Background & Aims

Previously we demonstrated that B cells and autoantibodies mediate chronic nociceptive sensitization in the mouse tibia fracture model of complex regional pain syndrome (CRPS) and in the mouse disc puncture (DP) model of chronic low back pain (1,2). Furthermore, we observed that CRPS patient antibodies were pronociceptive in muMT fracture mice lacking mature B cells and antibodies (3). These data support the hypothesis that tissue trauma generates pronociceptive autoantibodies capable of inducing chronic musculoskeletal pain states. The current study further tested this hypothesis in the monosodium iodoacetate (MIA) mouse model of osteoarthritis (OA).

Methods

MIA was injected into the knees of wildtype (WT) and muMT mice to evaluate pronociceptive adaptive immune responses in this widely utilized OA mouse model (4). Mice underwent bilateral hindlimb nociceptive behavioral testing from 1-24 weeks after MIA treatment. At 1 and 3 weeks after MIA treatment serum was collected for antibody transfer experiments and knee tissues were collected for western analyses. Serum antibodies were also collected from OA patients for pronociceptive testing in the muMT MIA mice.

Results

MIA treated WT mice developed up to 12 weeks of ipsilateral hindlimb mechanical allodynia, hyperalgesia, and unweighting, but these behavioral pain responses were absent in MIA treated muMT mice, indicating that pain responses to cartilage injury are B cell dependent. IgM collected from WT MIA mice and intraarticularly injected into the OA knees of muMT MIA mice caused nociceptive sensitization, and IgM immune complexes were observed in knee tissues of WT MIA mice. IgM collected from OA patients on a waiting list for knee replacement surgery was always pronociceptive after intraarticular injection in muMT MIA mice, but IgM collected from age and sex matched controls was never pronociceptive.

Conclusions

These data suggest that MIA treated muMT mice express neoantigens that are targeted by pronociceptive autoantibodies generated after cartilage injury in WT mice and in OA patients, and further support the pronociceptive autoimmunity hypothesis for the transition from tissue injury to chronic musculoskeletal pain state.

References

1. Guo, T.-Z., Shi, X., Li, W.-W., Wei, T., Clark, J.D., Kingery, W.S., Passive transfer autoimmunity in a mouse model of complex regional pain syndrome. Pain, 2017, 158:2410-2421. PMID 28891866

2. Guo, T.-Z., Shi, X., Li, W.-W., Wei, T., Peyman S., Clark, J.D., and Kingery, W.S., Pronociceptive autoantibodies in the spinal cord mediate nociceptive sensitization, loss of function, and spontaneous pain in the lumbar disk puncture model of chronic back pain, Pain, 2023, 164: 421-434. PMID: 35976729

3. Guo, T.-Z., Wei, T., Tajerian, M., Clark, J.D., Birklein, F., Goebel, A., Li, W.-W., Sahbaie, P., Escolano, F.L., Herrnberger, M., Kramer, H.H., Kingery, W.S., Complex regional pain syndrome patient IgM has pronociceptive effects in the skin and spinal cord of tibia fracture mice, Pain, 2020, 161: 797-809. PMID 31815913

4. Pitcher, T., Sousa-Valente, J., Malcangio, M., The Monoiodoacetate model of osteoarthritis pain in the mouse, J. Vis. Exp., 2016, 111: e53746

Presenting Author

Wade Kingery

Poster Authors

Wade Kingery

MD

Palo Alto Veterans Institute for Research

Lead Author

E-mail

David Clark

Veterans Affairs, Palo Alto Health Care System

Lead Author

E-mail

Tian-Zhi Guo MD

Palo Alto Veterans Institute for Research

Lead Author

E-mail

Xiaoyou Shi MD

Stanford University School of Medicine

Lead Author

E-mail

Tzuping Wei PhD

Palo Alto Veterans Institute for Research

Lead Author

E-mail

Wen-wu Li PhD

Stanford University School of Medicine

Lead Author

E-mail

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Pain in Chronic/Inflammatory Diseases