The Spike as Autoimmune Pied Piper: After Invading the Endothelium, the Spike Induces Autoimmune Disease via an Integrin-Mediated Mechanical Process
The RGD sequence in the Spike Protein provides a comprehensive and convincing explanation for the Spike invading organs and inducing autoimmune disease.
Integrin-mediated immune cell adhesion to endothelial cells under a shear force of blood flow. (A) Migration of immune cells under force—immune cells traveling through the blood vessel experience a shear force of the blood flow. Chemokines (green) are secreted by the endothelial cells lining the tissue displaying self-antigens; however, the chemokine gradient is highest near the infectious tissue. The chemokines slow down the flow rate of the migratory leukocytes towards the site of infection under the shear stress of blood flow, equivalent to 1 dyn/cm2. (B) Slip-bond formation and decrement in cell migration velocity—cells gradually decrease the speed along with the rise of chemokine gradient and tumble on the endothelial cells of the blood vessel. The selectin molecules, expressed by the leukocyte, interact with its counterpart expressed on the endothelial cells. However, their interaction under a shear force of blood flow causes the slippage of the bonds, allowing the cell to roll on the endothelial layer, while rolling numerous numbers of slip bond forms and breaks between the molecules like P-selectin, E-selectin, PSGL1, E-cadherin, etc. (C) Extended-closed integrins—the GPCR expressed on the leukocytes interacts with the chemokine to activate PI3K that induces Rap1–RIAM complex to activate talin for further binding with the β subunit cytosolic tail of integrin. This partially activates integrin from its bent-closed to extended-closed structure. (D) Integrin activation leading to focal adhesion—the extended-closed integrin gets activated, either by outside-in signaling by interacting with CAM while rolling on the endothelial layer or by inside-out signaling through sensing the force from talin–actin complex. The activation breaks the integrin salt bridge, transforming it into a thermodynamically unstable but active extended-open conformation. This forms integrin–ligand catch bonds under blood-flow shear force, resulting in complete adhesion of the immune cells to the endothelial layer. During this interaction, the force is transmitted through integrin both outside and inside the cell, which finally transduces downstream forming the focal adhesion. (E) Adhesion of cell—this focal adhesion regulates the cell's shape and migration and strictly adheres the cell on the endothelial layer by inducing the catch-bond formation. (F) Diapedesis—while remaining attached on the endothelial surface in the infected tissue, the self-reactive immune cells transmigrate in between adjacent cells by diapedesis towards the infected tissue region (Zhu et al., 2007b; Jahed et al., 2014; Huse, 2017).
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