Autoantibodies immuno-mechanically modulate platelet contractile force and bleeding risk

Oluwamayokun Oshinowo; Renee Copeland; Anamika Patel; Nina Shaver; Meredith E Fay; Rebecca Jeltuhin; Yijin Xiang; Christina Caruso; Adiya E Otumala; Sarah Hernandez; Priscilla Delgado; Gabrielle Dean; James M Kelvin; Daniel Chester; Ashley C Brown; Erik C Dreaden; Traci Leong; Jesse Waggoner; Renhao Li; Eric Ortlund; Carolyn Bennett; Wilbur A Lam; David R Myers

doi:10.1038/s41467-024-54309-8

Autoantibodies immuno-mechanically modulate platelet contractile force and bleeding risk

Nat Commun. 2024 Nov 25;15(1):10201. doi: 10.1038/s41467-024-54309-8.

Authors

Oluwamayokun Oshinowo^{1

2

3

4

5}, Renee Copeland^{1

2

3

4

5}, Anamika Patel⁶, Nina Shaver^{1

2

3

4

5}, Meredith E Fay^{1

2

3

4

5}, Rebecca Jeltuhin¹, Yijin Xiang², Christina Caruso^{2

3}, Adiya E Otumala^{1

2

4}, Sarah Hernandez⁷, Priscilla Delgado^{1

2

4}, Gabrielle Dean⁸, James M Kelvin¹, Daniel Chester⁹, Ashley C Brown⁹, Erik C Dreaden¹, Traci Leong¹⁰, Jesse Waggoner⁹, Renhao Li², Eric Ortlund⁶, Carolyn Bennett², Wilbur A Lam^{11

12

13

14

15}, David R Myers^{16

17

18}

Affiliations

¹ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
² Department of Pediatrics, Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, Emory University School of Medicine, Emory University, Atlanta, GA, USA.
³ Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA, USA.
⁴ Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.
⁵ Winship Cancer Institute of Emory University, Emory University, Atlanta, GA, USA.
⁶ Department of Biochemistry, Emory University School of Medicine, Emory University, Atlanta, GA, USA.
⁷ Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta, GA, USA.
⁸ Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, Atlanta, GA, USA.
⁹ Joint Department of Biomedical Engineering of University of North Carolina, Chapel Hill and North Carolina State University, Raleigh, NC, USA.
¹⁰ Department of Biostatistics & Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
¹¹ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA. wilbur.lam@emory.edu.
¹² Department of Pediatrics, Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, Emory University School of Medicine, Emory University, Atlanta, GA, USA. wilbur.lam@emory.edu.
¹³ Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA, USA. wilbur.lam@emory.edu.
¹⁴ Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA. wilbur.lam@emory.edu.
¹⁵ Winship Cancer Institute of Emory University, Emory University, Atlanta, GA, USA. wilbur.lam@emory.edu.
¹⁶ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA. david.myers@emory.edu.
¹⁷ Department of Pediatrics, Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, Emory University School of Medicine, Emory University, Atlanta, GA, USA. david.myers@emory.edu.
¹⁸ Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA. david.myers@emory.edu.

PMID: 39587073
DOI: 10.1038/s41467-024-54309-8

Abstract

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.

MeSH terms

Adolescent
Antibodies, Monoclonal / immunology
Autoantibodies* / blood
Autoantibodies* / immunology
Biomarkers / blood
Blood Platelets* / immunology
Child
Child, Preschool
Female
Hemorrhage* / immunology
Humans
Integrins / immunology
Integrins / metabolism
Male
Mechanotransduction, Cellular* / immunology
Purpura, Thrombocytopenic, Idiopathic / immunology
Single-Cell Analysis

Substances

Autoantibodies
Integrins
Antibodies, Monoclonal
Biomarkers

Abstract

MeSH terms

Substances

Grants and funding