Cytokine expression profiles in white blood cells of patients with small fiber neuropathy

Abstract

Background The role of cytokines in the pathophysiology, diagnosis, and prognosis of small fiber neuropathy (SFN) is incompletely understood. We studied expression profiles of selected pro- and anti-inflammatory cytokines in RNA from white blood cells (WBC) of patients with a medical history and a clinical phenotype suggestive for SFN and compared data with healthy controls. Methods We prospectively recruited 52 patients and 21 age- and sex-matched healthy controls. Study participants were characterized in detail and underwent complete neurological examination. Venous blood was drawn for routine and extended laboratory tests, and for WBC isolation. Systemic RNA expression profiles of the pro-inflammatory cytokines interleukin (IL)-1ß, IL-2, IL-8, tumor necrosis factor-alpha (TNF) and the anti-inflammatory cytokines IL-4, IL-10, transforming growth factor beta-1 (TGF) were analyzed. Protein levels of IL-2, IL-8, and TNF were measured in serum of patients and controls. Receiver operating characteristic (ROC)-curve analysis was used to determine the accuracy of IL-2, IL-8, and TNF in differentiating patients and controls. To compare the potential discriminatory efficacy of single versus combined cytokines, equality of different AUCs was tested. Results WBC gene expression of IL-2, IL-8, and TNF was higher in patients compared to healthy controls (IL-2: p = 0.02; IL-8: p = 0.009; TNF: p = 0.03) and discriminated between the groups (area under the curve (AUC) ≥ 0.68 for each cytokine) with highest diagnostic accuracy reached by combining the three cytokines (AUC = 0.81, sensitivity = 70%, specificity = 86%). Subgroup analysis revealed the following differences: IL-8 and TNF gene expression levels were higher in female patients compared to female controls (IL-8: p = 0.01; TNF: p = 0.03). The combination of TNF with IL-2 and TNF with IL-2 and IL-8 discriminated best between the study groups. IL-2 was higher expressed in patients with moderate pain compared to those with severe pain (p = 0.02). Patients with acral pain showed higher IL-10 gene expression compared to patients with generalized pain (p = 0.004). We further found a negative correlation between the relative gene expression of IL-2 and current pain intensity (p = 0.02). Serum protein levels of IL-2, IL-8, and TNF did not differ between patients and controls. Conclusions We identified higher systemic gene expression of IL-2, IL-8, and TNF in SFN patients than in controls, which may be of potential relevance for diagnostics and patient stratification.

Neuropathic pain; what we know and what we should do about it

“…Whilst some primary mediators have predominantly localized actions, others are released into the systemic circulation ( 38 , 82 ).…”

“…Blood borne inflammatory mediators ( 38 , 493 ) generated at the site of injury open tight junctions between capillary endothelial cells leading to increased permeability of the blood-brain barrier ( 192 ). This allows supra-spinal neurons to interact with blood cells and respond to the cytokines and chemokines they produce ( 195 ).…”

“…These not only include peripheral nerve trauma ( 13 , 23 , 28 , 29 ), amputation ( 30 ), brain trauma ( 14 , 20 ) or spinal cord injury ( 31 , 32 ). Neuropathic pain may also occur as a result of multiple sclerosis ( 33 , 34 ), stroke ( 14 , 35 ), fibromyalgia ( 36 , 37 ), small fiber neuropathy ( 38 ), post herpetic or trigeminal neuralgia ( 14 , 39 ), migraine ( 40 ), osteoarthritis ( 41 , 42 ), complex regional pain syndromes I and II ( 43 , 44 ), rheumatoid arthritis ( 45 ), painful diabetic neuropathy ( 46 , 47 ), autoimmune disease ( 48 ), viral infections such as HIV ( 49 – 51 ) or COVID 19 ( 52 ) and neuropathies associated with cancer per se ( 47 ) and/or chemotherapy ( 53 – 55 ). Neuropathic pain is also prevalent in individuals afflicted with posttraumatic stress disorder ( 56 ) and is a positive sign of rare yet debilitating Na + channelopathies ( 57 – 59 ).…”