to Blacks without Sickle Cell Disease or Trait

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 54-56 ◽  
Author(s):  
Ashima Singh ◽  
Amanda M. Brandow ◽  
Julie Panepinto
Keyword(s):  
United States ◽  
Type 1 Diabetes ◽  
Sickle Cell Disease ◽  
Propensity Score ◽  
Sickle Cell ◽  
Research Funding ◽  
Sickle Cell Trait ◽  
The United States ◽  
Cell Disease

Introduction: By August 1, 2020 in the United States, more than 3 million cases of Coronavirus disease 2019 (COVID-19) had been reported with more than 150,000 deaths due to this disease. Growing evidence suggests that individuals with the pre-existing conditions of hypertension, diabetes, cardiovascular disease and obesity are at a higher risk of more serious COVID-19 illness. However, the impact of COVID-19 on individuals with sickle cell disease and sickle cell trait as compared to those without sickle cell disease or trait is not known. The objective of this study was to determine the rate of hospitalization, disease symptoms and deaths due to COVID-19, in patients with sickle cell disease and sickle cell trait compared to Blacks without sickle cell disease or trait. Methods: We leveraged existing electronic health record (EHR) data from multiple sites that contribute data to a research network, TriNetX. TriNetX query platform was used to identify patients with COVID-19 infection based on ICD diagnoses codes or a positive COVID-19 result from a nucleic acid amplification with probe-based detection test, present any time after January 20, 2020 (this is when the first COVID-19 case was detected in the United States) within the patients' EHR data. We report rates of specific COVID-19 related outcomes among individuals with sickle cell disease and trait, calculated as % of patients in cohort with the particular outcome. Our outcomes of interest included COVD-19 related symptoms, hospitalization, and death, which occurred within 2 weeks of COVID diagnosis. We used propensity score matching (greedy nearest-neighbor matching algorithm with a caliper of 0.1 pooled standard deviations) to create balanced cohorts for comparing outcomes between individuals with sickle cell disease or trait and Blacks without sickle cell disease or trait. Risk ratios and risk differences are reported along with 95% confidence intervals. Given multiple outcomes of interest, we considered a more stringent two-sided alpha of less than &lt;0.01, based on a z-test, to determine statistical significance for differences in outcome rates. Results: As of July 15, 2020, there were 122 COVID-19 patients who had sickle cell disease and 172 COVID-19 patients who had sickle cell trait. Our comparator groups included 15,762 Blacks who were diagnosed with COVID-19 but did not have sickle cell trait/disease. COVID-19 patients with sickle cell disease were significantly younger and a higher proportion had asthma, type 1 diabetes and pre-existing liver conditions compared to Blacks without sickle cell trait/disease (Table 1). COVID-19 patients with sickle cell trait were significantly younger, a higher proportion were females, overweight/obese, and a higher proportion had asthma or type 1 diabetes compared to Blacks without sickle cell trait/disease (Table 1). The rate of respective outcomes for the three groups is shown in Figure 1. Propensity score matching yielded a cohort of patients such that there were no significant differences in demographic and clinical characteristics between patients with sickle cell disease/trait compared to Blacks without sickle cell trait/disease. After matching, COVID patients with sickle cell disease remained at a higher risk of hospitalization, pneumonia and pain compared to Blacks without sickle cell trait/disease (Table 2). The case fatality rates were not significantly different between those with sickle cell disease compared to Blacks. There were no significant differences in COVID outcomes between sickle cell trait and Blacks without sickle cell trait/disease, within the matched cohort. Conclusions: These data provide evidence that sickle cell disease imposes additional risk of severe COVID-19 illness and hospitalization, after balancing for age, gender and other preexisting conditions. The death rate between sickle cell disease and Blacks without sickle cell trait/disease was not significantly different. There are no significant differences in COVID-19 outcomes between sickle cell trait and Blacks without sickle cell trait/disease, after balancing for age, gender and other pre-existing conditions. Disclosures Brandow: NIH / NHLBI: Research Funding; Greater Milwaukee Foundation: Research Funding. Panepinto:HRSA: Research Funding; NINDS: Research Funding; NINDS: Research Funding; NHLBI: Research Funding.

scholarly journals Common Sense Model of Illness in Youth With Type 1 Diabetes or Sickle Cell Disease

2011 ◽  
Vol 16 (4) ◽  
pp. 270-280 ◽  
Author(s):  
Sally A. Huston ◽  
Christopher P. Houk
Keyword(s):  
Type 1 Diabetes ◽  
Sickle Cell Disease ◽  
Disease Control ◽  
Sickle Cell ◽  
Common Sense ◽  
Negative Consequences ◽  
Cell Disease ◽  
Common Sense Model ◽  
Sense Model

OBJECTIVES To qualitatively explore differences in Leventhal's common sense model (CSM) constructs between youth with type 1 diabetes (T1D) and sickle cell disease (SCD) and between different age groups and level of disease control. METHODS Two structured individual interviews were conducted in 24 youth with T1D (n=12) or SCD (n=12). Patients were between 8 and 21 years of age, had either good or poor disease control, and were seen at an outpatient children's hospital medical clinic. RESULTS Youth conceptualize their chronic disease in terms of identity, cause, timeline, control, and consequences: both cognitive and emotional dimensions are apparent. There was considerable contrast between discussions of youth with well- and poorly controlled T1D but little contrast between youth with well- and poorly controlled SCD. Surprisingly, youth with well-controlled T1D mentioned emotions most frequently. No youth with poorly controlled T1D described disease acceptance, but the majority of youth with well-controlled T1D did. Adolescents and young adults with good T1D control appear to understand disease cause, have better illness coherence, and habitually link discussion of symptoms and negative emotions with solutions. Youth with poorly controlled T1D appeared more likely to connect symptoms with negative consequences. Consequences included 1) disease symptoms, 2) the need to perform self-care activities, 3) physical outcomes, 4) health-system activities, 5) emotions, and 6) life impact. Interestingly, sickling crisis was mentioned more frequently by youth with good SCD control than by those with poor SCD control. Youth with SCD are distressed by others' judgmental perceptions and by feeling different from others. CONCLUSIONS In contrast to previous CSM work, youth with well-controlled T1D in this study discussed emotions more frequently than did those with poor control. Disease perceptions were similar between youth with well- and poorly controlled SCD. Results indicate there are noteworthy cognitive and emotional differences between youth with different types of disease and levels of disease control.

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