{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Intercellular adhesion molecule‐4 (ICAM‐4) is an erythroid‐specific member of the immunoglobulin superfamily that plays a multifaceted role in red blood cell function. Its primary function is to mediate cell–cell adhesion through specific interactions with multiple integrins. In the context of sickle cell disease, for example, physiologic stress signals (such as epinephrine) activate the cyclic adenosine monophosphate–protein kinase A pathway, which induces serine phosphorylation of ICAM‐4. This modification promotes binding to endothelial α"}, {"type": "i", "children": [{"type": "t", "text": "v"}]}, {"type": "t", "text": "β₃ integrin, thereby enhancing sickle red blood cell adhesion and contributing to vaso‐occlusive events."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its role in pathological adhesion, ICAM‐4 is essential for the formation and stability of erythroblastic islands within the bone marrow. These specialized niches rely on adhesive interactions between erythroid progenitors and macrophages, with ICAM‐4 engaging integrins such as α"}, {"type": "i", "children": [{"type": "t", "text": "v"}]}, {"type": "t", "text": " and CD11c/CD18 on macrophages to facilitate proper erythropoiesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, ICAM‐4 also functions as a ligand for platelet integrins (notably α_IIbβ₃), thereby potentially mediating red blood cell–platelet interactions in thrombosis. Detailed mutagenesis and domain‐mapping studies have defined distinct binding sites on ICAM‐4 for various integrins—including α_V-family members, β2 integrins, and α_IIbβ₃—and have underscored the modulatory influence of glycosylation on its adhesive properties."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Genetic studies of the ICAM4 gene have further characterized allelic variants that define the Landsteiner–Wiener (LW) blood group system. These polymorphisms not only have clinical relevance in transfusion medicine but may also influence the receptor’s adhesive interactions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these observations establish ICAM‐4 as a critical adhesion molecule in erythroid cells that governs red blood cell interactions with endothelial cells, platelets, and macrophages under both physiological and pathological conditions.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Rahima Zennadi, Patrick C Hines, Laura M De Castro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Epinephrine acts through erythroid signaling pathways to activate sickle cell adhesion to endothelium via LW-alphavbeta3 interactions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2004-01-0042"}], "href": "https://doi.org/10.1182/blood-2004-01-0042"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15308566"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15308566"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jing Zhang, Krithika Abiraman, Sasia-Marie Jones, et al. 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