Sex-Specific B Cell and Anti-Myelin Autoantibody Response After Peripheral Nerve Injury

Abstract

Immunotherapy holds promise as a non-addictive treatment of refractory chronic pain states. Increasingly, sex is recognized to impact immune regulation of pain states, including mechanical allodynia (pain from non-painful stimulation) that follows peripheral nerve trauma. This study aims to assess the role of B cells in sex-specific responses to peripheral nerve trauma. Using a rat model of sciatic nerve chronic constriction injury (CCI), we analyzed sex differences in (i) the release of the immunodominant neural epitopes of myelin basic protein (MBP); (ii) the levels of serum immunoglobulin M (IgM)/immunoglobulin G (IgG) autoantibodies against the MBP epitopes; (iii) endoneurial B cell/CD20 levels; and (iv) mechanical sensitivity behavior after B cell/CD20 targeting with intravenous (IV) Rituximab (RTX) and control, IV immunoglobulin (IVIG), therapy. The persistent MBP epitope release in CCI nerves of both sexes was accompanied by the serum anti-MBP IgM autoantibody in female CCI rats alone. IV RTX therapy during CD20-reactive cell infiltration of nerves of both sexes reduced mechanical allodynia in females but not in males. IVIG and vehicle treatments had no effect in either sex. These findings provide strong evidence for sexual dimorphism in B-cell function after peripheral nervous system (PNS) trauma and autoimmune pathogenesis of neuropathic pain, potentially amenable to immunotherapeutic intervention, particularly in females. A myelin-targeted serum autoantibody may serve as a biomarker of such painful states. This insight into the biological basis of sex-specific response to neuraxial injury will help personalize regenerative and analgesic therapies.

Cholesterol-dependent LXR transcription factor activity represses pronociceptive effects of estrogen in sensory neurons and pain induced by myelin basic protein fragments

“…No sexual dimorphism was observed in MBP 84-104 release ( Lee et al, 2022 ), interaction with Ncoa1 or regulation of LXR post-CCI. Sex- and injury-dependent changes in LXR ligands likely determine sex specificity and degree of anti-nociceptive LXR/RXR action.…”

“…As a result of our prior extensive biochemical, cell biological and functional analyses ( Chernov et al, 2018 ; Hong et al, 2017 ; Ko et al, 2016 ; Kobayashi et al, 2008 ; Lee et al, 2022 ; Liu et al, 2012 ; Remacle et al, 2018 ), we identified the bioactive 84–104 region of MBP proteolytically released between days 3 and 27 post-CCI ( Fig. 1 A).…”

“…Because endogenous MBP 84-104 release is observed in the injured only nerve ( Chernov et al, 2018 ; Hong et al, 2017 ; Kobayashi et al, 2008 ; Lee et al, 2022 ; Liu et al, 2012 ; Remacle et al, 2018 ), we were especially interested in Ncoa1 and its co-localization with the degraded MBP (dMBP) in nerve at day 3 post-CCI. Ncoa1 and dMBP co-distributed within the same myelinated Schwann cell-axon units ( Fig.…”

“…Loss of myelin integrity results in aberrant insertion of ion channels and ectopic excitability of A-afferents ( Devor, 2009 ; Wu et al, 2002 ; Zhu et al, 2012 ). In addition, traumatic PNS injury such as sciatic nerve chronic constriction injury (CCI) causes proteolytic release of bioactive pronociceptive MBP fragments such as MBP 84-104 ( Chernov et al, 2018 ; Hong et al, 2017 ; Ko et al, 2016 ; Kobayashi et al, 2008 ; Lee et al, 2022 ; Liu et al, 2012 ; Remacle et al, 2018 ), as illustrated ( Fig. 1 A).…”

“…1 MBP 84-104 suppresses LXRα/RXRα axis in sciatic nerve. A , The degraded (d)MBP fragment comprising the MBP 84-104 epitope is released in nerve between days 3 and 27 post-CCI ( Lee et al, 2022 ; Liu et al, 2012 ) (a schematic). B, Sequence alignment of the MBP central domain showing strong sequence conservation with 100% identity between human and rodent MBP 84-104 regions.…”