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Updated: Mar 13, 2026
Chronic Post-Ischemia Pain Model for Complex Regional Pain Syndrome Type-I in Rats
Published on: January 21, 2020
Identification of KRT16 as a target of an autoantibody response in complex regional pain syndrome
Maral Tajerian1, Victor Hung2, Hamda Khan2
1Veterans Affairs Palo Alto Health Care System Palo Alto, CA, USA; Department of Anesthesiology, Stanford University School of Medicine, Stanford, CA, USA; Palo Alto Veterans Institute for Research, Palo Alto, CA, USA.
Objective:
Using a mouse model of complex regional pain syndrome (CRPS), our goal was to identify autoantigens in the skin of the affected limb.
Methods:
A CRPS-like state was induced using the tibia fracture/cast immobilization model. Three weeks after fracture, hindpaw skin was homogenized, run on 2-d gels, and probed by sera from fracture and control mice. Spots of interest were analyzed by liquid chromatography-mass spectroscopy (LC-MS) and the list of targets validated by examining their abundance and subcellular localization. In order to measure the autoantigenicity of selected protein targets, we quantified the binding of IgM in control and fracture mice sera, as well as in control and CRPS human sera, to the recombinant protein.
Results:
We show unique binding between fracture skin extracts and fracture sera, suggesting the presence of auto-antigens. LC-MS analysis provided us a list of potential targets, some of which were upregulated after fracture (KRT16, eEF1a1, and PRPH), while others showed subcellular-redistribution and increased membrane localization (ANXA2 and ENO3). No changes in protein citrullination or carbamylation were observed. In addition to increased abundance, KRT16 demonstrated autoantigenicity, since sera from both fracture mice and CRPS patients showed increased autoantibody binding to recombinant kRT16 protein.
Conclusions:
Pursuing autoimmune contributions to CRPS provides a novel approach to understanding the condition and may allow the development of mechanism-based therapies. The identification of autoantibodies against KRT16 as a biomarker in mice and in humans is a critical step towards these goals, and towards redefining CRPS as having an autoimmune etiology.
Insights
Researchers identified autoantigens in complex regional pain syndrome (CRPS) skin, finding keratin 16 (KRT16) is a potential biomarker. Autoantibodies against KRT16 were detected in both CRPS mouse models and human patients, suggesting an autoimmune link.
Area of Science:
- Immunology
- Neuroscience
- Dermatology
Background:
- Complex Regional Pain Syndrome (CRPS) is a debilitating condition with unclear etiology.
- Autoimmune processes are increasingly suspected as a contributing factor in CRPS pathogenesis.
- Identifying specific autoantigens is crucial for understanding disease mechanisms and developing targeted therapies.
Purpose of the Study:
- To identify autoantigens present in the skin of the affected limb in a mouse model of CRPS.
- To validate the autoantigenicity of identified targets using sera from both animal models and human patients.
Main Methods:
- A tibia fracture and cast immobilization model was used to induce a CRPS-like state in mice.
- Skin extracts were analyzed using 2-D gel electrophoresis and liquid chromatography-mass spectroscopy (LC-MS).
- Autoantibody binding to recombinant proteins was quantified using sera from control and CRPS-affected mice and humans.
Main Results:
- Unique binding patterns between fracture skin extracts and sera from fractured mice indicated the presence of autoantigens.
- Keratin 16 (KRT16) was identified as a significantly upregulated protein with demonstrated autoantigenicity.
- Increased autoantibody binding to KRT16 was observed in sera from both CRPS mouse models and human CRPS patients.
Conclusions:
- The findings suggest an autoimmune contribution to CRPS, with KRT16 as a potential autoantigen.
- Identification of KRT16 autoantibodies serves as a critical biomarker in both mouse models and human CRPS.
- This research opens avenues for developing mechanism-based therapies and potentially redefining CRPS as an autoimmune condition.
