Activation of cutaneous immune responses in complex regional pain syndrome.
The pathogenesis of complex regional pain syndrome (CRPS) is unresolved, but tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are elevated in experimental skin blister fluid from CRPS-affected limbs, as is tryptase, a marker for mast cells. In the rat fracture model of CRPS, exaggerated sensory and sympathetic neural signaling stimulate keratinocyte and mast cell proliferation, causing the local production of high levels of inflammatory cytokines leading to pain behavior. The current investigation used CRPS patient skin biopsies to determine whether keratinocyte and mast cell proliferation occur in CRPS skin and to identify the cellular source of the up-regulated TNF-α, IL-6, and tryptase observed in CRPS experimental skin blister fluid. Skin biopsies were collected from the affected skin and the contralateral mirror site in 55 CRPS patients and the biopsy sections were immunostained for keratinocyte, cell proliferation, mast cell markers, TNF-α, and IL-6. In early CRPS, keratinocytes were activated in the affected skin, resulting in proliferation, epidermal thickening, and up-regulated TNF-α and IL-6 expression. In chronic CRPS, there was reduced keratinocyte proliferation, leading to epidermal thinning in the affected skin. Acute CRPS patients also had increased mast cell accumulation in the affected skin, but there was no increase in mast cell numbers in chronic CRPS.


CONCLUSIONS
The results of this study support the hypotheses that CRPS involves activation of the innate immune system, with keratinocyte and mast cell activation and proliferation, inflammatory mediator release, and pain.
Department of Neurology, University Medical Center, Mainz, Germany.
Frank
F
Birklein
School of Psychology and Exercise Science, Murdoch University, Perth, Australia.
Peter D
PD
Drummond
Stanford University Department of Anesthesia, Palo Alto, California; Anesthesiology Service, VA Palo Alto Health Care System, Palo Alto, California; Physical Medicine and Rehabilitation Service, VA Palo Alto Health Care System, Palo Alto, California.
Wenwu
W
Li
Department of Neurology, University Medical Center, Mainz, Germany.
Tanja
T
Schlereth
Department of Neurology, University Medical Center, Mainz, Germany.
Nahid
N
Albrecht
School of Psychology and Exercise Science, Murdoch University, Perth, Australia.
Philip M
PM
Finch
School of Psychology and Exercise Science, Murdoch University, Perth, Australia.
Linda F
LF
Dawson
Stanford University Department of Anesthesia, Palo Alto, California; Anesthesiology Service, VA Palo Alto Health Care System, Palo Alto, California.
J David
JD
Clark
Physical Medicine and Rehabilitation Service, VA Palo Alto Health Care System, Palo Alto, California. Electronic address: wkingery@stanford.edu.
Wade S
WS
Kingery
D000328:Adult; D000368:Aged; D001706:Biopsy; D049109:Cell Proliferation; D020918:Complex Regional Pain Syndromes / Q000473:pathology / Q000503:physiopathology*; D004817:Epidermis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D015603:Keratinocytes / Q000502:physiology; D008297:Male; D008407:Mast Cells / Q000473:pathology / Q000502:physiology; D008875:Middle Aged; D009929:Organ Size; D012867:Skin / Q000276:immunology* / Q000473:pathology; D012879:Skin Physiological Phenomena; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
C508600:IL6 protein, human; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha
Complex regional pain syndrome; immunology; keratinocytes; mast cells; pain