Immunodominant fragments of myelin basic protein initiate T cell-dependent pain.
BACKGROUND
The myelin sheath provides electrical insulation of mechanosensory Aβ-afferent fibers. Myelin-degrading matrix metalloproteinases (MMPs) damage the myelin sheath. The resulting electrical instability of Aβ-fibers is believed to activate the nociceptive circuitry in Aβ-fibers and initiate pain from innocuous tactile stimulation (mechanical allodynia). The precise molecular mechanisms, responsible for the development of this neuropathic pain state after nerve injury (for example, chronic constriction injury, CCI), are not well understood.


RESULTS
Using mass spectrometry of the whole sciatic nerve proteome followed by bioinformatics analyses, we determined that the pathways, which are classified as the Infectious Disease and T-helper cell signaling, are readily activated in the nerves post-CCI. Inhibition of MMP-9/MMP-2 suppressed CCI-induced mechanical allodynia and concomitant TNF-α and IL-17A expression in nerves. MMP-9 proteolysis of myelin basic protein (MBP) generated the MBP84-104 and MBP68-86 digest peptides, which are prominent immunogenic epitopes. In agreement, the endogenous MBP69-86 epitope co-localized with MHCII and MMP-9 in Schwann cells and along the nodes of Ranvier. Administration of either the MBP84-104 or MBP68-86 peptides into the naïve nerve rapidly produced robust mechanical allodynia with a concomitant increase in T cells and MHCII-reactive cell populations at the injection site. As shown by the genome-wide expression profiling, a single intraneural MBP84-104 injection stimulated the inflammatory, immune cell trafficking, and antigen presentation pathways in the injected naïve nerves and the associated spinal cords. Both MBP84-104-induced mechanical allodynia and characteristic pathway activation were remarkably less prominent in the T cell-deficient athymic nude rats.


CONCLUSIONS
These data implicate MBP as a novel mediator of pain. Furthermore, the action of MMPs expressed within 1 day post-injury is critical to the generation of tactile allodynia, neuroinflammation, and the immunodominant MBP digest peptides in nerve. These MBP peptides initiate mechanical allodynia in both a T cell-dependent and -independent manner. In the course of Wallerian degeneration, the repeated exposure of the cryptic MBP epitopes, which are normally sheltered from immunosurveillance, may induce the MBP-specific T cell clones and a self-sustaining immune reaction, which may together contribute to the transition of acute pain into a chronic neuropathic pain state.
Department of Anesthesiology, University of California, San Diego, 9500 Gilman Dr., Mail Box 0629, La Jolla, CA 92093-0629, USA.
Huaqing
H
Liu
Sergey A
SA
Shiryaev
Andrei V
AV
Chernov
Youngsoon
Y
Kim
Igor
I
Shubayev
Albert G
AG
Remacle
Svetlana
S
Baranovskaya
Vladislav S
VS
Golubkov
Alex Y
AY
Strongin
Veronica I
VI
Shubayev
D000595:Amino Acid Sequence; D000818:Animals; D018984:Epitopes, T-Lymphocyte / Q000009:adverse effects* / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D016056:Immunodominant Epitopes / Q000009:adverse effects* / Q000502:physiology; D008969:Molecular Sequence Data; D015166:Monitoring, Immunologic / Q000009:adverse effects; D004676:Myelin Basic Protein / Q000502:physiology*; D010146:Pain / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D011923:Rats, Nude; D017207:Rats, Sprague-Dawley; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology
D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; C436006:Mbp protein, rat; D004676:Myelin Basic Protein