Expansion and activation of distinct central memory T lymphocyte subsets in complex regional pain syndrome

Abstract

BackgroundComplex regional pain syndrome (CRPS) is a debilitating condition where trauma to a limb results in devastating persistent pain that is disproportionate to the initial injury. The pathophysiology of CRPS remains unknown; however, accumulating evidence suggests it is an immunoneurological disorder, especially in light of evidence of auto-antibodies in ~ 30% of patients. Despite this, a systematic assessment of all circulating leukocyte populations in CRPS has never been performed.MethodsWe characterised 14 participants as meeting the Budapest clinical criteria for CRPS and assessed their pain ratings and psychological state using a series of questionnaires. Next, we performed immunophenotyping on blood samples from the 14 CRPS participants as well as 14 healthy pain-free controls using mass cytometry. Using a panel of 38 phenotypic and activation markers, we characterised the numbers and intracellular activation status of all major leukocyte populations using manual gating strategies and unsupervised cluster analysis.ResultsWe have shown expansion and activation of several distinct populations of central memory T lymphocytes in CRPS. The number of central memory CD8+ T cells was increased 2.15-fold; furthermore, this cell group had increased phosphorylation of NFkB and STAT1 compared to controls. Regarding central memory CD4+ T lymphocytes, the number of Th1 and Treg cells was increased 4.98-fold and 2.18-fold respectively, with increased phosphorylation of NFkB in both populations. We also found decreased numbers of CD1c+ myeloid dendritic cells, although with increased p38 phosphorylation. These changes could indicate dendritic cell tissue trafficking, as well as their involvement in lymphocyte activation.ConclusionsThese findings represent the first mass cytometry immunophenotyping study in any chronic pain state and provide preliminary evidence of an antigen-mediated T lymphocyte response in CRPS. In particular, the presence of increased numbers of long-lived central memory CD4+ and CD8+ T lymphocytes with increased activation of pro-inflammatory signalling pathways may indicate ongoing inflammation and cellular damage in CRPS.

Pediatric Burn Survivors Have Long-Term Immune Dysfunction With Diminished Vaccine Response

“…CXCR3 expression on Bcells and a subset of double-negative T-cells was lower in patients than controls. The increase in central memory CD4+ T-cells and memory Tregs is consistent with the findings in a recent report that used mass cytometry to investigate blood immune subsets in complex regional pain syndrome, another condition in which inflammation persists long after the original injury (40).…”

“…The relatively small sample size is also a key limitation of this study and further patient recruitment will be important to validate findings from this cohort. Nevertheless, this study is comparable to those of others that have also identified changes in PBMC profiles associated with sustained pathology (40) and provides new insight into the possible consequences of acute burn injury and an important basis for further research. Most importantly, whilst these experiments provide observations of changes in these cell populations, functional assays will be critical to understand the potential clinical consequences of the observed disparity between groups.…”

MHCII-restricted T helper cells: an emerging trigger for chronic tactile allodynia after nerve injuries

“…Second, both central and effector memory CD4 + T cells were shown to be significantly increased in chronic neuropathic pain patients with carpal tunnel syndrome (CTS) and complex regional pain syndrome (CRPS), as compared to healthy controls. The upregulation of memory CD4 + T cells (presumably Th cells) would be an indicator of the history of Th cell activation against a particular antigenic stimulus in CTS patients [73,74]. To our surprise, however, significant decrease of inflammatory Th1 or Th17 cells and increase of antiinflammatory Th2 or Treg cells were found in patients with chronic neuropathic pain as compared to healthy controls [75][76][77].…”

Cytotoxic Immunity in Peripheral Nerve Injury and Pain

“…The percentage of CD56 bright CD16 + cells were slightly increased in patients with broadly defined severe chronic pain, however, generalized NK cell cytotoxic activity and the frequency of the major NK cell subsets were not significantly different (Yoon et al, 2018). In a study of 14 patients with complex regional pain syndrome (CRPS) and 14 controls, Russo and colleagues used mass cytometry to identify an expansion of both CD4 + and CD8 + memory T lymphocytes in patients compared to controls (Russo et al, 2019). NK cells (defined as CD56 + CD19 − CD3 − ) were more than 50% elevated in CRPS patient blood but this did not reach significance.…”