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B cells drive neuropathic pain–related behaviors in mice through IgG–Fc gamma receptor signaling

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Lacagnina, Michael J., Willcox, Kendal F., Boukelmoune, Nabila, Bavencoffe, Alexis, Sankaranarayanan, Ishwarya, Barratt, Daniel T., Zuberi, Younus A., Dayani, Dorsa +16 more·2024·Science Translational Medicine
DOI 10.1126/scitranslmed.adj1277PMC PMC11479571
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Abstract

Neuroimmune interactions are essential for the development of neuropathic pain, yet the contributions of distinct immune cell populations have not been fully unraveled. Here, we demonstrate the critical role of B cells in promoting mechanical hypersensitivity (allodynia) after peripheral nerve injury in male and female mice. Depletion of B cells with a single injection of anti-CD20 monoclonal antibody at the time of injury prevented the development of allodynia. B cell–deficient (muMT) mice were similarly spared from allodynia. Nerve injury was associated with increased immunoglobulin G (IgG) accumulation in ipsilateral lumbar dorsal root ganglia (DRGs) and dorsal spinal cords. IgG was colocalized with sensory neurons and macrophages in DRGs and microglia in spinal cords. IgG also accumulated in DRG samples from human donors with chronic pain, colocalizing with a marker for macrophages and satellite glia. RNA sequencing revealed a B cell population in naive mouse and human DRGs. A B cell transcriptional signature was enriched in DRGs from human donors with neuropathic pain. Passive transfer of IgG from injured mice induced allodynia in injured muMT recipient mice. The pronociceptive effects of IgG are likely mediated through immune complexes interacting with Fc gamma receptors (FcγRs) expressed by sensory neurons, microglia, and macrophages, given that both mechanical allodynia and hyperexcitability of dissociated DRG neurons were abolished in nerve-injured FcγR-deficient mice. Consistently, the pronociceptive effects of IgG passive transfer were lost in FcγR-deficient mice. These data reveal that a B cell–IgG–FcγR axis is required for the development of neuropathic pain in mice.

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  • IgG complexes can directly bind to peripheral somatosensory neurons to induce neuropathic pain through the B cell/IgG/Fc axis.

    “Through the B cell/IgG/Fc axis, IgG complexes can directly bind to the peripheral somatosensory neurons directly to induce neuropathic pain”

    From Nociplastic pain: the prominent role of non-neuronal cells in central and peripheral sensitization (2026) · cites this paper as [105]

    The Discussion reports IgG colocalization with neurons in mouse DRGs and says immune complexes may directly activate sensory neurons through Fcγ receptors. But it presents direct activation as a possibility, not an established mechanism, and explicitly says the study did not directly demonstrate that IgG forms complexes to induce allodynia. The cited passages provide no page numbers. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • IgG complexes binding to Fcγ receptors expressed on DRG neurons can evoke nociceptive activity in the absence of overt inflammation.

    “IgG complexes binding to Fcγ receptors expressed on DRG neurons can evoke nociceptive activity in the absence of overt inflammation (105, 115).”

    From Nociplastic pain: the prominent role of non-neuronal cells in central and peripheral sensitization (2026) · cites this paper as [105]

    The Results section on Fcγ receptors and the pronociceptive effect of IgG (page not provided) reports that IgG, likely in immune complexes, induces allodynia through FcγRs after nerve injury. The Discussion says these complexes may directly activate DRG neurons, but does not establish direct neuronal activation or the claimed absence of overt inflammation; the passive-transfer results also found no allodynia in mice without nerve injury. (LLM, conf=0.86)

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Authors
Lacagnina, M. J., Willcox, K. F., Boukelmoune, N., Bavencoffe, A., Sankaranarayanan, I., Barratt, D. T., Zuberi, Y. A., Dayani, D., Chavez, M. V., Lu, J. T., Farinotti, A. B., Shiers, S., Barry, A. M., Mwirigi, J. M., Tavares-Ferreira, D., Funk, G. A., Cervantes, A. M., Svensson, C. I., Walters, E. T., Hutchinson, M. R., Heijnen, C. J., Price, T. J., Fiore, N. T., & Grace, P. M.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • The University of Texas Health Science Center at Houston (US)
  • The University of Texas at Dallas (US)
  • The University of Adelaide (AU)
  • Karolinska Institutet (SE)
  • Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX 75080, USA.
  • Southwest Transplant Alliance (US)
  • ARC Centre for Nanoscale BioPhotonics (AU)
  • Rice University (US)
Corresponding author
Grace, Peter M.
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2024-09-25
Volume
16
Issue
766
Pages
eadj1277-eadj1277
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
DOI
10.1126/scitranslmed.adj1277
PMC
PMC11479571
OpenAlex
W4402826027
Cited by
60
References
6
Citations by year
2026: 25 · 2025: 33 · 2024: 2
FWCI
17.08
Type
journal article
Language
en
Open access
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
Funders
  • American Australian Association
  • Knut och Alice Wallenbergs Stiftelse
  • National Institutes of Health (W81XWH)
  • University of Texas MD Anderson Cancer Center (P30-CA-016672)
  • Medical Research Council
  • Australian Research Council (CE140100003)
  • National Health and Medical Research Council (DP110100297, 465423, FT180100565)
  • National Cancer Institute (P30CA016672)
  • National Institute of General Medical Sciences (T32GM108539)
  • National Institute of Neurological Disorders and Stroke (R01NS111521, U19NS130608, R01NS126252)
  • Medical Research and Materiel Command
Topics
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
  • Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
Keywords
neuropathic pain, B cells, IgG, Fc gamma receptor, mechanical allodynia, peripheral nerve injury, dorsal root ganglia, microglia, macrophages, sensory neurons, immune complexes, anti-CD20 monoclonal antibody, muMT mice, passive transfer, chronic pain, neuroimmune interactions
MeSH terms
Animals, B-Lymphocytes, Behavior, Animal, Female, Ganglia, Spinal, Humans, Hyperalgesia, Immunoglobulin G, Macrophages, Male, Mice, Inbred C57BL, Neuralgia, Signal Transduction, Receptors, IgG, Mice, Peripheral Nerve Injuries

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