Limb trauma can lead to the development of complex regional pain syndrome (CRPS), a potentially debilitating chronic state. Currently there is no consensus on either the pathogenesis or treatment for CRPS, and translational and CRPS tissue studies are clearly needed to identify therapeutic targets and effective treatments. Recent observations suggest that some CRPS patients express autoantibodies and respond profoundly to intravenous immunoglobulin treatment. Additional reports suggest that: 1) Langerhans antigen presenting cells proliferate in CRPS affected limbs, 2) that antinuclear autoantibodies are present in some CRPS patients, and 3) that genetic associations with specific HLA loci can be identified in some CRPS patients. Our own studies indicate that CRPS-like changes in the fracture mouse model are reliant upon antibody production, and that passive transfer autoimmunity occurs after transfusing serum from either fracture mice or CRPS patients into antibody deficient fracture mice. Moreover, after fracture in mice, exaggerated substance P signaling stimulates antibody accumulating in the skin, nerves, and spinal cord innervating the injured hindlimb and triggers Langerhans cell proliferation in the hindpaw skin. Furthermore, IgM serum antibodies obtained from fracture mice bind to dermal cell nuclear antigens in fracture limb skin, but not in contralateral intact hindlimb skin. These observations are potentially paradigm shifting. The central hypothesis guiding our work is that limb trauma causes the neural activation of the innate and adaptive systems of immunity, with the regional expression of neo-antigens ultimately supporting nociceptive sensitization. The primary objective of this proposal is to identify specific pharmacologic targets for the successful treatment of CRPS.
The specific aims are: 1) to map post-fracture changes in dendritic cell antigen recruitment, maturation, trafficking and adaptive immune responses in skin, lymph nodes, sciatic nerve, and spinal cord, 2) to determine whether passive-transfer autoimmunity occurs when immunoglobulin obtained from the fracture mice or from CRPS patients is injected into other mice, potentially rekindling CRPS-like sequelae in post-fracture mice with resolving CRPS symptoms, and in addition, to use mouse and CRPS patient antibodies to identify regionally restricted autoantigens fracture mouse skin, nerve, cord, and fracture callus, and in CRPS patient skin, and 3) to determine whether sensory neuropeptide or sympathetic adrenergic signaling is required for the development of post-traumatic autoimmune responses. These experiments will establish a rigorous foundation for exploring the mechanisms of post-traumatic autoimmunity, greatly improve our understanding of CRPS, identify specific molecular targets for future CRPS trials, and potentially suggest novel mechanisms supporting other enigmatic chronic pain syndromes.

Public Health Relevance

The studies described in this application use a translational mouse model of complex regional pain syndrome (CRPS) and patient serum and skin biopsies to advance our understanding of the regional changes in adaptive immunity observed in post-traumatic CRPS. It is anticipated that these investigations will provide foundational support for future CRPS clinical trials utilizing IVIG, rituximab B cell antibodies, and other FDA approved treatments for autoimmune diseases. The identification of novel target specific pharmacologic treatments for CRPS could reduce pain and enhance the quality of life in these patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS094438-03
Application #
9549139
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Oshinsky, Michael L
Project Start
2016-09-01
Project End
2021-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Palo Alto Veterans Institute for Research
Department
Type
DUNS #
624218814
City
Palo Alto
State
CA
Country
United States
Zip Code
94304
Shi, Xiaoyou; Guo, Tian-Zhi; Li, Wenwu et al. (2018) Exercise Reverses Nociceptive Sensitization, Upregulated Neuropeptide Signaling, Inflammatory Changes, Anxiety, and Memory Impairment in a Mouse Tibia Fracture Model. Anesthesiology 129:557-575
Guo, Tian-Zhi; Wei, Tzuping; Huang, Ting-Ting et al. (2018) Oxidative Stress Contributes to Fracture/Cast-Induced Inflammation and Pain in a Rat Model of Complex Regional Pain Syndrome. J Pain 19:1147-1156
Li, Wen-Wu; Guo, Tian-Zhi; Shi, Xiaoyou et al. (2018) Neuropeptide regulation of adaptive immunity in the tibia fracture model of complex regional pain syndrome. J Neuroinflammation 15:105
Birklein, Frank; Ibrahim, Alaa; Schlereth, Tanja et al. (2018) The Rodent Tibia Fracture Model: A Critical Review and Comparison With the Complex Regional Pain Syndrome Literature. J Pain 19:1102.e1-1102.e19
Li, Wen-Wu; Irvine, Karen-Amanda; Sahbaie, Peyman et al. (2018) Morphine Exacerbates Postfracture Nociceptive Sensitization, Functional Impairment, and Microglial Activation in Mice. Anesthesiology :
Guo, Tian-Zhi; Shi, Xiaoyou; Li, Wen-Wu et al. (2017) Passive transfer autoimmunity in a mouse model of complex regional pain syndrome. Pain 158:2410-2421