Abstract / Summary
Background and Objective: Chronic pain is a common and debilitating condition that affects roughly 25% of the population. Recently, B-cell and immunoglobulin (IgG) signaling have been implicated in preclinical models of neuropathic pain and recent transcriptomic data shows increased number of B-cells and IgGs in the dorsal root ganglia (DRG) of individuals with chronic pain. Here we investigated whether a subclass of IgG, IgG4, sensitizes human DRG neurons and whether IgGs from a patient with elevated expression of IGHG4 in the DRG induces pain hypersensitivity in mice through Fc{gamma} receptors (Fc{gamma}R). Methods: We analyzed spatial transcriptomic data from cervical DRGs obtained during arthrodesis for chronic pain, and assessed IgG4 and Fc{gamma}R1A/CD64 localization by immunohistochemistry. Human organ-donor DRG neurons were treated with recombinant IgG4 containing either a wild-type Fc domain or an aglycosylated Fc domain with reduced Fc{gamma}R binding and excitability was assessed by whole-cell patch-clamp electrophysiology. Total serum IgG from the patient with high IGHG4 expression was transferred intrathecally into B-cell-deficient mice or mice lacking active Fc{gamma}Rs after chronic constriction injury. Results: Bilateral C2 DRGs recovered from one of 8 patients with chronic pain had high IGHG4 expression. IGHG4-enriched regions colocalized with a B-cell transcriptomic signature, and IgG4 immunoreactivity was identified in the DRG manifesting as plaque-like structures. Further immunohistochemical analysis confirmed Fc{gamma}R1A/CD64 to be highly expressed in small-diameter sensory neurons. Wild-type recombinant IgG4 lowered rheobase, increased spontaneous firing, and enhanced current-evoked action potential firing in human DRG neurons compared with vehicle and aglycosylated IgG4. Patient-derived total IgG produced mechanical and thermal hypersensitivity in mature B-cell-deficient mice but not in activate Fc{gamma}R-deficient mice. Discussion: These findings identify IgG4 enrichment within a human sensory ganglion in chronic pain, andpain and demonstrate that IgG4 increases human sensory neuron excitability through an Fc{gamma} receptor-dependent mechanism. Patient IgG also promoted Fc{gamma}R-dependent pain hypersensitivity in vivo, supporting localized humoral immune signaling as a potential mechanism in a subset of patients with chronic pain.