Background & Aims
Recent work from our group and others suggests that B cells promote development of pain via production of IgG autoantibodies, which subsequently form immune complexes capable of binding to Fc gamma receptors in the dorsal root ganglia (DRG) to facilitate mechanical allodynia[1]. Strategies to enhance IgG clearance after nerve injury could provide a novel approach to treat neuropathic pain. Neonatal Fc gamma receptors (FcRn) greatly extend the serum half-life of IgG by binding the Fc portion of IgG thereby rescuing IgG from lysosomal degradation by recycling it back to the cell surface[2]. In this study, we examined IgG autoantibody production following chronic constriction injury (CCI) and assessed whether genetic depletion or blockade of FcRn is an effective therapeutic strategy to alleviate mechanical pain after peripheral nerve injury.
Methods
Male and female C57BL/6 and B6.129X1-Fcgrttm1Dcr/DcrJ (FcRn-) mice underwent chronic constriction injury (CCI) of the left sciatic nerve or sham injury (n=4-8 mice/sex/group). To assess whether blocking FcRn could alleviate pain, C57BL/6 mice received 3 intrathecal injections of Efgartigimod (Argenx, 5?g/5?L) or human IgG1 Fc fragment (BioXCell, 5?g/5?L) on days 7, 10 and 13 post-injury. Mice were tested for mechanical allodynia using von Frey and brush tests. Serum was collected via cardiac puncture 14 days post-CCI or sham surgery from C57BL/6 mice. Serum antibody binding of 120 autoantigens to specific IgG subtypes (IgG1, IgG2b, IgG2c and IgG3) was quantified using autoantigen microarray chips. Total IgG accumulation in the DRG following nerve injury was characterized via immunohistochemistry.
Results
Intrathecal delivery of Efgartigimod effectively alleviated mechanical allodynia for at least three weeks after CCI, compared to hIgG1-Fc fragment (F1,14=11.68 p=0.004). CCI resulted in increased serum autoantigen binding, specifically of IgG2b and IgG2c subtypes in males and IgG2c in females. Following CCI, FcRn- mice had reduced mechanical pain for at least two weeks, compared to wild-type controls (F1,14=12.02 p=.004). Both biologic and genetic interference with FcRn were accompanied by a reduction in IgG accumulation in the DRG following CCI, compared to controls.
Conclusions
These data demonstrate that FcRn blockade relieves neuropathic pain induced by CCI. Both FcRn blockade and genetic deletion of FcRn reduced IgG accumulation in the DRG. CCI results in the production of IgG2b/c autoantibodies, indicating that IgG2b/c class switching in B cells and formation of IgG-immune complexes with increased binding affinity for Fc gamma receptors III and IV contribute to the pathogenesis of neuropathic pain. These findings support a pronociceptive role for autoantigen-specific IgG following CCI and highlight the potential of FcRn blockers to enhance IgG autoantibody clearance thereby alleviating neuropathic pain.
References
[1]Lacagnina, M. J., Heijnen, C. J., Watkins, L. R. & Grace, P. M. Autoimmune regulation of chronic pain. Pain Rep 6, e905, doi:10.1097/PR9.0000000000000905 (2021).
[2]Pyzik, M., Kozicky, L. K., Gandhi, A. K. & Blumberg, R. S. The therapeutic age of the neonatal Fc receptor. Nat Rev Immunol, 1-18, doi:10.1038/s41577-022-00821-1 (2023).
[3]Huijbers, M. G. et al. Efgartigimod improves muscle weakness in a mouse model for muscle-specific kinase myasthenia gravis. Exp Neurol 317, 133-143, doi:10.1016/j.expneurol.2019.03.001 (2019).
[4]Ulrichts, P. et al. Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans. J Clin Invest 128, 4372-4386, doi:10.1172/JCI97911 (2018).
Presenting Author
Nathan T. Fiore
Poster Authors
Topics
- Models: Chronic Pain - Neuropathic