Chronic complex regional pain syndrome patient IgM has pronociceptive effects in the spinal cord, but not skin, of fracture mice

Abstract B cells and IgM antibodies mediate nociceptive sensitization in the mouse tibia fracture model of complex regional pain syndrome (CRPS). Previously we observed that injection of serum or IgM from early CRPS patients into muMT fracture mice lacking mature B cells and antibodies was always pronociceptive at 7 days after systemic injection or one hour after intrathecal or intradermal IgM injection, but systemically injected serum from chronic CRPS patients was rarely pronociceptive. The current study found that chronic CRPS patient IgM was always pronociceptive within an hour after intrathecal injection in fracture mice, whereas intradermal injection of IgM into the hindpaw was never pronociceptive. Chronic CRPS IgM had increased binding reactivity to glial fibrillary acidic protein (GFAP) and intrathecal injection of anti-GFAP antibody was pronociceptive in fracture mice. The slow onset of pronociceptive effects after systemic injection of early CRPS patient serum or IgM suggests gradual accumulation of pronociceptive IgM-antigen complexes in skin and spinal cord. Pronociceptive effects chronic CRPS IgM were blocked by a complement C5a receptor antagonist or a global cytokine inhibitor. These data suggest that initially CRPS patients generate pronociceptive IgM autoantibodies directed at skin and spinal cord neoantigens, but over time spinal neoantigens are primarily targeted.