Structural homology of myelin basic protein and muscarinic acetylcholine receptor: Significance in the pathogenesis of complex regional pain syndrome

Journal of Biological Chemistry

Eddinger

et al. 2020

In the peripheral nerve, mechanosensitive axons are insulated by myelin, a multilamellar membrane formed by Schwann cells. Here, we offer first evidence that a myelin degradation product induces mechanical hypersensitivity and global transcriptomics changes in a sex-specific manner. Focusing on downstream signaling events of the functionally active 84-104 myelin basic protein (MBP84-104) fragment released after nerve injury, we demonstrate that exposing the sciatic nerve to MBP84-104 via endoneurial injection produces robust mechanical hypersensitivity in female, but not in male, mice. RNA-Seq and systems biology analyses revealed a striking sexual dimorphism in molecular signatures of the dorsal root ganglia (DRG) and spinal cord response, not observed at the nerve injection site. Mechanistically, intra-sciatic MBP84-104 induced phospholipase C (PLC)-driven (females) and phosphoinositide 3-kinase-driven (males) phospholipid metabolism (tier 1). PLC/inositol trisphosphate receptor (IP3R) and estrogen receptor co-regulation in spinal cord yielded Ca2+-dependent nociceptive signaling induction in females that was suppressed in males (tier 2). IP3R inactivation by intrathecal xestospongin C attenuated the female-specific hypersensitivity induced by MBP84-104. According to sustained sensitization in tiers 1–2, T cell–related signaling spreads to the DRG and spinal cord in females, but remains localized to the sciatic nerve in males (tier 3). These results are consistent with our previous finding that MBP84-104–induced pain is T cell–dependent. In summary, an autoantigenic peptide endogenously released in nerve injury triggers multi-site, sex-specific transcriptome changes, leading to neuropathic pain only in female mice. MBP84-104 acts through sustained co-activation of metabolic, estrogen receptor–mediated nociceptive and autoimmune signaling programs.

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

A myelin basic protein fragment induces sexually dimorphic transcriptome signatures of neuropathic pain in mice

Chernov

Journal of Biological Chemistry

Eddinger

et al. 2020

“…Beucase MBP84-104 epitope is evolutionarily conserved among mammalian species [30], our ELISA detects anti-MBP(84-104) autoantibodies in female rats post-CCI and in female patients with multiple sclerosis [42]. Based on high structural homology of MBP84-104 with muscarinic M2 acetylcholine receptor, these ndings may re ect CRPS and other painful conditions [52]. An anti-MBP IgG, albeit not MBP(84-104)-speci c, may bene t nerve repair [60], but whether the autoantibodies have a functional role in pain remains to be determined in long-term models of pain.…”

Section: Discussionmentioning

confidence: 81%

B cell Activity and anti-MBP Autoantibody Response to Peripheral Nerve Injury is Sexually Dimorphic

Lee

Remacle

et al. 2020

Preprint

Background: Autoantibodies, a hallmark of autoimmune disorders, are thought to contribute to the pathogenesis of chronic pain. Mechanical hypersensitivity is a severe complication of peripheral nerve injury mediated through sex-specific activity of immune and glial cells. Whether B cell contribution to nerve injury and pain is sexually dimorphic remains unknown. Methods: CD20 immunoblotting and immunostaining was conducted in female and male sciatic nerve after chronic constriction injury (CCI). B cell/CD20 targeting by bolus intravenous (IV) Rituximab or control immunoglobulin (IVIG) therapy or vehicle was administered in female and male rats post-CCI, followed by von Frey mechanical sensitivity testing. The cryptic myelin basic protein (MBP) epitopes were identified by immunostaining (EMD-AB5864 Millipore antibody) in female and male CCI nerves. ELISA was used to detect serum autoantibodies against the immunodominant MBP(84-104) epitope was conducted in female and male rats post-CCI. Results: Infiltration of CD20-positive cells, presumably B cell, was observed in female and male nerve at one week post-CCI. A single bolus IV anti-CD20/Rituximab therapy at one week post-CCI reduced the degree of mechanical hypersensitivity in female, but not in male, rats. IVIG therapy and vehicle treatment had no effect in either sex. Sustained release of the cryptic MBP epitopes from myelin was observed in nerves post-CCI in both sexes. Remarkably, serum anti-MBP(84-104) autoantibody was detected in female, but not in male, rats post-CCI. Conclusions: B cell activity and autoantibody production after peripheral nerve injury are sexually dimorphic. In females, mechanical hypersensitivity arising due to autoimmune remodeling of myelin on sensory neuraxis is amenable to immunotherapeutic intervention.

“…IgM deficiency mitigates mechanical allodynia associated with a murine tibial fracture and cast immobilization model of CRPS, as IgM replacement from wild-type fracture mice resumed the pain-like behavior ( Li et al, 2014 , 2018 ). Based on the sequence homology between MBP(84–104) and M2 acetylcholine receptor, anti-MBP autoantibodies may contribute to CRPS ( Shubayev et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

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

Lee

Remacle

et al. 2022

Front. Cell. Neurosci.

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.