PROJECT SUMMARY
Effective treatments are elusive for the majority of patients with neuropathic pain, which is reflective of the
incomplete knowledge of the underlying mechanisms. Our proposal will advance mechanistic understanding of
peripheral neuropathic pain maintenance by investigating the differentiation and function of B cells after
peripheral nerve injury. Our long-term goal is to harness the disease-modifying potential of neuroimmune
signaling to treat neuropathic pain. As a step toward achieving this goal, the overall objective of this application
is to discover if and how B cells cause neuropathic pain after peripheral nerve injury. Our central hypothesis is
that peripheral nerve injury induces differentiation of B cells into plasma cells. The plasma cells secrete
autoantibodies that form complexes with autoantigens which maintain neuropathic pain by signaling through the
activating Fc gamma receptor (Fc¿R) subtypes (I, III, IV) along the pain neuraxis. We propose that insufficient
efferocytosis (deficient non-inflammatory clearance of apoptotic cells, leading to release of Danger Associated
Molecular Patterns (DAMPs)) at the site of nerve injury, triggers autoimmune B cell differentiation. This
hypothesis is based on strong evidence that plasma cells are pro-nociceptive, as we show that either constitutive
deficiency or pharmacological depletion of differentiating B cells protects male and female mice from neuropathic
pain. Our data also reveal that insufficient efferocytosis leads to B cell differentiation, as pharmacological
stimulation of efferocytosis at the time of peripheral nerve injury reduces immunoglobulin G (IgG) deposits in the
spinal dorsal horn. The rationale for testing our hypothesis is that deciphering this previously overlooked adaptive
immune response to peripheral nerve injury will reveal new and tractable therapeutic targets for neuropathic
pain. To accomplish the overall objective of this application, we will test the central hypothesis in a mouse model
of peripheral nerve injury across the following specific aims: 1) Define the function of B cell differentiation after
peripheral nerve injury. Validation studies will be performed in a piglet model of peripheral injury, and in biological
samples obtained from patients with lumbar radiculopathy; 2) Identify whether Fc¿R signaling maintains
neuropathic pain; and, 3) Determine whether insufficient efferocytosis induces B cell differentiation leading to
neuropathic pain. The proposed studies take a multidisciplinary approach, including pharmacologic and genetic
manipulations, flow cytometry, in situ hybridization, adoptive transfer, and assessment of evoked and operant
pain behaviors. As efferocytosis and downstream plasma cell differentiation have not been previously implicated
in traumatic neuropathic pain, our proposal is highly innovative and is expected to expand our paradigm for
neuroimmune regulation of peripheral neuropathic pain. The results will have significant impact on the treatment
of peripheral neuropathic pain by revealing new sites for therapeutic intervention.