Elevated levels of circulating invariant natural killer cell subsets are skewed toward Th2-like phenotype in children with sickle cell disease

Boulassel, Mohamed-Rachid; Al-Zubaidi, Abeer; Al-Zadjali, Shoaib; Al-Qarni, Zahra; Al-Naamany, Nidaa; Al-Yarabi, Ahmed; Elshinawy, Mohamed; Wali, Yasser

doi:10.1016/j.clim.2019.108308

Cited by 3 publications

(3 citation statements)

References 33 publications

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“…A total of 571 publications passed this screening (eFigure 1 in Supplement 1 , eTable 1 in Supplement 2 ). 8 , 11 , 12 , 13 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ...…”

Section: Methodsunclassified

Genetic Variation and Sickle Cell Disease Severity

Kirkham,

Estepp,

Weiss

et al. 2023

JAMA Netw Open

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ImportanceSickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD remain poorly understood.ObjectiveTo assess all reported genetic modifiers of SCD, evaluate the design of associated studies, and provide guidelines for future analyses according to modern genetic study recommendations.Data SourcesPubMed, Web of Science, and Scopus were searched through May 16, 2023, identifying 5290 publications.Study SelectionAt least 2 reviewers identified 571 original, peer-reviewed English-language publications reporting genetic modifiers of human SCD phenotypes, wherein the outcome was not treatment response, and the comparison was not between SCD subtypes or including healthy controls.Data Extraction and SynthesisData relevant to all genetic modifiers of SCD were extracted, evaluated, and presented following STREGA and PRISMA guidelines. Weighted z score meta-analyses and pathway analyses were conducted.Main Outcomes and MeasuresOutcomes were aggregated into 25 categories, grouped as acute complications, chronic conditions, hematologic parameters or biomarkers, and general or mixed measures of SCD severity.ResultsThe 571 included studies reported on 29 670 unique individuals (50% ≤ 18 years of age) from 43 countries. Of the 17 757 extracted results (4890 significant) in 1552 genes, 3675 results met the study criteria for meta-analysis: reported phenotype and genotype, association size and direction, variability measure, sample size, and statistical test. Only 173 results for 62 associations could be cross-study combined. The remaining associations could not be aggregated because they were only reported once or methods (eg, study design, reporting practice) and genotype or phenotype definitions were insufficiently harmonized. Gene variants regulating fetal hemoglobin and α-thalassemia (important markers for SCD severity) were frequently identified: 19 single-nucleotide variants in BCL11A, HBS1L-MYB, and HBG2 were significantly associated with fetal hemoglobin (absolute value of Z = 4.00 to 20.66; P = 8.63 × 10−95 to 6.19 × 10−5), and α-thalassemia deletions were significantly associated with increased hemoglobin level and reduced risk of albuminuria, abnormal transcranial Doppler velocity, and stroke (absolute value of Z = 3.43 to 5.16; P = 2.42 × 10−7 to 6.00 × 10−4). However, other associations remain unconfirmed. Pathway analyses of significant genes highlighted the importance of cellular adhesion, inflammation, oxidative and toxic stress, and blood vessel regulation in SCD (23 of the top 25 Gene Ontology pathways involve these processes) and suggested future research areas.Conclusions and RelevanceThe findings of this comprehensive systematic review and meta-analysis of all published genetic modifiers of SCD indicated that implementation of standardized phenotypes, statistical methods, and reporting practices should accelerate discovery and validation of genetic modifiers and development of clinically actionable genetic profiles.

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Section: Methodsunclassified

Genetic Variation and Sickle Cell Disease Severity

Kirkham,

Estepp,

Weiss

et al. 2023

JAMA Netw Open

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“…This may be considered as a limitation because other blood cells, such as neutrophils, endothelial cells and invariant natural killer cells, are also key players in the pathogenesis of SCA. 35,36 However, early studies have shown that MP derived from RBC and PLT are the most abundant in the circulation, while levels of MP originated from other blood cells are much less, and even undetectable in the blood. 12 Therefore, MP originated from other blood cells need to be further studied.…”

Section: Associations Among Levels Of Microparticles and Study Parame...mentioning

confidence: 99%

Impact of splenectomy on circulating microparticles in patients with sickle cell anemia

Boulassel,

Al‐Rubkhi,

Al‐Qasabi

et al. 2023

Int J Lab Hematology

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IntroductionCirculating microparticles (MP) are being described as potential biomarkers for disease activity in a variety of conditions including sickle cell anemia (SCA). However, relatively little is known about the influence of spleen status on MP levels in patients with SCA.MethodsUsing a prospective study design we characterize circulating MP in 144 patients with SCA in steady state by assessing their cellular origin and their relationships to spleen status defined by clinical and imaging findings. In addition, MP levels were studied according to demographic characteristics, clinical status, treatment modalities, and other hematological and biochemical parameters. Absolute plasma concentrations of MP were determined by flow cytometry.ResultsPatients with SCA displayed a 10‐fold increase in levels of MP derived from red blood cell (RBC) and platelets (PLT) when compared to their healthy counterparts (p < 0.0001). Splenectomized patients with SCA have more pronounced levels of MPRBC and MPPLT, and remained elevated after several weeks of follow‐up. Levels of MP were not significantly associated with spleen removal procedures, age, gender, clinical severity score, hydroxyurea therapy, hemoglobin F, and co‐existence of glucose‐6‐phosphate dehydrogenase deficiency.ConclusionCollectively, these results suggest that splenectomy affects circulating levels of MP regardless of the known SCA modifiers and correlates.

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“…É bem documentada a elevação da IL-33 em pacientes com doença falciforme e em bolsas de sangue estocadas de doadores da comunidade 196 . É um achado intrigante pois se postula que a IL-33 seja liberada dos núcleos celulares 269 . A fonte de ST2s na hemólise também não seria clara, pois a hipótese mais em voga é de que a IL-33 atua como repressor da síntese da ST2s na heterocromatina.…”

Section: Nãounclassified

Biomarcadores cardíacos em pacientes adultos com doenças falciformes

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À professora Sandra Fátima Menosi Gualandro, pela enorme paciência e carinho. Você sempre será um exemplo pessoal de integridade e dedicação. Nosso ambulatório só existe pela sua visão e persistência.À Daniela Menosi Gualandro, uma pessoa, médica e pesquisadora brilhante, agradeço pela ideia inicial do trabalho e pelo suporte nas dúvidas e nas análises.Ao Professor Vanderson Rocha, a excelência científica e o currículo incomparável escondem o seu grande diferenciala noção de que cada vida importa, que cada paciente que perdemos não é uma derrota mas sim uma pergunta a ser respondida.Ao Professor Rogério de Souza, pelos conselhos e auxílio em momentos tão difíceis. Não existe limite para seu sucesso e isso é resultado de sua inteligência e dedicação.À Professora Vera Maria Cury Salemi. Pela imensa disponibilidade, generosidade e carinho. Você não titubeou um instante em me auxiliar.Ao Professor Bruno Caramelli pelo apoio irrestrito e auxílio na parte técnica e administrativa Ao Renato de Aguiar Hortegal, pela ajuda na realização dos ecocardiogramas. Sua dedicação, conhecimento e disponibilidade são impressionantes.À Camila Rocon de Lima Andreta. Não tivemos contato pessoal, mas em cada conversa ou mensagem conheci uma pessoa que empenhou seu precioso tempo e conhecimento me auxiliando na leitura dos ecocardiogramas. Não há como recompensar, só agradecer imensamente.Ao Marcelo Dantas Tavares de Melo, pelo auxílo na leitura dos ecocardiogramas e pelas ideias de análise.A Iara Keiko Yokomizo, pelo auxílio na coleta, preservação e organização das amostras. Além da competência que todos conhecem você sempre me auxiliou com o seu carinho e palavras de incentivo.

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Elevated levels of circulating invariant natural killer cell subsets are skewed toward Th2-like phenotype in children with sickle cell disease

Cited by 3 publications

References 33 publications

Genetic Variation and Sickle Cell Disease Severity

Genetic Variation and Sickle Cell Disease Severity

Impact of splenectomy on circulating microparticles in patients with sickle cell anemia

Biomarcadores cardíacos em pacientes adultos com doenças falciformes

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