Neuropeptide regulation of adaptive immunity in the tibia fracture model of complex regional pain syndrome

Abstract

BackgroundBoth dysfunctional neuropeptide signaling and immune system activation are characteristic of complex regional pain syndrome (CRPS). Unknown is whether substance P (SP) or calcitonin gene-related peptide (CGRP) support autoantibody production and, consequently, nociceptive sensitization.MethodsThese experiments involved the use of a well-characterized tibia fracture model of CRPS. Mice deficient in SP expression (Tac1−/−) and CGRP signaling (RAMP1−/−) were used to probe the neuropeptide dependence of post-fracture sensitization and antibody production. The deposition of IgM in the spinal cord, sciatic nerves, and skin was followed using Western blotting, as was expression of the CRPS-related autoantigen cytokeratin 16 (Krt16). Passive serum transfer to B-cell-deficient muMT mice was used to assess the production of functional autoantibodies in CRPS model mice. The use of immunohistochemistry allowed us to assess neuropeptide-containing fiber distribution and Langerhans cell abundance in mouse and human CRPS patient skin, while Langerhans cell-deficient mice were used to assess the functional contributions of these cells.ResultsFunctional SP and CGRP signaling were required both for the full development of nociceptive sensitization after fracture and the deposition of IgM in skin and neural tissues. Furthermore, the passive transfer of serum from wildtype but not neuropeptide-deficient mice to fractured muMT mice caused enhanced allodynia and postural unweighting. Langerhans cells were increased in number in the skin of fracture mice and CRPS patients, and those increases in mice were reduced in neuropeptide signaling-deficient animals. Unexpectedly, Langerhans cell-deficient mice showed normal nociceptive sensitization after fracture. However, the increased expression of Krt16 after tibia fracture was not seen in neuropeptide-deficient mice.ConclusionsCollectively, these data support the hypothesis that neuropeptide signaling in the fracture limb of mice is required for autoantigenic IgM production and nociceptive sensitization. The mechanism may be related to neuropeptide-supported autoantigen expression.

Dermal nerve fibre and mast cell density, and proximity of mast cells to nerve fibres in the skin of patients with complex regional pain syndrome

“…This might form part of a broader disruption of neuro-immune interactions, as Langerhans cells (whose antigen-presenting properties are stimulated by neuropeptides) are more numerous in affected than unaffected skin in the CRPS tibia fracture model and in acute CRPS [30]; however, this reverses in patients with longstanding CRPS [40].…”

Structural homology of myelin basic protein and muscarinic acetylcholine receptor: Significance in the pathogenesis of complex regional pain syndrome

“…While CRPS has been long thought to arise as a result of an inflammatory process, more current work has it to be deemed an autoimmune condition. 1 – 3 , 5 – 12 Several observations lend strong support to this assertion. (i) The passive transfer of serum immunoglobulin G (IgG) antibodies from a CRPS patient, but not a normal patient, elicits CRPS-like pathology in mice.…”

“… 17 – 19 The MBP68-100 peptides are released in the nerve preceding morphological signs of demyelination, at day 1 after sciatic nerve chronic constriction injury (CCI), 16 suggesting release through a localized and precise proteolytic event. The IgM autoantibodies contribute to pain in a mouse model of CRPS 9 , 10 and serum IgM autoantibodies against the algesic MBP epitopes persist in CCI allodynia. 20 These data led us to suggest that MBP68-100 mediates tactile allodynia in the absence of overt neuropathological findings and contributes to autoimmune pathogenesis of neuropathic pain phenotypes mediated by myelinated A-afferent fibers.…”

“… 1 – 3 , 7 (iii) In a murine tibial fracture and cast immobilization model of CRPS, B-cell depletion in mice treated with CD20-neutralizing antibody or genetically lacking the ability to produce IgM (µMT mice) attenuated pain, which resumed after injection of serum IgM autoantibodies from wild-type to µMT-fracture mice. 9 , 10 Against this assertion serves the evidence from the multicenter randomized blinded placebo-controlled trial that 0.5 g/kg intravenous immunoglobulin immunotherapy produced no benefit in CRPS compared with placebo-treated patients. 8 …”

CGRP and Brain Functioning: Cautions for Migraine Treatment

“…Moreover, CGRP, while suppressing cell‐mediated (Th1) immunity, may facilitate the humoral (Th2) response. In particular, CGRP seems to activate the immune system in complex regional pain syndrome, leading to autoimmunity, which may contribute to the disorder . Similarly, via neurogenic inflammation and local immune activation, CGRP may participate in psoriasis and possibly rosacea and atopic dermatitis .…”