Amino acid sequence conservation of the algesic fragment of myelin basic protein is required for its interaction with CDK5 and function in pain

Abstract

The novel RNA-seq datasets were deposited in the GEO database under the accession number GSE107020.

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

“…The serum autoantibodies against MBP(84-104) are detected exclusively in females, starting at 1 week post-CCI, at the time when B cells in ltrate the nerve. While the IgM accumulation post-CCI and intraneural MBP(84-104)-induced pain [43] are both female-speci c, no IgM/IgG is detected two weeks after intraneural MBP(84-104) (data not shown), suggesting that nociceptive MBP actions [14,28,30,31,43] are largely autoantibody-independent. Autoantibodies are thought to contribute to persistent pain states via IgG/Fc receptor (FcR) and the complement system activation on the primary afferents [5-7, 9, 56-59].…”

“…We have previously established that the autoantigenic MBP epitopes that are concealed from immunosurveillance in healthy nerve are released post-injury by metalloproteases, including MMP-9 [14, 28-31, 42, 51-53]. Several peptides comprising the 87-VVHFF-91 motif of MBP, essential to T cell recognition [54], including MBP(84-104) and MBP(69-86), but not the Nterminal MBP(2-18) peptide (all human sequence and analyzed relative to a scrambled peptide), induce robust mechanical hypersensitivity in female rats [14,28,30,31]. In addition, injection of the rat-speci c MBP(69-86) peptide, matching the endogenously released MBP peptide detected in rat nerve by the AB5864 (EDM-Millipore) antibody, produces mechanical hypersensitivity in rats [28] in support of its autoantigenic action.…”

“…The AB5864 EDM-Millipore antibody generated against guinea pig MBP(69-86) peptide is used to differentiate demyelinating from intact neural tissues [47]. In peripheral (sciatic and spinal) nerves of female rats the degraded (d) MBP(69-86) reactivity is present at days 1-27 post-injury [14,[28][29][30]. Whether the MBP epitope is released in male nerves has not been tested.…”

“…Proteolytic release of cryptic immunodominant MBP epitopes contributes to autoimmune demyelinating pathologies, including multiple sclerosis and Guillain-Barre syndrome [22,23]. We have demonstrated that mechanical hypersensitivity associated with demyelination after a focal PNS trauma [24][25][26][27] is due in part to the targeted activity of the cryptic immunodominant MBP epitopes [14,[28][29][30]. We have shown that the peptides comprising the conserved α-helix 87-VVHFF-91 of MBP motif, including MBP(68-86) and MBP(84-104) peptides, administered by a bolus adjuvant-free intraneural (IN) injection into an intact sciatic nerve, trigger a sustained (weeks), T cell-dependent mechanical hypersensitivity in female rats [14,28,30,31].…”

“…We have demonstrated that mechanical hypersensitivity associated with demyelination after a focal PNS trauma [24][25][26][27] is due in part to the targeted activity of the cryptic immunodominant MBP epitopes [14,[28][29][30]. We have shown that the peptides comprising the conserved α-helix 87-VVHFF-91 of MBP motif, including MBP(68-86) and MBP(84-104) peptides, administered by a bolus adjuvant-free intraneural (IN) injection into an intact sciatic nerve, trigger a sustained (weeks), T cell-dependent mechanical hypersensitivity in female rats [14,28,30,31]. Blocking MBP epitope release using metalloproteinase inhibitors [14,28,29] or MBP epitope activity by active immunization with the altered/mutant MBP ligand [32] attenuates mechanical allodynia associated with sciatic nerve chronic constriction injury (CCI).…”