Are B cells the hidden drivers of neuroimmune interactions in neuropathic pain?

Aims: The aim of this study is to investigate the role of B cells and the IgG-FcγR axis in the development of neuropathic pain following peripheral nerve injury.

Methods: Researchers utilized a mouse model of chronic constriction injury (CCI) to mimic peripheral nerve damage. B cells were depleted using anti-CD20 antibodies, and their absence was further validated using genetically modified B cell-deficient mice. IgG accumulation in dorsal root ganglia (DRGs) and spinal cords was analysed through immunohistochemistry, RNA sequencing, and ELISA.

Results: The study revealed that B cell depletion with anti-CD20 prevented allodynia in mice, with B cell-deficient mice showing similar protection. Remarkably, reintroducing B cells restored pain behaviors, underscoring their critical role. Elevated levels of IgG were observed in injured dorsal root ganglia (DRGs) and spinal cords of mice and were also found in human DRGs from chronic pain patients, highlighting translational relevance. Passive transfer of IgG from injured mice induced pain behaviors but only in recipients with prior nerve injury, demonstrating specificity for injury-related antigens. Furthermore, these IgG-mediated effects were entirely abolished in FcγR-deficient mice, confirming the essential role of Fc gamma receptors in pain transmission.

Conclusions: B cells, through IgG production and FcγR signalling, are essential contributors to neuropathic pain.

Comments: The authors of this well-designed research provided compelling evidence placing B cells as critical contributors to the neuroimmune interactions underlying neuropathic pain, an area traditionally dominated by studies on T cells and macrophages. By utilizing multiple methods, including gene profiling, flow cytometry, and electrophysiological assessments, they reinforced the robustness of their findings. Translational validation in human tissues further strengthens the clinical relevance, suggesting IgG in DRGs as a potential biomarker for chronic pain. While the study successfully establishes the B cell-IgG-FcγR axis as crucial in neuropathic pain, some limitations remain. The specific autoantigenic targets involved in this process have yet to be identified, and the findings are primarily based on mouse models, which, although highly relevant, may not fully replicate the complexity of human neuropathic pain. Additionally, the timing and long-term effects of IgG's involvement beyond the initial pain phases require further exploration. This research significantly advances our understanding of the neuroimmune mechanisms behind chronic pain and opens new avenues for targeted therapies. The ability to block pain through B cell depletion suggests that immunomodulation could be a promising therapeutic strategy. However, the path to clinical application will require addressing the study's limitations, particularly identifying autoantigen targets and fully confirming the role of IgG in chronic pain conditions.

Ali Jaafar

Reference: Lacagnina MJ, Willcox KF, Boukelmoune N, Bavencoffe A, Sankaranarayanan I, Barratt DT, Zuberi YA, Dayani D, Chavez MV, Lu JT, Farinotti AB, Shiers S, Barry AM, Mwirigi JM, Tavares-Ferreira D, Funk GA, Cervantes AM, Svensson CI, Walters ET, Hutchinson MR, Heijnen CJ, Price TJ, Fiore NT, Grace PM. B cells drive neuropathic pain-related behaviors in mice through IgG-Fc gamma receptor signaling. Sci Transl Med. 2024 Sep 25;16(766):eadj1277. doi: 10.1126/scitranslmed.adj1277. Epub 2024 Sep 25. PMID: 39321269; PMCID: PMC11479571.

🔗 https://www.science.org/doi/10.1126/scitranslmed.adj1277