Immune dysregulation in patients with carpal tunnel syndrome

Moalem‐Taylor, Gila; Baharuddin, Benny; Bennett, Barbara; Krishnan, Arun V.; Huynh, William; Kiernan, Matthew C.; Lin, Cindy S.‐Y.; Shulruf, Boaz; Keoshkerian, Elizabeth; Cameron, Barbara; Lloyd, Andrew R.

doi:10.1038/s41598-017-08123-6

Cited by 19 publications

(30 citation statements)

References 78 publications

(83 reference statements)

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“…Increased tumour necrosis factor (TNF), IL-2 and soluble IL-2 receptor (sIL-2R) in the blood of CRPS patients provide supporting evidence of a Th1 response [ 19 , 27 ]. An increase in central memory CD4 + T lymphocytes is also found in carpal tunnel syndrome [ 61 ], whilst in vivo adoptive transfer of Th1 cells in rats lacking mature T lymphocytes potentiated neuropathic pain symptoms [ 62 ]. Our findings, together with previous literature, support a role for central memory Th1 lymphocytes in the exaggerated nociceptive signalling associated with CRPS.…”

Section: Discussionmentioning

confidence: 99%

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

Russo¹,

Fiore

Vreden

et al. 2019

J Neuroinflammation

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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.

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Section: Discussionmentioning

confidence: 99%

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

Russo¹,

Fiore

Vreden

et al. 2019

J Neuroinflammation

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“…For example, there are diseases in the differential diagnosis of CRPS that have been proven to involve T-cell activation and have been shown to have elevated sIL-2R levels, such as rheumatoid arthritis [ 13 , 18 ]. Recently, carpal tunnel syndrome (CTS)—which also needs to be considered in the differential diagnosis of CRPS of the upper limb—was shown to be associated with elevated percentages of central and effector memory CD4 + T-cells which is suggestive of changes in memory T-cell homeostasis in CTS [ 19 ]. Therefore, we consider it likely that serum sIL-2R levels may be elevated in CTS patients as well, although data on this is lacking so far.…”

Section: Discussionmentioning

confidence: 99%

Serum Soluble Interleukin-2 Receptor Does Not Differentiate Complex Regional Pain Syndrome from Other Pain Conditions in a Tertiary Referral Setting

Bharwani

Dirckx

Stronks

et al. 2020

Mediators of Inflammation

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Previously, we showed that serum soluble interleukin-2 receptor (sIL-2R) levels, a marker for T-cell activation, were higher in complex regional pain syndrome (CRPS) patients than in healthy controls, suggesting pathogenic T-cell activation in CRPS. Additionally, sIL-2R levels discriminated well between CRPS and healthy controls with a high sensitivity (90%) and specificity (89.5%), suggesting a possible role for sIL-2R in the diagnosis of CRPS. In order to further validate this marker in the diagnostic workup of CRPS, we conducted this prospective cohort study in which we determined sIL-2R levels in patients that were referred to our tertiary referral center with a suspicion of CRPS in a limb, and subsequently compared sIL-2R levels between the patients that were diagnosed with CRPS (CRPS group) and those who were not (no CRPS group). A group of anonymous blood bank donors were used as a healthy control group. Furthermore, we explored the relationship between sIL-2R and CRPS disease severity using the CRPS severity score. Median sIL-2R levels of both the CRPS group (2809.0 pg/ml; Q3-Q1: 3913.0-1589.0) and no CRPS group (3654.0 pg/ml; Q3-Q1: 4429.0-2095.5) were significantly higher than that of the control group (1515.0 pg/ml; Q3-Q1: 1880.0-1150.0): CRPS vs. controls, p < .001 ; no CRPS vs. controls, p < 0.001 . Serum sIL-2R levels did not differ significantly between the CRPS and no CRPS group. A statistically significant negative correlation was observed between sIL-2R levels and the CRPS severity score ( r s = − 0.468 , p = 0.024 ). Our results confirm our previous findings of higher sIL-2R levels in CRPS patients than in healthy controls. We further showed that serum sIL-2R cannot differentiate between CRPS and other pain conditions of a limb in a tertiary referral setting. Interestingly, a negative correlation was found between sIL-2R and CRPS disease severity; this finding warrants further research into the relationship between sIL-2R and CRPS disease severity.

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“…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].…”

Section: Clinical Evidencesmentioning

confidence: 72%

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

Ding¹,

Luo²,

Qi³

2020

J Neuroinflammation

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Nerve injury-induced chronic pain has been an urgent problem for both public health and clinical practice. While transition to chronic pain is not an inevitable consequence of nerve injuries, the susceptibility/resilience factors and mechanisms for chronic neuropathic pain after nerve injuries still remain unknown. Current preclinical and clinical studies, with certain notable limitations, have shown that major histocompatibility complex class II-restricted T helper (Th) cells is an important trigger for nerve injury-induced chronic tactile allodynia, one of the most prevalent and intractable clinical symptoms of neuropathic pain. Moreover, the precise pathogenic neuroimmune interfaces for Th cells remain controversial, not to mention the detailed pathogenic mechanisms. In this review, depending on the biology of Th cells in a neuroimmunological perspective, we summarize what is currently known about Th cells as a trigger for chronic tactile allodynia after nerve injuries, with a focus on identifying what inconsistencies are evident. Then, we discuss how an interdisciplinary perspective would improve the understanding of Th cells as a trigger for chronic tactile allodynia after nerve injuries. Finally, we hope that the expected new findings in the near future would translate into new therapeutic strategies via targeting Th cells in the context of precision medicine to either prevent or reverse chronic neuropathic tactile allodynia.

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Immune dysregulation in patients with carpal tunnel syndrome

Cited by 19 publications

References 78 publications

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

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

Serum Soluble Interleukin-2 Receptor Does Not Differentiate Complex Regional Pain Syndrome from Other Pain Conditions in a Tertiary Referral Setting

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

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