Family 5: Autoimmunity and Molecular Mimicry
Family overview. Autoimmune mechanisms arise via molecular mimicry (pathogen antigens resembling host proteins), bystander activation, or epitope spreading. They can target receptors, ion channels, intracellular proteins, or structural components, producing functional dysregulation even without tissue destruction.
Concrete mechanisms and ME/CFS evidence:
Anti-adrenergic receptor antibodies. Functional autoantibodies against β2-adrenergic receptors (β2-AR) and α1-adrenergic receptors (α1-AR) dysregulate autonomic and cardiovascular signalling; transfer of patient IgG to animals reproduces some autonomic symptoms, supporting pathogenicity.
Anti-muscarinic receptor antibodies. Autoantibodies against M3R and M4R muscarinic receptors disrupt cholinergic autonomic signalling, contributing to POTS, orthostatic intolerance, and reduced secretory function.
Anti-TRPM3 antibodies. Autoantibodies targeting TRPM3 channels on NK cells proposed as a direct mechanism of channel dysfunction, linking viral trigger → autoimmune response → channelopathy.
Molecular mimicry from viral antigens. EBV EBNA-1 peptides share structural similarity with human adrenergic receptor epitopes; SARS-CoV-2 spike protein shares epitopes with multiple human proteins. Post-infectious autoimmunity via this mechanism is under active investigation.
IgG-mediated mitochondrial fragmentation. Patient-derived IgG (target antigen not fully characterised) disrupts mitochondrial dynamics in endothelial cells, providing a direct link from humoral autoimmunity to metabolic dysfunction (Cox et al. 2023).
Anti-nuclear and other autoantibodies. A proportion of ME/CFS patients carry low-titre ANA and other non-organ-specific autoantibodies; clinical significance unclear but consistent with broader immune dysregulation.
Full discussion: Immune System Dysfunction.
Evidence status: Established (adrenergic and muscarinic autoantibodies replicated in multiple independent labs; mechanistic transfer studies support pathogenicity).