Elevated binding of proteins to immunogenic asialo and sialyl core 1, Lewis A, and Lewis Y structures was observed in plasma from patients with sickle cell disease, suggesting a heightened anti-glycan immune response. and anti-glycan antibodies in sickle cell disease remain understudied. Here, we compiled results acquired through lectin arrays, glycan arrays, and mass spectrometry to interrogate reddish blood cell glycoproteins and glycan-binding proteins found in the plasma of healthy individuals and individuals with sickle cell disease and sickle cell trait. Lectin arrays and mass spectrometry exposed an increase in 2,6 sialylation and a decrease in 2,3 sialylation and blood group antigens displayed on reddish blood cells. Improved binding of proteins to immunogenic asialo and sialyl core 1, Lewis A, and Lewis Y constructions was observed in plasma from individuals with sickle cell disease, suggesting a heightened anti-glycan immune response. Data modeling affirmed glycan manifestation and plasma protein binding changes in sickle cell disease but additionally revealed further changes in ABO blood group manifestation. Our data provide detailed insights Tazarotene into glycan changes associated with sickle cell disease and refer glycans as potential restorative targets. Visual Abstract Open in a separate window Intro Sickle cell disease (SCD), the most common hemoglobinopathy, affects up to 100?000 people in the United States and 13 million people worldwide.1 The inheritance of a homozygous mutation from valine to glutamic acid in the hemoglobin HbS chain causes polymerization of deoxy Tazarotene sickle hemoglobin within reddish blood cells (RBCs).2 In an oxygen-deprived state, RBCs take on a sickled shape and occlude blood vessels. Individuals are afflicted with anemia, pain crises, organ infarction, and infections; however, medical phenotypes vary and remain unpredictable. Additionally, a heterozygous mutation results in the sickle cell trait (SCT), with predominantly silent features.3 SCD requires a multifaceted approach for long-term treatment.4,5 Current SCD therapies remain limited, usually comprising hydroxyurea therapy, 6 and increasingly gene therapy and stem cell transplants to correct hemoglobin mutations.7,8 However, the repertoire of potential therapeutic targets continues to grow.9-11 For example, rivipansel, a glycomimetic pan selectin antagonist, which targeted E-selectin, showed reduced resolution occasions of vaso-occlusive episodes12 but ultimately failed to meet up with its treatment goals.13 Glycans (carbohydrates), biologically diverse cell surface molecules, 14 are often overlooked while potential mediators of vaso-occlusive crises in SCD.15 Sialic acid (SA; the ultimate do not eat me transmission) comprising glycan motifs on both and and test statistics performed showed a number of significant changes ( .05) in lectin binding between all sample types (95% CI bars shown; for full test results, observe supplemental Table 3). Lectin specificities and disease state preferences for each lectin are indicated. Pairwise moderated checks identified significant changes PRKCB in lectin binding between organizations (Number 1C). Healthy donors indicated more terminal fucose (LTL), mannose (NPA), and galactose (ABA and DBA) motifs compared with SCD individuals. LTL (blood group O), DBA (blood group A1), and NPA determine with blood group manifestation,33 indicating blood group loss in SCD RBCs. SCD individuals expressed more 2,6 SA moieties (SNA, SSA), in addition to terminal GalNAc (PTL-I) and complex bisecting .05 and greater than twofold difference in sickle cell/healthy average signal; Number 2) between SCD and healthy samples. Five glycans experienced a higher transmission in SCD samples, with all constructions altered with 2,6 SA (ranging from 2.5- to 18-fold differences; Number 2). Of the 9 glycans with higher signals in healthy donors, 3 constructions are classed as hybrid-type glycans (two- to fourfold variations), and 3e constructions were confirmed to feature 2,3 SA (two- to threefold variations; Number 2). .05) and fold switch (at least twofold) between control (n = 3) and SCD donors (n = 3). Coloured data points are glycans selected for display remaining and right from the storyline. (A) .05) with log2 fold changes between 2 and ?2 (95% CI bars demonstrated; for full test results, see Tazarotene supplemental Table 7). Glycan constructions for each numerical classification are shown with linkage info. Disease state preferences for each glycan will also be indicated. Glycan names can be found in supplemental Table 6. Samples were well separated based on disease state using.