Iron scavenging and myeloid cell polarization.

Myeloid cells that populate all human organs and blood are a versatile class of innate immune cells. They are crucial for sensing and regulating processes as diverse as tissue homeostasis and inflammation and are frequently characterized by their roles in either regulating or promoting inflammation. Recent studies in cultured cells and mouse models highlight the role of iron in skewing the functional properties of myeloid cells in tissue damage and repair. Here, we review certain emerging concepts on how iron influences and determines myeloid cell polarization in the context of its uptake, storage, and metabolism, including in conditions such as multiple sclerosis (MS), sickle cell disease, and tumors.

Post-transfusion biotin-labeled red blood cell survival studies in pediatric sickle cell disease with antibodies of uncertain significance.

BACKGROUND: Red blood cell (RBC) antibodies are common in multiply transfused patients with sickle cell disease (SCD). Unlike RBC alloantibodies, the potential of autoantibodies to cause post-transfusion hemolysis may be uncertain. Biotin-labeling provides a direct measurement of red cell survival (RCS) over time, thus can be used to assess the clinical significance of RBC antibodies. Antibodies to biotinylated RBC (B-RBC) occasionally are detected after exposure, which may impact B-RBC survival in subsequent RCS studies. STUDY DESIGN AND METHODS: Pediatric patients with SCD receiving monthly chronic transfusions underwent RCS studies, receiving aliquots of allogeneic RBC labeled at distinct densities of biotin (2-18 µg/mL). B-RBC survival was followed for 4 months post-transfusion, and B-RBC antibody screening for 6 months. Patients with warm autoantibodies (WAA) or B-RBC antibodies are reported here. RESULTS: RBC antibodies were detected during RCS in four patients: one with WAA, one with WAA followed by B-RBC-specific antibodies, and two with transient B-RBC antibodies within the first 5 weeks of exposure. B-RBC half-lives (T50) ranged 37.6-61.7 days (mean 47.8 days). There was no evidence of increased hemolysis or accelerated B-RBC clearance in the presence of WAA or B-RBC antibodies. DISCUSSION: Biotinylation of allogenic RBC can be used to assess the possible effects of RBC antibodies on transfusion survival in individual cases, particularly when it is uncertain if the detected antibodies may result in hemolysis. In the cases presented here, neither WAA nor B-RBC antibodies were associated with significant shortening of B-RBC survival in individuals with SCD.

Unswitched memory B cell deficiency in children with sickle cell disease and response to pneumococcal polysaccharide vaccine.

Early mortality in sickle cell disease (SCD) is attributed to increased infections due to loss of splenic function. Marginal zone B cells are important for initial opsonization of pathogens and can be absent in spleen histopathology in SCD. The frequency of unswitched memory B cells (UMBC), the circulating correlate of marginal zone B cells, reflects the immunologic function of the spleen. We hypothesized that asplenia in SCD is associated with alterations in the peripheral blood lymphocyte population and explored whether UMBC deficiency was associated with a clinical phenotype. We analyzed B cell subsets and clinical history for 238 children with SCD and 63 controls. The median proportion of UMBCs was lower in children with SCD compared with controls (4.7% vs. 6.6%, p < .001). Naïve B cells were higher in SCD compared with controls (80.6 vs. 76.3%, respectively, p = .02). UMBC frequency declined by 3.4% per year increase in age in SCD (95% CI: 2%, 4.7%, p < .001), but not in controls. A majority of children in all cohorts had an IgM concentration in the normal range for age and there were no differences between groups (p = .13). Subjects developed titers adequate for long-term protection to fewer serotypes in the polysaccharide vaccine than controls (14.7 vs. 19.4, p < .001). In this cohort, bacteremia was rare and specific clinical complications were not associated with UMBC proportion. In summary, UMBC deficiency occurs in SCD and is associated with age. Future studies should investigate B cell subsets prospectively and identify the mechanism of B cell loss in the spleen.

Seroprevalence of SARS-CoV-2 in pediatric hematology-oncology patients.

BACKGROUND: The COVID-19 pandemic disproportionately affected persons with underlying medical conditions. SARS-CoV-2 infection susceptibility and vaccine effectiveness in pediatric hematology-oncology patients were unknown. METHODS: From February to July 2022, anti-spike and anti-nucleocapsid Ig were assayed in 354 pediatric hematology-oncology subjects, including 53 oncology patients receiving chemotherapy (cancer), 150 patients with sickle cell disease (SCD), and 151 benign consult and long-term follow-up patients (controls). Participants completed a questionnaire. RESULTS: Frequencies of COVID-19 infection, defined by positive PCR/antigen test or anti-nucleocapsid Ig, were 62% in cancer, 71% in SCD, 52% in controls, with SCD statistically different than controls (p = .001). Infection was associated with COVID-19 exposure, Hispanic/Latino or Black/African American ethnicity, multi-family dwelling, sports participation; COVID-19 booster decreased association with infection. In COVID-19-positive cancer patients, 58% had positive anti-nucleocapsid and 76% had positive anti-spike (≥10 U/mL), compared to essentially 100% seroconversion in SCD and controls (p < .0001, p = .01, respectively). Infection led to high anti-spike (≥2500 U/mL) in 12% cancer, 14% SCD, and 15% controls (p = .93). Vaccination resulted in anti-spike positivity in 90% cancer, 100% SCD, and 100% controls (p = .06), and in high anti-spike in 20% cancer, 47% SCD, and 41% controls (p = .36). Of boosted subjects, one of two cancer, 6/6 SCD, and 19/19 controls exhibited high anti-spike. CONCLUSIONS: Cancer patients demonstrated similar SARS-CoV-2 infection frequency as controls, but diminished antibody response to infection and vaccination. SCD patients exhibited seroconversion indistinguishable from controls. Vaccination was associated with higher frequency of high anti-spike than infection; vaccination plus booster was most effective in eliciting high anti-spike antibody detectable beyond 90 days.

Prevalence of Red Blood Cell Alloimmunization Among Pediatric Patients With Sickle Cell Disease in Saudi Arabia.

OBJECTIVE: Sickle cell disease (SCD) is a common hereditary hemoglobin disorder worldwide. One of the main treatments for patients with SCD is the requirement for blood transfusions. Posttransfusion alloimmunization with red blood cell (RBC) antigens continues to be a major risk factor for SCD. The objective of this study was to determine the rate, nature, and risk factors of red cell alloimmunization among pediatric patients with SCD in our center and compare our results with published reports from Saudia Arabia SA, regional countries, and some international countries. MATERIALS AND METHODS: A retrospective chart review of patients with SCD at King Abdulaziz Medical City-Jeddah, between 2008 and 2019 was performed. Demographic characteristics and transfusion histories were recorded. Blood samples were analyzed for alloimmunization using immunohematologic techniques. RESULTS: In total, 121 patients were analyzed. Alloantibodies were detected in 21 patients (17.4%) and were mostly single in 15 patients (71.4%), anti-K (23.7%), anti-E (19.0%), and anti-S (9.5%). The other 6 patients (28.6%) had multiple alloantibodies, especially the combination of anti-C and anti-K (9.5%) and the combination of anti-C and anti-E (9.5%). Alloantibody levels were significantly higher in patients with frequent hospital admissions (>5 times annually), those who had an exchange blood transfusion, those younger than 3 years old, and those who received a larger number of blood units ( P ≤0.05). CONCLUSION: The rate of RBC alloimmunization is determined and considered relatively low compared with that in other nations. Matching for extended RBC antigens to include ABO, RH (D, C, c, E, e), K, Fy a , Fy b , Jk a , and Jk b antigens in the screening panel for donors and recipients is highly recommended to ensure better transfusion practices and avoid transfusion-related complications.

Case report: Persistent hypogammaglobulinemia and mixed chimerism after HLA class-II disparate-hematopoietic stem cell transplant.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for various hematological, immunological and metabolic diseases, replacing the patient's hematopoietic system with donor-derived healthy hematopoietic stem cells. HSCT can be complicated by early and late events related to impaired immunological recovery such as prolonged hypogammaglobulinemia post-HSCT. We present a 16-year-old female patient with sickle-cell disease who underwent HSCT with stem cells from a human leukocyte antigen (HLA) class-II mismatched family donor. While cellular recovery was good post-HSCT, the patient developed mixed chimerism and suffered from cervical lymphadenopathy, recurrent airway infections and cutaneous SLE. She presented with hypogammaglobulinemia and was started on immunoglobulin substitution therapy and antibiotic prophylaxis. B-cell phenotyping showed that she had increased transitional and naïve mature B cells, reduced memory B cells, and diminished marginal zone/natural effector cells. In-depth immunophenotyping and B-cell receptor repertoire sequencing ruled out an intrinsic B-cell defect by expression of activation-induced cytidine deaminase (AID), presence of somatic hypermutations and differentiation into IgG- and IgA-producing plasma cells in vitro. Immunohistochemistry and flow cytometry of lymph node tissue showed a clear block in terminal B-cell differentiation. Chimerism analysis of sorted lymph node populations showed that exclusively patient-derived B cells populated germinal centers, while only a minor fraction of follicular helper T cells was patient-derived. Given this discrepancy, we deduced that the HLA class-II disparity between patient and donor likely hinders terminal B-cell differentiation in the lymph node. This case highlights that studying disturbed cognate T-B interactions in the secondary lymphoid organs can provide unique insights when deciphering prolonged hypogammaglobulinemia post-HSCT.

Study of the antigenic characteristics of red blood cells units and their sickle cell disease recipients and the G6PD activity of transfused red blood cells units.

INTRODUCTION: Transfusion has a central place in the treatment of patients with sickle cell disease (SCD). Matching blood groups of red blood cell (RBC) units with the blood groups of the patient is essential to prevent alloimmunization and delayed hemolytic transfusion reaction. African ancestry donors have the best phenocompatibility with patients of the same origin, however their RBCs may present characteristic that can alter quality of the unit such as glucose-6-phosphate dehydrogenase (G6PD) deficiency. The objective is to analyze transfusion protocol, immunization rate and mismatch situations of SCD recipients and to evaluate the frequency of G6PD deficiency in RBCs units from African ancestry donors. METHODS: Samples of units transfused to SCD patients were analyzed. Transfusion data were collected from institutional databases. The activity of G6PD was measured in the segment of the RBC units. RESULTS: A total of 98 segments of units transfused to 37 SCD recipients in 41 transfusions episodes was collected. Among patients, 35.1% (n = 13) had no antibodies; 10.8% (n = 4) had antibodies against Fya/Fyb, Jka/Jkb, M/N, S/s; 21.6% (n = 8) against RH/K antigens. In all cases, the protocols were in line with the recommendations. G6PD deficiency was observed in 9 units, that were all collected from Afro-Caribbean donors. CONCLUSION: The transfusion protocol is established to prevent immunological reactions due to disparities in blood group antigens between donors and SCD recipients. However, the units of African ancestry donors, which allowed the best compatibility, displayed a high rate of G6PD deficiency. The storage and recovery impact of this deficiency must be evaluated.

Fatores de risco para aloimunização em pacientes com anemia falciforme / Risk factors for alloimmunization in patients with sickle cell anemia

OBJETIVO: Determinar a imunofenotipagem eritrocitária em doadores de sangue e em pacientes com anemia falciforme (SS) atendidos no Hemocentro de Alagoas e descrever a frequência e os fatores associados à aloimunização eritrocitária. MÉTODOS: Estudo transversal com 102 pacientes SS e 100 doadores de sangue. Realizou-se a fenotipagem eritrocitária, teste de Coombs Direto e Indireto e detecção de anticorpos irregulares por painel de hemácias fenotipadas. Os dados foram comparados por meio do teste de Mann-Whitney, qui-quadrado ou teste exato de Fisher. Para análise dos fatores associados à aloimunização utilizou-se a regressão logística univariada e múltipla. RESULTADOS: Os antígenos mais frequentes entre os pacientes e os doadores foram c, e, M, s, JK(a). Observaram-se diferenças significativas entre as frequências dos fenótipos dos pacientes e dos doadores em relação aos antígenos s, FY(a) e JK(b). Dos 79 pacientes transfundidos, 10 (12,7 por cento) apresentaram Coombs Indireto positivo. Detectaram-se 13 aloanticorpos, sete do sistema Rh, dois do Kell e quatro não identificados. Os fatores associados à aloimunização foram o intervalo de tempo entre a última transfusão e a data do teste e ter recebido mais de dez transfusões de hemácias. Receber mais de dez transfusões representou uma chance 16,39 (IC 95 por cento: 2,23-120,59) vezes maior de ser aloimunizado, em comparação aos que receberam menos que dez. CONCLUSÃO: A prevalência de aloimunização nos pacientes SS foi 12,7 por cento, sendo 70 por cento dos anticorpos encontrados pertencentes a grupos sanguíneos Rh e Kell. Este estudo mostra a importância da fenotipagem eritrocitária em doadores e receptores para diminuir o risco de aloimunização.

OBJECTIVE: To determine erythrocyte phenotyping in blood donors and patients with sickle cell anemia (SS) treated at Hemocentro of Alagoas and describe the frequency and factors associated with erythrocyte alloimmunization. METHODS: Cross-sectional study with 102 SS patients and 100 blood donors. The following tests were performed: erythrocyte phenotyping, Direct and Indirect antiglobulin test, and detection of irregular antibodies by panel of phenotyped red blood cells. Data were compared by Mann-Whitney, qui-square or Fisher’s exact tests. Factors associated with alloimmunization were studied by univariate and multiple logistic regression analysis. RESULTS: The most frequent antigens found in patients and blood donors were: c, e, M, s, JK(a). Significant differences were observed between the frequency of the phenotype of patients and donors in regard to antigens s, FY(a) and JK(b). Of 79 transfused patients, 10 presented positive Indirect Coombs. Thirteen alloantibodies were found, 7 of the Rh system, 2 of Kell and 4 were not identified. Factors associated with alloimmunization were the period of time between the last transfusion and the date of the test and more than 10 red blood cell transfusions. Patients who received more than 10 transfusions were 16.39 (95 percent CI: 2.23-120.59) times more likely to be alloimmunized than patients with fewer transfusions. CONCLUSION: The prevalence of alloimmunization in SS patients was 12.7 percent, with 70 percent of antibodies belonging to the Rh and Kell systems. This study shows the importance of performing erythrocyte phenotyping in blood donors and receptors to decrease the risk of alloimmunization.

Risk factors for alloimmunization by patients with sickle cell disease

Blood transfusion in patients with sickle cell disease (SCD) is limited by the development of alloantibodies to erythrocytes. In the present study, the frequency and risk factors for alloimmunization were determined. Transfusion records and medical charts of 828 SCD patients who had been transfused and followed at the Belo Horizonte Blood Center, Belo Horizonte, MG, Brazil, were retrospectively reviewed. Alloimmunization frequency was 9.9 percent (95 percent CI: 7.9 to 11.9 percent) and 125 alloantibodies were detected, 79 percent of which belonged to the Rhesus and Kell systems. Female patients developed alloimmunization more frequently (P = 0.03). The median age of the alloimmunized group was 23.3 years, compared to 14.6 years for the non-alloimmunized group (P < 0.0001). Multivariate analyses were applied to the data for 608 hemoglobin (Hb) SS or SC patients whose number of transfusions was recorded accurately. Number of transfusions (P = 0.00006), older age (P = 0.056) and Hb SC (P = 0.02) showed independent statistical associations with alloimmunization. Hb SC patients older than 14 years faced a 2.8-fold higher (95 percent CI: 1.3 to 6.0) risk of alloimmunization than Hb SS patients. Female Hb SC patients had the highest risk of developing alloantibodies. In patients younger than 14 years, only the number of transfusions was significant. We conclude that an increased risk of alloimmunization was associated with older patients with Hb SC, specially females, even after adjustments were made for the number of transfusions received, the most significant variable.

Alteraçöes imunológicas em pacientes com anemia falciforme / Immunological disorders in sickle cell disease

Objetivos: Nosso objetivo foi revisar as alteraçöes imunológicas em pacientes com anemia falciforme, englobando as causas da maior susceptibilidade às infecçöes e o papel das moléculas de adesäo, citocinas e inflamaçäo sobre a aderência anormal das hemácias falciformes ao endotélio vascular. Métodos: Os artigos para revisäo foram obtidos a partir dos dados do MEDLINE, onde analisou-se a literatura, nos idiomas inglês e português, sobre anemia falciforme e moléculas de adesäo. Resultados: A freqüência de infecçöes por germes 0encapsulados é alta em pacientes com anemia falciforme, principalmente pelo Streptococcus pneumoniae. Isto se deve ao fato de que as crises vaso-oclusivas recorrentes no baço resultam na atrofia do órgäo, com conseqüente diminuiçäo de sua funçäo, principalmente a de opsonizaçäo. A adesäo anormal dos glóbulos vermelhos falciformes ao endotélio vascular mantém baixos níveis de isquemia tecidual. Conclusäo: Pacientes com anemia falciforme säo mais sensíveis a infecçöes, principalmente pneumocócicas, de modo que há necessidade de profilaxia antibiótica e vacinaçäo anti-pneumocócica. A melhor compreensäo dos defeitos imunológicos que predispöem à inflamaçäo e vasculite constantes, pode ser fundamental na escolha das drogas que devem ser utilizadas para diminuir as complicaçöes vasculares da anemia falciforme

La placenta y el cordón umbilical del feto papiráceo en la anemia drepanocítica / The placenta and umbilical cord in papyraceous in sickle cell disease

Analizar la placenta y el cordón umbilical de un embarazo gemelar diamniónico-monocoriónico complicado con anemia de células falciformes y muerte intrauterina fetal es el propósito de este estudio. Análisis macro y microscópico de regiones de la placenta y del cordón umbilical del feto muerto fueron realizados, Inserción excéntrica del cordón, edema generalizado y colapso del mismo parecen ser la causa de muerte del feto papiráceo. Cambios degerativos fueron observados en el cordón umbilical y alteraciones placentarias demostraron una incrementada deposición de fobrinoide afectando el 40 por ciento de su disco placentario. Estos hallazgos son de importancia ya que la morbilidad del gemelo sobreviviente está en un alto riesgo. Como el síndrome de transfusión fetofetal ocurre en este tipo de placentación su posible aparición en los estadios tempranos del embarazo se discute en relación con otros factores que también son de elevado riesgo

Inmunodeficiencia celular asociada a la anemia drepanocitica / Cellular immunodeficiencia associated with sickle anemia

El estudio de la inmunidad celular en 38 pacientes adultos con anemia drepanocitica mostró una disminución significativa en el porcentaje de células formadoras de roseta espontánea y de linfocitos T reconocidos con un anticuerpo monoclonal anti-CD3. Esta alteración de las células T en sangre periférica al parecer ocurrió a expensas de la disminución de la subpoblación CD4+. Los estudios funcionales revelaron también una disminución significativa en la actividad de células citotóxicas naturales. Ninguno de los pacientes presentó anticuerpos contra los virus de la inmunodeficiencia humana tipo 1 y tipo 2 contra el HTLV-1 y el 60 %resultó seropositivo al citomegalovirus. No se encontró correlación entre las alteraciones detectadas y la presencia de anticuerpos contra este virus, el número de unidades de sangre transfundidas y el índice de infecciones anuales

Aspectos inmunologicos relacionados con la enfermedad por hemoglobinopatias / Immunologic aspects related to hemoglobinopathic diseases

The records of 96 patients with sickle cell disease were studied in relation to various immunological parameters. Age, sex, levels of total and fractionated serum protein and immunoglobulins, serum complements, antierythrocytic antibodies, circulating immune complexes, antiviral antibodies and lymphoid populations were taken into account. No major alterations in humoral immunity were found in this group of panamanian sickle cell patient

Infecçöes e imunidade na doença falciforme

A incidência de infecçöes bacterianas em pacientes com doença falciforme, particularmente na anemia falciforme, é elevada. Pneumonia, diarréia, infecçäo do sistema urinário, osteomielite, septicemia e meningite ocorrem, principalmente, nos pacientes mais jovens. A base fisiopatológica para a maior suscetibilidade a infecçöes nesta doença é complexa. Aparentemente, a hipofunçäo esplênica constitui o componente principal, sendo acompanhada de anormalidades de opsonizaçäo, da via alternativa do complemento, produçäo de anticorpos, funçäo leucocitária e imunidade celular. A profilaxia dos episódios infecciosos deve ser feita com imunizaçäo antipneumocócica e uso de penicilina

Pattern of splenic phagocytic function in Brazilian patients with sickle cell disease

The splenic function measured by the counts of pitted erythrocytes has been assessed in 87 patients with sickle cell disease (59 homozygotes for hemoglobin S (SS), 14 double heterozygotes for Hb S and beta zero thalassemia (S/beta zero thal), 4 S/beta+ thal and 10 SC patients) in Southeast Brazil. Results showed a progressive increase in pit counts according to age. The reduction pattern in the splenic function was similar for the SS, S/beta zero thal and S/beta+ thal patients, and over the age of 12 almost all patients presented counts compatible with severe splenic hypofunction. Patients with SC hemoglobinopathy presented slower development of hyposplenism and lower levels of pit counts even in advanced ages. Except for S/beta+ thal patients, the developmental pattern of hyposplenism was not different from that reported among patients in the United States and Jamaica