Background & Aims
Autoimmunity has been implicated in the development of pain in disorders such as rheumatoid arthritis and complex regional pain syndrome. In these disorders autoantibodies capable of influencing neuronal excitability via complement activation, Fc gamma receptor signaling, and/or disruption of ion channels, seem to play an important role in the development of pain [1]. Neuropathic pain can occur after damage to the somatosensory system [2]. Our previous data reveal that B cells contribute to the development of neuropathic pain after chronic constriction injury via a B cell-IgG- Fc gamma receptor axis [3]. However, the extent to which B cells play a role in neuropathic pain induced by other forms of traumatic nerve injury remains unknown. Here, we explored the mechanistic role of B cells in the development of pain in several post-injury neuropathy models.
Methods
Adult male and female Ighm-/- mice (muMT, lacking mature B cells) and their wildtype littermates, as well as C57BL/6 (WT) mice, were given one of several established nerve injury models: chronic constriction injury (CCI) of the sciatic nerve; sciatic nerve crush (SNC); spared nerve injury (SNI); or spinal nerve ligation (SNL) of the L5 spinal nerve. To test if depletion of B cells with anti-CD20 monoclonal antibody prevents post-injury allodynia, WT mice were given either anti-CD20 or IgG isotype control (200 ug, IV) at the time of injury. Allodynia was quantified using von Frey tests via the up-down method. Serum was collected from WT mice on day 14 post CCI or SNI, and IgG was isolated and transferred to muMT mice on days 14, 15, and 16 post CCI (40 ug/injection, IT). To assess if each of the injury models induced autoantibody production, serum was isolated from WT mice on day 14 post CCI, SNC, or SNI, and autoantigen binding was quantified via microarray chips.
Results
In models of CCI and SNC, muMT mice of both sexes were protected from allodynia when compared to wildtype littermates. Depletion of B cells via administration of anti-CD20 also protected WT mice from developing allodynia in CCI and SNC. In contrast, neither anti-CD20 treatment nor muMT genotype protected mice after SNI or SNL as compared to controls. However, passive transfer of IgG from donor CCI or SNI mice induced allodynia in recipient muMT CCI mice. Serum autoantigen binding was increased following multiple traumatic nerve injury models.
Conclusions
These data reveal a pro-nociceptive role for B cells in CCI- and SNC-induced neuropathic pain in both male and female mice. Although depletion of B cells is not sufficient to prevent the development of allodynia in SNI and SNL, pro-nociceptive antibodies are still produced. Thus, B cell differentiation to produce autoantigen-specific IgG may be a common consequence of peripheral nerve injury in general, but with differing contributions to the expression of allodynia.
References
1.Lacagnina MJ, Heijnen CJ, Watkins LR, Grace PM. Autoimmune regulation of chronic pain. Pain Rep. 2021 Mar 9;6(1):e905. doi: 10.1097/PR9.0000000000000905. PMID: 33981931; PMCID: PMC8108590.
2.Terminology: International association for the study of pain. International Association for the Study of Pain (IASP). (2023, July 20). https://www.iasp-pain.org/resources/terminology/#pain
3.Lacagnina MJ, Willcox KF, Boukelmoune N, Fiore NT, Bavencoffe A, Sankaranarayanan I, Barratt DT, Zuberi YA, Dayani D, Chavez MV, Lu JT, Bersellini Farinotti A, Shiers S, Barry AM, Mwirigi JM, Tavares-Ferreira D, Funk GA, Cervantes AM, Svensson CI, Price TJ, Walters ET, Hutchinson MR, Heijnen CJ, Grace PM. (2024). B cells drive neuropathic pain via IgG-Fc gamma receptor signaling. Manuscript in progress.
Presenting Author
Kendal Willcox
Poster Authors
Topics
- Models: Chronic Pain - Neuropathic