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

Abstract 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.