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Passive transfer autoimmunity in a mouse model of complex regional pain syndrome

Guo, Tian-Zhia; Shi, Xiaoyoua,b,c; Li, Wen-Wua,b,c; Wei, Tzupinga; Clark, John Davidb,c; Kingery, Wade S.a,*

doi: 10.1097/j.pain.0000000000001046
Research Paper

It has been proposed that complex regional pain syndrome (CRPS) is a posttraumatic autoimmune disease, and we previously observed that B cells are required for the full expression of CRPS-like changes in a mouse tibia fracture CRPS model. The current study used the mouse model to evaluate the progression of postfracture CRPS-like changes in wild-type (WT) and muMT fracture mice lacking B cells and antibodies. The pronociceptive effects of injecting WT fracture mouse serum antibodies into muMT fracture mice were also evaluated. Postfracture pain behaviors transitioned from being initially dependent on both innate and autoimmune inflammatory mechanisms at 3 weeks after fracture to being entirely mediated by antibody responses at 12 weeks after fracture and spontaneously resolving by 21 weeks after fracture. Furthermore, serum IgM antibodies from WT fracture mice had pronociceptive effects in the fracture limb when injected into muMT fracture mice. IgM antibody levels gradually increased in the fracture limb hind paw skin, sciatic nerve, and corresponding lumbar cord, peaking at 12 to 18 weeks after fracture and then declining. Immunohistochemistry localized postfracture IgM antibody binding to antigens in the fracture limb hind paw dermal cell nuclei. We postulate that fracture induces expression of neoantigens in the fracture limb skin, sciatic nerve, and cord, which trigger B cells to secret IgM antibodies that bind those antigens and initiate a pronociceptive antibody response. Autoimmunity plays a key role in the progression of nociceptive and vascular changes in the mouse fracture model and potentially contributes to the CRPS disease process.

IgM-mediated autoimmunity supports nocicieptive sensitization in a mouse fracture model of complex regional pain syndrome.

aPhysical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

bAnesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

cDepartment of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA

Corresponding author. Address: Physical Medicine and Rehabilitation Service (117), Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave, Palo Alto, CA 94304, USA. Tel.: 650-207-3733. E-mail address: (W.S. Kingery).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received February 17, 2017

Received in revised form July 21, 2017

Accepted August 21, 2017

© 2017 International Association for the Study of Pain
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