title: Autoimmunity contributes to nociceptive sensitization in a mouse model of complex regional pain syndrome.
abstract: Complex regional pain syndrome (CRPS) is a painful, disabling, chronic condition whose etiology remains poorly understood. The recent suggestion that immunological mechanisms may underlie CRPS provides an entirely novel framework in which to study the condition and consider new approaches to treatment. Using a murine fracture/cast model of CRPS, we studied the effects of B-cell depletion using anti-CD20 antibodies or by performing experiments in genetically B-cell-deficient (μMT) mice. We observed that mice treated with anti-CD20 developed attenuated vascular and nociceptive CRPS-like changes after tibial fracture and 3 weeks of cast immobilization. In mice with established CRPS-like changes, the depletion of CD-20+ cells slowly reversed nociceptive sensitization. Correspondingly, μMT mice, deficient in producing immunoglobulin M (IgM), failed to fully develop CRPS-like changes after fracture and casting. Depletion of CD20+ cells had no detectable effects on nociceptive sensitization in a model of postoperative incisional pain, however. Immunohistochemical experiments showed that CD20+ cells accumulate near the healing fracture but few such cells collect in skin or sciatic nerves. On the other hand, IgM-containing immune complexes were deposited in skin and sciatic nerve after fracture in wild-type, but not in μMT fracture/cast, mice. Additional experiments demonstrated that complement system activation and deposition of membrane attack complexes were partially blocked by anti-CD20+ treatment. Collectively, our results suggest that CD20-positive B cells produce antibodies that ultimately support the CRPS-like changes in the murine fracture/cast model. Therapies directed at reducing B-cell activity may be of use in treating patients with CRPS.
authors.affiliation: Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Wen-Wu
authors.initials: WW
authors.lastname: Li
authors.affiliation: Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
authors.forename: Tian-Zhi
authors.initials: TZ
authors.lastname: Guo
authors.affiliation: Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Xiaoyou
authors.initials: X
authors.lastname: Shi
authors.affiliation: Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Czirr
authors.affiliation: Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Trisha
authors.initials: T
authors.lastname: Stan
authors.affiliation: Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Peyman
authors.initials: P
authors.lastname: Sahbaie
authors.affiliation: Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
authors.affiliation: Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
authors.forename: Wade S
authors.initials: WS
authors.lastname: Kingery
authors.affiliation: Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: djclark@stanford.edu.
authors.forename: J David
authors.initials: JD
authors.lastname: Clark
mesh_terms: D000818:Animals; D018951:Antigens, CD20 / Q000378:metabolism; D015551:Autoimmunity / Q000502:physiology*; D016175:B-Lymphocyte Subsets / Q000473:pathology*; D020918:Complex Regional Pain Syndromes / Q000150:complications* / Q000209:etiology / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D050723:Fractures, Bone; D006614:Hindlimb / Q000503:physiopathology; D006930:Hyperalgesia / Q000503:physiopathology*; D007075:Immunoglobulin M / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D059225:Nociception / Q000502:physiology*; D010147:Pain Measurement; D017288:Pain Threshold; D013997:Time Factors
chemical_list: D018951:Antigens, CD20; D007075:Immunoglobulin M
keywords: Autoimmunity; B cell; Complex regional pain syndrome; Fracture; Pain