The Role of Ion Channels, Lipids, and IgG4 in SARS-CoV-2 Spike Protein Interactions and Immune Dysregulation

The SARS-CoV-2 spike protein exerts complex effects on immune regulation, vascular integrity, and ion channel function. Beyond its role in viral entry, evidence suggests that the spike protein perturbs ion homeostasis by interacting with calcium (Ca²⁺), potassium (K⁺), and sodium (Na⁺) channels, contributing to endothelial dysfunction, oxidative stress, and inflammation. Repeated exposure to spike protein through mRNA vaccination has also been linked to IgG4 class switching, a phenomenon associated with immune tolerance and chronic antigen exposure. While ion channel dysfunction and Fc receptor interactions are well-documented, the potential role of ion channel dysregulation in driving IgG4 class switching remains unexplored. This hypothesis posits that ion flux disturbances may shape the cytokine milieu—particularly interleukin-4 (IL-4) and interleukin-10 (IL-10) signaling—favoring a shift toward IgG4 dominance. Additionally, lipid nanoparticles (LNPs) used in mRNA vaccines could modulate ion channels, influencing immune signaling in ways that remain uncertain. Molecular mimicry between the spike protein and host proteins, including myosin and ion channel subunits, further raises concerns about potential autoimmune consequences. This review synthesizes current knowledge while identifying key gaps, highlighting the need for mechanistic studies to evaluate ion channel-mediated immune modulation. A deeper understanding of these processes is essential for mitigating potential risks and advancing targeted therapeutic approaches.