# Neural Immunoregulation of Post-Traumatic Autoimmunity

> **NIH NIH R01** · PALO ALTO VETERANS INSTIT FOR RESEARCH · 2020 · $335,881

## Abstract

PROJECT SUMMARY
 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.

## Key facts

- **NIH application ID:** 10001006
- **Project number:** 5R01NS094438-05
- **Recipient organization:** PALO ALTO VETERANS INSTIT FOR RESEARCH
- **Principal Investigator:** DAVID J. CLARK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $335,881
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001006

## Citation

> US National Institutes of Health, RePORTER application 10001006, Neural Immunoregulation of Post-Traumatic Autoimmunity (5R01NS094438-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001006. Licensed CC0.

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