Autoantibodies immuno-mechanically modulate platelet contractile force and bleeding risk

• Published in: Nature communications 2024-11, Vol.15 (1), p.10201-15, Article 10201
• Main Authors: Oshinowo, Oluwamayokun, Copeland, Renee, Patel, Anamika, Shaver, Nina, Fay, Meredith E., Jeltuhin, Rebecca, Xiang, Yijin, Caruso, Christina, Otumala, Adiya E., Hernandez, Sarah, Delgado, Priscilla, Dean, Gabrielle, Kelvin, James M., Chester, Daniel, Brown, Ashley C., Dreaden, Erik C., Leong, Traci, Waggoner, Jesse, Li, Renhao, Ortlund, Eric, Bennett, Carolyn, Lam, Wilbur A., Myers, David R.
• Format: Article
• Language: English
• Subjects: 13; 13/1; 14/1; 14/19; 14/34; 14/63; 147/28; 631/250/38; 631/80/79/1236; 631/80/79/2066; 639/166/985; 692/53/2421; Adolescent; Antibodies; Antibodies, Monoclonal - immunology; Autoantibodies; Autoantibodies - blood; Autoantibodies - immunology; Biomarkers; Biomarkers - blood; Bleeding; Blood Platelets - immunology; Child; Child, Preschool; Contractility; Disease control; Epitopes; Female; Fluorescence microscopy; Hemorrhage - immunology; Humanities and Social Sciences; Humans; Idiopathic thrombocytopenic purpura; Immunology; Integrins; Integrins - immunology; Integrins - metabolism; Male; Mechanics (physics); Mechanotransduction; Mechanotransduction, Cellular - immunology; Micropatterning; Modulation; Monoclonal antibodies; multidisciplinary; Pathophysiology; Patients; Pediatrics; Platelets; Purpura, Thrombocytopenic, Idiopathic - immunology; Science; Science (multidisciplinary); Signs and symptoms; Single-Cell Analysis; Symptomology; Therapeutic applications
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-54309-8

Altered mechanotransduction has been proposed as a putative mechanism for disease pathophysiology, yet evidence remains scarce. Here we introduce a concept we call single cell immuno-mechanical modulation, which links immunology, integrin biology, cellular mechanics, and disease pathophysiology and symptomology. Using a micropatterned hydrogel-laden coverslip compatible with standard fluorescence microscopy, we conduct a clinical mechanobiology study, specifically focusing on immune thrombocytopenia (ITP), an autoantibody-mediated platelet disorder that currently lacks a reliable biomarker for bleeding risk. We discover that in pediatric ITP patients ( n  = 53), low single platelet contraction force alone is a “physics-based” biomarker of bleeding (92.3% sensitivity, 90% specificity). Mechanistically, autoantibodies and monoclonal antibodies drive increases and decreases of cell force by stabilizing integrins in different conformations depending on the targeted epitope. Hence, immuno-mechanical modulation demonstrates how antibodies may pathologically alter mechanotransduction to cause clinical symptoms and this phenomenon can be leveraged to control cellular mechanics for research, diagnostic, and therapeutic purposes. Altered mechanotransduction has been proposed as a mechanism for disease pathophysiology, yet evidence remains scarce. Here, the authors show that antibodies from patients with bleeding disorders bind to integrins and modulate platelet cell contraction force, and this correlates with clinical symptoms.